@article {pmid40268841,
year = {2025},
author = {Ahmad, S and Ahmad, L and Adil, M and Sharma, R and Khan, S and Hasan, N and Aqil, M},
title = {Emerging nano-derived therapy for the treatment of dementia: a comprehensive review.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {40268841},
issn = {2190-3948},
abstract = {Dementia includes a variety of neurodegenerative diseases that affect and target the brain's fundamental cognitive functions. It is undoubtedly one of the diseases that affects people globally. The ameliorating the disease is still not known; the symptoms, however, can be prevented to an extent. Dementia encompasses Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, mixed dementia, and various other diseases. The aggregation of β-amyloid protein plaques and the formation of neurofibrillary tangles have been concluded as the foremost cause for the onset of the disease. As the cases climb, new neuroprotective methods are being developed in the form of new drug delivery systems that provide targeted delivery. Herbal drugs like Ashwagandha, Brahmi, and Cannabis have shown satisfactory results by not only treating the symptoms but have also been shown to reduce and ameliorate the formation of amyloid plaque formation. This article explores the intricate possibilities of drug delivery and the absolute use of herbal drugs to target neurodegenerative diseases. The various possibilities of nanotechnology currently available with new emerging techniques are also discussed.},
}

@article {pmid40268710,
year = {2025},
author = {de Azevedo Picinini, T and Oliveira, MK and Galarza, KM and Lüders, D and Ferraz, AX and Hamerschmidt, R and de Araújo, CM and de Lacerda, ABM},
title = {Behavioral Tests for Central Auditory Processing Evaluation in the Investigation of Early Manifestations of Cognitive Decline and Dementias: A Scoping Review.},
journal = {American journal of audiology},
volume = {},
number = {},
pages = {1-18},
doi = {10.1044/2025_AJA-24-00214},
pmid = {40268710},
issn = {1558-9137},
abstract = {PURPOSE: This scoping review aimed to identify behavioral tests for central auditory processing (CAP) assessment that can be used to investigate early manifestations of pathological cognitive decline in adults and the older adults. Early detection of cognitive decline and dementias is a strategy for delaying the progression of these clinical conditions.

METHOD: This scoping review was conducted using various online databases and gray literature sources, including the Latin American and Caribbean Literature in Health Sciences, PubMed/Medline, Scopus, Web of Science, Google Scholar, and ProQuest Dissertations & Theses. Studies were included if they assessed individuals who underwent behavioral tests for CAP evaluation and had completed at least one cognitive test.

RESULTS: A total of 1,190 references were retrieved from the databases, with 151 identified as duplicates. After screening 1,039 articles by title and abstract, eight studies were selected for full-text review, and five were included in the final synthesis. The behavioral tests for CAP evaluation used to investigate preclinical manifestations of cognitive decline and dementia were: Synthetic Sentence Identification With Ipsilateral Competing Message, Staggered Spondaic Word test, Dichotic Sentence Identification, and Dichotic Digits Test. Among these, dichotic tests were identified as having the strongest association with cognitive decline, probable Alzheimer's disease, or dementia.

CONCLUSIONS: The findings indicate that dichotic tests are the most frequently utilized behavioral tests for CAP evaluation and serve as valuable tools for detecting early manifestations of cognitive decline and dementias. These tests could play a significant role in the early diagnosis and management of cognitive impairments.},
}

@article {pmid40268578,
year = {2025},
author = {Dourlen, P and Kilinc, D and Landrieu, I and Chapuis, J and Lambert, JC},
title = {BIN1 and Alzheimer's disease: the tau connection.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.03.004},
pmid = {40268578},
issn = {1878-108X},
abstract = {Bridging integrator 1 (BIN1) is a ubiquitously expressed protein that plays a critical role in endocytosis, trafficking and cytoskeletal dynamics. In 2010, BIN1 gene was reported as a major genetic risk factor for Alzheimer's disease (AD), which shifted the focus on its physiological and pathophysiological roles in the brain (at a time when data available were scarce). In this review, we discuss the multiple cerebral roles of BIN1, especially in regulating synaptic function, and the strong link between BIN1 and tau pathology, supported by recent evidence ranging from genetic and clinical/postmortem observations to molecular interactions.},
}

@article {pmid40268467,
year = {2025},
author = {Tomita, K and Nakashima, KI and Yamaguchi, E and Itoh, A and Inoue, M},
title = {Dual Anti-inflammatory Actions of a Novel Retinoid X Receptor Agonist Derived from a Natural Compound in Microglial Cells.},
journal = {Biological & pharmaceutical bulletin},
volume = {48},
number = {4},
pages = {440-449},
doi = {10.1248/bpb.b25-00037},
pmid = {40268467},
issn = {1347-5215},
abstract = {Microglia-mediated neuroinflammation plays a critical role in the onset and progression of Alzheimer's disease. In a previous study, we synthesized 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid (6OHA) based on the structure of magnaldehyde B, a natural compound that our group identified as a retinoid X receptor (RXR) agonist. However, its potential effects on inflammation in microglial cells remain unexplored. In this study, we specifically focused on the early-phase inflammatory responses to lipopolysaccharide (LPS) and evaluated the inhibitory effects of 6OHA on BV-2 microglial cells following 2 h of LPS exposure. Similar to the existing RXR agonist bexarotene (Bex), 6OHA treatment (0.1 and 1 μM) resulted in a dose-dependent decrease in the mRNA levels of proinflammatory mediators, including interleukin-1β (Il1b), Il6, and inducible nitric oxide synthase. However, these effects on proinflammatory mediators were effectively abolished by the RXR antagonist UVI3003. Additionally, 6OHA promoted M2 microglia polarization after 24 h of treatment, as evidenced by the increased mRNA levels of the M2 marker genes arginase-1 (Arg1), C-C motif chemokine ligand 6 (Ccl6), Ccl17, and Ccl22. Notably, 6OHA induced a distinct set of M2 microglial markers compared with IL-4, a known M2 microglial inducer. Furthermore, the transcription of Arg1, a key M2 marker gene, is regulated by retinoic acid receptor/RXR heterodimers and the IL-4 signaling pathway. Collectively, 6OHA suppressed the early inflammatory responses to LPS and promoted M2 microglial polarization through a mechanism distinct from that of IL-4. Therefore, RXR agonists, including 6OHA and Bex, may exhibit dual anti-inflammatory effects and serve as novel modulators of neuroinflammation.},
}

@article {pmid40268162,
year = {2025},
author = {Sun, M and Wang, X and Lu, Z and Yang, Y and Lv, S and Miao, M and Chen, WM and Wu, SY and Zhang, J},
title = {Comparative study of SGLT2 inhibitors and metformin: evaluating first-line therapies for dementia prevention in type 2 diabetes.},
journal = {Diabetes & metabolism},
volume = {},
number = {},
pages = {101655},
doi = {10.1016/j.diabet.2025.101655},
pmid = {40268162},
issn = {1878-1780},
abstract = {BACKGROUND: - Type 2 diabetes (T2D) increases the risk of dementia by 1.5 to 2.5 times. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and metformin, widely used antidiabetic therapies, have demonstrated potential neuroprotective effects. Their comparative effectiveness in dementia prevention remains unknown.

METHODS: - This retrospective cohort study used the TriNetX global federated network, analyzing de-identified records from over 98 healthcare organizations. Adults with T2D initiating SGLT2i or metformin as first-line therapy were propensity score-matched (1:1). The primary outcome was overall dementia incidence, including vascular dementia, Alzheimer's disease, and other subtypes. Secondary outcomes included all-cause mortality. Time-to-event outcomes were assessed using Kaplan-Meier curves and Cox models.

RESULTS: - Among 74,975 matched patients in each cohort, SGLT2i use was associated with a lower incidence of overall dementia: 2.7% vs. 6.9%: adjusted hazard ratio (aHR) 0.80 [95% CI 0.76;0.84]. Reductions were observed in vascular dementia (0.8% vs. 2.0%; aHR 0.87), Alzheimer's dementia (1.1% vs. 3.2%; aHR, 0.76), and all-cause mortality (6.8% vs. 15.4%; aHR, 0.92). Benefits were pronounced in older adults, particularly those aged ≥80 years.

CONCLUSIONS: - SGLT2is significantly reduced dementia risk and mortality compared to metformin in T2D patients. These findings suggest SGLT2is may offer superior neuroprotective benefits, underscoring their potential as a first-line therapy for T2D. Further randomized trials are needed to confirm these results.},
}

@article {pmid40268142,
year = {2025},
author = {Liu, TH and Lin, YM and Yu, T and Wu, JY and Lai, CC},
title = {Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: A five-year retrospective cohort analysis of 160,752 patients.},
journal = {Diabetes research and clinical practice},
volume = {},
number = {},
pages = {112197},
doi = {10.1016/j.diabres.2025.112197},
pmid = {40268142},
issn = {1872-8227},
abstract = {OBJECTIVES: This study investigated the neuroprotective effects of sodium-glucose cotransporter-2 inhibitor (SGLT2i) in reducing dementia risk among older adults with type 2 diabetes mellitus (T2DM), compared to dipeptidyl peptidase-4 inhibitors (DPP4i).

METHODS: Using the TriNetX electronic health records network, we conducted a retrospective cohort study including adults aged ≥65 years with T2DM who initiated SGLT2i or DPP4i between January 1, 2013, and November 30, 2024. Propensity score matching was employed to create two balanced cohorts, with the primary outcome being new-onset dementia. Secondary outcomes included dementia-related drug use and subtypes of dementia, such as Alzheimer's disease and vascular dementia.

RESULTS: After propensity score matching, 80,376 patients were included in each group. SGLT2i use was associated with a significantly lower risk of developing dementia compared to DPP4i (hazard ratio [HR], 0.54; 95 % confidence interval [CI]: 0.51-0.57; p < 0.001). Similar reductions were observed for dementia-related drug use (HR, 0.69; 95 % CI: 0.64-0.74; p < 0.001), Alzheimer's disease (HR, 0.53; 95 % CI: 0.48-0.60; p < 0.001), and vascular dementia (HR, 0.52; 95 % CI: 0.46-0.58; p < 0.001). Subgroup analyses showed consistent protective effects.

CONCLUSION: Compared to DPP-4i, SGLT2i use is associated with a lower risk of dementia in older adults with T2DM, with consistent benefits observed across diverse populations and patient subgroups. These findings highlight the potential of SGLT2i as a preventive strategy for cognitive decline and support further investigation in randomized controlled trials.},
}

@article {pmid40268103,
year = {2025},
author = {Rodríguez-Mortera, R and Torres, P and Fernàndez-Bernal, A and Berdún, R and Ramírez-Núñez, O and Martín-Garí, M and Serrano, JC and He, JC and Prat, J and Pamplona, R and Uribarri, J and Portero-Otin, M},
title = {Non-enzymatic modification of aminophospholipids induces angiogenesis, inflammation, and insulin signaling dysregulation in human renal glomerular endothelial cells.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.04.030},
pmid = {40268103},
issn = {1873-4596},
abstract = {AIMS/HYPOTHESIS: Advanced glycation end-products (AGEs) formation in proteins are involved in healthy aging and a variety of diseases including Alzheimer's disease, atherosclerosis, and diabetic complications. However, the biological effects of the non-enzymatic modification of aminophospholipids (lipid-AGEs) at cellular level are poorly understood. This study aimed to investigate the effects of lipid-AGEs on angiogenesis, inflammation, insulin signaling, and mitochondrial function in human renal glomerular endothelial cells (HRGEC), exploring their potential role in the pathophysiology of diabetic nephropathy (DN).

METHODS: HRGEC cells were exposed to non-enzymatically modified phosphatidylethanolamine (PE) by AGEs (lipid-AGEs), non-modified PE (nmPE) (aminophospholipid without modification) was employed as a negative control, and lipopolysaccharides (LPS) as a positive control. Angiogenesis was assessed through vascular network formation metrics, including capillary area, junction density, and endpoints, under different extracellular matrices. Gene expression of inflammatory and angiogenic markers was quantified by RT-qPCR. Insulin signaling components, including IRS1 and AKT phosphorylation, were evaluated by immunoblotting. Mitochondrial function was assessed using high-resolution respirometry to determine ATP production rates from glycolysis and oxidative phosphorylation.

RESULTS: Lipid-AGEs induced dose-, time-, and matrix-dependent angiogenesis, with effects comparable to LPS, particularly in Engelbreth-Holm-Swarm ECM (capillary area increase: 25%, p<0.05). Lipid-AGEs significantly upregulated the inflammatory genes IL8 and NFKB (p<0.05), and the angiogenesis-related markers TGFB1 and ANGPT2 (p<0.05). Insulin signaling was disrupted, as lipid-AGEs enhanced inhibitory phosphorylation of IRS1 (Ser-1101, 1.8-fold increase, p<0.01) and modulated AKT (Ser-473) and p42/p44 ERK activation. At lower doses, lipid-AGEs reduced eNOS phosphorylation (p<0.05) impairing insulin responsiveness. High-resolution respirometry revealed that lipid-AGEs reduced basal oxygen consumption rates (OCR) by 20% (p<0.05), with no significant changes in glycolytic ATP production.

CONCLUSION: Lipid-AGEs induce angiogenesis, inflammation, and insulin signaling disruption in HRGEC, contributing to endothelial dysfunction. These findings underscore the potential role of lipid-AGEs in age-related decline of renal function, as well as the pathogenic potential in DN highlighting their relevance as therapeutic targets for mitigating vascular and metabolic complications in diabetes.},
}

@article {pmid40268067,
year = {2025},
author = {Wei, C and Liu, J and Wu, B and Shen, T and Fan, J and Lin, Y and Li, K and Guo, Y and Shang, Y and Zhou, B and Xie, H},
title = {Blockage of CCL3 with neutralizing antibody reduces neuroinflammation and reverses Alzheimer disease phenotypes.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2025.04.034},
pmid = {40268067},
issn = {1090-2139},
abstract = {BACKGROUND: Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer's disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL3 mRNA expression was abnormally upregulated in the brains of AD transgenic mice. Moreover, the levels of CCL3 in the serum of AD patients were significantly elevated and negatively correlated with their cognitive abilities. However, the role of CCL3 in AD neuroinflammation and pathological damages remains elusive.

METHODS: Using behavioral, histological, and biochemical methods, outcomes of CCL3 antibody treatment on neuropathology and cognitive deficits were studied in the APPswe/PS1dE9 mice.

RESULTS: In the present study, we reported that CCL3 protein expression was increased in the APPswe/PS1dE9 mice, whereas blockage of CCL3 with neutralizing antibody potently inhibited CCL3 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, CCL3 antibody significantly improved the learning and memory abilities of APPswe/PS1dE9 mice. In addition, CCL3 antibody treatment decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that CCL3 antibody treatment alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated NF-κB signaling pathway in APPswe/PS1dE9 mice was inhibited by CCL3 antibody treatment.

CONCLUSIONS: Collectively, our findings provide evidence that CCL3 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD.},
}

@article {pmid40268010,
year = {2025},
author = {Hafeez, E and Du, D and Ni, H and Zhu, K and Hu, F and Zhou, J and Chen, D},
title = {Regulation and mechanism of Bletilla striata polysaccharide on delaying aging in Drosophila melanogaster.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {143382},
doi = {10.1016/j.ijbiomac.2025.143382},
pmid = {40268010},
issn = {1879-0003},
abstract = {Bletilla striata polysaccharide (BSP) is a natural bioactive compound known for its promising health benefits, including antioxidant, immunomodulatory, and anti-inflammatory effects. However, its potential in combating aging remains largely unexplored. This study aims to investigate the anti-aging effects of BSP in the Drosophila melanogaster model. The results show that BSP supplementation significantly extends the lifespan of flies in a concentration-dependent manner, with the most pronounced effects observed at a concentration of 3 mg/mL. Lifespan extension is associated with enhanced antioxidative capacities, as evidenced by increased SOD and CAT activities, and decreased MDA content. Additionally, BSP ameliorates age-related symptoms, including improved climbing ability and enhanced intestinal barrier function. Furthermore, BSP supplementation enhances resistance to H2O2-induced oxidative and starvation stresses, attenuates the lead (Pb)-induced toxicity, and delays the onset of Alzheimer's phenotypes in flies. RNA-Seq analysis reveals that BSP supplementation leads to the differential expression of 992 genes. KEGG pathway analysis highlights significant changes in metabolic pathways, including galactose metabolism, starch and sucrose metabolism, and carbon metabolism. Key genes such as Mal-A1, Amy-d, Men-b, Pgm-1, Mdh1, and Hex-C are downregulated, while CG32026, CG11291, and Ald2 are upregulated. These findings suggest BSP exhibits significant anti-aging and protective properties, making it a potential therapeutic agent.},
}

@article {pmid40267876,
year = {2025},
author = {Chen, Y and Dong, H and Huang, X and Jiang, L and Jiang, Z and Li, L and Hu, J and Chen, WH},
title = {Discovery of fluorescent and theranostic probes for glycogen synthase kinase-3β in living cells and brain tissues: Detection and imaging in models of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {291},
number = {},
pages = {117639},
doi = {10.1016/j.ejmech.2025.117639},
pmid = {40267876},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) represents a progressive neurodegenerative disorder marked by complex pathologies. Glycogen synthase kinase-3β (GSK-3β) plays a pivotal role in AD pathogenesis, influencing key pathological processes such as hyperphosphorylation of tau and production of amyloid-beta. However, current methods for detecting GSK-3β in living cells and tissues are limited in sensitivity and real-time tracking. Herein, we reported a series of environment-sensitive fluorescent probes to detect GSK-3β in both living cells and brain slices. These probes exhibit fluorescence upon the binding of GSK-3β, providing high sensitivity and selectivity with minimal background interference. Compound 10c was further validated in an AD mouse model with elevated expression of GSK-3β, showing clear imaging in hippocampal regions. Compared to immunofluorescence, compound 10c demonstrated a lower background and faster labeling. In addition, this compound showed neuroprotective effects, supporting its potential as a theranostic tool in AD. These findings provide new tools for investigating the role of GSK-3β in AD and advancing targeted therapies.},
}

@article {pmid40267374,
year = {2025},
author = {Lee, JY and Han, K and Kim, J and Lim, JS and Cheon, DY and Lee, M},
title = {Association Between Metabolic Syndrome and Young-Onset Dementia: A Nationwide Population-Based Study.},
journal = {Neurology},
volume = {104},
number = {10},
pages = {e213599},
doi = {10.1212/WNL.0000000000213599},
pmid = {40267374},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Young-onset dementia (YOD) poses substantial societal and health care burdens. Although metabolic syndrome (MetS) is recognized as a contributor to late-onset dementia, its effect on YOD remains unclear. This study aimed to determine whether MetS and its individual components increase the risk of YOD, including all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD).

METHODS: We conducted a nationwide population-based cohort study using data from the Korean National Insurance Service. Individuals aged 40-60 who underwent national health check-ups in 2009 were included and followed until December 31, 2020, or age 65, whichever came first. MetS was defined according to established guidelines, incorporating measurements of waist circumference, blood pressure, fasting glucose, triglycerides, and high-density lipoprotein cholesterol. Covariates included age, sex, income level, smoking status, alcohol consumption, and comorbidities such as hypertension, diabetes, dyslipidemia, and depression. The primary outcome was incident all-cause YOD, defined as a dementia diagnosis before age 65; secondary outcomes included young-onset AD and VaD. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs.

RESULTS: A total of 1,979,509 participants (mean age, 49.0 years; 51.3% men; 50.7% with MetS) were included. Over an average follow-up of 7.75 years, 8,921 individuals (0.45%) developed YOD. MetS was associated with a 24% higher risk of all-cause YOD (adjusted HR 1.24, 95% CI 1.19-1.30), a 12.4% increased risk of AD (HR 1.12, 95% CI 1.03-1.22), and a 20.9% increased risk of VaD (HR 1.21, 95% CI 1.08-1.35). Significant interactions were noted with younger age (40-49 vs 50-59), female sex, drinking status, obesity, and depression.

DISCUSSION: In this large Korean cohort, MetS and its individual components were significantly associated with an increased risk of YOD. These findings suggest that interventions targeting MetS may help mitigate YOD risk. However, the observational design precludes definitive causal inferences, and reliance on claims data could introduce misclassification bias. Future research using longitudinal designs and comprehensive data collection is needed to validate and expand on these associations.},
}

@article {pmid40267333,
year = {2025},
author = {Heinze, T and Tuchtenhagen, M and Knüppel, S and Weber, D and Pohl, G and Jannasch, F and Schiborn, C and Schulze, MB and Grune, T and Schwerdtle, T},
title = {EPIC-Potsdam sub-cohort study: The early role of trace elements, oxidative stress, and anthropometrics in Alzheimer's disease and dementia onset.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333726},
doi = {10.1177/13872877251333726},
pmid = {40267333},
issn = {1875-8908},
abstract = {BackgroundSerum trace elements, anthropometric data, and oxidative stress markers are often altered in patients diagnosed with Alzheimer's disease (AD) or other types of dementia (OTD). However, these parameters are rarely examined together before disease onset in a single study population.ObjectiveThis nested case-control study aims to investigate anthropometric data, serum trace elements, exchangeable copper (CuEXC), and oxidative stress markers to identify early associations with the risk of AD or OTD.MethodsFrom the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort (DRKS-ID: DRKS00020593), the High Fat Diet, Microbiota, and Neuroinflammation in the Progression of Alzheimer study was generated. One hundred twenty-eight individuals who developed AD or OTD were identified, approximately 15.7 years after baseline data collection, and matched for age, sex, fasting status, and season of blood sampling with 512 controls. Serum levels of manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), selenium (Se), iodine (I), CuEXC, and plasma malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) were analyzed.ResultsCases and non-cases did not differ in anthropometric data or oxidative stress markers. Female cases exhibited a trend of elevated serum Cu and CuEXC levels compared to female non-cases. A higher Se/Cu ratio suggested an inverse association (OR = 0.72, 95% CI: 0.56-0.92), while an increased Cu/Zn ratio was positively associated (OR = 2.1, 95% CI: 1.1-4.1) with AD or OTD incidence.ConclusionsRatios of serum trace elements, rather than individual levels, show early associations with the risk of AD or OTD while anthropometric and oxidative stress markers did not.},
}

@article {pmid40267322,
year = {2025},
author = {Elmståhl, S and Ellström, K and Månsson, T and Basna, R and Siennicki-Lantz, A and Abul-Kasim, K},
title = {Associations between cerebral small vessel disease and reduced forced vital capacity and expiratory volume in a general healthy Swedish elder population study-Good Aging in Skåne.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333793},
doi = {10.1177/13872877251333793},
pmid = {40267322},
issn = {1875-8908},
abstract = {BackgroundCerebral small vessel disease (CSVD) is one of the most important causes of cognitive decline. Only a few previous studies have evaluated lung function measures in relation to brain neuropathological changes, and even less studies on specific lesions and areas that could shed light on mechanisms of CSVD.ObjectiveThe aim was to study the association between lung function and CSVD in the general elder population.Methods379 participants, aged 72-87 years from the general population study 'Good Aging in Skåne study (GÅS)'were investigated with a 3 T MRI brain examination and spirometry. Z-scores of FEV1 and FVC were calculated using the GLI 2012 equations. Age-adjusted associations between white matter hyperintensities (WMH), medial temporal lobe atrophy (MTA), lacunar infarction, cerebral atrophies and cerebral microbleeds and lung function were calculated and stratified for sex.ResultsDecreased FEV1 and FVC z-scores below ≤ -1.0 were both associated with increased risk of WMI and global cortical atrophy. Decreased FVC z-scores were also associated with MTA and lacunar infarction in women and precuneus atrophy in men. The associations for WMH, MTA and lacunar infarctions and higher STRIVE score were noted among women, but not among men. FEV1 z scores were not related to diabetes, coronary artery disease or stroke.ConclusionsLower lung function was associated to MRI markers of CSVD in this general healthy population, particularly with WMH, especially for women. Although possible shared risk factors exist between lung and heart disease, lung function should be recognized in future studies on CSVD.},
}

@article {pmid40267302,
year = {2025},
author = {Shu, MJ and Han, F and Zhai, FF and Zhang, DD and Zhou, LX and Ni, J and Yao, M and Cui, LY and Peng, B and Jin, ZY and Zhang, SY and Zhu, YC},
title = {The association between long-term trajectories of insulin resistance and brain structural integrity in middle-aged and older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251336333},
doi = {10.1177/13872877251336333},
pmid = {40267302},
issn = {1875-8908},
abstract = {BackgroundThe triglyceride-glucose (TyG) index is considered a robust surrogate for insulin resistance (IR). The relationship between the trajectory patterns of the TyG index and subsequent brain structure changes is still unclear.ObjectiveThis study investigates the relationship between 10-year trajectories of TyG-related indices and brain structural integrity in a 10-year follow-up.MethodsThis prospective study included 898 participants (mean age 55.6 years, 34.4% males) from the community-based Shunyi Study. IR was assessed using the TyG index, TyG-body mass index (BMI) index, TyG-waist circumference index, and TyG-waist-to-height ratio (WHtR) index. The group-based trajectory model was employed to identify the 10-year trajectories. Structural brain measurements included structural changes of the whiter matter (white matter hyperintensities (WMHs), fractional anisotropy, and mean diffusivity) and gray matter (brain parenchymal fraction (BPF), cortical thickness, and hippocampal volume). General linear models were utilized to examine the association between the trajectory patterns of TyG-related indices and brain structure.ResultsThree distinct trajectories of TyG-related indices were identified from 2013 to 2023. The high-level trajectory groups of TyG-related indices exhibited a greater volume of WMHs and were more susceptible to disruptions in white matter microstructural integrity. This association was most significant for the TyG-BMI and TyG-WHtR trajectory groups. No significant correlations were found for BPF and cortical thickness among the different TyG-related indices trajectories.ConclusionsThe findings suggest that long-term IR primarily damages brain white matter rather than causing structural changes in gray matter.},
}

@article {pmid40267299,
year = {2025},
author = {Culligan, J and Tasnim, N and Winter, P and Upthegrove, T and English, DF and Basso, JC},
title = {Methods for measuring interpersonal behavioral and neural synchrony during group music therapy for individuals with dementia and their caregivers: A case series study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334406},
doi = {10.1177/13872877251334406},
pmid = {40267299},
issn = {1875-8908},
abstract = {Background: Alzheimer's disease and related dementias (ADRD) are neurodegenerative disorders that afflict 1 in 9 older adults. As pharmacological interventions for ADRD are often ineffective and cause rampant side effects, interest has increased in finding adjunctive, non-pharmacological approaches. Music therapy may be especially beneficial for individuals with ADRD and their caregivers as music is a form of non-verbal communication. Objective: In this case series, we describe a 12-week group music therapy program for individuals with ADRD and their caregivers. Methods: Brain activity was recorded with hyperscanning electroencephalography (EEG) during each music therapy session from the individual with ADRD (n = 3), caregiver (n = 3), and music therapist (n = 1). Video recordings allowed for assessment of movement behavior and affective state responses. Results: This 12-week case series of group music therapy for individuals and their caregivers had a 66% retention and 95.8% adherence rate. We had success collecting behavioral and neural data using 360-degree video capture in combination with EEG. Video recordings allowed us to analyze affective state and nonverbal communication metrics. After pre-processing, neural recordings were clean and able to be analyzed for various neural metrics of interest. Conclusions: A human-centered design approach can be helpful for implementing longitudinal, non-pharmacological interventions in this vulnerable population. A team-science approach with a collective of creative arts therapists, neuroscientists, dementia care experts, creative technologists, and gerontology experts contributed to the conduction of this work. Future studies should examine the effects of music therapy on behavioral and neural outcomes, especially as it relates to interpersonal behavioral and neural synchrony.},
}

@article {pmid40267298,
year = {2025},
author = {Fohner, AE and Sitlani, CM and Jayadev, S and Bis, JC and Trittschuh, EH and Lopez, OL and Tracy, RP and Psaty, BM and Longstreth, WT and Seshadri, S},
title = {Plasma TAR DNA-binding protein 43 (TDP-43) levels in a population-based cohort of older adults: The cardiovascular health study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334820},
doi = {10.1177/13872877251334820},
pmid = {40267298},
issn = {1875-8908},
abstract = {Brain deposition of transactive response DNA-binding protein 43 (TDP-43) is a feature of neurodegenerative syndromes. We evaluated TDP-43 plasma concentrations in 1058 participants in the Cardiovascular Health Study (CHS), a population-based longitudinal cohort. The cohort was 38% male, 11% Black, had a mean age 75 years, and 261 people developed dementia over a mean of 5.5 years of follow up. Median TDP-43 levels were 211.0 pg/mL (IQR: 134.0-341.0 pg/mL). TDP-43 levels were not associated with cross-sectional or longitudinal change in cognitive scores, with plasma AD biomarkers, with brain MRI volumes, with incident dementia, or with demographic characteristics.},
}

@article {pmid40267294,
year = {2025},
author = {Jiang, H and Xiao, Z and Saleem, K and Zhong, P and Li, L and Chhetri, G and Li, P and Jiang, Z and Yan, Z and Feng, J},
title = {Generation of human induced pluripotent stem cell-derived cortical neurons expressing the six tau isoforms.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334831},
doi = {10.1177/13872877251334831},
pmid = {40267294},
issn = {1875-8908},
abstract = {BackgroundThe alternative splicing (AS) of MAPT, which encodes Tau, in the adult human brain produces six major isoforms that play critical roles in the pathogenesis of tauopathies including Alzheimer's disease. Previous efforts have failed to differentiate human induced pluripotent stem cells (hiPSCs) to cortical neurons expressing the six isoforms of Tau.ObjectiveWe aim to develop a differentiation method capable of producing the six Tau isoforms in hiPSC-derived cortical neurons.MethodsWe searched for the optimal concentration, duration and treatment window of morphogens in the differentiation of hiPSCs through embryoid bodies (EBs) to dorsal forebrain neuroepithelial cells then to cortical neurons.ResultsThe combined inhibition of WNT, SHH, and SMAD signaling in EBs generated neuroepithelial cells expressing appropriate dorsal forebrain markers, while suppressing ventral, midbrain, and hindbrain genes. Further differentiation in neurogenic and neurotrophic factors produced MAP2[+] neurons at day 18. The iPSC-derived neurons expressed markers of all cortical layers and exhibited synapse formation and synaptic physiology. In addition, MAP2[+] neurons and mitotic cells expressing radial glial markers formed aggregates that could be dissociated to produce mature neurons with similar properties. Most importantly, the six Tau isoforms were expressed from day 80 in a developmentally regulated manner, modeling the situation in human brains on an accelerated timeline.ConclusionsThis chemically defined differentiation method produces a key hallmark of mature human cortical neurons by expressing the six main splicing isoforms of Tau. It will greatly facilitate disease modeling and therapeutic discovery for many human brain disorders involving cortical neurons.},
}

@article {pmid40267292,
year = {2025},
author = {Wu, X and Yang, Q and Xie, Y and Xia, L and Li, J and An, W and Lu, X},
title = {Drug-targeted Mendelian randomization analysis combined with transcriptome sequencing to explore the molecular mechanisms associated with cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251335891},
doi = {10.1177/13872877251335891},
pmid = {40267292},
issn = {1875-8908},
abstract = {BackgroundCurrent therapies for cognitive impairment, including Alzheimer's disease (AD) and mild cognitive impairment, are limited by a lack of universal treatment and adverse effects associated with polypharmacy. Investigating genetic and molecular mechanisms underlying cognitive decline is critical for the development of targeted therapeutics.ObjectiveTo identify causal genes and potential therapeutic targets for cognitive impairment through integrative genomic analyses.MethodsGenome-wide association study data on cognitive impairment were combined with the expression quantitative trait loci (eQTL) data from the eQTLGen consortium. Mendelian randomization (MR) and colocalization analyses were employed to infer causal relationships. Gene Set Enrichment Analysis and Gene Set Variation Analysis evaluated the pathway and functional differences. Immune cell infiltration patterns and the immunometabolic pathways were assessed, followed by drug target prediction.ResultsMR analysis identified seven gene-eQTL pairs significantly associated with cognitive impairment. SMR colocalization prioritized three key genes: HNMT (histamine metabolism), TNFSF8 (inflammatory signaling), and S1PR5 (sphingolipid signaling). HNMT, TNFSF8, and S1PR5 had 39, 24, and 30 predicted targeted drugs, respectively, including arsenic trioxide, aspirin, and immunomodulators.ConclusionsThis study implicates HNMT, TNFSF8, and S1PR5 as potential therapeutic targets for cognitive impairment. Further validation is required to confirm their clinical relevance.},
}

@article {pmid40267290,
year = {2025},
author = {Zhang, W and Teng, F and Lan, X and Liu, P and Wang, A and Zhang, F and Cui, Z and Guan, J and Sun, X},
title = {A novel finding relates to the involvement of ATF3/DOCK8 in Alzheimer's disease pathogenesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251336266},
doi = {10.1177/13872877251336266},
pmid = {40267290},
issn = {1875-8908},
abstract = {BackgroundThe involvement of microglia is likely to be pivotal in the pathogenesis of Alzheimer's disease (AD) by modulating the deposition of amyloid-β (Aβ) plaques. The deletion of Dedicator of cytokinesis 8 (DOCK8) has a protective effect in mouse with neurodegenerative diseases.ObjectiveTo explore the underlying mechanism of DOCK8 in AD.MethodsIn present study, we first the detected the expression of DOCK8 in the hippocampal tissue of APP/PS1 mice. Then, the expression of DOCK8 was knocked down in the hippocampal tissue of APP/PS1 mice, and the effects of DOCK8 down-regulation on cognitive function, the microglia migration around Aβ plaques, and the cell division cycle 42 (Cdc42)/p38 mitogen-activated protein kinase (MAPK) signaling pathway were detected. Next, the effects of DOCK8 knockdown on Aβ-induced migration and activation of BV-2 cells as well as the MAPK signaling pathway were detected. Finally, the transcriptional regulation of DOCK by transcription factor 3 (ATF3) was detected by a dual luciferase reporter assay.ResultsDOCK8 expression exerts a significant upregulation in the hippocampus of APP/PS1 mice. However, following the DOCK8 knockdown, there was a significant recovery in the results of the behavioral tests and a notable reduction in microglial expression. Moreover, the high expression of DOCK8 mediated by ATF3 successfully triggered the Cdc42/p38 MAPK signaling pathway, thereby enhancing the migration and recruitment of microglia towards senile plaques, accelerating the production of Aβ plaques.ConclusionsATF3-mediated high expression of DOCK8 accelerates the production of Aβ plaques, and participates in the pathogenesis of AD.},
}

@article {pmid40267289,
year = {2025},
author = {Jeong, H and Kim, D and Na, S and Kim, B and Oh, JK and Choi, EK and Yoon, S and Bikson, M and Chung, YA and Song, IU},
title = {Repeated neuromodulation with low-intensity focused ultrasound in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333614},
doi = {10.1177/13872877251333614},
pmid = {40267289},
issn = {1875-8908},
abstract = {BackgroundLow-intensity focused ultrasound (LIFU), a non-invasive targeted brain stimulation technology, has shown promise for therapeutic applications in Alzheimer's disease (AD) patients. Despite its potential, the implications of repeated LIFU neuromodulation in AD patients remain to be investigated.ObjectiveThis pilot study evaluated the safety and potential to improve cognition and functional connectivity following repeated LIFU treatment in AD patients.MethodsTen early-stage AD patients underwent six sessions of neuronavigation-guided LIFU targeting the left dorsolateral prefrontal cortex (DLPFC) within 2-3 weeks, alongside ongoing standard pharmacotherapy. Neuropsychological assessments and resting-state functional magnetic resonance imaging were performed at baseline and eight weeks post-treatment.ResultsMemory performance (p = 0.02) and functional connectivity between the left DLPFC and both the left perirhinal cortex and left dorsomedial prefrontal cortex (corrected p < 0.05) significantly improved from baseline. Additionally, enhancements in memory performance were positively correlated with increases in functional connectivity of the left DLPFC with the left perirhinal cortex (Kendall's tau = 0.56, p = 0.03). No adverse events were reported during the LIFU treatments or at the subsequent follow-up.ConclusionsLIFU may have the therapeutic potential to enhance both brain network connectivity and memory functions in AD patients. Our results provide a basis for further research, including randomized sham-controlled trials and optimization of stimulation protocols, on LIFU as a supplementary or alternative treatment option for AD.Trial registrationClinical Research Information Service, KCT0008169, Registered on 10 February 2023.},
}

@article {pmid40267288,
year = {2025},
author = {Dubbelman, MA and Elias, U and Palmer, P and Dafni-Merom, A and Gazit, L and Udeogu, OJ and Wang, S and Papp, KV and Amariglio, RE and Arzy, S and Marshall, GA},
title = {Investigating the associations between tau and mental orientation among cognitively unimpaired individuals.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334781},
doi = {10.1177/13872877251334781},
pmid = {40267288},
issn = {1875-8908},
abstract = {BackgroundImpairments in orientation in space, time, and person occur frequently in Alzheimer's disease (AD) dementia. Subtle changes in orientation may arise in preclinical and prodromal disease stages. Thus, assessing orientation may help identify those on a trajectory toward AD dementia.ObjectiveTo investigate how orientation, measured using a novel artificial intelligence-based paradigm, relates to AD biomarkers (amyloid and tau) in cognitively unimpaired older adults.MethodsUsing an automated chatbot, 53 cognitively unimpaired participants (74.0 ± 5.5 years; 60% female) provided details about memories and relationships, recognition of historical event dates, and geographical locations. These details were then used to assess orientation to space, time, and person. For each domain separately, orientation accuracy was calculated by dividing the number of correct responses by response time. All participants underwent Pittsburgh compound-B (amyloid) and flortaucipir (tau) positron emission tomography. We analyzed the relationship between performance on the three orientation domains and retrosplenial, precuneus, neocortical, and medial temporal tau, and global amyloid.ResultsHigher retrosplenial and precuneus tau burden were associated with worse temporal orientation (β = -0.32, 95% confidence interval [95%CI] = [-0.59, -0.05] and β = -0.29, 95%CI = [-0.57, -0.01], respectively). Spatial or social orientation were not associated with amyloid or tau.ConclusionsThese results suggest that impaired temporal orientation is related to AD pathological processes, even before the onset of overt cognitive impairment, and may infer a role for personalized assessment of orientation in early diagnosis of AD.},
}

@article {pmid40267285,
year = {2025},
author = {Noguchi-Shinohara, M and Ozaki, T and Usui, Y and Shibata, S and Shima, A and Komatsu, J and Ono, K},
title = {Housing damage and forgetfulness following the 2024 Noto Peninsula earthquake, Japan.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251335005},
doi = {10.1177/13872877251335005},
pmid = {40267285},
issn = {1875-8908},
abstract = {On January 1, 2024, a major earthquake struck Japan's Noto Peninsula. From 2021 to 2023, we conducted a baseline survey. Four months after the disaster, we conducted a follow-up survey to investigate the relationship between house damage and forgetfulness in older adults without dementia. A total of 923 individuals were included. Among the respondents, 32.2% and 33.8% reported as suffered major house damages and increased forgetfulness, respectively. Multivariate analysis revealed major house damage was significantly associated with self-reported forgetfulness, which are partly mediated through sleep disturbance and sedentary behavior in the cognitively unimpaired and mild cognitive impairment groups, respectively.},
}

@article {pmid40267280,
year = {2025},
author = {Li, J and Zhang, F and Eisel, UL},
title = {Adverse events associated with lecanemab: A disproportionality analysis of data from the FDA adverse event reporting system.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333084},
doi = {10.1177/13872877251333084},
pmid = {40267280},
issn = {1875-8908},
abstract = {BackgroundLecanemab, a monoclonal antibody targeting amyloid-β plaques, is FDA-approved for early Alzheimer's disease (AD) treatment. However, safety data from daily clinical practice is limited.ObjectiveThis study aims to assess the adverse events (AEs) linked to lecanemab using the FDA Adverse Event Reporting System (FAERS) to inform better safety management.MethodsA retrospective pharmacovigilance study was conducted using FAERS data from Q1 2023 to Q2 2024. Disproportionality analysis, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), was applied to evaluate AEs where lecanemab was the primary suspect drug.ResultsFrom Q1 2023 to Q2 2024, 917 AEs related to lecanemab were recorded in the FAERS database, with 67.2% of patients aged between 65 and 85 years and 54.5% involving women. Disproportionality analysis identified significant AEs across 22 organ systems, particularly nervous system and psychiatric disorders. Common AEs included headache, amyloid-related imaging abnormalities, and infusion-related reactions, while sleep-related issues like somnolence, abnormal dreams, and poor-quality sleep were notable. Median onset time was 48 days, with serious outcomes in 14.3% of cases, including 70 hospitalizations and 15 deaths.ConclusionsThis pharmacovigilance analysis confirms known AEs of lecanemab and highlights new safety concerns, particularly its impact on sleep. These findings underscore the importance of ongoing monitoring and research to enhance lecanemab's safety profile in AD treatment. However, due to the limitations of FAERS, our analysis is imperfect in terms of important AEs such as therapy-related brain loss and death.},
}

@article {pmid40267277,
year = {2025},
author = {Wei, S and Li, C and Li, W and Yuan, F and Kong, J and Su, X and Huang, P and Guo, H and Xu, J and Sun, H},
title = {Glial changes and gene expression in Alzheimer's disease from snRNA-Seq and spatial transcriptomics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251330320},
doi = {10.1177/13872877251330320},
pmid = {40267277},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by cortical atrophy, glutamatergic neuron loss, and cognitive decline. However, large-scale quantitative assessments of cellular changes during AD pathology remain scarce.ObjectiveThis study aims to integrate single-nuclei sequencing data from the Seattle Alzheimer's Disease Cortical Atlas (SEA-AD) with spatial transcriptomics to quantify cellular changes in the prefrontal cortex and temporal gyrus, regions vulnerable to AD neuropathological changes (ADNC).MethodsWe mapped differentially expressed genes (DEGs) and analyzed their interactions with pathological factors such as APOE expression and Lewy bodies. Cellular proportions were assessed, focusing on neurons, glial cells, and immune cells.ResultsRORB-expressing L4-like neurons, though vulnerable to ADNC, exhibited stable cell numbers throughout disease progression. In contrast, astrocytes displayed increased reactivity, with upregulated cytokine signaling and oxidative stress responses, suggesting a role in neuroinflammation. A reduction in synaptic maintenance pathways indicated a decline in astrocytic support functions. Microglia showed heightened immune surveillance and phagocytic activity, indicating their role in maintaining cortical homeostasis.ConclusionsThe study underscores the critical roles of glial cells, particularly astrocytes and microglia, in AD progression. These findings contribute to a better understanding of cellular dynamics and may inform therapeutic strategies targeting glial cell function in AD.},
}

@article {pmid40267273,
year = {2025},
author = {He, F and Shi, WJ and Liu, W and Fan, JX and He, ZG and Zhang, YQ and Xiao, J and Ruan, WW and Gai, YK and Zhang, HL and Yang, BB and Qin, Y and Wang, H and Li, J and Wang, JL and Liu, S and Shi, LP and Chen, ZX and Jiang, WJ and An, N and Xue, PJ and Wang, ZH and Yang, RJ and Tian, PY and Chen, Z and Xiao, L and Yang, ZS and Feng, KB and Tan, WY and Sun, ZM and Xu, W and Shu, H and Wang, JZ},
title = {A mass-producible macaque model displays a durable Alzheimer-like cognitive deficit and hallmark amyloid-β/tau/neurofilament light chain pathologies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334316},
doi = {10.1177/13872877251334316},
pmid = {40267273},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive deficit and pathological accumulation of amyloid-β (Aβ) and tau proteins. The rodent models have contributed greatly to unravel AD pathogenesis, but these AD models have been shown a modest clinical translational effectiveness.ObjectiveTherefore, developing mass-producible primate AD models is promising for more effective drug development.MethodsHere, we constructed the AD monkey models by simultaneously infusing AAV-Tau and Aβ into different brain regions.ResultsThe induced monkeys showed a durable cognitive impairment lasting for at least 10 months after the modeling. Simultaneously, the increased levels of total tau and hyperphosphorylated tau (pTau) at several AD-associated sites, and neurofilament light chains (NfL) with altered Aβ level were detected at different time points in cerebrospinal fluid and/or plasma by using MSD kits. The increased brain accumulation of Aβ and tau proteins was also detected by positron emission tomography/magnetic resonance imaging and immunohistochemical staining. The model monkeys also had significant glial activation; an indicator of inflammation commonly seen in the brains of AD patients.ConclusionsTogether, this study provides mass-producible monkey models showing durable AD-like hallmark pathologies (Aβ, tau, NfL, i.e., ATN) and cognitive deficits. As monkeys are genetically and metabolically the closest to humans, these models will offer more effective drug discovery and development for AD.},
}

@article {pmid40267270,
year = {2025},
author = {De Anda-Duran, I and Hwang, PH and Drabick, DA and Andersen, SL and Au, R and Libon, DJ},
title = {Neuropsychological phenotypic characteristics in a cohort of community-based older adults: Data from the Framingham Heart Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334608},
doi = {10.1177/13872877251334608},
pmid = {40267270},
issn = {1875-8908},
abstract = {BackgroundNeuropsychological (NP) assessment is crucial for diagnosing prodromal and Alzheimer's disease and related dementia (ADRD) syndromes. Yet, traditional NP scores often overlook errors and the process by which summary scores are obtained; information that can provide deeper insights into cognitive impairments and clinical heterogeneity.ObjectiveTo classify community-dwelling adults into neurocognitive phenotypes, identify NP test errors and processes that differentiate between groups, and explore their association with brain imaging measures.MethodsFramingham Heart Study (FHS) data were analyzed, focusing on NP summary scores and errors derived from the Boston Process Approach. Latent class analysis identified distinct neurocognitive phenotypes. Regression analyses assessed the relationships with NP errors and brain MRI measures.ResultsA total of 1195 participants (mean age 69.6 and 56.3% women) were included. Cognitively normal (CN), moderate-mixed, and dysexecutive impairment groups were identified. The number of Trail Making Test - Part B (TMT-B) pen lifts and TMT-B examiner-corrected errors were associated with the dysexecutive phenotype and differentiated it from the CN group (OR = 1.39, 95% CI = 1.28-1.52, p < 0.001, AUC = 0.85 and OR = 3.40, 95% CI = 2.65-4.38, p < 0.001, AUC = 0.92; respectively). Similarly, Boston Naming Test (BNT) circumlocution errors were associated with the moderate-mixed phenotype and differentiated it from the CN group (OR = 1.87, 95% CI = 1.49-2.35, p < 0.001, AUC = 0.81). These scores were significantly associated with reduced hippocampal volumes.ConclusionsDetailed NP error and process analysis enhances traditional methods, offering a comprehensive approach to identifying and understanding cognitive impairments.},
}

@article {pmid40267266,
year = {2025},
author = {Singh-Reilly, N and Graff-Radford, J and Li, D and Mielke, MM and Machulda, MM and Schwarz, CG and Senjem, ML and Jack, CR and Lowe, VJ and Josephs, KA and Whitwell, JL},
title = {Aβ42/40 and p-tau 181 as disease biomarkers in atypical Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333450},
doi = {10.1177/13872877251333450},
pmid = {40267266},
issn = {1875-8908},
abstract = {BackgroundStudies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown.ObjectiveThe main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity.MethodsWe assessed whether plasma p-tau 181 and Aβ42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD.ResultsPlasma Aβ42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity.ConclusionPlasma Aβ42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.},
}

@article {pmid40267236,
year = {2025},
author = {Zhong, H and Zhu, J and Liu, S and Zhou, D and Long, Q and Wu, C and Zhao, B and Cheng, C and Yang, Y and Wu, Q and Wu, Y and Li, C and Wang, Z and Wu, J and Guo, X and Zhi, D and Deng, Y and Wu, L},
title = {Linking DNA methylation in brain regions to Alzheimer's disease risk: a Mendelian randomization study.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddaf053},
pmid = {40267236},
issn = {1460-2083},
support = {//University of Hawai'i Cancer Center/ ; },
abstract = {AIM: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.

METHODS: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). In our MR analyses, we integrated these mQTLs with single nucleotide polymorphisms (SNP)-ad risk summary statistics derived from 85 934 ad-related cases and 401 577 normal controls.

RESULTS: Among 62 554 cytosine-guanine dinucleotide (CpG) sites, we identified 597 CpG sites (CpGs) significantly associated with ad risk (false discovery rate (FDR) < 0.05). Of these, 289 were confirmed through colocalization and summary-based MR (SMR) analyses, including one CpG site in CRBLM, 285 in DLPFC, one in FCTX, two in PONS, and one in TCTX. By integrating gene expression data, we identified 19 CpG sites with consistent associations across methylation levels, expression of eight target genes, and ad risk, including novel regulatory mechanisms involving RITA1's modulation of cg11558705 and PCGF3's regulation of cg10009224.

CONCLUSION: Our findings highlight brain region-specific DNA methylation as a mediator of genetic risk for ad, offering insights into ad pathogenesis and identifying potential therapeutic targets.},
}

@article {pmid40267187,
year = {2025},
author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M},
title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.},
journal = {Science advances},
volume = {11},
number = {17},
pages = {eadq6077},
doi = {10.1126/sciadv.adq6077},
pmid = {40267187},
issn = {2375-2548},
mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; },
abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.},
}

*Adenosine Triphosphate/metabolism
Humans
Animals
*Protein Aggregation, Pathological/metabolism/pathology
Mice
*Neurons/metabolism
Induced Pluripotent Stem Cells/metabolism
Amyotrophic Lateral Sclerosis/metabolism/pathology
*Axons/metabolism
Viscosity
Mitochondria/metabolism
Protein Aggregates
Parkinson Disease/metabolism/pathology
DNA-Binding Proteins/metabolism
Alzheimer Disease/metabolism/pathology

@article {pmid40267096,
year = {2025},
author = {Tong, K and Dai, L and Rui, W and Zhang, Y and Fu, J and Liao, Y and Wang, W and Deng, M and Mi, Y and Li, Z},
title = {GC-MS, LC-MS, and network pharmacology analysis to investigate the chemical profiles and potential pharmacological activities in flower buds and flowers of Lonicera japonica Thunb.},
journal = {PloS one},
volume = {20},
number = {4},
pages = {e0320293},
doi = {10.1371/journal.pone.0320293},
pmid = {40267096},
issn = {1932-6203},
mesh = {*Lonicera/chemistry ; *Flowers/chemistry ; Network Pharmacology ; Gas Chromatography-Mass Spectrometry ; Chromatography, Liquid ; Humans ; *Plant Extracts/pharmacology/chemistry ; Liquid Chromatography-Mass Spectrometry ; },
abstract = {Lonicera japonica Thunb. (L. japonica) is an edible-medicinal herb. While the flower buds of L. japonica are commonly utilized for medicinal purposes, the flowers are often overlooked. However, it has been discovered that the flowers contain higher levels of certain active compounds compared to the flower buds. Despite this finding, there have been no reports on the potential differences in pharmacological efficacy between these compounds. Utilizing results from GC-MS and LC-MS, a total of 335 differential compounds were identified, of which 247 complied with Lipinski's Rule of Five concerning medicinal properties. Among these, 101 compounds were upregulated in the flower buds, while 146 compounds were upregulated in the flowers. Network pharmacology analysis revealed that the upregulated compounds from the flower buds and flowers targeted 143 and 185 core targets, respectively, with 116 being duplicates. The core target proteins among the duplicate targets were primarily involved in pathways related to cancer, lipid and atherosclerosis, hepatitis B, proteoglycans in cancer, and Alzheimer's disease. Meanwhile, the hub target proteins upregulated in the flowers enriched distinct pathways associated with human T-cell leukemia virus 1 infection, focal adhesion, the thyroid hormone signaling pathway, and fluid shear stress and atherosclerosis. Molecular docking results indicated that the upregulated compounds exhibited strong binding affinity to the core targets. This study provides insights into the differences in active components between the medicinal (flower buds) and non-medicinal (flowers) raw materials predicting the mechanisms of action of these active components and establishing a basis for the more rational utilization of L. japonica flowers.},
}

*Lonicera/chemistry
*Flowers/chemistry
Network Pharmacology
Gas Chromatography-Mass Spectrometry
Chromatography, Liquid
Humans
*Plant Extracts/pharmacology/chemistry
Liquid Chromatography-Mass Spectrometry

@article {pmid40266681,
year = {2025},
author = {Luo, M and Zhou, J and Sun, C and Chen, W and Fu, C and Si, C and Zhang, Y and Geng, Y and Chen, Y},
title = {APP β-CTF triggers cell-autonomous synaptic toxicity independent of Aβ.},
journal = {eLife},
volume = {13},
number = {},
pages = {},
doi = {10.7554/eLife.100968},
pmid = {40266681},
issn = {2050-084X},
support = {31671044//National Natural Science Foundation of China/ ; 91849204//National Natural Science Foundation of China/ ; 2016YFA0501901//National Program on Key Research Project of China/ ; 2019SHZDZX02//Shanghai Municipal Science and Technology Major Project/ ; },
mesh = {Animals ; *Amyloid beta-Protein Precursor/metabolism/genetics/toxicity ; Mice ; Rats ; Hippocampus/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Amyloid Precursor Protein Secretases/metabolism/genetics ; *Synapses/metabolism/pathology ; *Neurons/metabolism ; Aspartic Acid Endopeptidases/metabolism/genetics ; Synaptic Transmission ; Alzheimer Disease ; Dendritic Spines/metabolism/pathology ; rab5 GTP-Binding Proteins/metabolism ; Mice, Inbred C57BL ; },
abstract = {Aβ is believed to play a significant role in synaptic degeneration observed in Alzheimer's disease and is primarily investigated as a secreted peptide. However, the contribution of intracellular Aβ or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system in rat hippocampal slice culture. Here, these proteins/peptides were overexpressed in a single neuron, surrounded by thousands of untransfected neurons. Surprisingly, we found that APP induced dendritic spine loss only when co-expressed with BACE1. This effect was mediated by β-CTF, a β-cleavage product of APP, through an endosome-related pathway independent of Aβ. Neuronal expression of β-CTF in mouse brains resulted in defective synaptic transmission and cognitive impairments, even in the absence of amyloid plaques. These findings unveil a β-CTF-initiated mechanism driving synaptic toxicity irrespective of amyloid plaque formation and suggest a potential intervention by inhibiting the endosomal GTPase Rab5.},
}

Animals
*Amyloid beta-Protein Precursor/metabolism/genetics/toxicity
Mice
Rats
Hippocampus/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Amyloid Precursor Protein Secretases/metabolism/genetics
*Synapses/metabolism/pathology
*Neurons/metabolism
Aspartic Acid Endopeptidases/metabolism/genetics
Synaptic Transmission
Alzheimer Disease
Dendritic Spines/metabolism/pathology
rab5 GTP-Binding Proteins/metabolism
Mice, Inbred C57BL

@article {pmid40266679,
year = {2025},
author = {Umeda, T and Sakai, A and Uekado, R and Shigemori, K and Nakajima, R and Yamana, K and Tomiyama, T},
title = {Simply crushed zizyphi spinosi semen prevents neurodegenerative diseases and reverses age-related cognitive decline in mice.},
journal = {eLife},
volume = {13},
number = {},
pages = {},
doi = {10.7554/eLife.100737},
pmid = {40266679},
issn = {2050-084X},
mesh = {Animals ; *Ziziphus/chemistry ; Mice ; Disease Models, Animal ; *Cognitive Dysfunction/drug therapy/prevention & control ; *Neurodegenerative Diseases/prevention & control ; Male ; *Aging/drug effects ; *Plant Extracts/administration & dosage/pharmacology ; *Drugs, Chinese Herbal/administration & dosage ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. Oral administration of ZSS hot water extract ameliorated Aβ and tau pathology and cognitive impairment in mouse models of Alzheimer's disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved α-synuclein pathology and cognitive/motor function in Parkinson's disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging.},
}

Animals
*Ziziphus/chemistry
Mice
Disease Models, Animal
*Cognitive Dysfunction/drug therapy/prevention & control
*Neurodegenerative Diseases/prevention & control
Male
*Aging/drug effects
*Plant Extracts/administration & dosage/pharmacology
*Drugs, Chinese Herbal/administration & dosage
Amyloid beta-Peptides/metabolism

@article {pmid40266568,
year = {2025},
author = {Rodríguez-Mansilla, J and Chamizo-Gallego, P and González-Sánchez, B and Garrido-Ardila, EM and Torres-Piles, S and Rodríguez-Mansilla, MJ and De Toro-García, Á and Jiménez-Palomares, M},
title = {Virtual reality as a complementary therapy in the rehabilitation of balance and gait disorders in patients with mild cognitive impairment and Alzheimer's disease: Systematic review.},
journal = {Clinical rehabilitation},
volume = {},
number = {},
pages = {2692155251328619},
doi = {10.1177/02692155251328619},
pmid = {40266568},
issn = {1477-0873},
abstract = {ObjectiveTo analyse the benefits of virtual reality in the management of balance and gait disorders in people with Alzheimer's disease and cognitive impairment.Data sourcesPubMed, PEDro, Cochrane Library, Science Direct, Google Scholar and Epistemonikos.Review methodThis study is a systematic review (PROSPERO Registration number: CRD42023486083). The inclusion criteria were: randomised, cross-sectional, quasi-experimental controlled clinical trials involving patients diagnosed with mild cognitive impairment, dementia and Alzheimer's disease with a score of ≤23 on the MMSE test and age ≥60 years, and interventions conducted with virtual reality and conventional physiotherapy for the treatment of balance and gait disorders. The methodological quality and risk of bias assessment was performed with the PEDro scale.Results12 studies were included in the review (n = 476). Three studies applied virtual reality to both experimental and control groups, six applied virtual reality to the experimental group and conventional physiotherapy to the control, and three investigations applied virtual reality to the experimental group and no treatment to the control group. Virtual reality based rehabilitation significantly improved balance and gait, as well as cognitive level, functionality, postural control and mood of the patients compared to those participants who received conventional physiotherapy or no treatment.ConclusionStudies suggest that interventions based on virtual environments in older adults with early Alzheimer's disease can improve balance and gait impairments, postural control and executive function, delaying the deterioration caused by the disease. Furthermore, this therapy has a positive impact on cognitive and motivational performance in these patients.},
}

@article {pmid40266549,
year = {2025},
author = {Kakeda, S and Miki, Y and Kudo, K and Mori, H and Tokumaru, AM and Abe, O and Aoki, S and , },
title = {Practical brain MRI guidelines for anti-Aβ antibody treatment in early symptomatic Alzheimer's disease.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {40266549},
issn = {1867-108X},
abstract = {PURPOSE: These guidelines aim to support magnetic resonance imaging (MRI) diagnosis in patients receiving anti-amyloid β (Aβ) antibody treatment without restricting treatment eligibility.

MATERIALS AND METHODS: These guidelines were collaboratively established by Japan Radiological Society, The Japanese Society of Neuroradiology, and Japanese Society for Magnetic Resonance in Medicine by reviewing existing literature and the results of clinical trials.

RESULTS: Facility standards should comply with the "Optimal Use Promotion Guidelines" of Japan, and physicians should possess comprehensive knowledge of amyloid-related imaging abnormalities (ARIA) and expertise in brain MRI interpretation. The acquisition of knowledge regarding amyloid-related imaging abnormalities, brain MRI, anti-Aβ antibody introduction, and post-treatment diagnosis are also recommended.

CONCLUSION: These guidelines facilitate the accurate diagnosis and effective management of ARIA; ensure the safe administration of anti-Aβ drugs; and provide a framework for MRI facilities, includes staffing requirements and the use of MRI management systems.},
}

@article {pmid40266545,
year = {2025},
author = {Zhao, Y and Fei, L and Duan, Y},
title = {Combining GWAS Summary Data and Proteomics Identified Potential Drug Targets in Dementia.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40266545},
issn = {1559-1182},
abstract = {Due to progressive cognitive loss and subsequent incapability of daily life, the development of novel therapeutics is urgently needed for dementia patients. We performed a two-sample bi-directional Mendelian randomization (MR) analysis using summary-level statistics to identify causality between peripheral and cerebrospinal fluid (CSF) proteins and the risk of dementia. Genetic variants were subtracted from the Genome-Wide Association Studies (GWAS) results. Wald ratio (WR) and inverse-variance weighted (IVW) ratio were utilized to estimate the causal effects of plasma and CSF proteins on dementia. Reverse MR, Steiger filtering, Bayesian co-localization phenotype scanning, and external validation were integrated to strengthen the robustness of primary MR results. After sensitivity analysis, six circulating proteins were identified in three dementia classifications, whereas no causality was found in frontotemporal dementia (FTD). Elevated levels of circulating C1R protein increased the odds of developing Alzheimer's disease (AD), while PILRA and CELA2A were estimated to protect against the pathogenesis of AD; genetically predicted increase of α-synuclein and APOE elevated the occurrence of Dementia of Lewy Bodies (DLB); elevated level of circulating CRP was assessed to increase the onset of vascular dementia (VD). Our MR analyses identified a genetically predicted association between circulating C1R, PILRA, and CELA2A and the risk of AD, causal estimates between α-syn, APOE protein, and the onset of DLB, and a robust correlation between CRP and the etiology of VD. This study might guide the discovery of disease etiology and build up a novel disease-modifying paradigm of dementia.},
}

@article {pmid40266407,
year = {2025},
author = {Sharma, V and Verma, R and Singh, TG},
title = {Targeting hypoxia-related pathobiology in Alzheimer's disease: strategies for prevention and treatment.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {416},
pmid = {40266407},
issn = {1573-4978},
mesh = {*Alzheimer Disease/metabolism/prevention & control/pathology/therapy ; Humans ; *Hypoxia/metabolism/complications ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; Signal Transduction ; Mitochondria/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a neurodegenerative condition characterised by cognitive decline and memory impairment. Recent research highlights the important role of hypoxia, a state of insufficient oxygen availability, in exacerbating AD pathogenesis.

MATERIALS AND METHODS: Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the role of hypoxia mediated pathobiology in AD. Only peerreviewed articles published in reputable journals in English language were included. Conversely, non-peer-reviewed articles, conference abstracts, and editorials were excluded, along with studies lacking experimental or clinical relevance or those unavailable in full text.

CONCLUSION: Hypoxia exacerbates core pathological features such as oxidative stress, neuroinflammation, mitochondrial dysfunction, amyloid-beta (Aβ) dysregulation, and hyperphosphorylation of tau protein. These interlinked mechanisms establish a self-perpetuating cycle of neuronal damage, accelerating disease progression. Addressing hypoxia as a modifiable risk factor offers potential for both prevention and treatment of AD. Exploring hypoxia and the HIF signalling pathway may help counteract the neuropathological and symptomatic effects of neurodegeneration.},
}

*Alzheimer Disease/metabolism/prevention & control/pathology/therapy
Humans
*Hypoxia/metabolism/complications
Oxidative Stress
Amyloid beta-Peptides/metabolism
Animals
tau Proteins/metabolism
Signal Transduction
Mitochondria/metabolism

@article {pmid40266405,
year = {2025},
author = {Kachoueiyan, F and Kalkhoran, NY and Kalkhoran, AY and Kyada, A and Rekha, MM and Chaudhary, K and Barwal, A and Sead, FF and Joshi, KK},
title = {Butyrate: a key mediator of gut-brain communication in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {40},
number = {5},
pages = {189},
pmid = {40266405},
issn = {1573-7365},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Butyrates/metabolism ; *Gastrointestinal Microbiome/physiology ; *Brain/metabolism ; Animals ; *Brain-Gut Axis/physiology ; Blood-Brain Barrier/metabolism ; },
abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative disorder, represents a significant global health challenge, characterized by cognitive decline and neuroinflammation. Recent investigations have highlighted the critical role of the gut-brain axis in the pathogenesis of AD, particularly focusing on the influence of short-chain fatty acids (SCFAs), metabolites produced by the gut microbiota through the fermentation of dietary fiber. Among SCFAs, butyrate has emerged as a crucial mediator, positively impacting various pathological processes associated with AD, including epigenetic regulation, neuroinflammation modulation, maintenance of the blood-brain barrier (BBB), enhanced intestinal integrity, regulation of brain metabolism, and interference with amyloid protein formation as well as tau protein hyperphosphorylation. Furthermore, distinctions in butyrate profile and microbial communities have been observed between AD patients and healthy individuals, underscoring the importance of gut microbiota in AD progression. This review summarizes the current understanding of the many functions of butyrate in reducing the consequences of AD and emphasizes the possibility of addressing the gut microbiota as a therapeutic approach to managing AD.},
}

Humans
*Alzheimer Disease/metabolism
*Butyrates/metabolism
*Gastrointestinal Microbiome/physiology
*Brain/metabolism
Animals
*Brain-Gut Axis/physiology
Blood-Brain Barrier/metabolism

@article {pmid40266402,
year = {2025},
author = {Nazir, SS and Goel, D and Vohora, D},
title = {A network pharmacology-based approach to decipher the pharmacological mechanisms of Salvia officinalis in neurodegenerative disorders.},
journal = {Metabolic brain disease},
volume = {40},
number = {5},
pages = {190},
pmid = {40266402},
issn = {1573-7365},
mesh = {*Network Pharmacology/methods ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; Humans ; Molecular Docking Simulation/methods ; *Salvia officinalis/chemistry ; *Plant Extracts/pharmacology/therapeutic use ; },
abstract = {The present study aimed to assess the pharmacological mechanism of Salvia officinalis in Neurodegenerative disorders using a network pharmacology approach followed by molecular docking analysis. Phytoconstituents of S.officinalis were obtained from various databases, followed by the screening of active ingredients using the Swiss ADME web tool. Potential targets of active ingredients were identified using PubChem & SwissTargetPrediction. Genes related to Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) were gathered using online databases. Besides, the correlation between active ingredient targets and disease-associated genes was linked. Networks were constructed, visualized, and analyzed using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were performed using DAVID database. Decisively, Autodock was used for molecular docking. The results of network analysis identified 9 key active ingredients based on topological analysis of the active ingredient-candidate targets network. Also, the analysis revealed a shared target of 9 key active ingredients of S. officinalis that interacted with 133 AD-related targets whereas only 6 active ingredients interacted with 85 and 58 targets of PD and HD respectively. The core genes from the network were AKT1, BACE1, CASP3, MAPK1, TNF, and IL6. Furthermore, GO and KEGG enrichment analysis showed that FOXO, TNF, MAPK, PI3K-Akt, Rap 1, and neurotrophin signalling pathways as enriched, which were further evaluated by molecular docking suggesting the protective role of S. officinalis in neurodegenerative diseases. Our research reveals the therapeutic benefits of S. officinalis, which might play a crucial role in modulating neurodegenerative diseases.},
}

*Network Pharmacology/methods
*Neurodegenerative Diseases/drug therapy/genetics/metabolism
Humans
Molecular Docking Simulation/methods
*Salvia officinalis/chemistry
*Plant Extracts/pharmacology/therapeutic use

@article {pmid40266147,
year = {2025},
author = {Puagsopa, J and Tongviseskul, N and Jaroentomeechai, T and Meksiriporn, B},
title = {Recent Progress in Developing Extracellular Vesicles as Nanovehicles to Deliver Carbohydrate-Based Therapeutics and Vaccines.},
journal = {Vaccines},
volume = {13},
number = {3},
pages = {},
doi = {10.3390/vaccines13030285},
pmid = {40266147},
issn = {2076-393X},
support = {ALTF 336-2021//European Molecular Biology Organization/ ; 24030064//NEYE/ ; },
abstract = {Cell-derived, nanoscale extracellular vesicles (EVs) have emerged as promising tools in diagnostic, therapeutic, and vaccine applications. Their unique properties including the capability to encapsulate diverse molecular cargo as well as the versatility in surface functionalization make them ideal candidates for safe and effective vehicles to deliver a range of biomolecules including gene editing cassettes, therapeutic proteins, glycans, and glycoconjugate vaccines. In this review, we discuss recent advances in the development of EVs derived from mammalian and bacterial cells for use in a delivery of carbohydrate-based protein therapeutics and vaccines. We highlight key innovations in EVs' molecular design, characterization, and deployment for treating diseases including Alzheimer's disease, infectious diseases, and cancers. We discuss challenges for their clinical translation and provide perspectives for future development of EVs within biopharmaceutical research and the clinical translation landscape.},
}

@article {pmid40266020,
year = {2025},
author = {Bruno, D and Reilly, J},
title = {Editorial introduction to the special issue on biomarker-based diagnosis of Alzheimer's disease: A synthesis of the commentaries.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.12427},
pmid = {40266020},
issn = {1748-6653},
support = {R01DC013063//National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; },
abstract = {We introduce a special issue of the Journal of Neuropsychology dedicated to a recent paradigm shift in Alzheimer's disease diagnosis. Joint workgroups from the (US) National Institute on Aging and the Alzheimer's Association (NIA-AA) recently issued policy guidelines reclassifying Alzheimer's disease as a biological entity. These guidelines shift the onus of diagnosis in favour of protein biomarkers, relegating cognitive symptoms (e.g. subjective memory and language disorders) as supportive rather than core features. We invited experts in the study of Alzheimer's disease and Related Disorders (ADRDs) to express their views on this paradigmatic shift in dementia management. In this editorial, we synthesize some of the main points advanced in the commentaries. Contributors identified the promise of blood-based biomarker testing for improving equitable detection of dementia in large swathes of the world population. This enthusiasm was tempered by concerns about the biomarker-only diagnostic approach, including the potential for significant harm (e.g. stigma, depression, suicide) caused by labelling asymptomatic older adults who might otherwise never behaviourally express the underlying disease pathology.},
}

@article {pmid40265424,
year = {2025},
author = {Chellappan, MC and Vasu, S and Mahadevan, S and Kathiravan, MK and Saravanan, J and Naik, S and Thachil, KK},
title = {Scaffold Hopping and Optimization of Thiazole Hybrids as Selective PIN1 Inhibitors: A Computational Study.},
journal = {Medicinal chemistry (Shariqah (United Arab Emirates))},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734064376657250416071044},
pmid = {40265424},
issn = {1875-6638},
abstract = {BACKGROUND: Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphoserine/threonine-proline (pSer/Thr-Pro) motifs, presenting a unique therapeutic opportunity for addressing multiple disorders.

METHODS: A series of 140 thiazole compounds were created using the shape similarity technique with the intention of discovering effective PIN1 inhibitors with a new scaffold. The designed compounds were docked into the enzyme's ATP binding site, and the binding free energies for all docked conformations were calculated. The compounds were evaluated for their ADMET and drug-likeness properties. Following the identification of top candidates, molecular dynamics simulations were conducted to investigate the binding dynamics of the highest-scoring compound.

RESULTS: Based on computational findings, sixteen compounds were identified as potential PIN1 inhibitors. Among the sixteen compounds, four (S8Ba, S8Bb, S8Bd, and S8Bd) exhibited the most favorable ADMET profiles and robust interactions with key PIN1 residues. Molecular dynamics simulations confirmed that S8Ba and S8Bd exhibited the most promising activity over 100ns.

CONCLUSION: The results corroborated the docking outcomes, validating the selected hits as potential PIN1 inhibitors. This breakthrough could influence the development of therapeutic leads for combating diabetes, cancer, and Alzheimer's disease.},
}

@article {pmid40265276,
year = {2025},
author = {Mendonça, IP and Peixoto, CA},
title = {The Double-Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases.},
journal = {Journal of neurochemistry},
volume = {169},
number = {4},
pages = {e70069},
doi = {10.1111/jnc.70069},
pmid = {40265276},
issn = {1471-4159},
support = {CNPq;#301891/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; IAM-PROEP# 005-FIO-22//Instituto Aggeu Magalhães/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism ; *Neuroglia/metabolism/pathology/physiology ; Animals ; *Enteric Nervous System/pathology/metabolism ; },
abstract = {Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut-brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/pathology/metabolism
*Neuroglia/metabolism/pathology/physiology
Animals
*Enteric Nervous System/pathology/metabolism

@article {pmid40264898,
year = {2024},
author = {Kumar, J and Varela-Ramirez, A and Narayan, M},
title = {Development of novel carbon-based biomedical platforms for intervention in xenotoxicant-induced Parkinson's disease onset.},
journal = {BMEmat},
volume = {2},
number = {4},
pages = {},
pmid = {40264898},
issn = {2751-7446},
abstract = {Chronic exposure to herbicides, weedicides, and pesticides is associated with the onset and progress of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we have investigated whether quinic- and chlorogenic-acid-derived Carbon Quantum Dots (QACQDs and ChACQDs, respectively) protect against a (pesticide) paraquat-insult model of PD. Our results indicated that both types of CQDs intervened in the soluble-to-toxic transformation of the amyloid-forming model protein Hen Egg White Lysozyme (HEWL). Furthermore, QACQDs and ChACQDs demonstrated antioxidant activity while remaining biocompatible in a human neuroblastoma-derived cell line (SH-SY5Y) up to 5 mg/ml and protected the cell line from the environmental neurotoxicant (paraquat). Importantly, both CQDs were found to protect dopaminergic neuronal ablation in a paraquat model of Parkinson's disease using the nematode C. elegans. Our results are significant because both plant-derived organic acids cross the blood-brain barrier, making them attractive for developing CQD architectures. Furthermore, since the synthesis of these CQDs was performed using green chemistry methods from precursor acids that cross the BBB, these engineered bionanomaterial platforms are tantalizing candidates for preventing neurodegenerative disorders associated with exposure to environmental neurotoxicants.},
}

@article {pmid40264872,
year = {2025},
author = {Do, AT and Nguyen, TH and Pham, MQ and Nguyen, HT and Long, NP and Vu, VV and Phung, HTT and Ngo, ST},
title = {Tripeptides inhibit dual targets AChE and BACE-1: a computational study.},
journal = {RSC advances},
volume = {15},
number = {16},
pages = {12866-12875},
pmid = {40264872},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with amyloid-beta (Aβ) plaques and acetylcholine deficits being central pathological features. Inhibition of dual targets including acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) represents a promising strategy to address cholinergic deficits and amyloid pathology. In this study, we used computational approaches to evaluate 8000 tripeptides as potential dual inhibitors of AChE and BACE-1. Machine learning models revealed the four top-lead tripeptides including WHM, HMW, WMH, and HWM. Molecular docking simulations indicated that WHM possessed the most favorable interactions through hydrogen bonds, π-π stacking, and salt bridges with key catalytic residues in both enzymes. Molecular dynamics simulations confirmed the stability of the protein-ligand complexes, with WHM exhibiting the most consistent conformations and significant disruption of catalytic residue geometries. Free energy perturbation analysis further supported WHM's superior stability across both targets. ADMET predictions suggested moderate oral absorption and limited brain penetration, consistent with the typical behavior of peptide-based compounds. Overall, WHM demonstrated the strongest potential as a dual inhibitor of AChE and BACE-1, offering a promising lead for future therapeutic development in AD.},
}

@article {pmid40264648,
year = {2025},
author = {Liao, Y and Zhou, K and Lin, B and Deng, S and Qin, L and Weng, B and Yang, H and Pan, L},
title = {Associations between blood selenium and serum neurofilament light chain: results of a nationwide survey.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1490760},
pmid = {40264648},
issn = {1664-2295},
abstract = {BACKGROUND: Selenium (Se) is essential for many nervous system functions including memory, cognition and coordination, which has also been linked to a variety of neurological disorders, such as epilepsy, Alzheimer's disease (AD) and Parkinson's disease (PD). Serum neurofilament light chain (sNfL) is a biomarker of neurologic diseases. Studies on the relationship between blood Se and sNfL are limited.

METHODS: The National Health and Nutrition Examination Survey (NHANES) 2013-2014 data were employed to perform multivariate linear regression analysis and smooth curve fitting in order to investigate the relationship between blood Se and sNfL. Utilizing subgroup analyses and interaction tests, the stability of this relationship between populations was evaluated.

RESULTS: sNfL and blood Se had an inverse relationship in 1,036 individuals who were older than 20. According to the fully adjusted model, the sNfL decreased by 54.75 pg./mL for every unit increase in log blood Se [β = -54.75, 95% CI (-75.36, -34.14)]. The sNfL of individuals in the highest blood Se quartile decreased by 3.4 pg./mL in comparison to those in the lowest quartile [β = -3.40, 95% CI (-6.47, -0.32)]. This inverse association was more significant in those who were younger than 60 years old, male, normal weight, had a history of smoking and drinking.

CONCLUSION: Blood Se is inversely associated with sNfL in American adults. Our findings indicate that blood Se may have a potential protective effect against neuronal damage.},
}

@article {pmid40264463,
year = {2025},
author = {Tian, ZY and Jiang, B and Jin, M and Yu, XK and Chen, QL and Wang, JH},
title = {Alzheimer's disease and insomnia: a bibliometric study and visualization analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1542607},
pmid = {40264463},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the fastest-growing neurodegenerative disorder globally, with patient numbers expected to rise to 130 million by 2050. Insomnia, a prevalent comorbidity, exhibits a bidirectional relationship with AD: insomnia accelerates AD pathology, while AD worsens sleep disorders. This relationship has emerged as a key area of research. Current mechanisms involve oxidative stress, inflammatory responses, and glymphatic system dysfunction, yet a comprehensive review of these processes remains absent.

OBJECTIVE: To conduct a visual analysis of the relationship between Alzheimer's disease and insomnia using CiteSpace.

METHODS: Literature on "insomnia" and "Alzheimer's disease" published between January 1, 2000, and October 31, 2024, was retrieved from the Web of Science Core Collection. CiteSpace and VOSviewer software were used to analyze institutions, authors, and keywords.

RESULTS: A total of 1,907 articles were analyzed, revealing a consistent upward trend in publication volume. The United States and the Mayo Clinic were identified as leading contributors, producing 704 and 57 publications, respectively. Boeve Bradley F the most prolific author contributed 30 publications. Collaboration was actively observed among countries, institutions, and authors. High-frequency keywords identified were "Parkinson's disease," "cognitive impairment," and "sleep behavior disorder." Emerging research areas are likely to focus on "sleep quality" and the "glymphatic system."

CONCLUSION: This study is the first to apply bibliometric analysis to identify three key trends in AD and insomnia research: the dominance of the United States and Mayo Clinic, strong international collaboration, and a focus on critical areas such as cognitive impairment, the glymphatic system, and sleep interventions. Insomnia may accelerate AD progression via multiple pathways, indicating that enhancing sleep quality could provide new strategies for early intervention. Future research should prioritize advancing the clinical translation of sleep interventions and investigating the mechanisms of the glymphatic system.},
}

@article {pmid40264461,
year = {2025},
author = {Yohe, EO and Alonso, A and Drane, DL and Patel, SS and Schwinne, M and Epenge, E and Gikelekele, G and Herve, E and Kavugho, I and Tshengele, N and Mampunza, S and Mananga, L and Zhao, L and Qiu, D and Stringer, A and Saindane, AM and Ikanga, JN},
title = {Predictors of white matter hyperintensities in the elderly Congolese population.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1491477},
pmid = {40264461},
issn = {1663-4365},
abstract = {INTRODUCTION: White matter hyperintensities (WMHs) are strongly linked to cardiovascular risk factors and other health conditions such as Alzheimer's disease. However, there is a dearth of research on this topic in low-income countries and underserved populations, especially in the Democratic Republic of Congo (DRC) where the population is aging rapidly with increasing cardiovascular risk factors and dementia-related diseases. This study evaluates health factors associated with WMH in the elderly Sub-Saharan Africa (SSA), specifically Congolese adults.

METHODS: In a cross-sectional study of 77 people from the DRC, participants underwent neuroimaging to analyze WMHs volume and completed clinical evaluation, laboratory-based blood exams, self-reported questionnaires, and interviews. A simple linear regression model was conducted to test the association between WMHs and potential predictors (dementia, age, sex, hypertension, diabetes, tobacco abuse, stroke, high cholesterol, cardiovascular medication, and alcohol abuse). Stepwise selection and backward elimination analyses were performed to obtain the final model. Finally, a multiple linear regression model was conducted to assess the association between WMHs and variables retained in the final model (dementia, sex, and age).

RESULTS: Of the 77 individuals, 47 (61%) had dementia, 40 (52.6%) were males, and the mean age was 73 years (± 8.0 years standard deviation). In simple linear regression models, WMHs was significantly associated with dementia (expβ1 = 1.75, 95% CI = 1.14-2.71, p-value = 0.01) though it had a weak association with age (expβ1 = 1.03, 95% CI = 1.00-1.05, p-value = 0.05) and sex (male) (expβ1 = 0.66, 95% CI = 0.43-1.01, p-value = 0.05). In multiple linear regression models, WMHs was statistically significantly associated with dementia (expβ1 = 1.97, 95% CI = 1.31-2.95, p-value =0.001), male sex (expβ2 = 0.54, 95% CI = 0.36-0.80, p-value = 0.003), and age (expβ3 = 1.03, 95% CI = 1.00-1.06, p-value = 0.03). However, WMHs was not significantly associated with common cardiovascular risk factors, such as high blood pressure, diabetes, tobacco use, obesity, and high cholesterol levels.

DISCUSSION: WMHs is significantly associated with dementia, sex, and age in the Congolese population. Understanding these predictors may improve our ability to diagnose, assess, and develop preventative treatments for white matter disease in SSA/DRC populations, where neuroimaging is difficult to obtain.},
}

@article {pmid40264357,
year = {2025},
author = {Manoharan, MS and Lee, GC and Harper, N and Meunier, JA and Restrepo, MI and Jimenez, F and Karekatt, S and Branum, AP and Gaitan, AA and Andampour, K and Smith, AM and Mader, M and Noronha, M and Tripathy, D and Zhang, N and Moreira, AG and Pandranki, L and , and , and , and , and Sanchez-Reilly, S and Trinh, HD and Barnett, C and Angel, L and Segal, LN and Nicholson, S and Clark, RA and He, W and Okulicz, JF and Ahuja, SK},
title = {The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70063},
doi = {10.1111/acel.70063},
pmid = {40264357},
issn = {1474-9726},
support = {COVID19-8100-01//U.S. Department of Veterans Affairs/ ; IP1 CX000875-01A1//U.S. Department of Veterans Affairs/ ; AAI20042-001/NH/NIH HHS/United States ; R37AI046326/NH/NIH HHS/United States ; 1UM1TR004538/NH/NIH HHS/United States ; K23AG066933/NH/NIH HHS/United States ; T32DE014318/NH/NIH HHS/United States ; R21GM147800/NH/NIH HHS/United States ; FA8650-17-2-6816//United States Air Force (DoD)/ ; },
abstract = {Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face a 9.7-fold higher mortality rate-a risk equivalent to that of 55.5-year-olds with optimal IR-resulting in a 15.5-year gap in survival. Optimal IR preserves youthful immune profiles at any age, enhances vaccine responses, and reduces burdens of cardiovascular disease, Alzheimer's, and serious infections. Two key salutogenic evolutionary themes emerge: first, female-predominant IR, including TCF7, likely reflects evolutionary pressures favoring reproductive success and caregiving; second, midlife (40-70 years) is a critical window where optimal IR reduces mortality by 69%. After age 70, mortality rates converge between resilient and non-resilient groups, reflecting biological limits on longevity extension. TNFα-blockers restore salutogenesis pathways, indicating IR delays aging-related processes rather than altering aging rates. By reframing aging as a salutogenic-pathogenic balance, we establish TCF7-centered IR as central to healthy longevity. Targeted midlife interventions to enhance IR offer actionable strategies to maximize healthspan before biological constraints limit benefits.},
}

@article {pmid40264334,
year = {2025},
author = {Asante, JJ and Barger, SW},
title = {P-glycoprotein and Alzheimer's Disease: Threats and Opportunities.},
journal = {ASN neuro},
volume = {17},
number = {1},
pages = {2495632},
doi = {10.1080/17590914.2025.2495632},
pmid = {40264334},
issn = {1759-0914},
mesh = {*Alzheimer Disease/metabolism ; Humans ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism/genetics ; Animals ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 50 million people worldwide. One of the hallmark features of AD is the accumulation of amyloid β-peptide (Aβ) protein in the brain. P-glycoprotein (P-gp) is a membrane-bound protein expressed in various tissues, including the cerebrovascular endothelium. It plays a crucial role in the efflux of toxic substances, including Aβ, from the brain. Aberrations in P-gp levels or activity have been implicated in the pathogenesis of AD by promoting the accumulation of Aβ in the brain. Therefore, modulating the P-gp function represents a promising therapeutic strategy for treating AD. P-gp has multiple substrate binding sites, creating the potential for substrates to fall into complementation groups based on these sites; two substrates in the same complementation group may compete with one other, but two substrates in different groups may exhibit cooperativity. Thus, a given P-gp substrate may interfere with Aβ efflux whereas another may promote clearance. These threats and opportunities, as well as other aspects of P-gp relevance to AD, are discussed here.},
}

*Alzheimer Disease/metabolism
Humans
*ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism/genetics
Animals
Amyloid beta-Peptides/metabolism
*Brain/metabolism

@article {pmid40264328,
year = {2025},
author = {Kumar, L and Rana, R and Shaikh, NK and Thakur, A and Kashyap, S and Aggarwal, V and Jyothiraditya, V},
title = {Alzheimer's Disease and Polymeric Nanocarriers: Synergistic Advances in Targeted Drug Delivery.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266347890250409153450},
pmid = {40264328},
issn = {1873-4294},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a prominent neurodegenerative ailment characterized by the constraints of conventional therapies stemming from insufficient medication transport to the brain. This review examines the function of polymeric nanocarriers (PNCs) in improving therapeutic efficacy for Alzheimer's disease treatment.

METHODS: We analyze the principal obstacles to Alzheimer's disease drug delivery: the blood-brain barrier, the blood-cerebrospinal fluid barrier, and multidrug resistance proteins. The review examines three categories of PNCs: polymeric nanoparticles, polymeric micelles, and dendrimers, and their capacity to surmount these obstacles. Literature investigations used search engines like Pub- Med, Google Scholar, and ScienceDirect.

RESULTS: PNCs exhibit superior drug delivery via better biocompatibility, regulated release, and targeted delivery mechanisms. Recent studies demonstrate the effective delivery of several pharmaceuticals, including rivastigmine and galantamine, resulting in enhanced cognitive outcomes in Alzheimer's disease models. Patent research indicates an increase in innovation for PNC-based Alzheimer's disease treatments.

CONCLUSION: Despite ongoing hurdles in biocompatibility and scalability, PNCs exhibit significant potential to transform Alzheimer's disease treatment by improving medication delivery across biological barriers. Current investigations in nanotechnology and combinatorial medicines indicate a favorable outlook for PNC-based medicinal strategies.},
}

@article {pmid40264324,
year = {2025},
author = {Chauhan, A and Jain, S},
title = {Development of Brain Permeable Drugs and Novel Strategies to Overcome the Brain Barriers for Treatment Purposes.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128386983250410092649},
pmid = {40264324},
issn = {1873-4286},
abstract = {

The Blood-Brain Barrier (BBB), a dynamic and highly selective interface, regulates the exchange of molecules between the circulatory system and the Central Nervous System (CNS). While it protects the brain from toxins and pathogens, it also restricts the delivery of therapeutic agents, posing a significant challenge in treating CNS disorders such as Alzheimer's disease, Parkinson's disease, and glioblastoma. This manuscript explores the structural and functional complexity of the BBB, including the roles of tight junctions, adherens junctions, astrocytes, pericytes, and endothelial cells. It highlights the influence of drug physicochemical properties, such as lipophilicity, molecular weight, and hydrogen bonding, on BBB penetration. Current strategies to enhance drug delivery include nanotechnology-based carriers (liposomes, solid lipid nanoparticles, polymer-based carriers), receptor-mediated transcytosis, and cell-penetrating peptides. Emerging approaches like focused ultrasound with microbubbles, intranasal delivery, and exosome-mediated transport demonstrate significant potential for bypassing BBB constraints. Gene therapy, employing both viral and nonviral vectors, offers promise for addressing genetic CNS disorders. Despite advances, limitations, such as offtarget effects, limited delivery efficiency, and potential toxicity, remain critical barriers to clinical translation. Future research must prioritize multidisciplinary approaches integrating nanotechnology, personalized medicine, and enhanced understanding of BBB biology. Innovations in non-invasive, targeted delivery systems are essential to overcoming existing challenges and enabling effective treatment of CNS disorders. This review underscores the need for further exploration of these technologies to achieve sustained, site-specific drug delivery, thereby advancing therapeutic interventions for neurological diseases. Significance Statement: The blood-brain barrier (BBB) is a critical interface that protects the brain but limits drug delivery, posing challenges in treating CNS disorders. Advancing multidisciplinary approaches and innovative delivery systems is essential to overcome these limitations and enable effective therapies for neurological diseases.},
}

@article {pmid40264302,
year = {2025},
author = {Durosini, E and Anyanwu, M and Vendrame, T and Gianoncelli, A and Ribaudo, G},
title = {Mechanistic investigation on compounds from Amorpha fruticosa L. targeting acetylcholinesterase.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/14786419.2025.2495856},
pmid = {40264302},
issn = {1478-6427},
abstract = {Acetylcholinesterase (AChE) is the enzyme targeted by drugs used for the symptomatic treatment of cognitive decline associated with Alzheimer's disease. While in vitro data suggest the AChE inhibitory potential of A. fruticosa extracts and components such as rotenoids, in-depth mechanistic investigations are missing. A wide array of computational techniques, including ligand-based approaches, molecular docking, molecular dynamics, and machine learning-assisted toxicity prediction were enrolled in the current study, highlighting the rotenoid 6α,12α-dehydrodeguelin as a promising lead for the development of AChE inhibitors.},
}

@article {pmid40264239,
year = {2025},
author = {Zhang, W and Lukacsovich, D and Young, JI and Gomez, L and Schmidt, MA and Martin, ER and Kunkle, BW and Chen, XS and O'Shea, DM and Galvin, JE and Wang, L},
title = {DNA methylation signature of a lifestyle-based resilience index for cognitive health.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {88},
pmid = {40264239},
issn = {1758-9193},
support = {R01AG062634//US National Institutes of Health/ ; R01AG062634//US National Institutes of Health/ ; R01NS101483//US National Institutes of Health/ ; R61NS135587//US National Institutes of Health/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; K12TR004555//Miami Clinical and Translational Science Institute/ ; },
mesh = {Humans ; *DNA Methylation ; Male ; Female ; Aged ; *Life Style ; *Resilience, Psychological ; *Cognition/physiology ; Alzheimer Disease/genetics ; Aged, 80 and over ; *Cognitive Dysfunction/genetics ; Cohort Studies ; Epigenesis, Genetic ; },
abstract = {Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.},
}

Humans
*DNA Methylation
Male
Female
Aged
*Life Style
*Resilience, Psychological
*Cognition/physiology
Alzheimer Disease/genetics
Aged, 80 and over
*Cognitive Dysfunction/genetics
Cohort Studies
Epigenesis, Genetic

@article {pmid40264217,
year = {2025},
author = {Zhou, Z and Wang, Q and Liu, L and Wang, Q and Zhang, X and Li, C and Liu, J and Wei, Y and Gao, J and Fu, L and Wang, R},
title = {Correction: Investigating the Aβ and tau pathology in autosomal dominant Alzheimer's disease: insights from hybrid PET/MRI and network mapping.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {87},
pmid = {40264217},
issn = {1758-9193},
}

@article {pmid40264187,
year = {2025},
author = {Wang, S and Qi, C and Rajpurohit, C and Ghosh, B and Xiong, W and Wang, B and Qi, Y and Hwang, SH and Hammock, BD and Li, H and Gan, L and Zheng, H},
title = {Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {44},
pmid = {40264187},
issn = {1750-1326},
support = {093652/NS/NINDS NIH HHS/United States ; 020670/AG/NIA NIH HHS/United States ; 068031/AG/NIA NIH HHS/United States ; 066606/AG/NIA NIH HHS/United States ; Not applicable//Cure Alzheimer's Fund/ ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; },
mesh = {Animals ; *Epoxide Hydrolases/antagonists & inhibitors/metabolism ; *Microglia/drug effects/metabolism ; *Tauopathies/metabolism/drug therapy/pathology ; Mice ; Disease Models, Animal ; *Neuroprotection/drug effects/physiology ; Homeostasis/drug effects/physiology ; Mice, Knockout ; Humans ; Mice, Transgenic ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.

METHODS: Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions.

RESULTS: sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures.

CONCLUSION: These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways.},
}

Animals
*Epoxide Hydrolases/antagonists & inhibitors/metabolism
*Microglia/drug effects/metabolism
*Tauopathies/metabolism/drug therapy/pathology
Mice
Disease Models, Animal
*Neuroprotection/drug effects/physiology
Homeostasis/drug effects/physiology
Mice, Knockout
Humans
Mice, Transgenic
Neuroprotective Agents/pharmacology

@article {pmid40263752,
year = {2025},
author = {Xu, Z and Xiang, X and Feng, Y and Shi, X and Cai, L},
title = {Localized Intense Uptake in the Skull on 18F-Flortaucipir PET/CT.},
journal = {Clinical nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/RLU.0000000000005848},
pmid = {40263752},
issn = {1536-0229},
abstract = {18F-Flortaucipir, as a classical Tau protein visualizer, has been widely used in the diagnosis of neurodegenerative diseases, especially Alzheimer disease. This report describes a case of intense uptake of 18F-Flortaucipir at 2 sites of reduced bone mineral density in the skull, but no radioactivity uptake was seen on 18F-FDG and 18F-Florbetapir PET/CT imaging at the same lesion sites. The mechanism behind 18F-Flortaucipir uptake in focal osteopenia remains unclear. This study provides evidence for the mechanism of the above phenomenon.},
}

@article {pmid40263632,
year = {2025},
author = {},
title = {Microglia drive amyloid-β clearance in immunized patients with Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40263632},
issn = {1546-170X},
}

@article {pmid40263458,
year = {2025},
author = {Yuan, Z and Pavel, MA and Hansen, SB},
title = {GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {647},
pmid = {40263458},
issn = {2399-3642},
support = {RO1 NS112534//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {The γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAAR function. How lipids regulate the channel in the cell membrane is not fully understood. Here we employed super resolution imaging of lipids to demonstrate that the agonist GABA induces a rapid and reversible membrane translocation of GABAAR to phosphatidylinositol 4,5-bisphosphate (PIP2) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP2 clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABAAR associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions delay desensitization and enhance maximum current. In an Alzheimer's Disease (AD) mouse model with high brain cholesterol, GABAAR shifts into lipid rafts. Our findings suggest cholesterol is a signaling molecule and astrocytes regulates GABAARs in neurons by secreting cholesterol. The findings have implications for treating mood disorders and AD associated with altered brain lipids.},
}

@article {pmid40263406,
year = {2025},
author = {Slimi, H and Abid, S and Sayadi, M},
title = {Revolutionizing Alzheimer's disease detection with a cutting-edge CAPCBAM deep learning framework.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13925},
pmid = {40263406},
issn = {2045-2322},
abstract = {Early and accurate diagnosis of Alzheimer's disease (AD) is crucial for effective treatment. While the integration of deep learning techniques for AD classification is not entirely new, this study introduces CAPCBAM-a framework that extends prior approaches by combining Capsule Networks with a Convolutional Block Attention Module (CBAM). In CAPCBAM, standardized preprocessing of MRI images is followed by feature extraction using Capsule Networks, which preserve spatial hierarchies and capture intricate relationships among image features. The subsequent application of CBAM, employing both channel and spatial attention mechanisms, refines the feature maps to highlight the most clinically relevant regions. This dual-attention strategy offers clear advantages over conventional CNN methods, particularly in enhancing model generalization and mitigating information loss due to pooling. On the ADNI dataset, CAPCBAM achieved an impressive accuracy of 99.95%, with precision and recall both at 99.8%, an AUC of 0.99, and an F1-Score of 99.92%. Although the use of Capsule Networks and attention mechanisms has been explored previously, CAPCBAM distinguishes itself by its robust integration of these components. The study's advantages include improved feature extraction, faster convergence, and superior classification performance, making it a promising tool for the early detection of Alzheimer's disease.},
}

@article {pmid40263361,
year = {2025},
author = {Satake, Y and Taomoto, D and Wu, S and Godó, Á and Sato, S and Suzuki, M and Okura, F and Yagi, Y and Ikeda, M},
title = {The clinical significance of an AI-based assumption model for neurocognitive diseases using a novel dual-task system.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13989},
pmid = {40263361},
issn = {2045-2322},
support = {JP24uk1024001//Japan Agency for Medical Research and Development/ ; },
abstract = {Dual-task composed of gait or stepping tasks combined with cognitive tasks has been well-established as valuable tools for detecting neurocognitive disorders such as mild cognitive impairment and early-stage Alzheimer's disease. We previously developed a novel dual-task system with high accuracy for differentiating patients with neurocognitive disorders from healthy controls. In this study, we aimed to elucidate whether the output value obtained through artificial intelligence assumptions has clinical meaning other than diagnosis labelling. This is a retrospective cross-sectional study. Patients with Alzheimer's disease dementia, dementia with Lewy bodies, or mild cognitive impairment who participated in our previous dual-task experiment and completed all routine neuropsychological assessments at our hospital within one year of the experimental date were eligible for inclusion in the neurocognitive disorders group. Participants in the healthy control group were recruited from community-dwelling older adults. The correlation between the output value, "y-value", and each neuropsychological test: Mini-Mental State Examination (MMSE), Addenbrook's Cognitive Examination, Logical Memory tests, Frontal Assessment Battery, and digit span were assessed by Pearson's correlation coefficient. We also evaluated the correlation between the MMSE and those neurocognitive tests. To elucidate the diagnostic availability of the dual-task system and the MMSE on this dataset, we conducted a receiver operating characteristic analysis. We enrolled 97 participants in the neurocognitive disorders group: 42 with Alzheimer's disease dementia, 11 with dementia with Lewy bodies, and 44 with mild cognitive impairment. Additionally, 249 participants were included in the healthy control group. Although the y-value showed significant correlations with several tests, the MMSE demonstrated much stronger significant correlations with a broader range of cognitive tests. Meanwhile, its sensitivity and specificity were 0.969 and 0.912, respectively, and the area under the curve was 0.981, which was higher than the 0.934 of the MMSE. Our new AI-driven dual-task system has a high ability to predict neurocognitive disorders. However, the clinical significance of its output values is limited to screening for neurocognitive disorders and does not extend to estimating cognitive function. When using this system in clinical practice, it is essential to understand its limitations and select the appropriate usage scenarios.},
}

@article {pmid40263206,
year = {2025},
author = {Kolinger, GD and Sotolongo-Grau, O and Roé-Vellvé, N and Tartari, JP and Sanabria, Á and Pérez-Martínez, E and Koglin, N and Stephens, AW and Alegret, M and Tárraga, L and Gurruchaga, MJ and Ruiz, A and Boada, M and Bullich, S and Marquié, M and , and , },
title = {Quantification of baseline amyloid PET in individuals with subjective cognitive decline can identify risk of amyloid accumulation and cognitive worsening: the FACEHBI study.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {40263206},
issn = {1619-7089},
support = {115952//Innovative Medicines Initiative/ ; 115975//Innovative Medicines Initiative/ ; 115985//Innovative Medicines Initiative/ ; PI13/02434//Spanish ISCIII, Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER "Una manera de hacer Europa")/ ; PI16/01861//Spanish ISCIII, Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER "Una manera de hacer Europa")/ ; PI19/01240//Spanish ISCIII, Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER "Una manera de hacer Europa")/ ; PI19/01301//Spanish ISCIII, Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER "Una manera de hacer Europa")/ ; PI22/00258//Spanish ISCIII, Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER "Una manera de hacer Europa")/ ; PI22/01403//Spanish ISCIII, Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER "Una manera de hacer Europa")/ ; PMP22/00022//European Union (NextGenerationEU)/ ; CB06/05/2004//CIBERNED (ISCIII)/ ; CB18/05/00010//CIBERNED (ISCIII)/ ; AC19/00097//Joint program for neurodegenerative diseases (JPND)/ ; PR067/21//Agency for Innovation and Entrepreneurship/ ; PI17/01474//ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional/ ; TARTAGLIA//Programa Misiones de I+D en Inteligencia Artificial de la Secretaría de Estado de Digitalización e Inteligencia Artificial (SEDIA) del Ministerio de Asuntos Económicos y Transformación Digital/ ; 796706//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; PI19/00335//Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional/ ; },
abstract = {PURPOSE: Amyloid PET imaging is capable of measuring brain amyloid load in vivo. The aim of this study is to assess the relationship of the baseline amyloid with its accumulation over time and with cognition in individuals with subjective cognitive decline (SCD), giving a focus on those below Aβ positivity thresholds.

METHODS: 118 of 197 individuals with SCD from the Fundació ACE Healthy Brain Initiative underwent three [[18]F]florbetaben scans and the remaining 79 underwent two scans in a 5-year span. Individuals were categorised based on baseline Centiloid values (CL) into amyloid positive (Aβ+; CL > 35.7), Grey Zone (GZ; 20 < CL ≤ 35.7), and amyloid negative (Aβ-; CL ≤ 20). Relationship between conversion to mild cognitive decline (MCI) and baseline amyloid levels was assessed. Then, to focus on sub-threshold individuals with amyloid accumulation, the Aβ- group was split into two groups (N1 (CL ≤ 13.5) and N2 (13.5 < CL ≤ 20)), Aβ accumulation was determined, and a parametric image analysis of the Aβ accumulators in the N1 group was performed.

RESULTS: At baseline, 20 individuals were Aβ+, 8 GZ, 160 N1, and 9 N2. Higher Aβ load, older and less educated individuals presented increased risk of MCI-conversion. Longitudinally, 19% of N1 individuals were accumulators despite very low Aβ burden at baseline. Meanwhile, 89% of the N2 group accumulated Aβ as well as all GZ individuals (which had the highest rate of amyloid accumulation, 5.1 CL/year). In the parametric image analysis of N1 accumulators, a region within the precuneus was linked to increased Aβ over time.

CONCLUSION: Baseline amyloid levels differentiate individuals who accumulate amyloid over time and that are at risk for cognitive decline, including those at sub-threshold levels of Aβ. This can be valuable to identify pre-clinical AD in a SCD population.},
}

@article {pmid40263004,
year = {2025},
author = {Ebrahim, N and Al Saihati, HA and Alenzi, FQB and El-Sherbiny, M and Alsabeelah, NF},
title = {Corrigendum to "Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease: Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway" [Biomed. Pharmacother. 176 (2024) 116836].},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {118042},
doi = {10.1016/j.biopha.2025.118042},
pmid = {40263004},
issn = {1950-6007},
}

@article {pmid40262935,
year = {2025},
author = {Lai, LF and Li, X and Li, HZ and Li, ZM and Liu, L and Zhang, YY and Yang, H and Luo, BY and Yi, W and Xu, NG and Zhao, JY},
title = {[Electroacupuncture improves synaptic plasticity and cognitive dysfunction via down-regulating HDAC3 in mice of Alzheimer's disease].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {50},
number = {4},
pages = {375-383},
doi = {10.13702/j.1000-0607.20240214},
pmid = {40262935},
issn = {1000-0607},
abstract = {OBJECTIVES: To observe the effect of electroacupuncture(EA) on histone deacetylase 3 (HDAC3), synaptic plasticity and N-methyl-D-aspartate (NMDA) receptors in the hippocampus of mice with Alzheimer's disease(AD), so as to explore the underlying mechanism of EA in treatment of AD.

METHODS: 5XFAD mice were randomly divided into EA group, model group and sham-acupuncture group, with 13 mice in both the EA group and the model group, and 7 mice in the sham-acupuncture group. Thirteen wild-type mice from the same litter were taken as the normal control group. The mice in the EA group received EA at "Baihui" (GV20)and "Dazhui" (GV14) for 15 min once daily, 6 times a week for 4 weeks. The mice in the sham-acupuncture group received sham EA, i.e., the needle was inserted into the rubber clay which was placed on the surface of the corresponding acupoints. The novel object recognition(NOR), Y-maze and Morris water maze(MWM) tests were used to observe the cognitive functions of mice. Electrophysiological technique was used to detect long-term potentiation (LTP) of the hippocampal neurons and Western blot was used to detect the relative expressions of HDAC3 and NMDAR-related receptors (NMDAR1, NMDAR2A, NMDAR2B) in the hippocampus.

RESULTS: Compared with the normal control group, 5XFAD mice in the model group showed decreased(P<0.01, P<0.05) preference index for new object recognition, alternative arm ratio (AAR), number of times crossing the original platform, percentage of time and distance traveled in the target quadrant, NMDAR2B, NMDAR2A and NMDAR1 protein expression levels, with prolonged(P<0.01) escape latency, and increased (P<0.05) protein relative expression of HDAC3. At the same time, with high-frequency stimulation, the slope of fEPSP was decreased(P<0.01, P<0.05)in the 5XFAD mice. After EA intervention, comparison between the EA and the model groups revealed that, the preference index for new object recognition, AAR were increased (P<0.01, P<0.05) in the EA group, the escape latency was shortened (P<0.05), and the number of times crossing the platform, percentage of time and distance traveled in the target quadrant, the slope of fEPSP, and the protein relative expressions of NMDAR2B, NMDAR2A and NMDAR1 in the hippocampus were increased (P<0.01, P<0.05), while the protein relative expression of HDAC3 decreased (P<0.01). Compared with sham-acupuncture group, the above indexes improved to different degree in the EA group (P<0.01, P<0.05).

CONCLUSIONS: EA of GV20 and GV14 can restore the impaired LTP and improve the cognitive impairment, which may be related to increasing the expressions of NMDA-related receptor proteins and down-regulating the expression of HDAC3 in the hippocampus of 5XFAD mice.},
}

@article {pmid40262859,
year = {2025},
author = {Sun, D and Yang, T and Wang, M and Pang, J and Li, F},
title = {Sub-chronic exposure of hexaconazole may induce metabolic and neuropathic diseases: The evidence from gut microbiota.},
journal = {Pesticide biochemistry and physiology},
volume = {210},
number = {},
pages = {106398},
doi = {10.1016/j.pestbp.2025.106398},
pmid = {40262859},
issn = {1095-9939},
abstract = {The high-frequency detection and long persistence of hexaconazole (Hex) in agricultural products and environment poses potential risk to non-targeted organisms which should pay special attention to. Intestinal flora plays an important role in host health by prevention the occurrence of various diseases. Therefore, in this study, the disturbance of Hex on intestinal function and flora in rats had been studied at environmental related concentrations to evaluate the potential risk of Hex. Our results showed that Hex exposure induced serious oxidative stress and inflammation in intestinal tract. Meanwhile, it notably decreased the tight connectivity in colonic cell leading to the dysfunction of intestinal barrier. Moreover, 16sRNA gene sequencing showed that Hex exposure significantly disturbed the composition and structures of gut microbiota by decrease beneficial bacteria and increase pathogenic bacteria. Further, the metabolites and SCFAs that related to neuropathic and metabolic diseases in colonic contents were also significantly affected by Hex exposure. The pathways of membrane transport, replication and repair, lipid metabolism, and neurodegenerative diseases had been seriously interfered. The obtained results referred that Hex exposure may pose potential risk to metabolic system causing obesity, metabolic syndrome, and cardiovascular as well as nervous system inducing Parkinson's diseases, Alzheimer's diseases, and depression. Our study provided a new sight to study the mechanisms of Hex induced toxicity effects from the aspect of gut microbiota which could help for prevention the risk induced by Hex.},
}

@article {pmid40262845,
year = {2025},
author = {Bakchine, S and Colosimo, C and Emilsson, E and Jónsdóttir, SE and Massacesi, L and Nonino, F and Religa, D and Richard, E and Weydt, P and Wolters, FJ},
title = {Concerns about the approval of lecanemab for Alzheimer's disease.},
journal = {BMJ (Clinical research ed.)},
volume = {389},
number = {},
pages = {r778},
doi = {10.1136/bmj.r778},
pmid = {40262845},
issn = {1756-1833},
}

@article {pmid40262818,
year = {2025},
author = {Iacobucci, G},
title = {Lecanemab: Experts criticise European Commission approval of Alzheimer's drug.},
journal = {BMJ (Clinical research ed.)},
volume = {389},
number = {},
pages = {r796},
doi = {10.1136/bmj.r796},
pmid = {40262818},
issn = {1756-1833},
}

@article {pmid40262685,
year = {2025},
author = {Ke, J and Li, J and Yu, M},
title = {Letter to the editor regarding "Exploring the bidirectional relationships between alzheimer's disease and cerebral small vessel disease: Insights from mendelian randomization".},
journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association},
volume = {},
number = {},
pages = {108326},
doi = {10.1016/j.jstrokecerebrovasdis.2025.108326},
pmid = {40262685},
issn = {1532-8511},
}

@article {pmid40262663,
year = {2025},
author = {Hamieh, N and Ansart, M and Guinebretiere, O and Lekens, B and Gantzer, L and Durrleman, S and Nedelec, T},
title = {Longitudinal comparative analysis of antidepressants and anti-anxiety medications in Alzheimer's and Parkinson's diseases: insights from French and British health records.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jad.2025.04.094},
pmid = {40262663},
issn = {1573-2517},
abstract = {BACKGROUND: Depression and anxiety coexist with Alzheimer's disease (AD) and Parkinson's disease (PD), yet their progression trajectories vary, necessitating a thorough examination of prescription patterns for antidepressants and anti-anxiety drugs pre- and post-diagnosis.

OBJECTIVES: To systematically compare the prescriptions of antidepressant and anti-anxiety drugs across AD and PD over 10 years before and after initial diagnosis in the UK and France.

METHODS: Data on 19,954 patients with AD, 25,267 with PD from the UK, 17,463 with AD, 10,333 with PD from France were extracted from The Health Improvement Network database. For both countries, we compared the odds of prescribed antidepressants and anti-anxiety drugs for each diagnosis group, over 10 years before and after diagnosis, using logistic regressions adjusting for age, sex, and drug prescriptions for chronic diseases.

RESULTS: Antidepressant prescriptions showed a significant rise from 25 % 5-10 years before the initial AD diagnosis to 50 % within the first 5 years post-diagnosis. AD Patients were more likely to be prescribed antidepressants than PD patients [Odds ratios ranging from 1.02 to 1.13 in the UK and 1.09-1.36 in France] and conversely PD patients were more likely to be prescribed anti-anxiety drugs [0.83-0.84 in the UK and 0.85-0.90 in France] several years before their diagnosis. AD patients sustained elevated antidepressant prescriptions up to 5 years after diagnosis.

CONCLUSION: These findings offer insights into disease-specific psychological impacts and underscore the necessity for further investigation into prescription patterns and their implications on patient outcomes.},
}

@article {pmid40262568,
year = {2025},
author = {Tuna, RW and Achmad, NA and Kurniawan, I and Khairiyah, and Asaf, MB and Sapiun, Z and Himawan, A and Dominguez-Robles, J and Aswad, M and Permana, AD},
title = {Development of thermosensitive mucoadhesive gel incorporated lipid microspheres of donepezil for enhanced nose-to-brain delivery.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/09205063.2025.2492455},
pmid = {40262568},
issn = {1568-5624},
abstract = {Alzheimer's disease (ALZ) is a chronic disease that affects the brain neurons leading to dementia. Donepezil (DPZ), a first-line treatment for ALZ is a potent symptomatic therapeutic agent. However, the oral and transdermal route represents non-targeted delivery, causing various adverse effects. This study presents the successful incorporation of a DPZ-loaded lipid microsphere (DPZ-LM) system into a thermosensitive-mucoadhesive gel (TMG), thereby enhancing the delivery of DPZ through the nose-to-brain route. To optimize the formulations, several evaluations were conducted, resulting in an optimized formulation of LM using Compritol[®] exhibited particle size of 8.75 µm, 98.44% of DPZ entrapped, and 93.40% of DPZ loaded in the system with a sustained release manner in the in vitro studies. The TMG-DPZ-LM was prepared using Pluronic[®] F127 and F68, as the gelling agents, with the addition of sodium alginate, as the mucoadhesive polymer. Following incorporation into TMG-DPZ-LM, the system exhibited excellent physicochemical properties and effective nasal delivery in ex vivo permeation has found that 88.58 ± 12.53 µg/cm[2] and retention studies with a mean concentration of 0.0077 mg of retention DPZ in porcine nasal mucosa. The in vivo pharmacokinetic studies demonstrated that the administration of TMG-DPZ-LM via the nose-to-brain route resulted in a significant (p < 0.05) increase in the Cmax, with 207.24 ± 5.16 µg/cm[3] of DPZ in the brain that exhibited a significantly different profile compared to the other route and formulation. The TMG-DPZ-LM system that was developed in this study was considered to have improved its efficacy in the treatment of ALZ.},
}

@article {pmid40262123,
year = {2025},
author = {Turgut, GÇ and Pepe, NA and Ekiz, YC and Şenol, H and Şen, A},
title = {Therapeutic Potential of Nitrogen-Substituted Oleanolic Acid Derivatives in Neuroinflammatory and Cytokine Pathways: Insights From Cell-Based and Computational Models.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e202500269},
doi = {10.1002/cbdv.202500269},
pmid = {40262123},
issn = {1612-1880},
abstract = {This study was conducted to investigate the mechanism of the potential and anti-inflammatory properties of nitrogen-substituted oleanolic acid derivatives that can be used to treat neuroinflammatory diseases. Nitrogen-containing oleanolic acid derivatives have been evaluated for their anti-neuroinflammatory effects in vitro in neuronal and monocytic cell lines at nontoxic doses, and the production of cytokines (TNF-α, IL-6 and IL-17), the inflammatory enzyme induced nitric oxide synthase (iNOS) and NF-κB signalling under LPS-stimulated conditions, and the expression of genes associated with Alzheimer's disease have been assessed. In addition, molecular docking and molecular dynamics simulation assessments are conducted in silico. Key protein markers of neurodegenerative diseases, especially Alzheimer's disease and neuroinflammation, TAU protein levels, and microglial activation, as well as ionised calcium-binding adaptor protein-1 (IBA1) levels, were significantly reduced with the addition of oleanolic acid derivatives. LPS-induced NF-κB luciferase reporter activity and iNOS activity were significantly inhibited, approaching the levels in uninduced controls. The mRNA expression of proinflammatory cytokines critical for neuroinflammation, such as TNF-α, NF-κB, IL-6 and IL-17, was reduced twofold to sevenfold. Furthermore, the molecular docking and MD simulation analyses revealed potential interactions with the TNF-α and NF-κB proteins. These findings underscore the potential of oleanolic acid derivatives, particularly compound 16, as candidates for further development as therapeutic agents for neurodegenerative diseases associated with chronic inflammation.},
}

@article {pmid40262111,
year = {2025},
author = {Ghanbarian, E and Khorsand, B and Petersen, KK and Nallapu, BT and Sajjadi, SA and Lipton, RB and Ezzati, A and , },
title = {Cerebrospinal fluid inflammatory cytokines as prognostic indicators for cognitive decline across Alzheimer's disease spectrum.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251335915},
doi = {10.1177/13872877251335915},
pmid = {40262111},
issn = {1875-8908},
abstract = {BackgroundNeuroinflammation actively contributes to the pathophysiology of Alzheimer's disease (AD); however, the value of neuroinflammatory biomarkers for disease-staging or predicting disease progression remains unclear.ObjectiveTo investigate diagnostic and prognostic utility of inflammatory biomarkers in combination with conventional AD biomarkers.MethodsData from 258 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with cerebrospinal fluid (CSF) biomarkers of amyloid-β (Aβ), tau, and inflammation were analyzed. Clinically meaningful cognitive decline (CMCD) was defined as a ≥ 4-point increase on the Alzheimer's Disease Assessment Scale Cognitive Subscore 11. Predictor variables included demographics (D: age, sex, education), APOE4 status (A), inflammatory biomarkers (I), and classic AD biomarkers of Aβ and p-tau181 (C). Models incorporating inflammatory biomarkers assessed their contribution to improving baseline diagnostic classification and 1-year CMCD prediction.ResultsAt 1-year follow-up, 27.1% of participants experienced CMCD. Adding inflammatory biomarkers to models with D and A variables (DA model) improved classification of cognitively normal (CN) versus mild cognitive impairment (MCI) and CN versus Dementia (p < 0.001). Similarly, inflammatory markers enhanced classification in models including C (DAC model), for CN versus MCI (p < 0.01) and CN versus Dementia (p < 0.001). Predictive performance for CMCD was improved in individuals with MCI and dementia in both models (all p < 0.05). In addition, the DAI model outperformed the DAC model in predicting CMCD for MCI and Dementia groups (both p < 0.05).ConclusionsAddition of CSF inflammatory biomarkers to biomarkers of AD improves diagnostic accuracy of clinical disease stage at baseline and add incremental value to AD biomarkers for prediction of cognitive decline.},
}

@article {pmid40262110,
year = {2025},
author = {Libon, DJ and Swenson, R and Langford, DT and Cosentino, S and Price, CC and Lamar, M and Emrani, S and Au, R and Andersen, S and Chen, MH and Ashendorf, L and Thompson, L},
title = {Precision neurocognition: An emerging diagnostic paradigm leveraging digital cognitive assessment technology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251325725},
doi = {10.1177/13872877251325725},
pmid = {40262110},
issn = {1875-8908},
abstract = {Strategies that may modify Alzheimer's disease (AD) and other dementia disorders are being developed. To maximize the benefits of these strategies, it is critical that indicators suggesting neurocognitive decline are identified as early as possible. 'Precision neurocognition' is a heuristic that seeks to develop methodologies capable of identifying subtle behavior(s) that may flag emerging AD and other dementia related syndromes. Recent research suggests that digital neuropsychological assessment technology may be the platform that can realize the goals of precision neurocognition, i.e., the early detection of neurocognitive difficulties that are prognostic for mild cognitive impairment (MCI) and dementia. Past research associating 100% correct or statistically within normal limits responding using neuropsychological tests with time-based parameters obtained while participants undergo assessment is reviewed. Recent research with community dwelling and memory clinic participants examined test scores obtained using commonly available neuropsychological tests. This research extracted a number of discrete latency measures that clearly dissociate between groups, despite final test scores that are either 100% correct or statistically within normal limits. In sum, past research using digitally administered neuropsychological tests suggests that the goals of precision neurocognition as related to the early identification of neurodegenerative illness may be realized via an analysis of time derived, process-based behavior using digital assessment technology. Latency or time-based parameters as described in recent research could form the basis of a range of neurocognitive biomarkers for identifying people at risk for developing AD, other dementing disorders, and MCI.},
}

@article {pmid40262108,
year = {2025},
author = {Derboghossian, G and Pituch, K and Anthony, M and Salisbury, D and Lin, FV and Yu, F},
title = {Relationships among cardiorespiratory fitness, brain age, and neurodegeneration in older adults with amnestic mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333613},
doi = {10.1177/13872877251333613},
pmid = {40262108},
issn = {1875-8908},
abstract = {BackgroundThere is growing evidence that cardiorespiratory fitness (CRF) mitigates the likelihood of dementia caused by Alzheimer's disease and may underlie the cognitive benefits observed from aerobic exercise. Previous evidence further demonstrates neurodegeneration is the biological substrate for cognitive deterioration and younger brain age may protect the brain from the deleterious effects of neurodegeneration. However, little is known about the relationships between CRF, brain age, and neurodegeneration in older adults with amnestic mild cognitive impairment (aMCI).ObjectiveThe aim of this cross-sectional study was to examine associations between CRF, brain age, and neurodegeneration among individuals with aMCI, using baseline data from the Aerobic exercise and Cognitive Training (ACT) trial, which examined the cognitive effects and underlying mechanisms of a 6-month ACT in older adults with aMCI.MethodsCRF was measured with peak oxygen uptake (VO2peak), from a symptom-limited peak cycle-ergometer test. Brain age and hippocampal volume were obtained from structural magnetic resonance imaging. Brain age was estimated using brainageR. Descriptive statistics and bivariate correlations were assessed. Linear regression models were used to analyze the relationships between CRF, brain age, and hippocampal volume, while adjusting for covariates. All analyses were conducted using R (version 4.3.2).ResultsThe sample (N = 141) averaged 73.66 ± 5.78 years of age, 16.91 ± 2.89 years of education, 27.46 ± 5.15 in BMI, and 23.49 ± 2.16 on Montreal Cognitive Assessment, with 53% male and 92.2% White. The mean brain age was 72.37 ± 7.89 years with 3157.31 ± 449.35 mm[3] hippocampal volume. No association was found between CRF, brain age, and hippocampal volume.ConclusionsFuture studies need to explore other brain indicators related to CRF.Trial RegistryClinicalTrials.gov, https://clinicaltrials.gov/study/NCT03313895, NCT03313895, October 18, 2017.},
}

@article {pmid40262107,
year = {2025},
author = {Kshirsagar, S and Deshmukh, H and Reddy, AP and Reddy, AP and Reddy, PH},
title = {Grounding as a complementary intervention for Alzheimer's disease: Mechanisms, evidence, and potential therapeutic applications.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334666},
doi = {10.1177/13872877251334666},
pmid = {40262107},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Despite extensive research efforts, effective curative treatments remain elusive, emphasizing the need for innovative therapeutic strategies. Grounding, or earthing, involves direct physical contact with the Earth's surface to facilitate the absorption of negatively charged electrons into the body. This practice has gained attention for its potential to reduce inflammation, oxidative stress, and cortisol dysregulation, which are significant contributors to AD pathology. This review examines the biological mechanisms by which grounding may influence AD, including its antioxidative effects that mitigate oxidative stress and its anti-inflammatory properties that reduce neuroinflammation. Grounding may also improve sleep quality and stress management, factors known to exacerbate AD progression. Evidence from preclinical and clinical studies highlights its potential to protect neuronal health by targeting oxidative and inflammatory pathways. Additionally, the safety, feasibility, and cost-effectiveness of grounding are discussed, making it a practical complementary approach to existing AD therapies. While the preliminary evidence is promising, the review emphasizes the need for robust clinical trials to validate grounding's efficacy specifically in AD populations. By integrating grounding into standard care protocols, it may be possible to enhance the overall therapeutic outcomes and improve the quality of life for individuals with AD. Grounding represents a novel, non-pharmacological intervention that could complement existing treatments by addressing both the physiological and psychological aspects of this complex disease.},
}

@article {pmid40261930,
year = {2025},
author = {Paulson, AL and Zhang, L and Prichard, AM and Singer, AC},
title = {40 Hz sensory stimulation enhances CA3-CA1 coordination and prospective coding during navigation in a mouse model of Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {17},
pages = {e2419364122},
doi = {10.1073/pnas.2419364122},
pmid = {40261930},
issn = {1091-6490},
support = {R01 NS109226/NS/NINDS NIH HHS/United States ; 2RF1NS109226//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1AG078736//HHS | NIH | National Institute on Aging (NIA)/ ; NA//David and Lucile Packard Foundation (PF)/ ; 5F31AG066410//HHS | NIH (NIH)/ ; T32 NS007480-18//HHS | NIH (NIH)/ ; NA//Fulton County Elder Health Science Fellowship/ ; NA//Wright Family/ ; NA//J. Norman and Rosalyn Wells Fellowship/ ; NA//McCamish Foundation/ ; NA//Friends and Alumni of Georgia Tech/ ; CDA2 E4544-W//VA | Center for Integrated Healthcare, U.S. Department of Veterans Affairs (CIH, VA)/ ; NA//BrightFocus Foundation (BFF)/ ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; Mice ; *CA1 Region, Hippocampal/physiopathology/physiology ; Disease Models, Animal ; *Spatial Navigation/physiology ; Mice, Transgenic ; *CA3 Region, Hippocampal/physiopathology/physiology ; Male ; Photic Stimulation ; Acoustic Stimulation ; Humans ; },
abstract = {40 Hz sensory stimulation ("flicker") has emerged as a new technique to potentially mitigate pathology and improve cognition in mouse models of Alzheimer's disease (AD) pathology. However, it remains unknown how 40 Hz flicker affects neural codes essential for memory. Accordingly, we investigate the effects of 40 Hz flicker on neural representations of experience in the hippocampus of the 5XFAD mouse model of AD by recording 1,000s of neurons during a goal-directed spatial navigation task. We find that an hour of daily exposure to 40 Hz audio-visual stimulation over 8 d leads to higher coordination between hippocampal subregions CA3 and CA1 during navigation. Consistent with CA3's role in generating sequential activity that represents future positions, 40 Hz flicker exposure increased prospective coding of future positions. In turn, prospective coding was more prominent during efficient navigation behavior. Our findings show how 40 Hz flicker enhances key hippocampal activity during behavior that is important for memory.},
}

Animals
*Alzheimer Disease/physiopathology/therapy
Mice
*CA1 Region, Hippocampal/physiopathology/physiology
Disease Models, Animal
*Spatial Navigation/physiology
Mice, Transgenic
*CA3 Region, Hippocampal/physiopathology/physiology
Male
Photic Stimulation
Acoustic Stimulation
Humans

@article {pmid40261888,
year = {2025},
author = {Johnson, KJ and Johnson, K and Grant, A and Taglialatela, G and Micci, MA},
title = {Photobiomodulation therapy increases neural stem cell pool in aged 3xTg-AD mice.},
journal = {PloS one},
volume = {20},
number = {4},
pages = {e0321668},
doi = {10.1371/journal.pone.0321668},
pmid = {40261888},
issn = {1932-6203},
mesh = {Animals ; *Alzheimer Disease/pathology/therapy/metabolism/radiotherapy/genetics ; *Low-Level Light Therapy ; Mice, Transgenic ; Mice ; *Neural Stem Cells/radiation effects/metabolism/cytology/pathology ; Neurogenesis/radiation effects ; Hippocampus/pathology/radiation effects/metabolism ; Disease Models, Animal ; tau Proteins/metabolism ; *Aging ; },
abstract = {Presently approved Alzheimer's Disease (AD) therapeutics are designed for targeted removal of the AD-related toxic protein aggregate amyloid-β (Aβ) and have only shown moderate efficacy at slowing disease progression. Reversal of cognitive decline requires both removal of toxic aggregates and repair of the cellular systems damaged by decades of exposure to these aggregates. Adult hippocampal neurogenesis (AHN) is one such system that is known to be affected early and severely in the development of AD. Moreover, preserved AHN is associated with cognitive resilience to AD neuropathology. Therefore, targeted therapies to improve or enhance neurogenesis should be considered in addition to the removal of toxic protein aggregates. Photobiomodulation (PBM) using 670 nm LED light has been shown to induce synaptic resilience to and removal of AD-related toxic protein aggregates. In this study, we aimed to assess the effect of PBM on a mouse model of advanced AD neuropathology. Transgenic 3xTg-AD mice (15- to 17-month old) were randomized to receive PBM or SHAM therapy for one month, followed by neuropathological assessments. Our results show that one month of PBM therapy reduces hyperphosphorylated tau burden and partially rescues AHN in aged 3xTg-AD mice as compared to SHAM-treated transgenic mice. These data support the notion that PBM has the potential to be an effective non-invasive therapy to help preserve AHN and reduce cognitive dysfunction in moderate to advanced AD.},
}

Animals
*Alzheimer Disease/pathology/therapy/metabolism/radiotherapy/genetics
*Low-Level Light Therapy
Mice, Transgenic
Mice
*Neural Stem Cells/radiation effects/metabolism/cytology/pathology
Neurogenesis/radiation effects
Hippocampus/pathology/radiation effects/metabolism
Disease Models, Animal
tau Proteins/metabolism
*Aging

@article {pmid40261606,
year = {2025},
author = {Alam, P and Arshad, MF and Sharma, P},
title = {Structural Dynamics and Network Pharmacology for the Discovery of Inhibitors Targeting DYRK1 A in Neurological Disorders.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40261606},
issn = {1559-1182},
support = {RSPD2025R945//King Saud University/ ; },
abstract = {Neurological disorders, including Down syndrome, Alzheimer's disease, and autism spectrum disorders, involve intricate disruptions in brain function and development. DYRK1A (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) has become an essential target in these diseases because it helps neurons grow, differentiate, and change shape. Overexpression of DYRK1A is connected to problems with neurodevelopment, memory loss, and tauopathies, which makes it an essential target for therapy. Therefore, inhibiting the DYRK1A protein aids in maintaining the normal brain molecular mechanism. Herein, we have identified three major natural compounds, ZINC000043552589, ZINC000001562130, and ZINC000059779788, as potential inhibitory candidates. These compounds exhibited a strong binding affinity with the DYRK1A protein during virtual screening and molecular docking. During the virtual screening analysis, the binding scores of these compounds were more than -11.0 kcal/mol. Further, hydrogen and hydrophobic interactions strengthen their binding with the DYRK1A protein. The MD simulation analysis also confirmed the structural dynamic stability of the compounds. Moreover, the total free binding energy calculated via the MM/GBSA method was found to be -54.06 kcal/mol for ZINC000043552589, -39.01 kcal/mol for ZINC000001562130 and -50.26 kcal/mol for ZINC000059779788. These values further confirm the binding affinity strength of the compounds with the target protein. DFT analysis revealed distinct HOMO-LUMO energy gaps and orbital distributions across the compounds, highlighting their varied electronic characteristics and charge-transfer potentials. Network pharmacology analysis further highlighted multiple potential gene targets for the selected compounds, providing insights into their broader therapeutic implications. This analysis suggests these natural compounds may modulate additional pathways relevant to neurodevelopmental and neurodegenerative diseases.},
}

@article {pmid40261451,
year = {2025},
author = {Szabo, C},
title = {"Doctored: fraud, arrogance, and tragedy in the quest to cure Alzheimer's": an important new book with direct relevance to GeroScience.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40261451},
issn = {2509-2723},
}

@article {pmid40261388,
year = {2025},
author = {Nishigaki, A and Ishikawa, H and Nishiguchi, Y and Tachibana, K and Kato, N and Matsuda, K and Mori, Y and Matsuyama, H and Matsuura, K and Ii, Y and Wakita, H and Oikawa, S and Tomimoto, H and Shindo, A},
title = {Alpha-1-acid glycoprotein as a potential serum biomarker for cerebral amyloid angiopathy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333802},
doi = {10.1177/13872877251333802},
pmid = {40261388},
issn = {1875-8908},
abstract = {BackgroundCerebral amyloid angiopathy (CAA) is a form of cerebral small vessel disease (SVD) associated with Alzheimer's disease, intracerebral hemorrhage, and cognitive decline. Despite its clinical significance, no reliable serum biomarker exists for early diagnosis or monitoring of disease progression.ObjectiveThis study hypothesizes that α1-acid glycoprotein (α1-AGP) and other serum biomarkers can aid CAA diagnosis and assessment using gel-based mass spectrometry. A comparative analysis was performed to investigate associations between serum biomarkers and radiological scores.MethodsSerum proteins from individuals with probable or possible CAA (n = 10), classified using the modified Boston criteria, and age-matched controls (n = 10) were analyzed via two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF-MS). Candidate proteins were validated using enzyme-linked immunosorbent assay (ELISA). Outcome measures included biomarker diagnostic accuracy, assessed by receiver operating characteristic (ROC) curve analysis, and correlations between α1-AGP levels and CAA-SVD scores.ResultsFour proteins-hemopexin, complement C3, complement C9, and α1-AGP-were significantly elevated, while apolipoprotein A-1 was reduced in the CAA group. ELISA confirmed higher α1-AGP levels in individuals with CAA (p < 0.0001). ROC analysis demonstrated that α1-AGP could indicate the presence of CAA with a sensitivity and specificity of 1.00 (95%CI: 1.000, 1.000). Additionally, α1-AGP levels correlated with the CAA-SVD score (R[2] = 0.783).Conclusionsα1-AGP may serve as a novel serum biomarker for CAA. Larger cohorts and external validation are required to substantiate these findings and determine their clinical relevance.},
}

@article {pmid40261356,
year = {2025},
author = {Babalola, DO and Adewale, BA and Okwunze, KF and Mohammed, TT and Oduguwa, IO and Igwe, HA and Farombi, T and Akinyemi, RO},
title = {Knowledge and attitudes about dementia and dementia genetics in a cohort of geriatric clinic attendees in Nigeria.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333816},
doi = {10.1177/13872877251333816},
pmid = {40261356},
issn = {1875-8908},
abstract = {BackgroundPopulation ageing in Africa will increase the burden of Alzheimer's disease and related dementias within the next few decades. Despite the potential for discovery of novel genetic risks in African populations, there is still a paucity of dementia genetic research among indigenous Africans.ObjectiveWe aimed to investigate the knowledge and attitudes of elderly population in Nigeria about dementia and dementia genetics.MethodsOne hundred clinic attendees (aged ≥60 years) recruited at the University College Hospital, Ibadan, Nigeria were surveyed using an interviewer-administered questionnaire consisting of the Dementia Knowledge Assessment Scale (DKAS) and other items assessing knowledge and attitudes about dementia genetics.ResultsThe mean age (±SD) of participants was 71.0 (±7.1) years, and the mean (±SD) DKAS score was 8.87 (±10.84). Only 10% were considered to have good knowledge of dementia (i.e., DKAS score ≥26). Attempts by participants to translate "dementia" in their local languages revealed misleading themes in their perception of the condition. Of the 42 participants who claimed to know what dementia is, 32 (76.2%) of them had poor knowledge (i.e., DKAS <26). Twenty-one participants were aware of the existence of genetic risk factors for dementia, but none could name a dementia risk gene. Seventy participants expressed willingness to undergo genetic testing to assess their risk of dementia.ConclusionsThere is a poor level of knowledge about dementia and dementia genetics among the elderly population in Nigeria. Public health education and community engagement is important for maximizing the impact of dementia genetic studies in Africa.},
}

@article {pmid40261311,
year = {2025},
author = {Chen, HM and Shen, K and Ji, L and McGrath, C and Chen, H},
title = {Patterns and trends in the burden of Alzheimer's disease and related dementias in China (1990-2021) and predictions to 2040.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333108},
doi = {10.1177/13872877251333108},
pmid = {40261311},
issn = {1875-8908},
abstract = {BackgroundThe epidemiology of Alzheimer's disease and related dementias (ADRD) in China is understudied as compared to global levels.ObjectiveThe aim of this study was to examine the trend of dementia epidemiology in China from 1990 to 2021 and provide predictions for the next two decades.MethodsThe Global Burden of Disease study (GBD) 2021 were used to analyze the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) rates due to ADRD in China and globally. Joinpoint regression analysis was used to analyze the epidemiological trends from 1990 to 2021. A forecast of ADRD prevalence trends was conducted utilizing Autoregressive Integrated Moving Average (ARIMA) models.ResultsChina was experiencing a growing burden of ADRD. As of 2021, the number of people with dementia in China had risen to 56.85 million (95%CI: 49.38, 64.98), up from 21.80 (95%CI: 19.07, 24.84) million in 1990. The prevalence, incidence, mortality, and DALY rates all indicated a greater disease burden among the Chinese population compared to global levels, with a significantly higher burden in the female group. The projected prevalence rate was expected to increase by 60% compared to the current prevalence rate.ConclusionsAs the population in China continues to age, ADRD presents an undeniable challenge. To mitigate the growing burden of ADRD and improve the overall health of the population, it is essential to establish a comprehensive plan that focuses on increasing public awareness and enhancing the quality of life for all, with special attention given to women.},
}

@article {pmid40261309,
year = {2025},
author = {Osaki, T and Oki, Y and Kumagai, R and Ono, R and Yasuda, H and Nagai, Y and Kowa, H},
title = {Longitudinal deterioration of subjective cognitive decline in apolipoprotein ε4 carriers and improvement of subjective cognitive decline by multi-domain intervention for prevention of dementia: The cognitive function instrument assessment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251332647},
doi = {10.1177/13872877251332647},
pmid = {40261309},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline represents an early stage of mild cognitive impairment, with the Cognitive Function Instrument (CFI) serving to subjectively evaluate the decline in daily living activities associated with this minor cognitive decline.ObjectiveTo examine how CFI scores change with apolipoprotein E ε4 (ApoE4) carriage, objective cognitive decline, and dementia prevention intervention. We aimed to assess CFI's usefulness in the early dementia risk identification.MethodsThis study involved 196 older adults with normal cognition in a randomized controlled intervention trial. CFI was assessed every six months from baseline to 18 months, using the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC) to measure cognitive decline. We employed a mixed model for repeated measures to compare the CFI scores at 18 months in the ApoE4, ADCS-PACC, and allocation groups.ResultsCFI scores increased in ApoE4 carriers and decreased in the intervention group, with significant differences observed in the CFI score changes at 18 months between carriers and non-carriers and among the allocation groups (p = 0.002, p = 0.026, respectively). However, there was no significant difference in the CFI score change among ADCS-PACC groups (p = 0101).ConclusionsWe observed CFI scores worsening over time in individuals with ApoE4 and showing a tendency to deteriorate over time in those with objective cognitive decline. These findings suggest that the CFI may be able to identify high-risk individuals for dementia at an early stage. Furthermore, the improvement in the CFI score is considered a significant finding when considering future measures for subjective cognitive decline.},
}

@article {pmid40261306,
year = {2025},
author = {Stamatelos, P and Beratis, IN and Hatzaki, P and Economou, A and Andronas, N and Pavlou, D and Fragkiadaki, SP and Kontaxopoulou, D and Bonakis, A and Stefanis, L and Yannis, G and Papageorgiou, SG},
title = {Mild cognitive impairment, Alzheimer's disease dementia, and predictors of driving cessation: A 7-year longitudinal prospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333705},
doi = {10.1177/13872877251333705},
pmid = {40261306},
issn = {1875-8908},
abstract = {BackgroundPatients with dementia face driving difficulties and, at some point, cease driving.ObjectiveWe sought to identify predictors of driving cessation among patients with mild cognitive impairment (MCI) or mild Alzheimer's disease dementia (AD).MethodsWe enrolled in this longitudinal study patients with MCI, AD (Clinical Dementia Rating < 2) and cognitively normal (NC) individuals. At baseline evaluation, participants underwent a neurological, neuropsychological and driving simulator assessment. Re-evaluations after 48 and 84 months included a structured interview with the patients and their caregiver. Primary endpoints were driving cessation, death and progression to dementia.Results109 individuals were included (32 NC, mean age 65.8 years/47 MCI, mean age 69.1 years/30 AD, mean age 72.8 years). Dangerous driving events during follow-up were referred for 45% and 59% of MCI and AD patients, respectively. 18 MCI (38%, mean time to cease 35 months) and 25 AD (83%, mean time to cease 15 months) patients ceased driving during follow-up. 36% of MCI patients progressed to dementia during follow-up. Cox Regression multivariate analysis revealed age (Hazard Ratio-HR 1.080), semantic verbal fluency-SVF (HR 0.822) and Tandem Walking Test modified with simultaneous reverse number counting-mTWT (HR 1.099) as significant predictors of driving cessation. Simulator accident probability reached statistical significance only in the univariate model (HR 1.040).ConclusionsAge, SVF and mTWT are significant predictors of driving cessation among MCI and AD patients. Driving simulator may be a promising component of driving evaluation. Large-scale studies are prerequisite for the implementation of a multi-disciplinary driving fitness evaluation protocol.},
}

@article {pmid40261294,
year = {2025},
author = {Yang, X and Chi, L and Qiao, M and Huang, A and Wu, H and Chen, S and Fan, J and Lin, X and Chen, J and , },
title = {The effect of C-reactive protein and interleukin-3 on mild cognitive impairment with APOE ɛ4.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333149},
doi = {10.1177/13872877251333149},
pmid = {40261294},
issn = {1875-8908},
abstract = {BackgroundThe apolipoprotein E ε4 allele (APOE ε4) and inflammation are associated with Alzheimer's disease (AD) pathology. Mild cognitive impairment (MCI) is considered the preclinical and early stage of AD. However, the comprehensive effects of APOE ε4 and inflammatory mediators on MCI patients with specific APOE ε4 genotypes remain poorly understood.ObjectiveOur study aimed to explore how different numbers of the APOE ε4 alleles affect plasma C-reactive protein (CRP) and interleukin-3 (IL-3) levels and their associations with brain structure.MethodsA total of 339 MCI patients from the Alzheimer's Disease Neuroimaging Initiative study were enrolled. We compared their plasma concentrations of CRP and IL-3, cognitive performance, and cerebrospinal fluid (CSF) AD biomarkers levels across different APOE ε4 genotypes. Structural magnetic resonance imaging was utilized to measure gray matter volume outcomes. Pearson correlation analysis was used to explore the associations between the above indicators.ResultsPlasma CRP levels increased in the APOE ε4 carriers, but IL-3 expression notably decreased, and the homozygous state is the most significant. A negative correlation between CRP and several cognitive abilities was observed only in APOE ε4 homozygotes. Additionally, a positive correlation between IL-3, cognitive scores, and CSF biomarker levels was confirmed only in APOE ε4 homozygotes. Imaging data demonstrated that the gray matter volume of the right middle frontal gyrus was associated with CRP only in APOE ε4 non-carriers.ConclusionsOur study demonstrated that peripheral inflammatory mediators' effect on cognitive function and brain structure in MCI patients differs based on their APOE ε4 allele carrier status.},
}

@article {pmid40261292,
year = {2025},
author = {Wang, S and Ni, J and Wei, M and Li, T and Shi, J and Tian, J and , },
title = {Impact of obesity on neuropsychiatric symptoms in Alzheimer's disease: Insights from the ADNI cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251331974},
doi = {10.1177/13872877251331974},
pmid = {40261292},
issn = {1875-8908},
abstract = {BackgroundObesity is a major global health issue linked to increased risks of dementia, including Alzheimer's disease (AD). While the association between obesity and neuropsychiatric symptoms (NPS) in AD remains underexplored, identifying these links could aid in weight management in AD patients.ObjectiveThis study investigates the relationship between body mass index (BMI) and NPS in AD dementia patients, focusing on the potential mediating role of systemic inflammation.MethodsWe employed Generalized Additive Models (GAMs) to explore the relationship between BMI and NPS, as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q). Participants were classified into ideal, overweight, and obese groups based on WHO criteria. Longitudinal analyses assessed the trajectory of NPI-Q scores in different groups over a one-year follow-up.ResultsBMI significantly affects NPI-Q total scores and specific symptoms, including delusions, hallucinations, agitation/aggression, elation/euphoria, disinhibition, irritability/lability, aberrant motor behavior, nighttime disturbances, and appetite/eating disturbances. Obese patients exhibited higher NPI-Q total scores and greater severity in symptoms such as hallucinations, agitation/aggression, elation/euphoria, apathy/indifference, disinhibition, aberrant motor behavior, and nighttime disturbances. Additionally, CRP and complement C3 were identified as mediators in the relationship between obesity and NPS, highlighting the role of systemic inflammation.ConclusionsThis study demonstrates that obesity is associated with a heightened burden of NPS in AD dementia patients. The identification of CRP and complement C3 as mediators suggests inflammation plays a crucial role in the association between obesity and NPS. These findings underscore the importance of addressing obesity and its inflammatory consequences in managing NPS among this vulnerable population.},
}

@article {pmid40261286,
year = {2025},
author = {Bannon, SM and McCage, S and Walker, K and Brewer, J and Ahmad, N and Cornelius, T and Parker, RA and Dams-O'Connor, K and Dickerson, B and Ritchie, CS and Vranceanu, AM},
title = {Resilient together for dementia: A qualitative study of couples' treatment preferences to address distress early after diagnosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251332658},
doi = {10.1177/13872877251332658},
pmid = {40261286},
issn = {1875-8908},
abstract = {BackgroundDespite technological advances and earlier and more confident diagnoses, there is a lack of post-diagnosis support for couples navigating the challenges of early dementia. Clinically elevated emotional distress is common for both partners after diagnosis, and interferes with the health, relationships, and adjustment of both partners if not addressed.ObjectiveOur objective was to gather in-depth information on couples' preferences to inform the development of a proposed dyadic intervention addressing emotional distress early (within 6 months) after one partners' receipt of a dementia diagnosis.MethodsWe recruited couples after a recent dementia diagnosis (N = 16 dyads; 32 participants) from a large academic medical center via direct provider referrals for 60-min virtual dyadic interviews. Data were analyzed using a hybrid inductive-deductive approach to thematic analysis.ResultsWe identified themes within 3 a-priori determined domains. For dyadic intervention format (domain 1), couples preferred to participate in sessions together and to have flexible options for telehealth and in-person participation. Preferences for intervention content (domain 2) included information on dementia, skills to reduce distress and promote resiliency, and support to communicate about the diagnosis and related stress. Barriers and facilitators (domain 3) included denial or hesitation, resource constraints, and interests in learning skills and connecting to others.ConclusionsWe gathered comprehensive information that could be used to adapt existing dyadic interventions and to tailor support to match couples' preferences early after dementia diagnoses. Early interventions should prioritize flexible delivery of information and skills to couples to support adaptive coping following dementia diagnoses.},
}

@article {pmid40261284,
year = {2025},
author = {Ahn, H and Cha, WJ and Woo, DH and Ha, S and Kim, K and Choi, H and Byun, MS and Jung, G and Yi, D and Lee, DY},
title = {Performance on the Rey-Osterrieth complex figure test in non-demented middle-aged and elderly Koreans.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251332663},
doi = {10.1177/13872877251332663},
pmid = {40261284},
issn = {1875-8908},
abstract = {BackgroundExisting studies on Rey-Osterrieth Complex Figure (ROCF) performance in South Korea have not fully accounted for key demographic factors and often include limited sample sizes. This study examines ROCF performance in a non-demented aging sample to explore cognitive variability and provide comparative data for future research.ObjectiveThis study investigates the effects of age, education, and gender on performance on the ROCF test copy, immediate recall, and delayed recall trials for middle-aged and elderly Koreans.MethodsThe ROCF was administered to 461 community-dwelling, non-demented adults aged 50 to 90 years (M = 70.1, SD = 8.4), with 0 to 25 years of education (M = 11.4, SD = 4.7). We analyzed cognitive performance across age groups (50-59, 60-69, 70-79, and 80-90 years), education levels (0-8, 9-12, ≥13 years), and gender to characterize cognitive variability in a non-demented aging sample. Analysis of variance and stepwise multiple regression analyses were conducted to assess the relative contributions of the demographic variables.ResultsLower education levels, advanced age, and female gender were associated with poorer performance. Education accounted for the greatest variation in the copy trials, whereas age accounted for the largest portion of the variance in the recall trials.ConclusionsThe findings highlight the necessity of accounting for age, education, and gender when interpreting ROCF test scores in aging populations, especially in South Korea where educational attainment among older adults varies widely. Based on these findings, we established reference values stratified by these demographic variables for middle-aged and older Korean adults.},
}

@article {pmid40260643,
year = {2025},
author = {Jia, NN and Yao, MF and Zhu, CX and He, MJ and Zhu, HF and Chen, ZY and Huang, HP and Qiao, C},
title = {Chronic Intermittent Hypoxia-Induced Neural Injury: Pathophysiology, Neurodegenerative Implications, and Therapeutic Insights.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {4},
pages = {e70384},
doi = {10.1111/cns.70384},
pmid = {40260643},
issn = {1755-5949},
support = {JC2024024//Basic Research Foundation of Zhenjiang/ ; JY202232//Jiangsu Research Hospital Association for Precision Medication/ ; BK20241858//National Science Foundation of Jiangsu Province/ ; M2022071//Medical Research Project of Jiangsu Provincial Health Commission/ ; JSYCTD202402//Zhenjiang Jinshan Talent Flexible Introduction Program/ ; LKZ2024011//Key Research Project on Elderly Health in Jiangsu Province/ ; },
mesh = {Humans ; Animals ; *Hypoxia/complications/physiopathology/pathology/metabolism ; *Sleep Apnea, Obstructive/complications/physiopathology ; Blood-Brain Barrier/metabolism ; *Neurodegenerative Diseases/etiology/physiopathology/pathology/therapy/metabolism ; Oxidative Stress/physiology ; },
abstract = {Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a sleep-related respiratory disorder that poses a global threat to human health. Chronic intermittent hypoxia (CIH) is its main pathological feature. With the advancements in medical research, the study of CIH-induced neural injury has gained increasing attention. Studies have shown that CIH can lead to or aggravate neuroinflammation and apoptosis by increasing blood-brain barrier (BBB) permeability, promoting oxidative stress, activating glial cells, and triggering multiple signaling pathways, ultimately resulting in neural injury. These processes contribute to the development of Alzheimer's disease, Parkinson's disease, and stroke. This review aims to summarize the progress in CIH-induced neural injury and explore various underlying mechanisms, with the goal of providing new insights for the development of therapeutic interventions targeting CIH-related neural damage.},
}

Humans
Animals
*Hypoxia/complications/physiopathology/pathology/metabolism
*Sleep Apnea, Obstructive/complications/physiopathology
Blood-Brain Barrier/metabolism
*Neurodegenerative Diseases/etiology/physiopathology/pathology/therapy/metabolism
Oxidative Stress/physiology

@article {pmid40260486,
year = {2025},
author = {Bonakdarpour, B and Schafer, R and Takarabe, C and Barbieri, E and Miller, J and Miller, SS},
title = {Virtual group singing programs for well-being in healthy older adults and persons with neurocognitive disorders during early COVID-19 pandemic: A perspective from Chicago.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333155},
doi = {10.1177/13872877251333155},
pmid = {40260486},
issn = {1875-8908},
abstract = {BackgroundDuring the COVID-19 pandemic, older adults experienced health declines due to isolation. Group singing is known to enhance social, emotional, and physical well-being, but its feasibility in virtual formats was unclear.ObjectiveTo assess the feasibility of virtual group singing for cognitively healthy (CH) adults and individuals with neurocognitive disorders (NcD) during the pandemic.MethodTwo teleconferencing programs were conducted for participants aged >55: (1) a sing-along series with 52 weekly sessions of familiar music and (2) a choir program with structured weekly rehearsals culminating in a virtual concert. Retrospective surveys assessed anxiety reduction, social connection, and physical well-being using Likert scales and participants provided open-ended responses. Quantitative data were analyzed with ordinal regression and probability modeling, while qualitative themes were explored with Fisher's exact test.ResultsParticipants reported high levels of satisfaction across all measures. Sing-along programs provided greater satisfaction, particularly through reminiscence (p = 0.003). Choir participants noted enhanced intellectual well-being (p = 0.017). NcD participants were less satisfied with social connection but showed similar overall satisfaction levels compared to CH participants.ConclusionsVirtual group singing was feasible during periods of isolation as supported by satisfaction of the participants with pertaining to anxiety reduction, social connection and physical well-being. Sing-along programs provided emotional satisfaction through reminiscence (connection to past), while choir programs offered intellectual stimulation through multiple rehearsals. These findings highlight the potential of virtual singing to promote stability, connection, and well-being for older adults during times of disruption.},
}

@article {pmid40260403,
year = {2025},
author = {Asadi, Y and Moundounga, RK and Chakroborty, A and Pokokiri, A and Wang, H},
title = {FOXOs and their roles in acute and chronic neurological disorders.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1538472},
pmid = {40260403},
issn = {2296-889X},
abstract = {The forkhead family of transcription factors of class O (FOXOs) consisting of four functionally related proteins, FOXO1, FOXO3, FOXO4, and FOXO6, are mammalian homologs of daf-16 in Caenorhabditis elegans and were previously identified as tumor suppressors, oxidative stress sensors, and cell survival modulators. Under normal physiological conditions, FOXO protein activities are negatively regulated by phosphorylation via the phosphoinositide 3-kinase (PI3K)-Akt pathway, a well-known cell survival pathway: Akt phosphorylates FOXOs to inactivate their transcriptional activity by relocalizing FOXOs from the nucleus to the cytoplasm for degradation. However, under oxidative stress or absent the cellular survival drive of growth factors, FOXO proteins translocate to the nucleus and upregulate a series of target genes, thereby promoting cell growth arrest and cell death and altering mitochondrial homeostasis. FOXO gene expression is also regulated by other transcriptional factors such as p53 or autoregulation by their activities and end products. Here we summarize the structure, posttranslational modifications, and translocation of FOXOs linking to their transcriptional control of cellular functions, survival, and death, emphasizing their role in regulating the cellular response to some acute insults and chronic neurological disorders. This review will conclude with a brief section on potential therapeutic interventions that can be used to modulate FOXOs' activities when treating acute and chronic neurological disorders.},
}

@article {pmid40260265,
year = {2025},
author = {Yin, L and Du, Y and Ge, M and Zhang, X and Du, X and Wu, X},
title = {Rod-Shaped NanoZnTPyP Paper-Based Sensor for Visual Detection of Dopamine in Human Plasma.},
journal = {Journal of analytical methods in chemistry},
volume = {2025},
number = {},
pages = {9981628},
pmid = {40260265},
issn = {2090-8865},
abstract = {Dopamine (DA) is a catecholamine neurotransmitter secreted by the human adrenal medulla and is related to many medical diseases. The rapid and sensitive detection of DA levels in physiological media is attracting attention. This paper has developed a fluorescence paper-based sensor using CdTe quantum dots (QDs)-rod nanozinc 5, 10, 15, 20-tetra (4-pyridyl)-21H-23H-porphine (nanoZnTPyP) for sensitive and visual detection of DA. After adding DA, the original quenching fluorescence of the CdTe QDs-rod nanoZnTPyP sensor was effectively restored. The detection mechanism may be that the oxidation of DA to the alkaline CdTe QDs-rod nanoZnTPyP solution produced DA-quinine, and the recovery of fluorescence was caused by the electronic effect of DA-quinine and rod-shaped nanoZnTPyP. The detection range is 0.5∼10 nmol/L, and the limit of detection (LOD) is 0.38 nmol/L (S/N = 3). The sensor system was used on paper device to detect significant changes in the fluorescent color of DA at different concentrations. In addition, this method has been successfully used for the determination of DA in human plasma. The sensor system is simple, easy to operate, and has high selectivity for possible DA interfering substances, which provided new ideas for detecting DA and Parkinson's disease, Alzheimer's disease, and other DA-related diseases.},
}

@article {pmid40260242,
year = {2025},
author = {Li, Z and Gong, C},
title = {NLRP3 inflammasome in Alzheimer's disease: molecular mechanisms and emerging therapies.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1583886},
pmid = {40260242},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/drug therapy/etiology/therapy ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors/immunology ; *Inflammasomes/metabolism/immunology/antagonists & inhibitors ; Animals ; Amyloid beta-Peptides/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuroinflammation, with no definitive cure currently available. The NLRP3 inflammasome, a key mediator of neuroinflammation, has emerged as a critical player in AD pathogenesis, contributing to the accumulation of β-amyloid (Aβ) plaques, tau hyperphosphorylation, and neuronal damage. This review explores the mechanisms by which the NLRP3 inflammasome is activated in AD, including its interactions with Aβ, tau, reactive oxygen species (ROS), and pyroptosis. Additionally, it highlights the role of the ubiquitin system, ion channels, autophagy, and gut microbiota in regulating NLRP3 activation. Therapeutic strategies targeting the NLRP3 inflammasome, such as IL-1β inhibitors, natural compounds, and novel small molecules, are discussed as promising approaches to mitigate neuroinflammation and slow AD progression. This review underscores the potential of NLRP3 inflammasome inhibition as a therapeutic avenue for AD.},
}

Humans
*Alzheimer Disease/metabolism/immunology/drug therapy/etiology/therapy
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors/immunology
*Inflammasomes/metabolism/immunology/antagonists & inhibitors
Animals
Amyloid beta-Peptides/metabolism
Reactive Oxygen Species/metabolism

@article {pmid40260186,
year = {2025},
author = {Piñol-Ripoll, G and Salas Carrillo, M and , },
title = {Clinicians' Perspectives of Twice-Weekly Rivastigmine Patches for Alzheimer's Disease Treatment in Spain: The VIITAL 2S Study.},
journal = {Patient preference and adherence},
volume = {19},
number = {},
pages = {1105-1118},
pmid = {40260186},
issn = {1177-889X},
abstract = {PURPOSE: Administration routes and dosage significantly impact Alzheimer's disease (AD) treatment effectiveness, as compliance in older patients depends on interactions between concomitant treatments, complex dosages, adverse effects, or medication tolerance. This study aims to describe patient and caregiver preferences concerning treatment with rivastigmine twice-weekly transdermal patches from the neurologists' and geriatricians' perspectives.

METHODS: VIITAL-2S was an ecological study based on aggregated data. A total of 250 Spanish neurologists and geriatricians answered a survey on the use, adherence, patient and caregiver satisfaction, and safety (skin tolerability) of twice-weekly rivastigmine patches.

RESULTS: Most participating physicians reported having over 11 years of experience in their specialty. According to their responses, patients with AD attending Neurology and Geriatrics were usually in mild-moderate condition, and a mean of 61.4% received rivastigmine. Around 60% of patients lived with a family member, and over 80% had a caregiver, mainly their partner/spouse or other relative. Of note, more than half of patients attending Neurology and nearly 75% of patients in Geriatrics received 4-10 medications daily. Both specialists recommended the transdermal formulation to patients receiving rivastigmine. In 33.8% and 41.0% of patients receiving daily patches, neurologists and geriatricians, respectively, recommended switching to twice-weekly patches, considering higher administration comfort and caregiver preferences. Physicians reported high/very high satisfaction with twice-weekly patches in nearly 80% of patients. Comparing twice-weekly to daily patches, they observed higher comfort, more caregiver satisfaction, and enhanced adherence. Both specialists manifested preferring twice-weekly rivastigmine patches over daily ones, especially to increase caregivers' comfort, for patients without full-week caregiver support, and in cases of poor compliance with previous treatments.

CONCLUSION: Neurologists and geriatricians consider the twice-weekly rivastigmine patch formulation beneficial for AD treatment in terms of treatment compliance, skin tolerability, satisfaction and comfort for patients and caregivers.},
}

@article {pmid40260118,
year = {2025},
author = {Khullar, S and Huang, X and Ramesh, R and Svaren, J and Wang, D},
title = {NetREm: Network Regression Embeddings reveal cell-type transcription factor coordination for gene regulation.},
journal = {Bioinformatics advances},
volume = {5},
number = {1},
pages = {vbae206},
pmid = {40260118},
issn = {2635-0041},
abstract = {MOTIVATION: Transcription factor (TF) coordination plays a key role in gene regulation via direct and/or indirect protein-protein interactions (PPIs) and co-binding to regulatory elements on DNA. Single-cell technologies facilitate gene expression measurement for individual cells and cell-type identification, yet the connection between TF-TF coordination and target gene (TG) regulation of various cell types remains unclear.

RESULTS: To address this, we introduce our innovative computational approach, Network Regression Embeddings (NetREm), to reveal cell-type TF-TF coordination activities for TG regulation. NetREm leverages network-constrained regularization, using prior knowledge of PPIs among TFs, to analyze single-cell gene expression data, uncovering cell-type coordinating TFs and identifying revolutionary TF-TG candidate regulatory network links. NetREm's performance is validated using simulation studies and benchmarked across several datasets in humans, mice, yeast. Further, we showcase NetREm's ability to prioritize valid novel human TF-TF coordination links in 9 peripheral blood mononuclear and 42 immune cell sub-types. We apply NetREm to examine cell-type networks in central and peripheral nerve systems (e.g. neuronal, glial, Schwann cells) and in Alzheimer's disease versus Controls. Top predictions are validated with experimental data from rat, mouse, and human models. Additional functional genomics data helps link genetic variants to our TF-TG regulatory and TF-TF coordination networks.

https://github.com/SaniyaKhullar/NetREm.},
}

@article {pmid40260095,
year = {2024},
author = {Hernandez Rico, AN and Flórez Vargas, B and Guadarrama Vega, S and Pino Pinzón, CJ and Agamez Insignares, CP},
title = {Evaluation of loneliness and its associated factors in caregivers of patients with dementia: a cross-sectional study.},
journal = {Colombia medica (Cali, Colombia)},
volume = {55},
number = {3},
pages = {e2006604},
pmid = {40260095},
issn = {1657-9534},
mesh = {Humans ; Cross-Sectional Studies ; *Loneliness/psychology ; *Caregivers/psychology/statistics & numerical data ; *Dementia/nursing/therapy/psychology ; Male ; Female ; Colombia/epidemiology ; Aged ; Middle Aged ; *Social Support ; Prevalence ; Aged, 80 and over ; Adult ; Friends/psychology ; },
abstract = {OBJECTIVE: To identify the levels of loneliness and the factors associated with the prevalence of loneliness in caregivers of patients with dementia.

METHODS: An observational cross-sectional study was conducted, including unpaid caregivers of patients with dementia who were receiving home care in Bogotá, Colombia. The prevalence of loneliness was estimated using the UCLA Loneliness Scale. Participants were also assessed regarding their satisfaction with providing care and whether they felt they received the necessary emotional support from family and friends. The association between loneliness and the patient's clinical variables, as well as the sociodemographic characteristics of the caregiver, was evaluated by calculating the odds ratio (OR) between the groups.

RESULTS: A total of 52 caregivers of patients with dementia were included. Severe loneliness was present in 5.77% of caregivers, while 26.92% experienced moderate loneliness. All caregivers reported feeling satisfied with providing care to their relatives, and 71% felt that their family or friends provided the emotional support they required. Loneliness was more common among caregivers of patients with total functional dependence (OR: 4.061, p= 0.0278). Conversely, the perception of receiving emotional support from family and friends was identified as a potential protective factor against loneliness (OR: 0.184, p= 0.0104).

CONCLUSIONS: The prevalence of loneliness in this study is lower than that reported in previous studies. All caregivers reported satisfaction in providing care; most perceived adequate emotional support from family and friends. These factors could be contributing to the lower prevalence of loneliness observed.},
}

Humans
Cross-Sectional Studies
*Loneliness/psychology
*Caregivers/psychology/statistics & numerical data
*Dementia/nursing/therapy/psychology
Male
Female
Colombia/epidemiology
Aged
Middle Aged
*Social Support
Prevalence
Aged, 80 and over
Adult
Friends/psychology

@article {pmid40260083,
year = {2025},
author = {Shi, Z and Ma, X and Tang, T and Wang, M and Zheng, H and Chen, Y and Hu, J and Mueller, A and Houle, TT and Marcantonio, ER and Xie, Z and Shen, Y},
title = {Association between retinal layer thickness and postoperative delirium in older patients.},
journal = {General psychiatry},
volume = {38},
number = {2},
pages = {e101740},
pmid = {40260083},
issn = {2517-729X},
abstract = {BACKGROUND: Postoperative delirium is one of the most common complications in the older surgical population, but its pathogenesis and biomarkers are largely undetermined. Retinal layer thickness has been demonstrated to be associated with cognitive function in mild cognitive impairment and patients with Alzheimer's disease. However, relatively little is known about possible retinal layer thickness among patients with postoperative delirium.

AIMS: We aimed to investigate the relationship between retinal layer thickness and postoperative delirium in this cross-sectional study.

METHODS: The participants (≥65 years old) having elective surgery under general anaesthesia were screened via medical records from Shanghai 10th People's Hospital. Preoperative macular thickness and peripapillary retinal nerve fibre layer (RNFL) thickness were measured using optical coherence tomography (OCT). The Confusion Assessment Method (CAM) algorithm and CAM-Severity (CAM-S) were used to assess the incidence and severity of postoperative delirium on the first, second and third days after surgery.

RESULTS: Among 169 participants (mean (standard deviation (SD) 71.15 (4.36) years), 40 (24%) developed postoperative delirium. Notably, individuals who developed postoperative delirium exhibited thicker preoperative macular thickness in the right eye compared with those who did not (mean (SD) 283.35 (27.97) µm vs 273.84 (20.14) µm, p=0.013). Furthermore, the thicker preoperative macular thickness of the right eye was associated with a higher incidence of postoperative delirium (adjusted odds ratio 1.593, 95% confidence interval (CI) 1.093 to 2.322, p=0.015) and greater severity (adjusted mean difference (β)=0.256, 95% CI 0.037 to 0.476, p=0.022) after adjustment for age, sex and Mini-Mental State Examination (MMSE) scores. However, such a difference or association did not appear in the left macular or bilateral peripapillary RNFL thicknesses.

CONCLUSIONS: Current findings demonstrated that preoperative macular thickness might serve as a potential non-invasive marker for the vulnerability of developing postoperative delirium in older surgical patients. Further large-scale validation studies should be performed to confirm these results.},
}

@article {pmid40260080,
year = {2025},
author = {Khan, MS and Qureshi, N and Khan, R and Son, YO and Maqbool, T},
title = {CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer's disease: progress and prospects.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1578138},
pmid = {40260080},
issn = {1662-5102},
abstract = {CRISPR/Cas9 technology has revolutionized genetic and biomedical research in recent years. It enables editing and modulation of gene function with an unparalleled precision and effectiveness. Among the various applications and prospects of this technology, the opportunities it offers in unraveling the molecular underpinnings of a myriad of central nervous system diseases, including neurodegenerative disorders, psychiatric conditions, and developmental abnormalities, are unprecedented. In this review, we highlight the applications of CRISPR/Cas9-based therapeutics as a promising strategy for management of Alzheimer's disease and transformative impact of this technology on AD research. Further, we emphasize the role of CRISPR/Cas9 in generating accurate AD models for identification of novel therapeutic targets, besides the role of CRISPR-based therapies aimed at correcting AD-associated mutations and modulating the neurodegenerative processes. Furthermore, various delivery systems are reviewed and potential of the non-viral nanotechnology-based carriers for overcoming the critical limitations of effective delivery systems for CRISPR/Cas9 is discussed. Overall, this review highlights the promise and prospects of CRISPR/Cas9 technology for unraveling the intricate molecular processes underlying the development of AD, discusses its limitations, ethical concerns and several challenges including efficient delivery across the BBB, ensuring specificity, avoiding off-target effects. This article can be helpful in better understanding the applications of CRISPR/Cas9 based therapeutic approaches and the way forward utilizing enormous potential of this technology in targeted, gene-specific treatments that could change the trajectory of this debilitating and incurable illness.},
}

@article {pmid40259919,
year = {2025},
author = {Jung, YH and Jo, HY and Kim, DH and Oh, YJ and Kim, M and Na, S and Song, HY and Lee, HJ},
title = {Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {4903-4917},
pmid = {40259919},
issn = {1178-2013},
mesh = {Humans ; *Parkinson Disease/therapy/metabolism ; *Alzheimer Disease/therapy/metabolism ; *Exosomes/metabolism ; *Mitochondria/metabolism ; Animals ; Neurons/metabolism ; Signal Transduction ; Organelle Biogenesis ; Mitophagy ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are representative neurodegenerative diseases with abnormal energy metabolism and altered distribution and deformation of mitochondria within neurons, particularly in brain regions such as the hippocampus and substantia nigra. Neurons have high energy demands; thus, maintaining a healthy mitochondrial population is important for their biological function. Recently, exosomes have been reported to have mitochondrial regulatory potential and antineurodegenerative properties. This review presents the mitochondrial abnormalities in brain cells associated with AD and PD and the potential of exosomes to treat these diseases. Specifically, it recapitulates research on the molecular mechanisms whereby exosomes regulate mitochondrial biogenesis, fusion/fission dynamics, mitochondrial transport, and mitophagy. Furthermore, this review discusses exosome-triggered signaling pathways that regulate nuclear factor (erythroid-derived 2)-like 2-dependent mitochondrial antioxidation and hypoxia inducible factor 1α-dependent metabolic reprogramming. In summary, this review aims to provide a profound understanding of the regulatory effect of exosomes on mitochondrial function in neurons and to propose exosome-mediated mitochondrial regulation as a promising strategy for AD and PD.},
}

Humans
*Parkinson Disease/therapy/metabolism
*Alzheimer Disease/therapy/metabolism
*Exosomes/metabolism
*Mitochondria/metabolism
Animals
Neurons/metabolism
Signal Transduction
Organelle Biogenesis
Mitophagy
Brain/metabolism

@article {pmid40259571,
year = {2025},
author = {Saez-Calveras, N and Ishii, M},
title = {Hydrate to keep the amyloid away.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251331590},
doi = {10.1177/13872877251331590},
pmid = {40259571},
issn = {1875-8908},
abstract = {Despite older adults being more susceptible to dehydration, the relation between hydration and Alzheimer's disease and related dementias (ADRD) remains largely unexplored. A recent study by Jee Wook Kim and colleagues examined the association between daily fluid intake and ADRD neuroimaging biomarkers in 287 cognitively normal older adults. They found that lower daily fluid intake was associated with greater brain Aβ deposition and cerebrovascular injury. Here, we discuss the strengths and limitations of this study. We further highlight the potential for reverse causality and how hydration may play a role in the clinic and future ADRD research studies.},
}

@article {pmid40259570,
year = {2025},
author = {Mehdipanah, R and Briceño, EM and Malvitz, M and Chang, W and Heeringa, SG and Zahuranec, DB and Levine, DA and Langa, KM and Gonzales, XF and Garcia, N and Khan, N and Morgenstern, LB},
title = {Ethnic disparities in care needs among individuals with cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334819},
doi = {10.1177/13872877251334819},
pmid = {40259570},
issn = {1875-8908},
abstract = {BackgroundAs more individuals with cognitive impairment and dementia (CID) remain at home, greater needs arise, necessitating additional support.ObjectiveTo examine ethnic differences in the needs of individuals with CID among Mexican American (MA) and non-Hispanic White (NHW) participants.MethodsAdults 65 + with possible cognitive impairment (Montreal Cognitive Assessment score < 26), and their caregivers living in Nueces County, Texas, were included. We used the Camberwell Assessment of Need for the Elderly (CANE) tool to study the needs (accommodations, self-care, continence, physical health, emotional well-being, social relationships, and availability of support networks) and their domains of individuals with CID including environmental, physical, psychological and social needs. Using negative binomial and Poisson regressions, ethnic differences were examined within each domain.ResultsA total of 473 participants were included. NHW participants (N = 150) were slightly older (75.5 versus 72.7 years) and had higher rates of MCI and dementia (55% versus 47%) compared to MA participants (N = 323). All participants reported high levels of needs (met or unmet). Furthermore, although NHW participants reported having fewer social needs (met or unmet) compared to MA participants (Incident Rate Ratio [IRR]=-0.79; 97.5%CI:0.63-0.98), NHW participants had a greater level of unmet needs when it came to social needs compared to MA participants (IRR = 1.85; 97.5%CI:1.33-2.57).ConclusionsFindings indicate high levels of needs among individuals with CID. There also exist ethnic differences, with NHW participants having greater unmet needs in social areas. Enhancing access to resources and support systems is essential for equitable support for individuals with CID across various ethnic backgrounds.},
}