@article {pmid41384835,
year = {2025},
author = {An, B and Auger, SA and Lutsey, PL and Mielke, MM and Yu, F and Hoogeveen, RC and Gottesman, RF and Zhang, L and Meyer, M and Sullivan, KJ and Zantek, ND and Alonso, A and Walker, KA and Li, D},
title = {Association of LDL cargo proteins with white matter hyperintensity volume in older adults from the atherosclerosis risk in communities study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401480},
doi = {10.1177/13872877251401480},
pmid = {41384835},
issn = {1875-8908},
abstract = {BackgroundLow-density lipoprotein cholesterol (LDL-C) has been associated with Alzheimer's disease (AD) pathology and other neuroimaging measures, such as brain volume and white matter hyperintensity (WMH) volume.ObjectiveIn this exploratory study, we examined cross-sectional associations between LDL cargo proteins and AD-related outcomes.MethodsWe randomly selected 65 participants without dementia with amyloid PET and brain MRI data available in the Atherosclerosis Risk in Communities. We used a mass spectrometry-based technique to quantify proteins in LDL isolated from plasma collected at the ARIC Visit 5. Linear or logistic regression was applied to evaluate the associations between individual LDL protein or LDL-C and (1) brain amyloid deposition (yes or no), (2) temporal-parietal meta-ROI brain volume (a biomarker of AD-related neurodegeneration), or (3) WMH volume, adjusting for covariates.ResultsParticipants' average age was 76.3 years with a standard deviation of 5.4, and females comprised 53.8% (35 out of 65). The estimated effect sizes of many LDL protein's associations with these neuroimaging measures were larger than that of LDL-C. The strongest association was higher LDL apolipoprotein C1 (apoC1) and lower WMH volume. Each SD increment of LDL apoC1 LDL was associated with a lower WMH volume of 7243.1 mm[3] (95% CI [-10482.0, -4004.1]; a BH-adjusted p = 0.002). In comparison, each SD increment of LDL-C (in mg/dL) was associated with a lower WMH volume of 1676.1 mm[3] (95% CI [-5425.9, 2073.7]; a BH-adjusted p of 0.90).ConclusionsThis study suggests that increased LDL apoC1 was linked to decreased WMH volume in older adults without dementia.},
}

@article {pmid41384834,
year = {2025},
author = {Wang, J and Li, H and Wang, Y and Meng, F and Liu, Z and Zhao, T and Xu, P and Guo, C and Zhu, Y},
title = {Effects of virtual reality-based therapy on cognitive and psychological outcomes in older adults with predementia: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404046},
doi = {10.1177/13872877251404046},
pmid = {41384834},
issn = {1875-8908},
abstract = {BackgroundPredementia, encompassing subjective cognitive decline (SCD) and mild cognitive impairment (MCI), represents an early phase of neurodegeneration with a heightened risk of progression to dementia. This stage offers a critical window for intervention. Virtual reality (VR) enhances neuroplasticity in predementia via multisensory stimulation, addressing research gaps. ObjectiveTo assess the impact of VR-based interventions on cognitive abilities, emotional well-being, and instrumental activities of daily living (IADL) in individuals with predementia conditions.MethodsA search of seven databases identified studies involving seniors aged ≥65 with SCD or MCI. Eligible studies compared conventional cognitive training or usual care as controls. Quality was assessed using the Cochrane Risk of Bias Tool, and evidence certainty was graded using the GRADE framework.ResultsTwelve randomized controlled trials were included. The meta-analysis revealed that, in comparison to control groups, VR-based cognitive interventions had superior effects on subjective cognitive complaints (SMD = -4.06, 95% CI [-4.86, -3.25]), learning and memory (SMD = 0.41, 95% CI [0.02, 0.80]), working memory (SMD = -0.06, 95% CI [-0.08, -0.03]), verbal fluency (SMD = 0.49, 95% CI [0.03, 0.94]), spatial cognition (SMD = 1.43, 95% CI [0.77, 2.10]), and IADL (SMD = 0.77, 95% CI [0.14, 1.40]).ConclusionsVR-based cognitive interventions could improve objective cognitive performance, subjective cognitive complaints, and IADL in predementia. Future research should prioritize optimizing the intervention protocols and enhancing the geriatric-specific VR-based cognitive intervention.},
}

@article {pmid41384832,
year = {2025},
author = {Villarejo Galende, A and González-Sánchez, M and Hilario, A and Llamas-Velasco, S and Morenas-Rodríguez, E and Muñoz-García, MI and Ramos-González, A and Pérez-Martínez, DA and Blanco-Palmero, VA},
title = {Severe symptomatic amyloid-related imaging abnormalities in Alzheimer's disease: Two case reports and systematic review of reported cases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404505},
doi = {10.1177/13872877251404505},
pmid = {41384832},
issn = {1875-8908},
abstract = {BackgroundAmyloid-related imaging abnormalities (ARIA) are a recognized complication of anti-amyloid monoclonal antibodies for Alzheimer's disease (AD). While typically asymptomatic, a subset of patients develops severe clinical symptoms and radiological findings requiring intensive management. Data on their presentation, treatment, and outcomes remain limited.ObjectiveWe report two cases and analyze the clinical features of all published cases of severe symptomatic ARIA, with a focus on associated risk factors, therapeutic approaches, and patient outcomes.MethodsWe report two cases of severe symptomatic ARIA in patients treated with gantenerumab. A systematic review was conducted following PRISMA guidelines using MEDLINE, Web of Science, and manual reference screening. We included case reports and series providing individual-level data on symptomatic ARIA episodes classified as severe by clinical criteria. Demographic, genetic, clinical, radiological, therapeutic, and outcome data were extracted.ResultsThirty-six cases were included (2 new and 34 from 21 publications). Fifteen cases were associated with lecanemab, 10 with gantenerumab, 6 with donanemab, and 5 with other antibodies. APOE ε4 was present in 62.5%, including 10 ε4/ε4 homozygotes. Baseline MRI showed hemorrhagic markers in 10 cases, including superficial siderosis in 2 of the 5 patients with isolated macrohemorrhages. Most episodes occurred within 6 months of treatment. Symptoms included altered consciousness (75%), focal deficits (66.7%), seizures (38.9%), and headache (36.1%). ARIA-E resolved in all non-fatal cases. Corticosteroids were used in 72%. Among the patients whose outcome data were available, 15 patients recovered completely, 10 had persistent deficits, and 10 died.ConclusionsSevere symptomatic ARIA is a rare but serious adverse effect of anti-amyloid therapy. Standardized diagnostic and therapeutic guidelines are needed to minimize ARIA-related morbidity and mortality.PROSPERO registration no. CRD420251055067.},
}

@article {pmid41384831,
year = {2025},
author = {Choi, YH and Kim, H and Hong, S and Baek, C and Wang, B and Shim, Y and Hong, YJ and Byun, S and Song, IU and Na, S and Won, WY and Park, SK and Ryu, SY and Hahn, C and Shin, HE and Cho, AH and Lim, E and Lim, HK and Kang, DW and Kim, HJ and Choi, H and Yoon, B and Kim, W and Lim, JS and Yang, DW},
title = {Deep-learning analysis of speech using mel-spectrograms for the assessment of mild cognitive impairment and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401202},
doi = {10.1177/13872877251401202},
pmid = {41384831},
issn = {1875-8908},
abstract = {BackgroundSpeech abnormalities are recognized as early indicators of Alzheimer's disease (AD) and mild cognitive impairment (MCI).ObjectiveTo determine whether deep-learning models trained on mel-spectrograms of brief speech tasks can (i) discriminate individuals with MCI and AD from cognitively normal controls (NC) and (ii) estimate cognitive status with clinically useful accuracy.MethodsSpeech from 594 participants (185 NC, 231 MCI, 178 AD) was recorded through a mobile application that included 11 cognitive-linguistic tasks. Audio was converted into mel-spectrogram images and processed using a VGG16-based deep-learning model with transfer learning and fine-tuning of block 5. Task-specific feature vectors were extracted, concatenated, and used to train a deep neural network. The dataset was split into training, validation, and test sets (3:1:1), and five-split cross-validation was performed.ResultsThe model demonstrated an overall accuracy of 72.4% in classifying NC from the abnormal group (MCI and AD), with sensitivity and specificity of 72.5% and 72.2%, respectively, a balanced accuracy of 72.4%, and an AUC of 0.997. In binary classifications, the model achieved 82.9% accuracy (balanced accuracy 82.9%, AUC 0.992) for NC versus AD, 70.7% accuracy (balanced accuracy 70.3%, AUC 0.956) for NC versus MCI, and 77.5% accuracy (balanced accuracy 78.9%, AUC 0.889) for MCI versus AD. Tasks such as serial subtraction, storytelling, and picture description contributed most to classification performance, indicating their effectiveness in capturing cognitive deficits.ConclusionsMel-spectrogram-based deep-learning analysis of speech shows promise as a rapid, non-invasive, and language-independent screening tool for early cognitive impairment, with potential advantages over traditional assessments such as the Mini-Mental State Examination.},
}

@article {pmid41384830,
year = {2025},
author = {Caldichoury, N and Morales-Asencio, B and Coronado, JC and Ripoll-Córdoba, D and Mendoza-Ruvalcaba, N and Quispe-Ayala, C and Camargo, L and Boza-Calvo, C and Quincho-Apumayta, R and Castellanos, C and Cárdenas, J and García de la Cadena, C and Martínez, J and Florez, Y and Mori, N and Castillo-Tamara, E and Calle, U and Bada, W and Varón, C and Porto, MF and Ramos-Henderson, M and Miranda-Pacheco, J and Salazar, D and Alcos-Flores, K and Palomino-Torres, E and Ardila-Duarte, C and Patiño-Rivera, AR and Gargiulo, PA and López, N},
title = {Subjective memory complaints in Latin American older adults: Prevalence and risk factors.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400666},
doi = {10.1177/13872877251400666},
pmid = {41384830},
issn = {1875-8908},
abstract = {BackgroundSubjective memory complaints (SMC) are linked to an increased risk of neurocognitive disorders (NCD).ObjectiveTo estimate the prevalence of SMC and their association with sociodemographic and clinical factors in 3285 older adults (OA) from ten Latin American and Caribbean (LAC) countries.MethodThis population-based analysis used secondary data from an international multicenter study on NCD prevalence during the COVID-19 pandemic. Cognitively healthy participants were identified based on clinical criteria, cognitive assessments, and expert consensus. Participants were categorized as with (WSMC; n = 602) or without SMC (NSMC; n = 2683). Sociodemographic and clinical variables were recorded. Cognitive performance was assessed using the Montreal Cognitive Assessment-Short Version (MoCA-T), depressive symptoms with the 15-item Geriatric Depression Scale (GDS-15), and functional decline with the Eight-Item Informant Interview (AD8). Mean difference analyses and logistic regressions were performed.ResultsThe regional prevalence of SMC was 18.33%, ranging from 11.59% in Guatemala to 26.30% in Peru. OA with SMC showed lower education, poorer cognitive performance, and higher rates of anxiety, falls, and fractures. Regression models revealed significant associations between SMC and lower education (p < 0.001), emotional distress (p < 0.001), age (p = 0.024), anxiety (p = 0.017), infrequent and occasional falls (p = 0.017; p = 0.002), and fractures (p = 0.028).ConclusionsSMC are prevalent among LAC older adults and are associated with multiple risk factors, highlighting their public health relevance and potential as early indicators of NCD risk.},
}

@article {pmid41384827,
year = {2025},
author = {Farsi, DN and Abadalkareem, R and Linden, GJ and McKay, GJ and McEvoy, CT and McAlinden, M and Winning, L and Hurley, M and Kelly, J and Passmore, PA and Holmes, C and Patterson, CC and Teeling, JL and McGuinness, B},
title = {Periodontitis and incident cognitive decline and dementia: A 15-year prospective cohort study of older men residing in Northern Ireland.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401563},
doi = {10.1177/13872877251401563},
pmid = {41384827},
issn = {1875-8908},
abstract = {BackgroundPeriodontitis is a chronic bacterial infection that elicits systemic inflammation. While retrospective studies have linked periodontal pathogens with Alzheimer's disease (AD) and dementia, few have combined cognitive assessments, pathogen exposure, and inflammatory markers.ObjectiveTo investigate the longitudinal risk between periodontitis, cognitive impairment and dementia.MethodsWe examined the relationship between periodontitis and onset of mild cognitive impairment (MCI) and dementia over 15.6 years (SD 1.6) in older men from Northern Ireland enrolled in the PRIME-COG cohort, using logistic regression. We also assessed associations between exposure to periodontal pathogens and blood inflammatory markers.ResultsAmong 642 men, baseline periodontitis was not significantly associated with later onset of dementia and/or MCI (severe versus mild/none, OR 0.83, 95% CI 0.45-1.50, p = 0.923). However, having more teeth predicted lower risk (OR 0.95, 95% CI 0.91-0.99, p = 0.023). Dementia and/or MCI was associated with higher serum IL-6, IL-8, and IFN-γ at baseline, and IL-8 and TGF-β at follow-up. IgG levels to periodontal pathogens remained stable in men who developed dementia and/or MCI but declined in cognitively normal men. A positive correlation between IgG to periodontal pathogens and proinflammatory cytokines was observed in men who developed dementia and/or MCI.ConclusionsClinical periodontitis was not associated with dementia or MCI onset, but tooth retention was protective. Elevated inflammatory markers in affected men suggest systemic inflammation may contribute to cognitive decline. Larger, more diverse cohort studies are needed to clarify the role of periodontal disease in dementia and AD risk.},
}

@article {pmid41384825,
year = {2025},
author = {Hreha, K and Ashner, MC and Peskoe, S and Downer, B and Reistetter, T and Palta, P and Wruck, L and Gottesman, RF and Windham, BG and Whitson, HE},
title = {Prevalence of pre-stroke and stroke-related vision impairments and their association with mild cognitive impairment and dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404018},
doi = {10.1177/13872877251404018},
pmid = {41384825},
issn = {1875-8908},
abstract = {BackgroundVision impairment is a risk factor for mild cognitive impairment (MCI) among stroke survivors, but it is unclear if this association is driven by vision impairment present before or due to the stroke, and if similar associations exist with dementia.ObjectiveTo (1) characterize the prevalence of pre-stroke and stroke-related vision impairment(s) among stroke survivors, and (2) quantify associations of vision impairment with dementia and cognitive impairment (MCI/dementia).MethodsUsing participants from the Atherosclerosis Risk in Communities (ARIC) dataset with adjudicated incident strokes, we gathered descriptive statistics on the cohort, assessed if vision impairment was present at the time of incident stroke, and classified the impairments as pre-stroke or stroke-related. Multivariable logistic regression was used to estimate the association between these types of vision impairment and post-stroke cognitive impairment.ResultsAmong 233 incident stroke survivors (mean = 69 years old and 50.2% female sex), 23.2% with pre-stroke vision impairment and 18.9% with stroke-related vision impairment, there were 124 (53%) cases of cognitive impairment (n = 76 MCI, n = 48 dementia). Stroke-related vision impairment was significantly associated with higher odds of dementia (ref = normal/MCI) (adjusted odds ratio (aOR) = 2.32, 95% confidence interval (CI) = 1.08-4.92, p = 0.029), but not any cognitive impairment (ref = normal) (aOR = 1.33 95% CI = 0.67-2.70, p = 0.425). Further adjusting for stroke severity score attenuated the association of stroke-related vision impairment with dementia (aOR = 2.0, 95% CI = 0.90, 4.32, p = 0.08).ConclusionsStroke-related vision impairment, but not pre-stroke vision impairment, was associated with higher odds of dementia. There is evidence that stroke severity could, at least partially, explain the observed association.},
}

@article {pmid41384822,
year = {2025},
author = {Guy, TO and Ghanem, A and Berry, DS and Hernandez, NC and Sharma, VD and Chapman, S and Cosentino, S and Louis, ED},
title = {Blood-based Alzheimer's disease biomarkers and cognitive decline in essential tremor.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404035},
doi = {10.1177/13872877251404035},
pmid = {41384822},
issn = {1875-8908},
abstract = {BackgroundTwo epidemiological studies demonstrated an association between essential tremor (ET) and prevalent dementia as well as substantially elevated risks of incident dementia among ET cases. At this early point, the underlying pathophysiology of ET-dementia is not known. In vivo biomarkers of Alzheimer's disease (AD) and neurodegeneration could help bridge the gap between the pathophysiological processes that present in the context of ET-dementia.ObjectiveExamine blood concentrations of t-tau, p-tau181, p-tau217, Aβ42/40, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in ET with a range of cognitive diagnoses.Methods40 ET cases (mean age = 81.5 ± 7.3; including 20 normal cognition (NC), 12 cognitively normal with some weaknesses, 4 mild cognitive impairment, and 4 dementia) were enrolled in a study of cognitive performance in ET, during which phlebotomy was performed.ResultsGreater cognitive difficulty was associated with higher blood concentrations of p-tau217, p-tau181, GFAP, and NfL, and a lower Aβ42/40 ratio (p tests for trend < 0.05). Cases with dementia had marginally higher concentrations of p-tau217 (p = 0.06) and higher concentrations of GFAP and NfL (p < 0.05) than cases with NC. Furthermore, higher concentrations of p-tau217, GFAP, and NfL were associated with lower cognitive test scores across multiple cognitive domains (p < 0.05).ConclusionsAlbeit based on a small sample of cases, our findings suggest a potential role of blood-based biomarkers as markers for cognitive function in ET patients. Cognitive decline in ET may be due to underlying neurodegenerative processes involving tau and perhaps Aβ pathology.},
}

@article {pmid41384508,
year = {2025},
author = {Karahan, H and Hartigan, K and Al-Amin, MM and John, SK and McCord, B and Wijeratne, HRS and Acri, DJ and Smith, DC and Dabin, LC and Cordero, HMR and Kim, B and Lee, DH and Kim, J},
title = {Deletion of neuronal Idol ameliorates Alzheimer's disease-related pathologies via APOE receptors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70949},
doi = {10.1002/alz.70949},
pmid = {41384508},
issn = {1552-5279},
support = {R01AG053242/AG/NIA NIH HHS/United States ; NIRG-12-240682/ALZ/Alzheimer's Association/United States ; //Indiana University Strategic Research Initiative/ ; //Indiana University Precision Health Initiative/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; Mice ; *Neurons/metabolism/pathology ; *Apolipoproteins E/metabolism ; Mice, Knockout ; Reelin Protein ; *Receptors, LDL/metabolism ; *Brain/metabolism/pathology ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Microglia/metabolism ; *Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {INTRODUCTION: Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aβ) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL), an enzyme that ubiquitinates LDLR for degradation, would increase endogenous LDLR levels and attenuate amyloid pathology.

METHODS: To investigate the cell-type-specific role of IDOL, we generated Idol conditional knockout mice on an Aβ-amyloidosis mouse model and performed biochemical, histological, and multi-omics analyses.

RESULTS: We demonstrated that neuronal, but not microglial, Idol deletion reduced amyloid accumulation and altered brain LDLR and APOE levels, indicating the critical role of neuronal IDOL-LDLR in amyloid pathology. In addition, neuronal Idol deletion increased the levels of Reelin receptors important for synaptic function, and single-nuclei RNA sequencing revealed significant changes associated with synaptic organization.

DISCUSSION: Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer's disease pathogenesis by regulating the levels of brain APOE receptors.

HIGHLIGHTS: Neuronal, but not microglial, Idol deletion reduces amyloid burden and modulates brain APOE and LDLR levels. Deletion of neuronal Idol increases the levels of APOER2 and VLDLR, the Reelin receptors, in the brain. Single-nuclei RNA sequencing highlights the neuronal IDOL's impact on inhibitory neurons and synaptic organization. Targeting neuronal IDOL may provide multiple therapeutic benefits in Alzheimer's disease by modulating APOE receptors.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics
Mice
*Neurons/metabolism/pathology
*Apolipoproteins E/metabolism
Mice, Knockout
Reelin Protein
*Receptors, LDL/metabolism
*Brain/metabolism/pathology
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Microglia/metabolism
*Ubiquitin-Protein Ligases/genetics/metabolism

@article {pmid41384297,
year = {2026},
author = {Zhou, B and Li, L and Qiu, X and Wu, J and Xu, L and Shao, W},
title = {[Retracted] Long non‑coding RNA ANRIL knockdown suppresses apoptosis and pro‑inflammatory cytokines while enhancing neurite outgrowth via binding microRNA‑125a in a cellular model of Alzheimer's disease.},
journal = {Molecular medicine reports},
volume = {33},
number = {2},
pages = {},
doi = {10.3892/mmr.2025.13772},
pmid = {41384297},
issn = {1791-3004},
abstract = {Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the cell apoptotic data shown in Fig. 5A were strikingly similar to data appearing in different form in another article written by different authors at different research institutes that had already been published in the journal Cell Cycle; moreover, the lens smudging patterns underlying the neurite outgrowth experimental data shown in Figs. 2D and 5C matched that of data shown in other figures of the same article published in journal Cell Cycle, suggesting these data may have been derived from the same original source. Owing to the fact that the contentious data mentioned above had already apparently been published previously, the Editor of Molecular Medicine Reports has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 1489‑1497, 2020; DOI: 10.3892/mmr.2020.11203].},
}

@article {pmid41384038,
year = {2025},
author = {Zainal Abidin, S and Razali, NN and Cheah, PS and Ling, KH},
title = {Biogenesis and function of circular RNAs and their implications in the Down syndrome brain.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1708015},
pmid = {41384038},
issn = {1664-8021},
abstract = {Circular RNAs (circRNAs), a class of covalently closed, non-coding RNAs, have recently emerged as crucial regulators of gene expression. They exert their roles through microRNA (miRNA) sponging, transcriptional regulation, and interactions with RNA-binding proteins (RBPs). Increasing evidence suggests that circRNAs play important roles in neurodevelopmental disorders, including Down syndrome (DS). DS is a condition caused by trisomy of chromosome 21 and characterised by intellectual disability (ID), neuroinflammation, and increased risk of early-onset Alzheimer's disease (AD). Aberrant circRNA expression in DS may contribute to pathogenesis by disrupting competing endogenous RNA (ceRNA) networks, modulating synaptic plasticity, and influencing key molecular pathways, including EZH2-mediated chromatin remodelling, immune response regulation, and neuronal differentiation. Despite these emerging insights, the role of circRNAs in DS remains largely underexplored compared to their well-recognised functions in cancer and other neurological disorders. Most current studies have focused on transcriptomic analyses, identifying differentially expressed circRNAs and predicting their interactions with miRNAs and mRNAs. However, these findings require further experimental validation to uncover the precise mechanisms through which circRNAs contribute to DS pathophysiology. This review highlights the association of circRNAs with DS, emphasising their dysregulation and mechanistic interactions with miRNAs and mRNAs. It further explores how these circRNA-mediated mechanisms may contribute to intellectual disability and impaired neurodevelopment, based on current evidence.},
}

@article {pmid41383962,
year = {2025},
author = {Li, X and Zhang, C and Liu, D and Shang, H and Wang, K and Lin, X and Zheng, J},
title = {Causal Relationships Between Neuropathic Pain and Alzheimer's Disease: A Multi-Omics Mendelian Randomization Study with Exploratory Evidence of a Potential Protective Role of Diabetic Neuropathy.},
journal = {Journal of pain research},
volume = {18},
number = {},
pages = {6527-6544},
pmid = {41383962},
issn = {1178-7090},
abstract = {BACKGROUND: Neuropathic pain (NP) frequently co-occurs with Alzheimer's disease (AD), yet the causal relationship and underlying molecular mechanisms between the two remain unclear, necessitating further investigation to elucidate their intrinsic connection.

METHODS: This study employed a bidirectional two-sample Mendelian randomisation (MR) approach to systematically analyse the association between six NP subtypes and AD. Concurrently, functional annotation and transcriptomic analysis were conducted using the GTEx v10 and GEO GSE156184 databases to explore potential molecular mechanisms.

RESULTS: The study revealed a significant inverse causal effect of diabetic neuropathy (DN) on AD risk (OR=0.86, 95% CI: 0.77~0.95, P IVW=0.0043), with sensitivity analyses confirming the robustness of this finding. Further analysis indicated that DN-associated SNPs regulate four tissue-specific genes including FAM200A and GPC2. These genes exhibit differential expression in the DN transcriptome and are significantly enriched in key pathways such as mitochondrial function and autophagy.

CONCLUSION: This study provides the first evidence that DN may exert a protective effect against AD by regulating the aforementioned tissue-specific genes and associated pathways. This finding challenges the conventional understanding that chronic pain exacerbates AD and offers novel potential targets for developing therapeutic strategies. However, due to population limitations in the study, further experimental validation remains necessary.},
}

@article {pmid41383957,
year = {2025},
author = {Brown, CA and Das, SR and Detre, JA and Nasrallah, IM and Yushkevich, PA and McMillan, CT and Wolk, DA},
title = {Fully individualized models for cross-sectional and longitudinal network-based tau spread.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41383957},
issn = {2837-6056},
abstract = {Heterogeneity in regional tau burden limits evaluation of disease progression using one-size-fits-all approaches. Prior work using tau positron emission tomography (PET) has highlighted the important role of connectivity to epicenters of tau pathology in explaining this heterogeneity. However, previous studies using population-based epicenters or connectomes fall short of a fully individualized approach to predicting regional tau burden. We use diffusion MRI-derived structural connectomes to assess the prediction of regional tau burden using distance along individual structural connectomes from individualized epicenters of tau pathology both cross-sectionally and longitudinally. Fully individualized models of connectivity and epicenters outperformed models using either population-based connectomes or epicenters in explanation of cross-sectional and longitudinal regional tau burden, improved prediction in validation datasets, and produced stronger single-subject level prediction. Together, these findings demonstrate the power of a fully individualized approach to explain regional tau heterogeneity and provide the strongest in vivo evidence to date for network-based spread of tau pathology.},
}

@article {pmid41383949,
year = {2025},
author = {Zhang, N and Zhao, Z and Chen, X and Yao, H and Zhu, M and Ma, S and Wang, H and Yin, X and Zhou, Y and Zheng, C and Li, J and Pan, J and Wang, K and Yang, B and Wang, Y and Fan, J and Gong, Y and Liu, R and Zeng, J and Fan, X and Shentu, Y},
title = {Downregulation of forkhead box O1 (FOXO1) acetylation ameliorates cognitive dysfunction by inhibiting endoplasmic reticulum stress-regulated neuronal apoptosis in APP/PS1 transgenic mice.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {183-201},
pmid = {41383949},
issn = {2770-730X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that affects the central nervous system. Silent information regulator sirtuin 1 (SIRT1) may deacetylate and suppress forkhead box O (FOXO) activities to promote neuronal survival. FOXO1 is involved in the regulation of metabolism, senescence, stress response, and apoptosis. Moreover, endoplasmic reticulum stress (ERS) mediates cell apoptosis. Therefore, this study aimed to determine whether the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice.

METHODS: We used APP/PS1 transgenic mice to construct an in vivo AD model. Additionally, we used β-amyloid (Aβ)-incubated HT22 cells and primary neurons (PNs) for in vitro analyses. Cognitive function was assessed using novel object recognition, the Morris water maze, and fear conditioning. Discrepancies between wild-type (WT) and APP/PS1 transgenic mice were evaluated using an unpaired t test. In addition, one-way analysis of variance was conducted for behavioral assessments and other tests involving four distinct groups, followed by a Tukey's honestly significant difference test for post hoc pairwise comparisons.

RESULTS: The expression of SIRT1 was downregulated (in animal experiments, WT mice vs. APP/PS1 mice, n = 3, p = 0.002; in cell experiments, HT22 cells vs. HT22 cells + Aβ1-42, n = 3, p = 0.001; primary neurons vs. primary neurons + Aβ1-42, n = 3, p < 0.001), whereas FOXO1 acetylation was upregulated both in vivo and in vitro (in animal experiments, WT mice vs. APP/PS1 mice, n = 3, p < 0.001; in cell experiments, HT22 cells vs. HT22 cells + Aβ1-42, n = 3, p = 0.004; primary neurons vs. primary neurons + Aβ1-42, n = 3, p < 0.001), leading to cognitive dysfunction, Aβ plaque deposition, and neuronal apoptosis. Quercetin, a SIRT1 agonist, reversed these changes (For SIRT1, APP/PS1 mice vs. Quercetin-treated APP/PS1 mice, n = 3, p = 0.014; HT22 cells + Aβ1-42 vs. HT22 cells + Aβ1- 42 + Quercetin, n = 3, p = 0.003; primary neurons + Aβ1-42 vs. primary neurons + Aβ1-42 + Quercetin, n = 3, p = 0.014. For ac-FOXO1, APP/PS1 mice vs. Quercetin-treated APP/PS1 mice, n = 3, p < 0.001; HT22 cells+ Aβ1-42 vs. HT22 cells + Aβ1-42 + Quercetin, n = 3, p = 0.023; primary neurons + Aβ1- 42 vs. primary neurons + Aβ1-42 + Quercetin, n = 3, p = 0.003). However, the FOXO1 antagonist AS1842856 invalidated the positive effects of quercetin in APP/PS1 transgenic mice (ac-FOXO1: Quercetin-treated APP/PS1 mice vs. AS1842856-treated APP/PS1 mice, n = 3, p < 0.001). Quercetin counteracted FOXO1 acetylation and ERS-mediated apoptosis. In contrast, AS1842856 promoted these processes in vivo and in vitro.

CONCLUSION: Our findings demonstrate that the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis.},
}

@article {pmid41383948,
year = {2025},
author = {Mu, L and Wang, Y},
title = {The role of gut microbiota-derived metabolites in neuroinflammation.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {131-144},
pmid = {41383948},
issn = {2770-730X},
abstract = {Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation-bile acids, trimethylamine-N-oxide, and indole derivatives-as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.},
}

@article {pmid41383947,
year = {2025},
author = {Schwartz, SS and Rhea, EM and Banks, WA and Herman, ME},
title = {Beta cells to brain cells: The pivotal role of insulin and glucose metabolism in Alzheimer's disease.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {145-164},
pmid = {41383947},
issn = {2770-730X},
abstract = {The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.},
}

@article {pmid41383945,
year = {2025},
author = {Li, S and Walczak, P and Ji, X and Boltze, J},
title = {Targeting peripheral processes to protect the central nervous system.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {117-119},
pmid = {41383945},
issn = {2770-730X},
}

@article {pmid41383898,
year = {2025},
author = {Çankaya, Ş and İpek, L and Ayyıldız, S and Sayman, D and Karaca, R and Ayyıldız, B and Velioğlu, HA and Öktem, EÖ and Hanoğlu, L and Yuluğ, B},
title = {The Adaptive Role of Entorhinal Cortical Thickness in Post-COVID 19 Cognitive Impairment.},
journal = {Noro psikiyatri arsivi},
volume = {62},
number = {4},
pages = {310-314},
pmid = {41383898},
issn = {1300-0667},
abstract = {INTRODUCTION: Only limited information is still available concerning cognitive dysfunctions and cortical thickness in individuals who recovered from mild COVID-19 infections and did not require hospitalization. Our aim was to evaluate if the highly adaptive potential of cortical thickness might play a critical role in COVID-19-related cognitive disorder in a compensatory manner.

METHODS: Fifteen individuals with no history of medical, neurological, or psychiatric disease and with positive COVID-19 test results, and sixteen healthy age and education-matched healthy controls identified from the official hospital health system were evaluated in terms of cognitive scores using Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog) and brain MRI cortical thickness measurements using FreeSurfer, Version 7.4.0.

RESULTS: An increased cortical thickness in the right entorhinal cortex (EC) and impaired cognition (increased ADAS score) were observed in the post-COVID 19 group as compared to the controls confirmed by the student's t test (respectively, p=0.006, p<0.001).The apparent correlation observed between cognitive impairment and increased entorhinal cortical thickness in our COVID-19 patients might suggest a continuum pathophysiology between healthy and COVID-19 affected brains that was not evident in previous COVID-19 cases with cognitive impairment.

CONCLUSION: Our findings of increased entorhinal cortical thickness, together with impaired cognitive scores, may indicate a flexible role of EC thickness in compensatory mechanisms of cognition.},
}

@article {pmid41383893,
year = {2025},
author = {Güleç, ZN and Ercan, M and Erdoğan, Y and Oğuz, K and Uyar, A and Burhanoğlu, BB and Uslu, Ö and Erata, MC and Eker, MÇ and Gönül, AS},
title = {The Effects of Late-Onset Depression on Brain Activity During an Episodic Memory Task.},
journal = {Noro psikiyatri arsivi},
volume = {62},
number = {4},
pages = {302-309},
pmid = {41383893},
issn = {1300-0667},
abstract = {INTRODUCTION: Late-onset depression (LOD) has been implicated in irreversible cognitive decline, potentially mirroring early Alzheimer's Disease (AD) pathology. This study aimed to investigate brain activity differences during an episodic memory (EM) task in LOD patients compared to healthy controls (HC).

METHODS: We recruited 15 LOD patients and 13 HC matched for age and gender. Participants completed a face-name association task during functional magnetic resonance imaging (fMRI) focusing on both the encoding and retrieval phases of EM.

RESULTS: The statistical contrast between the groups revealed that the HC group showed increased activity in the left visual association cortex (VAC) and left caudate compared to the LOD group during the encoding task. During the face recognition task, the HC group showed increased activity in the right caudate, and during the name recognition task, they showed increased activity in the right frontal eye field (FEF) compared to the LOD group.

CONCLUSION: The differences observed between the HC and LOD groups in the VAC, caudate, and FEF suggest early changes in maintaining attention, goal-directed learning, EM formation, and coordination of information from storage to retrieval before apparent impairment develops in LOD. Although we did not find statistically significant activations in areas linked to increased vulnerability to AD, our findings of hypoactivation in regions responsible for visual processing and attentional orienting in LOD patients are consistent with hypoactivation patterns observed in AD patients in previous research. These results enhance our understanding of the neural mechanisms underlying memory impairments in LOD and their potential overlap with AD pathology.},
}

@article {pmid41383880,
year = {2025},
author = {Falasca, NW and Ferretti, A and Granzotto, A and Sensi, SL and Franciotti, R and , },
title = {Machine learning models of Alzheimer's disease spectrum using blood tests.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70228},
pmid = {41383880},
issn = {2352-8729},
abstract = {INTRODUCTION: The diagnosis of Alzheimer's disease (AD) traditionally relies on cerebrospinal fluid and plasma levels of amyloid beta and phosphorylated tau. Although informative, these biomarkers represent a narrow, hypothesis-driven approach to intercept the disease.

METHODS: Data-driven analysis was applied on demographic data, apolipoprotein E (APOE) ε4 allele, and 82 biomarkers obtained from blood tests of healthy controls (HC), mild cognitive impairment that remained stable within 36 months following blood collection (sMCI), and patients with AD.

RESULTS: Statistical analyses revealed differences among groups in many cholesterol-related analytes. APOE ε4 and analytes such as amino acids, lipoproteins, and fatty acids emerged as the most influential features in machine learning (ML) classification algorithms. Glycolysis-related metabolites and amino and fatty acids were predictive for distinguishing sMCI and AD from HC.

DISCUSSION: These findings support the hypothesis that systemic alterations also occur during the preclinical stages of dementia, which can be detected by ML models on blood biomarkers.

HIGHLIGHTS: Machine learning on blood tests detects preclinical cognitive decline.Glycolysis metabolites are predictive for distinguishing stable MCI and AD from HC.Amino acids, lipoproteins, and fatty acids are the most predictive features.Inflammatory and metabolic biomarkers represent a biosignature of cognitive health.},
}

@article {pmid41383879,
year = {2025},
author = {Rubio-Guerra, S and Sánchez-Saudinós, MB and Sala, I and Videla, L and Bejanin, A and Estanga, A and Ecay-Torres, M and de Luis, CL and Rami, L and Tort-Merino, A and Castellví, M and Pozueta, A and García-Martínez, M and Gómez-Andrés, D and Lage, C and López-García, S and Sánchez-Juan, P and Balasa, M and Lladó, A and Altuna, M and Tainta, M and Arranz, J and Zhu, N and Alcolea, D and Lleó, A and Fortea, J and Rodríguez, ER and Sánchez-Valle, R and Martínez-Lage, P and Illán-Gala, I},
title = {Development of amyloid-negative neuropsychological norms using GAMLSS.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70224},
pmid = {41383879},
issn = {2352-8729},
abstract = {INTRODUCTION: Recent research has suggested increased sensitivity of Alzheimer's disease (AD)-negative neuropsychological norms; concurrently, generalized additive models for location, scale, and shape (GAMLSS) have emerged as a promising alternative to traditional norming approaches. Here, we developed amyloid β-negative (Aβ-) next-generation norms (NGN) for a comprehensive neuropsychological battery using GAMLSS.

METHODS: We included N = 987 cognitively normal (CN) individuals from a Spanish multicenter study with extensive neuropsychological data and cerebrospinal fluid AD biomarker assessment. NGN were developed using GAMLSS based on the performance of n = 774 Aβ- CN individuals aged 30-90 years.

RESULTS: Age-, education-, and sex-adjusted z-scores were obtained for 14 measures covering the main cognitive domains (memory, language, attention/executive, and visuospatial functions). A user-friendly calculator for the z-scores was made available in an open-access ShinyApp to facilitate their application.

DISCUSSION: NGN may improve the detection of objective cognitive impairment in clinical and research settings.

HIGHLIGHTS: Brain amyloid β (Aβ) is associated with poorer performance in cognitively normal individuals.We provide GAMLSS-based Aβ-negative norms for 14 neuropsychological measures.Age, education, and often sex significantly influence cognitive performance.An online calculator for the demographically adjusted z-scores is freely available.},
}

@article {pmid41383878,
year = {2025},
author = {Rubio-Guerra, S and Sala, I and Sánchez-Saudinós, MB and Videla, L and Bejanin, A and Estanga, A and Ecay-Torres, M and de Luis, CL and Rami, L and Tort-Merino, A and Castellví, M and Pozueta, A and García-Martínez, M and Gómez-Andrés, D and Lage, C and López-García, S and Sánchez-Juan, P and Balasa, M and Lladó, A and Altuna, M and Tainta, M and Arranz, J and Zhu, N and Alcolea, D and Lleó, A and Fortea, J and Rodríguez, ER and Sánchez-Valle, R and Martínez-Lage, P and Illán-Gala, I},
title = {Amyloid-negative neuropsychological norms: Added value in the era of biomarkers and disease-modifying therapies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70223},
pmid = {41383878},
issn = {2352-8729},
abstract = {INTRODUCTION: We previously applied generalized additive models for location, scale, and shape to derive amyloid β-negative next-generation norms (NGN) for a comprehensive neuropsychological battery. Here, we evaluated the accuracy of NGN in detecting cognitive impairment compared to traditional norms (TN).

METHODS: This multicenter study included N = 2405 participants classified as cognitively normal (CN, n = 987) or with mild cognitive impairment (MCI, n = 1418) using conventional criteria. All participants underwent neuropsychological testing and cerebrospinal fluid Alzheimer's disease (AD) biomarker assessment. We used actuarial neuropsychological criteria to reclassify all participants using TN and NGN. Diagnostic groups were compared on cognitive performance, AD biomarker positivity, and longitudinal cognitive trajectories.

RESULTS: Nineteen percent of TN-classified CN participants were diagnosed with MCI by NGN, whereas 3% of TN-classified MCI were identified as CN by NGN. NGN demonstrated stronger associations with neuropsychological performance, AD biomarkers, and progression than TN.

DISCUSSION: NGN enhance the detection of objective cognitive impairment, with direct implications for clinical practice and research.

HIGHLIGHTS: Next-generation norms (NGN) reclassify one of every five cases from cognitively normal (CN) to mild cognitive impairment (MCI).This group shows poor cognitive performance and a high prevalence of amyloid β positivity.NGN-based diagnosis of MCI predicts cognitive progression on follow-up.Results indicate that NGN improve the detection of objective cognitive impairment.NGN can inform biomarker use, therapy indication, and clinical trial design.},
}

@article {pmid41383817,
year = {2025},
author = {Villino-Rodríguez, R and Ríos-Rivera, MM and Montoya-Murillo, G and Patricio Baldera, J and Salazar-Londoño, S and Rodríguez-Oroz, MC and Borda, MG and Jiménez-Huete, A and Riverol, M},
title = {Clinical and neuropsychological features associated with progression in subjective cognitive decline.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1680762},
pmid = {41383817},
issn = {1663-4365},
abstract = {BACKGROUND AND OBJECTIVES: Subjective Cognitive Decline (SCD) is recognized as an early indicator of neurodegeneration, yet factors that predict its progression to mild cognitive impairment (MCI) or dementia remains not fully understood. In this study, we aim to identify clinical and neuropsychological features associated with the progression of SCD.

METHODS: 450 persons with SCD were included, consisting in 319 non progressors (SCDnp) and 131 progressors (SCDp) to MCI or dementia due to AD. The study was conducted at the Clínica Universidad de Navarra Memory Clinic between 2001 and 2017. We included data on medical interviews and neuropsychological evaluations. Differences between SCDnp and SCDp were assessed and, to evaluate the association between exposure variables and progression in time, proportional-hazards Cox models were applied. In addition to the exposure variables, the models were adjusted for age, sex, and years of education.

RESULTS: At baseline, SCDp were older, had a higher prevalence of hypertension and hypercholesterolemia and had worst performance on tests related to processing speed, verbal fluency, visual memory, verbal memory, and executive functioning. Factors associated with progression at follow-up were lower scores in some cognitive tests: MMSE, TMT-B, and the CERAD regarding trial 1 of immediate recall, trial 2 of immediate recall, trial 3 of immediate recall and the delay recall score.

DISCUSSION: Lower scores on global cognition, executive functioning and verbal memory tests were predictors of progression to MCI or dementia in patients with SCD. These findings underscore the importance of nuances in neuropsychological evaluation, even with a normal score, for detecting high-risk individuals for early intervention.},
}

@article {pmid41383815,
year = {2025},
author = {Zhang, R and Liu, YY and Xia, X and Li, X},
title = {Unvalidated efficacy and significant risks hinder clinical use of deep cervical lymphatic-venous anastomosis for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1671741},
pmid = {41383815},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the pathological accumulation of amyloid-beta (Aβ) plaques and tau tangles. Recent studies suggest that dysfunction of the cerebral lymphatic clearance system may contribute to the progression of AD. This review critically examines the potential of deep cervical lymphatic-venous anastomosis (LVA) as a treatment for enhancing brain protein clearance and reducing cognitive decline in AD patients. Although animal models indicate that improving lymphatic drainage could facilitate Aβ clearance, clinical evidence is still insufficient. Current studies often have small sample sizes, short follow-up periods, and methodological weaknesses. Despite preliminary reports of cognitive improvements in small-scale clinical trials, the efficacy of LVA remains unproven, making widespread clinical adoption premature. Ethical concerns and technical challenges also pose significant barriers to clinical implementation. Rigorous randomized controlled trials (RCTs) are necessary to assess the long-term safety and efficacy of LVA for treating AD. Furthermore, the establishment of clear ethical and regulatory frameworks is essential before clinical use.},
}

@article {pmid41383776,
year = {2025},
author = {Pirhanov, A and Rodriguez, C and Tashakori-Asfestani, F and Gonsoulin, R and Santiago, R and Tobunluepop, K and Erhunmwunsee, E and Puri, S and Arbaciauskaite, M and He, W and Wolozin, B and Cho, Y},
title = {Nanobodies targeting hnRNPA2/B1 and tau.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.21.689763},
pmid = {41383776},
issn = {2692-8205},
abstract = {Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is an RNA-binding protein that mislocalizes to the cytoplasm and forms stress-induced granules in tauopathy and multisystem proteinopathy. It also preferentially interacts with oligomeric tau and is required for tau-mediated neurodegeneration in a mouse model of Alzheimer's disease. To study endogenous hnRNPA2/B1 and tau, we generated nanobodies that specifically recognize these proteins. We screened yeast surface display nanobody libraries using an avidity-enhanced screening strategy that enabled selection of binders against short peptide ligands. This led to isolation of anti-hnRNPA2/B1 and anti-tau nanobodies with defined epitopes. Directed evolution of the anti-hnRNPA2/B1 nanobody improved binding affinity by over 20-fold but caused cytoplasmic aggregation, demonstrating a tradeoff between affinity and intracellular behavior. Although the final nanobodies retained modest affinities, they showed robust intracellular colocalization with their targets. Furthermore, fusion to ubiquitin ligase adaptor domains significantly decreased hnRNPA2/B1 and tau levels. Collectively, these nanobodies provide valuable tools for studying hnRNPA2/B1 and tau dynamics in their native cellular context.},
}

@article {pmid41383762,
year = {2025},
author = {Ku, TS and Mullett, SJ and Sui, Z and Zeng, L and Ding, Y and Yocum, AK and MacDonald, M and Gelhaus, SL and Kofler, J and Sweet, RA},
title = {Proteomic Analysis in Alzheimer's Disease with Psychosis Reveals Separate Molecular Signatures for Core AD Proteinopathy and Postsynaptic Density Disruption.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.26.690872},
pmid = {41383762},
issn = {2692-8205},
abstract = {BACKGROUND AND HYPOTHESIS: Alzheimer's disease with psychosis (AD+P) is a subgroup of AD patients with more rapid cognitive deterioration. While our previous study showed that AD+P is associated with loss of prefrontal cortex postsynaptic density (PSD) proteins, identifying proteins in the broader cellular environment that influence PSD loss addresses a critical knowledge gap about synaptic dysfunction mechanisms in early disease stages.

STUDY DESIGN: We conducted a proteomic analysis comparing prefrontal grey matter cortex tissue homogenates from elderly normal controls (n=18), individuals with AD+P (n=61), and individuals with AD-P (n=48), all with Braak stages 3-5.

STUDY RESULTS: AD+P showed the most pronounced alterations relative to controls (178 proteins with q<0.05), although alterations in AD-P and AD+P relative to controls were highly similar (R²=0.965, p<0.001). Weighted-gene correlation network analysis (WGCNA) identified four modules significantly associated with disease status comparing AD subjects to controls, but none differed significantly between AD+P and AD-P. We identified 15 proteins significantly correlated with PSD yield across all samples, including ENPP6, linked to AD+P by GWAS. Additionally, PSD yield-associated proteins showed minimal overlap with altered AD proteins (1 of 137). WGCNA revealed one module significantly correlated with PSD yield across all samples, enriched for inflammatory terms.

CONCLUSIONS: Our findings suggest a model in which AD+P arises from the combination of quantitative alterations within a shared AD proteome profile and a superimposed set of protein alterations correlated with PSD yield that are largely independent of the shared AD proteome, conferring distinct mechanisms of synaptic vulnerability and psychosis risk.},
}

@article {pmid41383524,
year = {2025},
author = {Zhang, X and Zhong, M and Li, Y and Wang, H and Xi, G and Wang, F and Cheng, C and Shi, Y},
title = {Oral microbiota and central nervous system diseases: A review.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {1},
pages = {79-94},
pmid = {41383524},
issn = {2770-730X},
abstract = {Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health. Impaired homeostasis of the oral microbiota can lead to pathological changes, resulting in central nervous system (CNS) diseases. However, the mechanisms and clinical value of how the oral microbiome influences the brain remain unclear. This review summarizes recent clinical findings on the role of the oral microbiota in CNS diseases and proposes potential approaches to understand the way the oral microbiota and brain communicate. We propose three underlying patterns involving neuroinflammation, neuroendocrine regulation, and CNS signaling between oral microbiota and CNS diseases. We also summarize the clinical characteristics and potential utilization of the oral microbiota in ischemic stroke, Alzheimer's and Parkinson's disease, intracranial aneurysms, and mental disorders. Although the current findings are preliminary and clinical evidence is incomplete, oral microbiota is a potential biomarker for the clinical diagnosis and treatment of CNS diseases.},
}

@article {pmid41383520,
year = {2025},
author = {Saxena, SK and Sharma, D and Kumar, S and Maurya, VK and Ansari, S and Malhotra, HS and Singh, A},
title = {Decoding the role of large heat shock proteins in the progression of neuroinflammation-mediated neurodegenerative disorders.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {1},
pages = {48-62},
pmid = {41383520},
issn = {2770-730X},
abstract = {Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases (NDs). Potential neurotoxic changes in the intra- and extracellular environment are typical hallmarks of many NDs. Treatment of ND is challenging, as the symptoms in these patients arises when a significant numbers of neurons have already been destroyed. Heat shock proteins (HSPs) can bind to recipient cells that are susceptible to stress, such as neurons, in the extracellular environment, therefore enhancing stress resistance. Among all, HSP60, HSP70, and HSP90 are highly conserved molecular chaperones involved in protein folding and assembly, maintaining cellular homeostasis in the central nervous system. Notably, α-synuclein accumulation is a major pathophysiology in Parkinson's disease, where HSP90 modulates the assembly of α-synuclein in vesicles to prevent its accumulation. Moreover, HSP90 regulates the activity of the glycogen synthase kinase-3β protein, which is crucial in diabetes mellitus-associated neurocognitive disorder. Therefore, understanding the molecular mechanism by which HSPs facilitate protein aggregation and respond to inflammatory stimuli, including metabolic disease such as diabetes, is essential for understanding the significance of HSPs in NDs. This review emphasizes the role of various HSPs in the progression of NDs such as Alzheimer's, Parkinson's, multiple sclerosis, and Huntington's disease, including diabetes, which is one of the major risk factors for neurodegeneration.},
}

@article {pmid41383377,
year = {2024},
author = {Hanumanthappa, R and Parthasarathy, A and Heggannavar, GB and Pc, K and Nanjaiah, H and Kumbhar, R and Devaraju, KS},
title = {Recent advances in therapeutic strategies for Alzheimer's and Parkinson's disease using protein/peptide co-modified polymer nanoparticles.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {4},
pages = {255-275},
pmid = {41383377},
issn = {2770-730X},
abstract = {The blood-brain barrier (BBB), which protects the brain from foreign molecules, makes delivery of drugs to the central nervous system is challenging. Nanoparticles (NPs) have been used over the past decade as drug delivery systems for the treatment of many disorders with great results. However, the effectiveness of NPs in delivering drugs to the brain for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD) is limited by the BBB. A recent breakthrough in nanotechnology delivery systems involves the use of surface-modified polymer NPs that enhance drug absorption and transport across the BBB; however, the technology still has some limitations. Studies conducted over the past few years have demonstrated that NPs modified with peptides or proteins can effectively cross the BBB via specific receptors, thus enhancing their delivery efficiency. In this review, we explore the use of polymer NPs combined with peptides and proteins for the treatment of AD and PD. This discussion focuses on the pathophysiology of these diseases, the BBB, and the potential of therapeutics based on co-modifying NPs with peptides and proteins. Additionally, we outline future directions for the use of polymer NPs conjugated with these biomolecules.},
}

@article {pmid41383373,
year = {2024},
author = {Chen, J and Chen, J and Liang, C and Liu, C and Jie, L and Liu, B and Yang, X},
title = {Liver enzyme and risk of vascular dementia: A univariable and multivariable Mendelian randomization of European descent.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {4},
pages = {310-317},
pmid = {41383373},
issn = {2770-730X},
abstract = {BACKGROUND: Observational studies have indicated a link between liver enzymes and dementia, but the causal relationship remains uncertain. We conducted a two-sample Mendelian randomization (MR) study to investigate potential causal links between liver function markers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyltransferase [GGT]) and various forms of dementia (all-cause dementia, Alzheimer's disease [AD], vascular dementia [VaD], and frontotemporal dementia [FTD]).

METHODS: Genome-wide association study (GWAS) data of liver enzyme levels with 517 single nucleotide polymorphisms from 315,572 individuals of European descent were considered as exposures. Additional GWAS data on dementia from the FinnGen consortium and the UK Biobank were used as outcomes. The causal relationship was evaluated using univariable MR (UVMR) and multivariable MR (MVMR) methods. UVMR approaches such as inverse variance weighting (IVW), MR-Egger, weighted median, simple mode, and weighted mode were used, with IVW as primary. MVMR techniques, such as extended versions of IVW, MR-Egger, and Q-minimization methods, were used to assess causal effects. The robustness of the MR analysis findings was verified through heterogeneity, horizontal pleiotropy, and leave-one-out analyses.

RESULTS: MVMR analysis demonstrated that a genetically determined one standard deviation rise in blood GGT levels was associated with an increased risk of VaD (IVW: odds ratio = 1.007, 95% confidence interval = 1.002-1.011, p = 0.010). These findings remained consistent after adjusting for confounding variables in MVMR analysis. Sensitivity analyses further supported the causal relationship. However, no significant links were observed between ALT, AST, ALP, and all-cause dementia, VaD, AD, or FTD.

CONCLUSIONS: Our study suggests clinical implications, demonstrating that high blood GGT concentrations are potential causal risk factors for VaD in European populations. Further research is needed to uncover the underlying biological mechanisms between GGT and VaD and validate the clinical relevance of early prevention and intervention strategies.},
}

@article {pmid41383223,
year = {2025},
author = {Hirano, S and Zhou, L and Ouchi, M and Suwa, S},
title = {Daily life experiences of an older woman with Alzheimer's disease residing alone as recorded in her diaries.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251396055},
pmid = {41383223},
issn = {2542-4823},
abstract = {BACKGROUND: In Japan, the aging population is rapidly increasing, with more older persons residing alone. Among them, individuals with dementia face unique challenges in maintaining daily life and self-identity.

OBJECTIVE: This study aimed to clarify what an older woman living with Alzheimer's disease, who resided alone, experienced in her daily life based on the diaries she kept.

METHODS: The contents of 13 diary books belonging to Aki (a pseudonym), an older woman with dementia who lived alone at home, were quantitatively analyzed using KH Coder, and a co-occurrence network was created. In addition, qualitative content analysis of the diary contents was performed for each subgraph obtained from this network.

RESULTS: Across all years, most days with entries had only 1 entry. However, as the years passed, the number of days with multiple entries increased. The co-occurrence network consisted of 8 subgraphs. According to the content in each subgraph, Aki experienced "sorrow and loneliness due to forgetfulness". However, Aki made efforts such as "recording the current time," "writing in a notebook to maintain my proper character". The analyses also revealed her experience of trying to live positively, as reflected in statements such as "I will live positively even though my siblings passed away, leaving me all alone."

CONCLUSIONS: Keeping a diary may have been an important means to complement her memory function and orientation, and to inspire motivation to live positively even after the loss of her family members, moreover as well as maintaining her self-esteem.},
}

@article {pmid41383118,
year = {2025},
author = {Peeples, LB and Chrzanowski, L and Mast, BT},
title = {Preparedness as a Bridge: How Religious Coping Shapes Acceptance of Death in Dementia Caregiving.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/07317115.2025.2601447},
pmid = {41383118},
issn = {1545-2301},
abstract = {OBJECTIVES: This study examined the role of religious coping and preparedness in shaping caregivers' acceptance of death following the loss of a care recipient with Alzheimer's disease or related dementias. Two competing path models were tested to determine whether preparedness serves as a mediator or an outcome in the relationship between religious coping and acceptance.

METHODS: Data were drawn from the bereavement battery of the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) study. The analytic sample included 41 bereaved caregivers who completed measures of positive and negative religious coping, preparedness for death, and acceptance of death. Path analyses were conducted in R using the lavaan package.

RESULTS: Bivariate analyses indicated that both positive and negative religious coping were significantly associated with greater preparedness, and preparedness was strongly related to acceptance. The first path model, where preparedness predicted coping and acceptance, showed poor global fit. In contrast, the second model, where coping predicted preparedness, which in turn predicted acceptance, showed excellent fit.

CONCLUSIONS: Preparedness emerged as a mechanism linking religious coping with acceptance, highlight an important pathway for supporting caregivers in bereavement.

CLINICAL IMPLICATIONS: Findings suggest that interventions focused on religious coping enhance preparedness which improves caregivers' acceptance in the bereavement process.},
}

@article {pmid41383055,
year = {2025},
author = {Brodman, ST and Heaton, N and Triana-Baltzer, G and Zeng, X and Gogola, A and Kamboh, MI and Villemagne, VL and Lopez, OL and Kolb, H and Deek, RA and Cohen, AD and Karikari, TK},
title = {Plasma biomarkers, brain amyloid-beta pathology, and cortical thickness in a non-Hispanic White and Black/African American middle-aged community cohort: The HCP-CoBRA study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70985},
doi = {10.1002/alz.70985},
pmid = {41383055},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; R01AG083874//NIH/NIA)/ ; //Karikari Laboratory/ ; U24AG082930 P30 AG066468 RF1 AG077474 R01 AG083156 R37 AG023651 R01 AG025516 R01 AG073267 R01 AG075336 R01 AG072641 P01 AG025204//NIH/NIA/ ; U01 NS131740 U01 NS141777//NIH/NINDS/ ; R01 MH108509/MH/NIMH NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; HT94252320064//DoD/ ; //Anbridge Charitable Fund/ ; //University of Pittsburgh/ ; },
mesh = {Humans ; Female ; Male ; *Amyloid beta-Peptides/metabolism/blood ; Biomarkers/blood ; Black or African American ; Middle Aged ; Positron-Emission Tomography ; Aged ; tau Proteins/blood ; White People ; Magnetic Resonance Imaging ; Cohort Studies ; *Brain/pathology/diagnostic imaging/metabolism ; *Brain Cortical Thickness ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; *Cerebral Cortex/pathology/diagnostic imaging ; Alzheimer Disease/pathology ; White ; },
abstract = {INTRODUCTION: We evaluated plasma biomarker association with, and classification accuracies for, amyloid beta-positron emission tomography (Aβ-PET) and cortical thickness in the biracial Human Connectome Project-Connectomics in Brain Aging (HCP-CoBRA) cohort (53% Black/African American [B/AA] and 47% non-Hispanic White [NHW]).

METHODS: In n = 218 participants (median age 62, range: 57-71] years, 65% female and 15% Aβ-PET positive), plasma biomarkers (phosphorylated tau-181 [p-tau181], p-tau217, p-tau231, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], and Aβ42/Aβ40) were compared to Aβ-PET and magnetic resonance imaging (MRI) neuroimaging indicators.

RESULTS: Plasma p-tau217 (Johnson & Johnson and ALZpath [areas under the curve [AUCs] = 0.915 vs. 0.919]) had high sensitivity and specificity (>85%) for Aβ-PET status. All plasma biomarkers except p-tau231 effectively ruled out Aβ pathology (negative predictive value [NPV] >95%) but only Johnson & Johnson p-tau217+ was good for confirmation (covariate-adjusted positive predictive value [PPV] = 0.909). The plasma biomarkers performed poorly for identifying cortical thickness status but were elevated according to joint Aβ-PET and neurodegeneration profiles. Plasma biomarker accuracies for Aβ-PET positivity were unaffected by self-identified race, except for ALZpath p-tau217 (p = 0.024). However, correlations with Aβ-PET standardized uptake value ratio varied by self-identified race.

DISCUSSION: Plasma p-tau217 is a promising tool for Alzheimer's disease-associated Aβ pathology in older/middle-aged individuals. However, apparent race-related performances should be further studied.

HIGHLIGHTS: Plasma phosphorylated tau-217 (p-tau217) and glial fibrillary acidic protein (GFAP) best predicted abnormal brain amyloid beta-positron emission tomography (Aβ-PET). Plasma p-tau217 accurately identified abnormal Aβ-PET (Johnson & Johnson p-tau217: area under the curve [AUC] = 0.9145, 95% confidence interval [CI] = 0.8367-0.9923; ALZpath p-tau217: AUC = 0.9198, 95% CI = 0.8585-0.981) followed by GFAP and Aβ42/40 ratio (GFAP: AUC = 0.8529, 95% CI = 0.7485-0.9573; Aβ42/40:AUC = 0.7962, 95% CI = 0.6581-0.9346). All plasma biomarkers performed poorly in identifying cortical thickness, despite being higher according to combined Aβ-PET and neurodegeneration profiles. Correlations of p-tau217 (Johnson & Johnson p < 0.001), p-tau181 (p = 0.005), and Aβ42/40 (p = 0.004) with Aβ-PET in predicting amyloid burden were stronger in self-identified non-Hispanic Whites vs Black/African Americans. Biomarker accuracies for Aβ-PET positivity were unaffected by self-identified race, except ALZpath p-tau217 (p = 0.024).},
}

Humans
Female
Male
*Amyloid beta-Peptides/metabolism/blood
Biomarkers/blood
Black or African American
Middle Aged
Positron-Emission Tomography
Aged
tau Proteins/blood
White People
Magnetic Resonance Imaging
Cohort Studies
*Brain/pathology/diagnostic imaging/metabolism
*Brain Cortical Thickness
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
*Cerebral Cortex/pathology/diagnostic imaging
Alzheimer Disease/pathology
White

@article {pmid41383049,
year = {2025},
author = {Pyun, JM and Park, YH and Kim, S and Nho, K and , },
title = {Polygenic risk score predicts pathologically confirmed cerebral amyloid angiopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70958},
doi = {10.1002/alz.70958},
pmid = {41383049},
issn = {1552-5279},
support = {RS-2024-00461936//National Research Foundation of Korea (Ministry of Science and ICT)/ ; P30 AG010133/NH/NIH HHS/United States ; P30 AG072976/NH/NIH HHS/United States ; R01 AG081951/NH/NIH HHS/United States ; R01 LM012535/NH/NIH HHS/United States ; U01 AG072177/NH/NIH HHS/United States ; U19 AG074879/NH/NIH HHS/United States ; AACSFD-24-1310485/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/genetics/pathology/diagnostic imaging ; Female ; Male ; Magnetic Resonance Imaging ; Aged ; Biomarkers ; *Multifactorial Inheritance ; *Alzheimer Disease/pathology/genetics ; Risk Factors ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Genetic Risk Score ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) both involve amyloid beta (Aβ) accumulation in vessels and brain parenchyma, respectively. As Aβ-targeting therapies emerge, CAA draws attention due to its link with amyloid-related imaging abnormalities (ARIA), underscoring the need for biomarkers beyond magnetic resonance imaging (MRI).

METHODS: CAA polygenic risk scores (CAA-PRS) were generated in 105 ADNI participants, and their predictive ability for pathological CAA was evaluated, including in subgroups with high amyloid burden or without MRI-visible CAA markers.

RESULTS: CAA-PRS was significantly associated with pathological CAA (OR = 1.766, p < 0.001), with an AUC of 0.783 overall and 0.766 (OR = 1.780, p = 0.002) in those with high amyloid burden. A marginal association was observed in MRI-negative individuals.

DISCUSSION: CAA-PRS may serve as a complementary biomarker to imaging for identifying high-risk individuals with CAA, particularly in the context of Aβ-targeting therapies and ARIA risk.

HIGHLIGHTS: CAA-PRS is generated. CAA-PRS is associated with pathologically confirmed CAA. CAA-PRS is associated with CAA in individuals with high amyloid burden.},
}

Humans
*Cerebral Amyloid Angiopathy/genetics/pathology/diagnostic imaging
Female
Male
Magnetic Resonance Imaging
Aged
Biomarkers
*Multifactorial Inheritance
*Alzheimer Disease/pathology/genetics
Risk Factors
Aged, 80 and over
Brain/pathology/diagnostic imaging
Amyloid beta-Peptides/metabolism
Genetic Risk Score

@article {pmid41382294,
year = {2025},
author = {Su, X and Takayanagi, R and Maeda, H and Saido, TC and Ohshima, T},
title = {Sex-related upregulation of bone morphogenetic protein signaling inhibits adult neurogenesis in APP[NL-G-F] alzheimer's disease model mice.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {103},
pmid = {41382294},
issn = {2042-6410},
support = {JP22K06464//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Neurogenesis/physiology ; Female ; Male ; Up-Regulation ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction ; Mice, Inbred C57BL ; *Bone Morphogenetic Proteins/metabolism ; *Sex Characteristics ; Hippocampus/metabolism ; Mice ; Neural Stem Cells ; Estrogens/pharmacology ; },
abstract = {BACKGROUND: Bone morphogenetic proteins (BMPs) have been reported in many studies to be related to adult neurogenesis. Neurogenic impairment is a hallmark of Alzheimer's disease (AD), while the involvement of BMPs remains unclear.

METHODS: AD models were established using APP[NL-G-F] transgenic mice and C57BL/6 mice subjected to intracerebral injection of Aβ(25-35) peptide. Female APP[NL-G-F] mice received pharmacological inhibitor treatment, whereas Neuro2a cells were exposed to estrogen stimulation in vitro. Immunofluorescence staining was conducted to evaluate hippocampal neural stem cell proliferation. The hippocampus and cellular pellets were isolated, and quantitative PCR (qPCR) was employed to determine mRNA expression levels.

RESULTS: Our study revealed that APP[NL-G-F] mice and Aβ-injected mice exhibited impaired neurogenesis in the brain, with a clear sex-dependent difference only in APP mice. Several BMPs were markedly upregulated in the hippocampus of AD model mice, with significantly higher expression in females than in males. BMP inhibitor attenuated neural stem cell proliferation deficits in female APP[NL-G-F] mice. Estrogen stimulation robustly enhanced BMP6 expression in Neuro2a cells.

CONCLUSIONS: Our findings reveal a sex-dependent impairment of neurogenesis in APP[NL-G-F] mice driven by BMP signaling. Blocking BMP signaling enhances adult neural stem cell proliferation in female APP[NL-G-F] mice, providing a potential therapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Neurogenesis/physiology
Female
Male
Up-Regulation
Mice, Transgenic
Disease Models, Animal
Signal Transduction
Mice, Inbred C57BL
*Bone Morphogenetic Proteins/metabolism
*Sex Characteristics
Hippocampus/metabolism
Mice
Neural Stem Cells
Estrogens/pharmacology

@article {pmid41382275,
year = {2025},
author = {Nolt, GL and Golden, LR and Thorpe, SP and Funnell, JL and Stephens, IO and Hernandez, G and MacLean, SM and Lucido, CC and Brock, CR and Pallerla, AV and Adreon, DR and Williams, HC and Morganti, JM and Johnson, LA},
title = {Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03639-5},
pmid = {41382275},
issn = {1742-2094},
support = {T32 AG078110/NH/NIH HHS/United States ; RF1NS118558/NH/NIH HHS/United States ; R01AG081421/NH/NIH HHS/United States ; P20 GM148326/GM/NIGMS NIH HHS/United States ; },
abstract = {Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms.},
}

@article {pmid41382170,
year = {2025},
author = {Jannati, A and Thompson, K and Toro-Serey, C and Gomes-Osman, J and Banks, RE and Higgins, C and Showalter, J and Bates, D and Tobyne, S and Pascual-Leone, A},
title = {Concurrent detection of cognitive impairment and amyloid positivity with a multimodal machine learning-enabled digital cognitive assessment.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {261},
pmid = {41382170},
issn = {1758-9193},
mesh = {Humans ; *Machine Learning ; *Cognitive Dysfunction/diagnosis/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Aged ; Neuropsychological Tests ; *Alzheimer Disease/diagnosis ; Biomarkers/blood ; Aged, 80 and over ; tau Proteins/metabolism ; Brain/metabolism/diagnostic imaging ; Middle Aged ; },
abstract = {BACKGROUND: Early identification of cognitive impairment and brain pathology associated with Alzheimer's disease (AD) is essential to maximize benefits from lifestyle interventions and emerging pharmacologic disease-modifying treatments (DMT). Digital cognitive assessments (DCAs) can quickly capture an array of metrics that can be used to train machine-learning (ML) models to concurrently evaluate different outcomes. DCAs have the potential to optimize clinical workflows and enable efficient assessment of cognitive function and the likelihood of a given underlying pathology.

METHODS: We assessed the ability of a multimodal ML-enabled DCA, the Digital Clock and Recall (DCR), to concurrently estimate brain amyloid-beta (Aβ) status and detect cognitive impairment, as compared with traditional cognitive assessments, including the MMSE, RAVLT, a DCA, Cognivue[®], and blood-based biomarkers in 930 participants from the Bio-Hermes-001 clinical study.

RESULTS: Aβ42/40, p-tau181, APS, and p-tau217 poorly classified cognitive impairment (AUCs: 0.61; 0.63; 0.63; 0.70, respectively), but accurately classified Aβ status (AUCs: 0.81; 0.78; 0.85, 0.89, respectively). MMSE, RAVLT, and Cognivue poorly classified Aβ status (AUCs: 0.70, 0.73, 0.70, respectively). However, separate multimodal, DCR-based ML classification models, run in parallel, accurately classified both cognitive impairment (AUC = 0.83) and Aβ-PET status (AUC = 0.81).

CONCLUSIONS: DCAs that leverage digital technologies to generate advanced metrics, such as the DCR, enable accurate and efficient detection of cognitive impairment associated with AD pathology. They have the potential to empower health systems and primary care providers to help their patients make timely treatment decisions.},
}

Humans
*Machine Learning
*Cognitive Dysfunction/diagnosis/metabolism
*Amyloid beta-Peptides/metabolism
Male
Female
Aged
Neuropsychological Tests
*Alzheimer Disease/diagnosis
Biomarkers/blood
Aged, 80 and over
tau Proteins/metabolism
Brain/metabolism/diagnostic imaging
Middle Aged

@article {pmid41381974,
year = {2025},
author = {Kim, NJ and Mishra, A and Chowdhury, NF and Anderson, SD and Vega, OM and Chaudhari, NN and Buetow, KH and Thompson, PM and Irimia, A},
title = {Deep neural networks and genome-wide associations reveal the polygenic architecture of local brain aging.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41381974},
issn = {2509-2723},
support = {R01 AG 079957/AG/NIA NIH HHS/United States ; },
abstract = {Local brain age (LBA) is a regional metric of brain aging that offers a spatially resolved alternative to global brain age, but whose genetic basis is unexplored. This study reports the first genome-wide association study of cortical LBA, as estimated by a deep neural network from the T1-weighted magnetic resonance images of 41,708 cognitively normal adults in the UK Biobank. We identified 1,212 single-nucleotide polymorphisms (SNPs) significantly associated with LBA in at least one brain region. Genes mapped to these SNPs are involved in developmental, metabolic, immune, and cytoskeletal pathways. Dimensionality reduction of SNP association profiles uncovered three clusters linked to morphogenetic, cytoskeletal, and immuno-epigenetic processes, helping to relate neuroanatomic, immunosenescent and epigenetic mechanisms of brain aging. Top variants are mapped to KCNK2, NUAK1, GMNC, MSL2, and to other genes implicated in neurodevelopment and neurodegeneration. Spatial clustering of LBA-associated variants in default mode, limbic, and motor network regions parallel regional vulnerability to Alzheimer's disease and frontotemporal dementia. These findings establish a polygenic architecture for regional brain aging and support LBA as a genetically informed phenotype for studying aging-related neurodegeneration. Our results suggest that cortical aging is not governed by isolated loci but by coordinated genetic programs-rooted in development, metabolism, and cellular structure-that confer lifelong patterns of regional brain vulnerability and resilience. This first genetic dissection of spatially specific brain aging reveals a polygenic landscape of coordinated genetic programs, developmentally encoded and metabolically maintained during senescence. This study reframes aging as an anatomically specific genetic process reflecting the varying structural vulnerabilities observed across neurodegenerative diseases.},
}

@article {pmid41381867,
year = {2025},
author = {Yao, XQ and Jiao, SS and Saadipour, K and Zeng, F and Wang, QH and Zhu, C and Shen, LL and Zeng, GH and Liang, CR and Wang, J and Liu, YH and Hou, HY and Xu, X and Su, YP and Fan, XT and Xiao, HL and Lue, LF and Zeng, YQ and Giunta, B and Zhong, JH and Walker, DG and Zhou, HD and Tan, J and Zhou, XF and Wang, YJ},
title = {Correction: p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41380-025-03375-5},
pmid = {41381867},
issn = {1476-5578},
}

@article {pmid41381752,
year = {2025},
author = {Tang, Y and Nishimura, Y and Li, N and Li, H and Salimi, A and Ishida, K and Sakti, AW and Nakai, H and Parida, R and Lee, JY},
title = {Insights into proton transfer dynamics in histidine tautomers of amyloid-β (1-40).},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-025-01790-x},
pmid = {41381752},
issn = {2399-3669},
support = {2022R1A2C1092044//National Research Foundation of Korea (NRF)/ ; },
abstract = {Histidine tautomerization within amyloid beta (Aβ) peptides is crucial in understanding the molecular mechanisms underlying Alzheimer's disease and its potential therapeutic strategies. Despite its significance, the proton transfer dynamics between histidine residues in Aβ-40 at the protein level remain insufficiently explored due to the complexity of solvent effects and the computational challenges of large-scale simulations. This study conducted fully quantum mechanical molecular dynamics (QM-MD) simulations coupled with metadynamics (MTD) to investigate the tautomerization process between histidine tautomers in Aβ-40 within an aqueous environment. Using the divide-and-conquer density-functional tight-binding (DC-DFTB) method, a system of ~3000 atoms was modeled to capture the atomic-scale interactions. MTD simulations revealed that water molecules mediate the tautomerization of histidine residues, HIS 13 and HIS 14, stabilizing specific tautomeric forms. The two-dimensional well-tempered MTD (2D WTMTD) results identified a reaction barrier of approximately 3.51 kcal mol[-1] for tautomerization. This study represents the first comprehensive QM-MD/MTD investigation of histidine tautomerization in amyloid beta peptides, offering insights into the tautomerization process.},
}

@article {pmid41381656,
year = {2025},
author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR},
title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30121-2},
pmid = {41381656},
issn = {2045-2322},
support = {BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; },
abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.},
}

@article {pmid41381599,
year = {2025},
author = {Yun, J and Chun, MY and Zetterberg, H and Blennow, K and Gonzalez-Ortiz, F and Ashton, NJ and Shin, D and Yoon, S and Yoo, H and Kim, JP and Ham, H and Gu, Y and Kim, HJ and Moon, SH and Cho, H and Choi, JY and Byun, BH and Park, SY and Ha, JH and Na, DL and Seo, SW and Jang, H},
title = {Integrative analysis of AT classification, plasma biomarkers, and cognitive trajectories across diverse dementia syndromes.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30117-y},
pmid = {41381599},
issn = {2045-2322},
support = {#2023-00356//the Swedish Research Council/ ; #2017-00915//the Swedish Research Council/ ; No. 101053962//the European Union's Horizon Europe research and innovation program/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//the Alzheimer Drug Discovery Foundation (ADDF), USA/ ; #ADSF-21-831376-C//the AD Strategic Fund and the Alzheimer's Association/ ; #FO2022-0270//the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, the Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; No. 860197//the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie/ ; JPND2021-00694//the European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL/ ; #AF-930351//the Swedish Alzheimer Foundation/ ; #FO2017-0243//Hjärnfonden, Sweden/ ; #ALFGBG-715986//the Swedish state under the agreement between the Swedish government and the County Councils/ ; JPND2019-466-236//the European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//the Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//the Alzheimer's Association 2022-2025 Grant/ ; RS-2020-KH106434//the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2020-KH107436//the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; #SMX1250081//Future Medicine 20*30 Project of the Samsung Medical Center/ ; 2024-ER1003-01//the "Korea National Institute of Health" research project/ ; RS-2019-NR040057//the Korea government (MSIT)/ ; RS-2025-02223212//the Ministry of Health & Welfare, Republic of Korea/ ; RS-2022-KH125667//the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea/ ; },
abstract = {This study aimed to examine amyloid-β (Aβ) and tau (AT) biological stages, plasma biomarkers, and cognitive trajectories according to AT stages in Alzheimer's disease-related cognitive impairment (ADCI), subcortical vascular cognitive impairment (SVCI), and frontotemporal dementia (FTD). A total of 275 participants (42 cognitively unimpaired [CU], 132 ADCI, 73 SVCI, and 28 FTD) underwent Aβ and tau positron emission tomography for assessment of AT stages. Participants with cognitive impairment (ADCI, SVCI, and FTD) were classified according to clinical stages of mild cognitive impairment or dementia. Plasma biomarkers were analysed, and cognitive trajectories were assessed using mixed-effects models over 6.1 years. SVCI and FTD showed more advanced clinical stages than ADCI at equivalent AT stages. SVCI participants had higher plasma glial fibrillary acidic protein (P = 0.012) and neurofilament light chain (P = 0.025) than CU participants in the A - T- stage. In the A - T- stage, SVCI (β = -0.738, P = 0.002) and FTD (β = -4.016, P < 0.001) showed faster cognitive decline than CU, but not ADCI. In the A + T - stage, ADCI (β = -0.634, P = 0.005) and SVCI (β = -0.690, P = 0.006) showed faster decline than CU. In the A + T + stage, only ADCI exhibited significantly faster decline than CU (β = -1.856, P = 0.008). Distinct plasma biomarker profiles and cognitive trajectories characterise ADCI, SVCI, and FTD across AT classification, highlighting the heterogeneity in pathophysiological mechanisms across dementia types.},
}

@article {pmid41381446,
year = {2025},
author = {Malakhov, MM and Pan, W},
title = {Co-expression-wide association studies link genetically regulated interactions with complex traits.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {11061},
pmid = {41381446},
issn = {2041-1723},
support = {R01 AG065636/AG/NIA NIH HHS/United States ; RF1 AG067924/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Genome-Wide Association Study/methods ; Alzheimer Disease/genetics/blood ; Parkinson Disease/genetics/blood ; *Multifactorial Inheritance/genetics ; Proteomics/methods ; Transcriptome/genetics ; Cholesterol/blood ; Proteome/genetics ; *Gene Expression Regulation ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Genetic Predisposition to Disease ; Male ; },
abstract = {Transcriptome- and proteome-wide association studies (TWAS/PWAS) have proven successful in prioritizing genes and proteins whose genetically regulated expression modulates disease risk, but they ignore potential co-expression and interaction effects. To address this limitation, we introduce the co-expression-wide association study (COWAS) method, which can identify pairs of genes or proteins whose genetically regulated co-expression is associated with complex traits. COWAS first trains models to predict expression and co-expression from genetic variation, and then tests for association between imputed co-expression and the trait of interest while also accounting for direct effects from each exposure. We applied our method to plasma proteomic concentrations from the UK Biobank, identifying dozens of interacting protein pairs associated with cholesterol levels, Alzheimer's disease, and Parkinson's disease. Notably, our results demonstrate that co-expression between proteins may affect complex traits even if neither protein is detected to influence the trait when considered on its own. We also show how COWAS can help to disentangle direct and interaction effects, providing a richer picture of the molecular networks that mediate genetic effects on disease outcomes.},
}

Humans
*Genome-Wide Association Study/methods
Alzheimer Disease/genetics/blood
Parkinson Disease/genetics/blood
*Multifactorial Inheritance/genetics
Proteomics/methods
Transcriptome/genetics
Cholesterol/blood
Proteome/genetics
*Gene Expression Regulation
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Genetic Predisposition to Disease
Male

@article {pmid41381439,
year = {2025},
author = {Ang, S and Zhang, X and Hong, J and Xue, K and Li, J and Du, X and Gao, Y and Wang, X and Li, X and Chen, B and Li, Y and Zhang, J and Liu, S},
title = {The safety and efficacy of gamma frequency auditory and visual stimulation in the treatment of alzheimer's disease: a systematic review and meta-analysis.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {523},
pmid = {41381439},
issn = {2158-3188},
support = {82271546//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2025-ZZ-004//National Clinical Key Specialty Construction Program - Independent Research Project/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and significant global health burden. Current treatments offer limited benefits, highlighting the need for novel therapies. Gamma-frequency auditory and visual stimulation (GFAVS), utilizing 40 Hz neuromodulation, has gained attention as a non-invasive treatment for cognitive deficits and underlying pathophysiology in AD.

OBJECTIVE: This systematic review and meta-analysis aimed to assess the safety and efficacy of GFAVS in treating Alzheimer's disease (AD) and mild cognitive impairment (MCI).

METHODS: A comprehensive literature search across multiple databases (PubMed, Cochrane Library, MEDLINE, Web of Science, and Embase) was performed up to November 2025. Controlled trials involving adults (≥50 years) with AD or MCI, using GFAVS, were included. Meta-analyses assessed adverse events, cognitive function, and brain changes.

RESULTS: Eleven studies (341 participants) were included. GFAVS was safe, with no significant increase in overall adverse events (RR = 0.99, P = 0.93; RD = -0.01, P = 0.93). However, GFAVS significantly increased the risk of tinnitus (RR = 6.46, P = 0.08; RD = 0.16, P = 0.01). GFAVS significantly improved structural brain changes (SMD = 1.74, P = 0.02), especially in mixed AD and MCI populations (SMD = 3.05, P < 0.00001). Nevertheless, no significant improvements were observed in cognitive function (SMD = 0.16, 95% CI [-0.36 to 0.68], P = 0.55) or activities of daily living (SMD = 0.53, 95% CI [-1.26 to 2.33], P = 0.56), despite the observed structural brain changes. High heterogeneity was observed.

CONCLUSION: GFAVS appears to be well tolerated and may induce structural brain alterations in individuals with Alzheimer's disease or mild cognitive impairment; however, its impact on cognition or daily functioning remains to be established. Large-scale, rigorously designed trials are required to clarify optimal protocols and address the observed heterogeneity.},
}

@article {pmid41381239,
year = {2025},
author = {van den Broek, SL and Bratteby, K and Aguilar, X and Tran, TA and Syvänen, S and Sehlin, D},
title = {Radionuclide Selection Influences Imaging Outcomes in Immuno-PET with a Brain-Penetrating Anti-Amyloid-β Antibody.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271194},
pmid = {41381239},
issn = {1535-5667},
abstract = {Bispecific antibodies exploiting receptor-mediated transcytosis offer a promising strategy to overcome limited blood-brain barrier permeability in Alzheimer disease immunotherapy and imaging. Lecanemab-Fab8D3 (Lec-Fab8D3), a bispecific amyloid-β (Aβ) antibody with enhanced brain delivery, may complement lecanemab immunotherapy as an immuno-PET imaging agent. Here, we systematically assess how the choice of radionuclide affects PET detection of Lec-Fab8D3 within the brain to evaluate its potential as a companion diagnostic. Methods: Lec-Fab8D3 was conjugated to an octadentate derivative of desferrioxamine (DFO*) or NODAGA for [89]Zr and [64]Cu radiolabeling, respectively, or directly radioiodinated with [124]I. PET imaging was performed in the Tg-ArcSwe Aβ mouse model and wild-type (WT) littermates at multiple time points after radiotracer administration, followed by biodistribution, autoradiography, and Aβ quantification to assess brain uptake, specificity, and distribution. Results: PET imaging demonstrated high cortical brain uptake of all 3 radiotracers in Tg-ArcSwe mice. Labeling with the metals [89]Zr and [64]Cu produced the highest overall brain signal in both Tg-ArcSwe and WT mice. [[89]Zr]Zr-DFO*-Lec-Fab8D3 and [[124]I]I-Lec-Fab8D3 demonstrated the greatest discrimination between Tg-ArcSwe and WT mice, with [[124]I]I-Lec-Fab8D3 exhibiting the most pronounced regional differences. Ex vivo analyses corroborated the PET findings, and immunostaining confirmed radiotracer colocalization with Aβ deposits. Conclusion: Immuno-PET imaging with radiolabeled Lec-Fab8D3 enables specific detection of brain Aβ pathology. Because of its residualizing properties, [89]Zr produced the highest overall signal, whereas [124]I yielded greater regional contrast, despite lower total brain signal. These findings enhance our understanding of the intrabrain distribution of bispecific antibodies and highlight the importance of radionuclide selection and its impact on immuno-PET outcomes.},
}

@article {pmid41381091,
year = {2025},
author = {Shi, Q and Zhan, D and Wang, W and Wu, X and Sheng, S and Wang, Y},
title = {Causal associations between cognitive impairments and retinal diseases: A two-sample Mendelian randomization study.},
journal = {The Journal of international medical research},
volume = {53},
number = {12},
pages = {3000605251404265},
doi = {10.1177/03000605251404265},
pmid = {41381091},
issn = {1473-2300},
mesh = {Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Retinal Diseases/genetics/complications ; *Alzheimer Disease/genetics ; *Cognitive Dysfunction/genetics ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Macular Degeneration/genetics ; Dementia, Vascular/genetics ; *Lewy Body Disease/genetics ; },
abstract = {ObjectiveThis study employed a bidirectional two-sample Mendelian randomization approach to investigate the causal links between Alzheimer's disease, Lewy body dementia, vascular dementia, and various retinal diseases.MethodsSummary data from large-scale genome-wide association studies of European ancestry were used to select genetic variants as instrumental variables. Causal estimates were derived using the inverse variance-weighted method, complemented by Mendelian randomization-Egger, weighted median, and weighted mode analyses to ensure robustness.ResultsGenetically predicted Alzheimer's disease was associated with a reduced risk of disorders of the choroid and retina (odds ratio = 0.93, 95% confidence interval: 0.88-0.98), retinal detachments and breaks (odds ratio = 0.90, 95% confidence interval: 0.84-0.97), and retinal detachment with retinal break (odds ratio = 0.84, 95% confidence interval: 0.74-0.95). Lewy body dementia was negatively associated with age-related macular degeneration (odds ratio = 0.88, 95% confidence interval: 0.79-0.98), disorders of the choroid and retina (odds ratio = 0.96, 95% confidence interval: 0.93-0.99), and degeneration of the macula (odds ratio = 0.93, 95% confidence interval: 0.88-0.98). Vascular dementia showed negative associations with age-related macular degeneration (odds ratio = 0.93, 95% confidence interval: 0.87-0.99) and degeneration of the macula (odds ratio = 0.96, 95% confidence interval: 0.93-0.99). Conversely, reverse Mendelian randomization indicated that genetic liability to macular degeneration and choroidal/retinal disorders was causally associated with cognitive performance and a reduced risk of Alzheimer's disease.ConclusionsFindings support inverse causal relationships in which specific dementias may reduce retinal disease risk and vice versa, suggesting complex shared biological mechanisms.},
}

Humans
*Mendelian Randomization Analysis
Genome-Wide Association Study
*Retinal Diseases/genetics/complications
*Alzheimer Disease/genetics
*Cognitive Dysfunction/genetics
Polymorphism, Single Nucleotide
Genetic Predisposition to Disease
Macular Degeneration/genetics
Dementia, Vascular/genetics
*Lewy Body Disease/genetics

@article {pmid41380794,
year = {2025},
author = {Robinson-Cooper, L and Davidson, S and Koutoubi, R and Zhang, K and Park, H and Barker-Haliski, M},
title = {Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115586},
doi = {10.1016/j.expneurol.2025.115586},
pmid = {41380794},
issn = {1090-2430},
abstract = {Presenilin 2 (PSEN2) variants increase risk of Alzheimer's disease (AD) and unprovoked seizures. Yet, age-related PSEN2 contributions to seizure susceptibility are understudied. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptor (KARs) availability. Kainic acid (KA) is a KAR agonist that evokes severe seizures in mice. We hypothesized that PSEN2 knockout (KO) mice would show reduced latency to KA-induced seizures, increased seizure burden, worsened 7-day survival, and altered hippocampal KAR expression compared to wild-type (WT) controls. Using repeated low-dose systemic KA administration to 3-4- and 12-15-month-old PSEN2 KO versus WT mice, we quantified acute seizure latency and neuropathology. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes 7 days after seizures or sham to assess the impact of PSEN2 loss and seizures on hippocampal KARs. Young PSEN2 KO mice were more seizure-prone than WTs, while genotype did not change latency to first seizure. Aged females seized faster than young females and experienced greater mortality, unlike males. There was no difference in KAR subunit expression between young mouse genotypes and regardless of seizure history. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 after seizures, however, astrocytic GluK2 upregulation only occurred in WTs. GluK5 expression was significantly reduced in aged seizure-naïve PSEN2 KO versus WT mice, while total GluK2 expression did not differ. Seizure-induced astrocytic GluK5 expression only occurred in WT mice in CA3, while astrocytic GluK2 expression occurred in both. Thus, PSEN2 loss may impair age-related hippocampal KAR expression, implicating KARs as understudied contributors to AD-related seizures.},
}

@article {pmid41380753,
year = {2025},
author = {Ding, H and Wu, S and Huang, D and Shan, L},
title = {Astrocyte regulates neuroinflammation and myelination in BCCAO-Related cognitive impairment via the PIAS1-STAT1 pathway.},
journal = {Brain research},
volume = {},
number = {},
pages = {150107},
doi = {10.1016/j.brainres.2025.150107},
pmid = {41380753},
issn = {1872-6240},
abstract = {Vascular dementia (VaD) ranks as the second most common form of cognitive impairment worldwide, surpassed only by Alzheimer's disease (AD), yet its pathophysiological mechanisms are still not fully understood. This study sought to explore the mechanisms underlying secondary cognitive decline after transient cerebral ischemia, employing a temporary bilateral common carotid artery occlusion (BCCAO) model to mimic clinical cerebral ischemia-reperfusion (I/R) conditions. Dynamic detection of model mice revealed no significant loss of hippocampal neurons after surgery. Nevertheless, at 12 weeks post-surgery, the mice exhibited obvious myelin loss accompanied by cognitive decline. Further intervention studies showed that the microglial depleter PLX5622 failed to effectively rescue myelin damage and cognitive impairment, while astrocytes remained persistently activated. Analysis of the differential expression profile of astrocytes from a VaD patient brain tissue database identified Protein Inhibitor of Activated STAT1 (PIAS1) as a key regulator, which was significantly downregulated in the astrocytes of VaD patients-this finding was validated in model mice. Behavioral assessments revealed that targeted overexpression of PIAS1 in astrocytes, achieved through adeno-associated viral (AAV) delivery, markedly ameliorated cognitive deficits, attenuated myelin injury, and suppressed astrocytic inflammatory responses. In parallel, in vitro studies using primary astrocyte cultures demonstrated that PIAS1 exerts its anti-inflammatory effects by modulating the signal transducer and activator of transcription 1 (STAT1) signaling pathway. In summary, the findings of this study demonstrate that reduced expression of PIAS1 in astrocytes following mild cerebral ischemia plays a crucial role in triggering secondary cognitive deficits and myelin degeneration. Furthermore, PIAS1 regulates astrocyte-mediated inflammatory responses via a STAT1-dependent pathway, offering new perspectives on the underlying mechanisms of VaD and potential therapeutic interventions.},
}

@article {pmid41380294,
year = {2025},
author = {Cacciamani, F and Houot, M and Tezenas du Montcel, S and Thibeau-Sutre, E and Vannini, P and Migliaccio, RL},
title = {Multimodal neural correlates of cognitive awareness in aging and Alzheimer's disease.},
journal = {NeuroImage. Clinical},
volume = {49},
number = {},
pages = {103922},
doi = {10.1016/j.nicl.2025.103922},
pmid = {41380294},
issn = {2213-1582},
abstract = {Impaired cognitive awareness-anosognosia-is a core symptom of Alzheimer's disease (AD), yet its neural correlates remain poorly defined. This study examined how cognitive awareness, measured both cross-sectionally and longitudinally via subject-informant discrepancy on the Everyday Cognition (ECog) questionnaire, relates to three AD biomarkers: amyloid burden, glucose hypometabolism, and cortical atrophy. We included 785 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), spanning cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia. All biomarkers were assessed at baseline across the same 86 cortical regions, enabling anatomically harmonized, cross-modality comparisons. Linear mixed models incorporating all three biomarkers revealed no significant associations in CN. In MCI, declining awareness was associated with widespread cortical amyloid deposition (significant in 80/86 regions), sparing some limbic areas. Atrophy in 11 regions-including limbic, lateral temporal, and occipital cortices-also predicted awareness decline (all p < 0.044). In AD, no significant associations were found between amyloid and awareness, suggesting a plateau effect at advanced stages. In both MCI and AD, lower baseline glucose metabolism in the left posterior cingulate cortex (PCC) was associated with poorer awareness (MCI: β ± SE = - 0.14 ± 0.04, p = 0.006; AD: β ± SE = - 0.24 ± 0.07, p = 0.042). No significant biomarker-time interactions were found in AD, suggesting relatively stable awareness levels at advanced disease stages. These findings indicate that anosognosia in AD is linked to distinct biomarker and regional profiles that vary by disease phase. Multimodal analysis across harmonized regions reveals the left PCC as a robust metabolic correlate of awareness, underscoring its potential as a key target in understanding and monitoring self-awareness impairment in neurodegenerative disease.},
}

@article {pmid41380234,
year = {2025},
author = {Zhu, X and Wang, Z and Tang, Q and Shi, L and Li, B and Jin, Y},
title = {Self-assembled DNA micelle-GNP for simultaneous detecting miRNAs of Alzheimer's disease via lateral flow assays.},
journal = {Biosensors & bioelectronics},
volume = {295},
number = {},
pages = {118300},
doi = {10.1016/j.bios.2025.118300},
pmid = {41380234},
issn = {1873-4235},
abstract = {Alzheimer's disease (AD), a leading age-related neurodegenerative disorder, causes severe memory loss and cognitive impairment. Although no definitive cure currently exists, early diagnosis and continuous monitoring can help slow disease progression. Herein, we developed a lateral flow assay (LFA) for portable and sensitive detection of AD-related miRNA. DNA micelles (DM) were first designed to carry more gold nanoparticle (GNP) for improving the sensitivity of visual assay. Three types of DM-GNP probes were constructed for simultaneous detection of miR-34a, miR-125b, and miR-15a. These target miRNAs were visually identified within 20 min, with detection limits of 25 pM, 50 pM, and 10 pM, respectively. Importantly, the LFA enabled multiplexed miRNA detection without cross-interference. Importantly, the LFA platform enabled multiplexed miRNA detection without cross-interference. Therefore, the DM-GNP probe provides a sensitive and practical tool for LFA-based biosensing, offering a cost-effective, specific, and portable strategy for detecting AD-related miRNAs and other biomarkers.},
}

@article {pmid41379977,
year = {2025},
author = {},
title = {Erratum for the Report "Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice" by A. Ittner et al.},
journal = {Science (New York, N.Y.)},
volume = {390},
number = {6778},
pages = {eaee4634},
doi = {10.1126/science.aee4634},
pmid = {41379977},
issn = {1095-9203},
}

@article {pmid41379906,
year = {2025},
author = {Zhang, L and Li, L and Cao, P and Yang, J and Zaiane, OR and Wang, F},
title = {An Efficient Transfer Learning With Prompt Learning for Brain Disorders Diagnosis.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3625375},
pmid = {41379906},
issn = {2168-2208},
abstract = {The limited availability of training data significantly restricts the performance of deep supervised models for brain disease diagnosis. It is crucial to develop a learning framework through cross-disease transfer learning that can extract more information from the limited data. To address this challenge, we concentrate on prompt learning and endeavor to extend its application to the brain networks. Specifically, we propose a novel prompt learning framework called BPformer, which integrates knowledge transferred across diseases via specific prompts while keeping the original architecture of BPformer unchanged. The specific prompts incorporate 1) a mask prompt to determine whether the edges are noisy or discriminating, 2) disorder prompts for modeling consistent and disorder-specific knowledge, and 3) adaptive instance-level prompts to account for inter-individual variations. We evaluate BPformer on the private center Nanjing Medical University dataset, the public Autism Brain Imaging Data Exchange dataset, and the public Alzheimer's Disease Neuroimaging Initiative dataset. We demonstrate the effectiveness of the proposed model across various disease classification tasks, including major depressive disorder, bipolar disorder, alzheimer's disease, and autism spectrum disorder diagnoses. In addition, the proposed method enables disease interpretability and subtype analysis, empowering physicians to provide patients with more accurate and fine-grained treatment plans.},
}

@article {pmid41379854,
year = {2025},
author = {Shehadeh, A and Malak, MZ and Harazni, L and Mousa, FA},
title = {Spiritual Coping Among Palestinian Muslim Family Caregivers of People With Dementia: A Qualitative Study.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012251408700},
doi = {10.1177/14713012251408700},
pmid = {41379854},
issn = {1741-2684},
abstract = {Caring for a family member with dementia is highly challenging. Many family caregivers rely on spirituality and religion to cope, particularly in Palestine, where health and social support services are severely limited. This study aimed to explore how spirituality is used by Muslim family caregivers of people with dementia in Palestine. A qualitative exploratory design was employed. Semi-structured in-depth interviews were conducted with a convenience sample of 21 participants from January to March 2025. Data were analyzed using content analysis. Participants had a mean age of 47.4 (±5.8) years, were all adult children of their care recipients, and were predominantly female (90.5%). The analysis revealed several interconnected spiritual coping strategies, categorized into four major themes: "blessing in disguise", focusing on the afterlife, stoicism, and intermissions. Spirituality is vital for supporting Muslim family caregivers of people with dementia. The findings can inform the development of high-quality, tailored, and culturally sensitive spiritual care interventions.},
}

@article {pmid41379750,
year = {2025},
author = {Soncini, C and Chiari, A and Rothman, KJ and Martini, N and Cherubini, A and Despini, F and Costanzini, S and De Girolamo, G and Tondelli, M and Vinceti, G and Zamboni, G and Teggi, S and Maffeis, G and Vinceti, M and Filippini, T},
title = {Environmental factors and risk of early-onset dementia: a population-based case-control study.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-22},
doi = {10.1159/000549445},
pmid = {41379750},
issn = {1423-0208},
abstract = {INTRODUCTION: Dementia with symptom onset before the age of 65 is referred to as early-onset dementia (EOD). Many gaps exist regarding EOD etiology, including the role of environmental factors.

METHODS: We conducted a population-based case-control study in Modena province, Northern Italy, enrolling and geocoding 326 EOD cases and 1941 sex- and age-matched controls, to investigate the association of traffic-related benzene, green spaces around the place of residence, and exposure to artificial outdoor light at night. We used non-linear modeling to assess the relation between environmental variables and disease risk, overall and separately for Alzheimer's dementia (AD) and non-AD.

RESULTS: Green spaces generally showed an inverse association with EOD risk that was almost linear for AD and inverted U-shaped for non-AD. We observed a weak positive association between traffic-related benzene exposure and EOD risk that seemed limited to AD, with little change in risk for non-AD. Exposure to light at night showed an inverse linear association with small differences across the two disease subgroups. Analyses stratified by sex and age showed generally stronger (but statistically imprecise) associations in females and older individuals.

CONCLUSION: Overall, these results are consistent with some environmental influences on EOD risk, particularly with a beneficial effect of green spaces and light at night, as well as a possible adverse role of air pollution, particularly for AD.},
}

@article {pmid41379747,
year = {2025},
author = {Hoang, MT and Le, NT and Thi Hoai Nguyen, T and Nguyen, TD and Nguyen, TX and Ngoc Nguyen, A and Kim Dang, T and Thanh Nguyen, B and Thi Thanh Nguyen, H and Pham, T and Nguyen, AT and Nguyen, TA and Vu, HTT},
title = {Polypharmacy following dementia diagnoses in Vietnam: results from real-world data in outpatient settings.},
journal = {Gerontology},
volume = {},
number = {},
pages = {1-20},
doi = {10.1159/000550017},
pmid = {41379747},
issn = {1423-0003},
abstract = {INTRODUCTION: Polypharmacy might be clinically appropriate if it improves health outcomes of people with dementia. However, polypharmacy was associated with higher risks of impairment in cognitive, physical, and emotional abilities. Several studies on polypharmacy among people with dementia were performed globally, but not in Vietnam. This study aimed to investigate the epidemiology of polypharmacy among people with dementia in Vietnam.

METHODS: This retrospective cohort study included outpatient individuals who were diagnosed with dementia between 01 January 2023 and 15 April 2024 in the Vietnam National Geriatric Hospital. Data was extracted from medical records, including dementia diagnosis, drug utilization, medical history before dementia diagnosis, comorbidities, and sociodemographic. The monthly quantity of drugs used was categorized as 'no polypharmacy' 0-4 drugs, 'polypharmacy' ≥5 drugs, and 'hyperpolypharmacy' ≥10 drugs. The primary outcome was the incidence of polypharmacy following dementia diagnosis. The prescription of potentially inappropriate medications in people with dementia, identified by using the American Geriatrics Society Beers criteria, was also evaluated. Multivariable logistic regression was employed to find associated risk factors of polypharmacy.

RESULTS: During the follow-up from dementia diagnosis to 30 June 2024, there were 64 people having polypharmacy (median age at dementia diagnosis 73.5, 68.8% females) and 342 people without polypharmacy (median age at dementia diagnosis 74.0, 64.0% females). Age at dementia diagnosis, sex, regions of residence and education were not associated with having polypharmacy in people with dementia. Compared to people with Alzheimer's disease, significantly higher probabilities of having polypharmacy were seen in people with vascular dementia (odds ratio (OR) 4.63, 95% confidence interval (CI) 2.16 - 9.92), and other dementias (OR 4.61, 95% CI 2.31 - 9.18). People with dementia at severe stage were at lower chance of having polypharmacy (OR 0.19, 95% CI 0.05 - 0.63). Potentially inappropriate medications were more frequent in the polypharmacy group (n = 27, 42.2%), compared to the non-polypharmacy group (n = 59, 17.3%). Prescribing antipsychotics in the polypharmacy group doubled that in the non-polypharmacy group (34.4% versus. 16.1%).

DISCUSSION/CONCLUSION: Lower incidence of polypharmacy among people with dementia compared to previous studies might either imply the improvement in managing the prescription of potentially inappropriate medications or be underestimated by not including inpatient individuals. Future studies are necessary to clarify the impact of polypharmacy on health outcomes of people with dementia.},
}

@article {pmid41379647,
year = {2025},
author = {Xu, J and Bai, L and Wang, T and Yi, Z and Han, H and Dong, P},
title = {Combining Retip Retention Time Prediction with High-Resolution Mass Spectrometry: A Systematic Analysis of Schisandra chinensis-Evodia Conducted for the First Time.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c05620},
pmid = {41379647},
issn = {1520-6882},
abstract = {Schisandra chinensis-Evodia Herbal Pair (SEHP) is one of the classic Chinese herbal formulas for treating Alzheimer's disease (AD), but its complex chemical composition renders traditional analytical methods inefficient. Retention time (RT) provides complementary information to mass spectrometry, supporting qualitative identification. To enhance identification accuracy and efficiency, this study pioneered the integration of Retip retention time prediction with five machine learning models (Random Forest, BRNN, XGBoost, LightGBM, and Keras) for the systematic identification of SEHP chemical constituents. Using UPLC-Q-Exactive Orbitrap MS technology combined with MS-DIAL and Compound Discoverer software, 165 compounds were identified, including alkaloids, organic acids, and lignans. The LightGBM model achieved high-precision RT prediction within a ±1 min tolerance, significantly reducing false positive identification rates. Through in vivo experiments, 56 parent compounds and 281 metabolites were identified in plasma, urine, feces, liver, and brain tissues of 3xTg-AD mice, revealing their Phase I and II metabolic characteristics. Network pharmacology and molecular docking analysis suggested that SEHP may exert anti-AD effects by regulating key targets such as TNF, AKT1, STAT3, and inflammation-related pathways, including PI3K and MAPK. This study established an efficient and reliable strategy for identifying Chinese herbal medicine components and analyzing their in vivo metabolism, providing scientific evidence for the pharmacodynamic basis and mechanism of action of SEHP.},
}

@article {pmid41379535,
year = {2025},
author = {Jayakody, O and Ceïde, M and Verghese, J and Carrera, R and Doriwala, H and Agrawal, S and Pa, J and Blumen, H},
title = {Feasibility of a Virtual Reality Intervention Protocol to Improve Cognitive and Behavioral Skills in Older Adults at Increased Risk of Developing Dementia.},
journal = {JMIR formative research},
volume = {9},
number = {},
pages = {e77111},
doi = {10.2196/77111},
pmid = {41379535},
issn = {2561-326X},
mesh = {Humans ; *Dementia/prevention & control ; Feasibility Studies ; Aged ; Pilot Projects ; *Virtual Reality ; Female ; Male ; *Cognition ; Aged, 80 and over ; },
abstract = {This pilot study offers preliminary evidence that a virtual meal-preparation task is feasible for older adults and highlights that the community engagement studios are an effective approach to generate community-informed strategies to enhance intervention designs and reach.},
}

Humans
*Dementia/prevention & control
Feasibility Studies
Aged
Pilot Projects
*Virtual Reality
Female
Male
*Cognition
Aged, 80 and over

@article {pmid41379352,
year = {2025},
author = {Mohanty, R and Wheatley, S and Chiotis, K and Marseglia, A and Westman, E and , },
title = {Distinct cerebrovascular pathways underlying Alzheimer's disease-related neurodegeneration.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {64},
pmid = {41379352},
issn = {1432-0533},
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/complications ; Female ; Male ; Aged, 80 and over ; Aged ; *Brain/pathology/diagnostic imaging ; *Cerebrovascular Disorders/pathology/diagnostic imaging ; White Matter/pathology ; Cerebrovascular Circulation/physiology ; Neuroimaging ; Cerebral Amyloid Angiopathy/pathology ; Arteriolosclerosis/pathology ; },
abstract = {The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer's disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = - 20, 95% CI - 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < - 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = - 0.2, 95% CI - 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/complications
Female
Male
Aged, 80 and over
Aged
*Brain/pathology/diagnostic imaging
*Cerebrovascular Disorders/pathology/diagnostic imaging
White Matter/pathology
Cerebrovascular Circulation/physiology
Neuroimaging
Cerebral Amyloid Angiopathy/pathology
Arteriolosclerosis/pathology

@article {pmid41379271,
year = {2025},
author = {Hein, ZM and Karikalan, B and Gopalakrishna, PK and Dhevi, K and Alkatiri, A and Hussan, F and Mohd Moklas, MA and Jagadeesan, S and Che Ramli, MD and Che Mohd Nassir, CMN and Vishnumukkala, T},
title = {Toward a Unified Framework in Molecular Neurobiology of Alzheimer's Disease: Revisiting the Pathophysiological Hypotheses.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {282},
pmid = {41379271},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/physiopathology/pathology/genetics/metabolism ; Animals ; *Neurobiology ; },
abstract = {Despite decades of research, Alzheimer's disease (AD) remains without a curative therapy. While amyloid- and tau-centered approaches have dominated the field, failures of monotherapeutic strategies underscore the need for a broader system-level understanding. Here, this review critically revisits the principal hypotheses of AD pathogenesis, including the amyloid cascade, tauopathy, neuroinflammation, cholinergic dysfunction, oxidative and mitochondrial stress, metal dyshomeostasis, autophagy-lysosomal failure, genetic susceptibility, and infectious triggers. This review synthesizes molecular and cellular evidence from human genetics, neuropathology, and experimental models, correcting common misconceptions and emphasizing interactions between pathways. Neuroinflammation is increasingly recognized as a central hub linking amyloid, tau, and vascular factors, while mitochondrial and lysosomal dysfunctions emerge as amplifiers of proteotoxic stress. Genetic studies highlight apolipoprotein-E ε4 (APOE ε4) as the strongest common risk allele, but also implicate genes involved in endosomal trafficking, lipid metabolism, and immune regulation. Taken together, AD is best understood as a multi-hit disorder in which converging processes, rather than a single driver, dictate disease initiation and progression. This narrative review proposes a systems neurobiology framework that integrates these mechanisms and identifies key points of convergence amenable to therapeutic targeting and biomarker development. Finally, this reappraisal aims to inform future research directions and guide the rational design of multi-target interventions.},
}

Humans
*Alzheimer Disease/physiopathology/pathology/genetics/metabolism
Animals
*Neurobiology

@article {pmid41379242,
year = {2025},
author = {Nguyen, TH and Wang, CH and Wang, SL and Nguyen, AD and Phan, TQ and Nguyen, VB},
title = {High-Level Scale Bioproduction of Prodigiosin Using a Novel Designed Culture Medium Completely Based on Organic By-Products and its Potential Anti-Alzheimer Effect: An Experimental and Virtual Study.},
journal = {Current microbiology},
volume = {83},
number = {1},
pages = {73},
pmid = {41379242},
issn = {1432-0991},
support = {NSTC 112-2923-B-032-001//National Science and Technology Council/ ; },
mesh = {*Prodigiosin/pharmacology/chemistry/metabolism/biosynthesis ; *Culture Media/chemistry/metabolism ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/pharmacology/metabolism/chemistry ; Humans ; Fermentation ; },
abstract = {The red microbial pigment - prodigiosin has attracted much attention in research due to its multiple bioactivities, which can be applied in various fields. Production prodigiosin with an eco-friendly strategy is currently an interesting and prioritized research topic. This study introduces an innovative production approach utilizing a novel, eco-friendly culture medium system that completely replaces expensive commercial nutrients with a combination of low-cost organic byproducts (shrimp shell powder and groundnut oil cake). This new approach yielded a remarkably high prodigiosin concentration (7520 mg/L) in an exceptionally short cultivation time (8 h) during large-scale fermentation. Beyond sustainable production, this research identified a novel therapeutic potential for prodigiosin in managing Alzheimer's disease via its ability to block cholinesterase enzymes, which are key targets in Alzheimer's therapy. Besides the experimental approach, computational simulations were used to predict the drug-likeness, pharmacokinetics, and safety profiles of prodigiosin in two forms (neutral and cationic). Notably, molecular docking and DFT analysis revealed effective interactions of prodigiosin with cholinesterase enzymes, with the cationic form showing a more promising capacity for protein target interaction. This study provided scientific insights into the eco-friendly cultural medium for prodigiosin production, its anti-cholinesterase activity, and potential properties through virtual simulations.},
}

*Prodigiosin/pharmacology/chemistry/metabolism/biosynthesis
*Culture Media/chemistry/metabolism
Molecular Docking Simulation
*Alzheimer Disease/drug therapy
*Cholinesterase Inhibitors/pharmacology/metabolism/chemistry
Humans
Fermentation

@article {pmid41379219,
year = {2025},
author = {Taylor, LW and Simzer, EM and Young, LFP and Holt, K and Spires-Jones, TL and Durrant, CS},
title = {Confirmation of p-tau Ser356's association with Alzheimer's disease pathology and lowering in response to WZ4003 treatment in brain slice cultures. Reply to: "Phospho-tau Ser356 is mostly confined to pre-NFT neurons in Alzheimer's pathology".},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {63},
pmid = {41379219},
issn = {1432-0533},
support = {UKDRI-Edin005//UK Dementia Research Institute/ ; RADF-2019a-001//Race Against Dementia/ ; AS-PG-21-006/ALZS_/Alzheimer's Society/United Kingdom ; },
}

@article {pmid41383372,
year = {2024},
author = {Liu, Y and Guo, Y and Yu, J},
title = {Blood-based biomarkers of Alzheimer's disease: Standardization and comprehensiveness.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {4},
pages = {246-254},
pmid = {41383372},
issn = {2770-730X},
abstract = {Population aging is sweeping across the globe, resulting in a striking prevalence of Alzheimer's disease (AD) and dementia and a heavy economic burden. Given the time window of 10-20 years from pathological initiation to clinically detected cognitive impairment, early detection can significantly impact the prevention and control of AD. The invasiveness and high cost of cerebrospinal fluid biomarkers and positron emission tomography-computed tomography imaging limit large-scale disease screening. However, blood-based biomarkers (BBMs) lack these disadvantages, shedding light on their usefulness in the large-scale identification and prevention of AD. Prominent advancement has recently been made regarding BBMs of AD co-pathology (amyloid β, tau protein, neurofilament light polypeptide, and glial fibrillary acidic protein) to improve their accuracy as clinical diagnostics of AD to a level comparable to that of canonical methods, facilitating the large-scale clinical implementation of diagnostic tests with higher precision. To briefly summarize, the prospects of AD BBMs rely on standardization and comprehensiveness. Calibrating the sample collection procedure and clarifying the boundaries for indices and abnormalities are beneficial for constructing a canonical diagnostic assay. The comprehensive assembly of heterogeneous clinical evidence guarantees the accuracy of diagnosis and improves the workflow for early identification.},
}

@article {pmid41383699,
year = {2024},
author = {Huang, S and Zhang, M},
title = {The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {2},
pages = {100-119},
pmid = {41383699},
issn = {2770-730X},
abstract = {Cerebral ischemia-reperfusion (I/R) injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke (AIS). It has been found that the brain renin-angiotensin system, especially the angiotensin II type 1 receptor (AT1R) pathway, plays a significant role in cerebral I/R injury. This pathway is involved in processes such as oxidative stress, neuroinflammation, apoptosis, and it affects cerebrovascular autoregulation and the maintenance of blood-brain barrier. AT1R blocker (ARB), widely used as an antihypertensive agent, has demonstrated stroke prevention capabilities in numerous prospective studies, independent of its antihypertensive characteristics. Studies focusing on neurological diseases like Alzheimer's disease, Parkinson's disease, and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions. Preclinical studies have shown that ARBs can reduce infarct volume and brain edema, inhibit multiple signaling pathways associated with I/R injury, restore energy levels in damaged brain regions, and rescue the penumbra by promoting neovascularization in cerebral I/R models. These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of AIS. Therefore, this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for AIS. It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progress made on ARBs in I/R models.},
}

@article {pmid41383445,
year = {2024},
author = {Zhu, Y and Liao, L and Gao, S and Tao, Y and Huang, H and Fang, X and Yuan, C and Gao, C},
title = {Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {1},
pages = {16-32},
pmid = {41383445},
issn = {2770-730X},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well-established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy-related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high-frequency rTMS (HF-rTMS) regimen has value in AD therapy, and that promising single-site protocols, such as HF-rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.},
}

@article {pmid41379198,
year = {2025},
author = {Le, LTHL and Lee, G and Shin, JW and Shim, YM and Kim, SI and Park, SH and Won, JK and Lee, MJ},
title = {Phospho-tau Ser356 is mostly confined to pre-NFT neurons in Alzheimer's pathology.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {62},
pmid = {41379198},
issn = {1432-0533},
support = {RS-2021-NR059245//National Research Foundation of Korea/ ; },
}

@article {pmid41379030,
year = {2025},
author = {Rouhbakhsh, H and Farkhari, N and Khatami, SH and Ehtiati, S and Masoumian Hosseini, M and Soleimani, Y and Rashidi, MR and Tajalli, H and Ahmadi-Kandjani, S and Boostanipour, A and Karimi, AM and Karima, S},
title = {Heparin and fluoride drive distinct tau (4R/1 N) aggregation pathways to fibrils and granular oligomers, as revealed by Raman spectroscopy.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/07391102.2025.2598636},
pmid = {41379030},
issn = {1538-0254},
abstract = {The aggregation of the tau protein into pathological assemblies is a pivotal event in Alzheimer's disease and related tauopathies. Understanding how different cofactors influence the Tau aggregation pathway is crucial for elucidating disease mechanisms. This study directly compares the aggregation pathways of human Tau (hTau441, 4 R/1 N) induced by heparin with those induced by aluminum/sodium fluoride (AlF3/NaF). We employed time-resolved Raman spectroscopy, a technique uniquely suited for label-free, real-time secondary structure analysis of intrinsically disordered proteins in solution, to monitor structural transitions. Our results reveal two distinct trajectories: Heparin drives a classical pathway of progressive β-sheet enrichment, culminating in mature fibrils. In stark contrast, fluoride conditions suppress β-sheet formation and stabilize granular, nonfibrillar oligomers. These findings suggest that the neurotoxicity associated with fluoride may not arise from accelerating fibril formation but from diverting tau into an off-pathway oligomeric state. This work establishes Raman spectroscopy as a powerful tool for mechanistic studies of protein aggregation and identifies fluoride as a modulator of Tau misfolding with significant pathological implications.},
}

@article {pmid41378924,
year = {2025},
author = {Liang, Z and Tang, T and Wu, J and Yang, H and Zou, Y and Dai, J and Liu, X and Yang, J},
title = {A Dual-Targeted Fluorescent Probe with a Semicurcumin Structure for Imaging β-Amyloid and α-Synuclein Aggregates.},
journal = {Bioconjugate chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.bioconjchem.5c00454},
pmid = {41378924},
issn = {1520-4812},
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most prevalent neurodegenerative disorders, both characterized by abnormal protein folding. Amyloid-β (Aβ) and α-synuclein (α-syn) are often associated with these diseases, which might occur simultaneously in later stages. In this study, we developed a dual-target fluorescent probe, DiFboron-6, designed to specifically target Aβ and α-syn aggregates. DiFboron-6 exhibited excellent fluorescence properties, with 59-fold and 49-fold increases in fluorescence intensity upon binding to Aβ and α-syn aggregates, respectively. The probe demonstrated strong binding affinity to both proteins, with dissociation constants of KdAβ = 12.4 nM and Kdα-syn = 174 nM. Mouse brain slice staining and in vitro experiments further confirmed that DiFboron-6 could clearly label both protein plaques and effectively cross the blood-brain barrier (BBB). DiFboron-6 has been shown to effectively detect both Aβ and α-syn aggregates, thereby serving as a dual-target detection tool. Its unique structure offers a promising foundation for the development of future dual-target probes.},
}

@article {pmid41378779,
year = {2025},
author = {Begines, P and Fernández-Bolaños, JG and López, Ó},
title = {An updated patent review of acetylcholinesterase inhibitors for the treatment of alzheimer's disease (2021 - present).},
journal = {Expert opinion on therapeutic patents},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543776.2025.2602702},
pmid = {41378779},
issn = {1744-7674},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex and not fully elucidated etiology. An exponential rise in its incidence underscores the urgent need for effective therapeutic strategies. AD imposes a significant economic burden on public healthcare systems and on patient's families.

AREAS COVERED: This manuscript focuses on the review of potent acetylcholinesterase (AChE) inhibitors, either through chemical synthesis or isolation from natural sources, aimed at restoring acetylcholine levels. Most of the compounds discussed act as multitarget agents and are categorized into four groups: drug derivatives (9 patents), heterocyclic scaffolds (16 patents), natural products from plant extracts (12 patents), and synthetic compounds inspired by natural templates (18 patents).

EXPERT OPINION: AChE inhibition remains a compelling target in AD drug design, as it enhances acetylcholine levels and can alleviate cognitive decline. Furthermore, inhibitors that interact with the peripheral anionic site (PAS) of AChE may reduce β-amyloid self-aggregation, thereby preventing the deposition of neurotoxic peptides in the brain. However, targeting AChE alone is insufficient for the development of effective therapeutics. A multitarget approach, combining AChE inhibition with pharmacophores addressing β-amyloid aggregation, neuroinflammation, oxidative stress, and other pathological hallmarks, holds greater promise for the development of more efficient anti-Alzheimer's agents.},
}

@article {pmid41378466,
year = {2025},
author = {Cohen, AS and Divers, R and Calamia, M and Masucci, M and Granrud, OE and Corporandy, A and Warren, KK and Elvevåg, B and Chandler, C and Diaz-Asper, C},
title = {Speech pause and speech rate for evaluating Alzheimer's and mild cognitive impairment: A meta-analysis.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/S1355617725101677},
pmid = {41378466},
issn = {1469-7661},
abstract = {OBJECTIVE: Evaluating pauses in natural speech is a promising strategy for improving reliability, validity, and efficiency in assessing cognitive functions in people with mild cognitive impairment (MCI) and Alzheimer's dementia (AD).

METHOD: We conducted a quantitative meta-analysis of studies employing automated pause analysis. We included measures of speaking rate for comparison.

RESULTS: We identified 13 studies evaluating pause measures and 8 studies of speaking rate in people with MCI (n's = 276 & 109, respectively) and AD (n's = 170 & 81, respectively) and healthy aged controls (n's = 492 & 231, respectively). Studies evaluated speech across various tasks, including standard neuropsychological, reading, and free/conversational tasks. People with AD and MCI showed longer pauses than controls at approximately 1.20 and 0.62 standard deviations, respectively, though there was substantial heterogeneity across studies. A more modest effect, of 0.66 and 0.27 SDs, was observed between these groups in speech rate. The largest effects were observed for standardized memory tasks.

CONCLUSIONS: Of the many ways that speech can be objectified, pauses appear particularly important for understanding cognition in AD. Pause analysis has the benefit of being face valid, interpretable in ratio format as a reaction time, tied to known socio-cognitive functions, and relatively easy to measure, compute, and interpret. Automation of speech analysis can greatly expand the assessment of AD and potentially improve early identification of one of the most devastating and costly diseases affecting humans.},
}

@article {pmid41378346,
year = {2025},
author = {Bayahya, AY and Jammal, F and Banjar, H and Eassa, FE and Talabay, O and Alamri, SH},
title = {Multi-model deep learning for dementia detection: addressing data and model limitations.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1638022},
pmid = {41378346},
issn = {1662-4548},
abstract = {INTRODUCTION: Deep neural network architectures have transformed medical imaging, particularly in structural MRI (sMRI) classification. However, existing state-of-the-art deep learning models face limitations in preprocessing and feature extraction when classifying dementia-related conditions. This study addresses these challenges by evaluating multiple architectures for dementia diagnosis.

METHODS: This study assessed eight pretrained convolutional neural networks (CNNs), a Vision Transformer (ViT), a multimodal attention model, and a capsule network (CapsNet) for classifying three classes: dementia, mild cognitive impairment (MCI), and healthy controls. The dataset, obtained from ADNI, was balanced across classes and comprised 10,000 training images per class, 3,000 validation images per class, and 850 test images per class. Classification was performed using 2D slices from sMRI scans. Performance metrics included accuracy, specificity, and sensitivity.

RESULTS: Among all evaluated models, the 3D-CNN and multimodal attention models achieved the highest performance, with accuracies of 84% and 86%, specificities of 83% and 86%, and sensitivities of 84% and 86%, respectively. The ViT and CapsNet models achieved 100% sensitivity for Alzheimer's disease (AD) but demonstrated low precision for AD (43%) and 0% for other classes, indicating class imbalance effects. All models showed reduced performance and bias toward certain classes.

DISCUSSION: The findings highlight the limitations of current architectures in sMRI dementia classification, including suboptimal feature extraction and class-specific biases. While certain models, such as multimodal attention and 3D-CNN, performed better overall, precision and generalization remain challenges. Future work should focus on improved data representation through advanced computer vision methods and architectural modifications to enhance diagnostic accuracy and computational efficiency.},
}

@article {pmid41378250,
year = {2025},
author = {Ochoa, KL and Heredia, AG and Piedra, CC and Arias, RJ and Ortiz, BJ and Dominguez-Gortaire, JA},
title = {Association between Alzheimer's disease and Porphyromonas gingivalis products in murine models: A systematic review.},
journal = {World journal of biological chemistry},
volume = {16},
number = {4},
pages = {111156},
pmid = {41378250},
issn = {1949-8454},
abstract = {BACKGROUND: Alzheimer's disease is a neurodegenerative dementia characterized by accumulation of β-amyloid plaques, tau hyperphosphorylation, and neuroinflammation. Recent research has highlighted a potential relationship between chronic oral infections and neurodegeneration, particularly the involvement of Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis. Experimental mouse models have been used to explore how P. gingivalis products contribute to neuroinflammatory and degenerative processes. However, a comprehensive synthesis of these findings is lacking. This systematic review evaluates the role of P. gingivalis-derived factors in triggering Alzheimer's-like pathology, with an emphasis on bacterial products and host immune responses. We hypothesize that P. gingivalis products exacerbate neuroinflammation and pathology in mouse models of Alzheimer's disease.

AIM: To link gingival P. gingivalis bacteria-associated products with the onset and progression of Alzheimer's disease-like pathology in mouse models.

METHODS: This systematic review followed the 2020 PRISMA guidelines. A comprehensive search was conducted in five databases (PubMed, Scopus, ScienceDirect, Sage, SpringerLink) for original studies between 2014 and 2024. Studies included mouse models to evaluate the effect of P. gingivalis or its products on Alzheimer's-like pathologies. Exclusion criteria were in vitro, human, or review studies. Twenty-three studies met the inclusion criteria. Bacterial components and activated host factors were extracted, categorized, and analyzed using narrative synthesis and descriptive statistics.

RESULTS: In 24 studies, lipopolysaccharides (54.84%) and gingipains (25.81%) were the most frequently reported P. gingivalis products. These factors activated toll-like receptors (TLR2/TLR4), microglia, and astrocytes, increasing levels of interleukin 1 beta, tumor necrosis factor-alpha, and other proinflammatory cytokines. The host response included β-amyloid accumulation, Tau hyperphosphorylation, and changes in blood-brain barrier permeability. Glial cells were the most frequently mentioned host factors (n = 15), followed by proteins (n = 13) and cytokines (n = 11). These interactions promoted cognitive impairment, synaptic dysfunction, and neurodegeneration in mouse models, supporting a role for P. gingivalis in Alzheimer's-like pathology.

CONCLUSION: P. gingivalis products induce neuroinflammatory responses and Alzheimer's-like pathology in mouse models, supporting their role as contributors to neurodegeneration and potential targets for preventive strategies.},
}

@article {pmid41378232,
year = {2025},
author = {Ray, BN and Ustinova, KI and Langenderfer, JE},
title = {Effects of Rehabilitative Device on Parkinsonian Gait.},
journal = {International journal of exercise science},
volume = {18},
number = {7},
pages = {1422-1439},
pmid = {41378232},
issn = {1939-795X},
abstract = {Parkinson's disease (PD) is second in occurrence among neurodegenerative disorders after Alzheimer's disease and significantly impacts gait and mobility. This research tested the effect of the NewGait rehabilitative device in PD impaired individuals. Twenty individuals with PD participated in this study. Walking gait for three conditions were analyzed: Normal, wearing NewGait and Post-NewGait. Standard spatial and temporal analysis measures as well as nonlinear measures from recurrence quantification were compared to determine any effects of the device on walking gait. NewGait was perceived to be both comfortable to wear as well as resulted in increased ease of movement. Step width was increased while wearing NewGait while step length was unchanged. No differences were found in temporal measures: cadence, stride time and double support time. Wearing NewGait resulted in a slight, but not significant decrease in walking velocity compared to Normal. Post-NewGait gait velocity was increased compared to wearing NewGait. Based only on these standard linear spatiotemporal measures, NewGait is somewhat intrusive for gait Parkinsonian individuals, resulting in a less effective gait. The recurrence-based analysis however, found that compared to Normal, Determinism and Laminarity was increased while wearing NewGait and Post-NewGait. Entropy was also increased while wearing NewGait and there was a tendency towards increased Entropy while walking after wearing NewGait. These results suggest NewGait allows for greater predictability and complexity of the gait pattern with increased dynamic stability than walking without NewGait. Therefore, there is potential for longer-term beneficial effects of NewGait in rehabilitation of Parkinsonian gait.},
}

@article {pmid41378217,
year = {2025},
author = {Li, W and Huang, W and Zhou, P and Yao, Y and Cai, B and Ye, S},
title = {Sporoderm-removed ganoderma lucidum spore powder (S-GLSP) alleviates neuroinflammation injury by regulating microglial polarization through inhibition of NLRP3 inflammasome activation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1690192},
pmid = {41378217},
issn = {1663-9812},
abstract = {INTRODUCTION: Sporoderm-Removed Ganoderma lucidum Spore Powder (S-GLSP), derived from the spores of the medically valued fungus Ganoderma lucidum, exhibits diverse pharmacological activities and shows considerable potential in the treatment of Alzheimer's disease (AD). However, its underlying mechanisms of action remain incompletely elucidated. This study aims to investigate the protective effects of S-GLSP against AD and to explore the molecular mechanisms involved.

MATERIALS AND METHODS: The chemical profile of S-GLSP extract was characterized using LC-MS/MS. Alzheimer's disease models were established both in vivo and in vitro: a rat model was induced by D-galactose combined with intracerebroventricular injection of Aβ, while a cellular model was stimulated with LPS. The neuroprotective effects of S-GLSP were assessed through behavioral tests and hematoxylin-eosin (HE) staining. Immunofluorescence staining, Western blot (WB), RT-qPCR, and ELISA were employed to evaluate microglial polarization and NLRP3 inflammasome activation. Cell viability was measured using MTT and EdU assays. Finally, NLRP3 knockdown was performed to verify whether S-GLSP modulates microglial polarization via regulation of the NLRP3 inflammasome.

RESULTS: A total of 42 chemical compounds were identified in S-GLSP, including flavonoids, alkaloids, terpenoids, saccharides, phenolics, fatty acids, nucleosides, amino acids, and other. S-GLSP treatment alleviated neuronal damage, improved learning and memory deficits, and reduced the expression of phosphorylated tau (p-tau) in AD model rats. Further experiments in vitro and in vivo showed that S-GLSP downregulated M1 phenotypic markers (CD86, iNOS, TNF-α) and upregulated M2 markers (CD206, Arg-1, IL-10). Moreover, S-GLSP inhibited NLRP3 inflammasome activation and regulated the secretion of IL-1β and IL-18, effects that were consistent with those observed following NLRP3 knockdown.

CONCLUSION: Our findings demonstrate that S-GLSP alleviates Alzheimer's disease pathology by inhibiting NLRP3 inflammasome activation, promoting a shift in microglial polarization from the M1 to the M2 phenotype, and modulating the release of inflammatory cytokines. This study provides novel mechanistic insights into the therapeutic potential of S-GLSP for AD.},
}

@article {pmid41378205,
year = {2025},
author = {Kui, L and Wang, G and Huang, J and Yang, X and Yu, J and Li, X and Peng, H and Leng, B and Jiao, Y and Zhang, Z},
title = {Therapeutic efficacy and mechanisms of gentiopicroside in various diseases.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1634722},
pmid = {41378205},
issn = {1663-9812},
abstract = {Gentiopicroside (GPS), a secoiridoid glycoside found in traditional medicinal plants such as Gentiana scabra Bunge, exhibits diverse pharmacological properties, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, antidiabetic, antitumor, and skin disease-modulating effects. This review consolidates current research on GPS, highlighting its mechanisms of action across various diseases. GPS modulates key signaling pathways, such as NF-κB and MAPK, to suppress pro-inflammatory cytokines and oxidative stress. It activates the Keap1-Nrf2 pathway to enhance cellular antioxidant defenses and exhibits direct free radical scavenging capabilities. In neurodegenerative diseases like Alzheimer's and Parkinson's, GPS reduces amyloid-β accumulation and dopaminergic neuron loss, respectively. Its hepatoprotective effects include mitigating chemical- and alcohol-induced liver damage by regulating lipid metabolism and reducing fibrosis. GPS also improves insulin sensitivity in diabetes and inhibits tumor cell proliferation and migration. Additionally, GPS shows promise in treating skin conditions like psoriasis and enhancing wound healing. Despite its therapeutic potential, current evidence is limited by methodological gaps, preclinical inconsistencies and weak clinical evidence (no large-scale randomized controlled trials [RCTs]). Challenges such as low bioavailability and the need for further clinical validation remain. Future research should focus on optimizing GPS formulations and conducting rigorous RCTs, standardizing botanical drug characterization, translating preclinical findings into effective therapies.},
}

@article {pmid41377997,
year = {2025},
author = {Monteiro, R and Dunn, JT and Rodriguez, G and Fisher, DW and Dong, H},
title = {Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8031077/v1},
pmid = {41377997},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is frequently accompanied by neuropsychiatric symptoms (NPS), among which apathy, one of the most prevalent and burdensome, accelerates cognitive decline and disease progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing of AD subjects revealed abnormal immune gene expression uniquely associated with apathy. In this study, we investigated whether these changes are also linked to apathy-like behavior in 5xFAD mice, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies these behaviors. We first validated the expression of apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-month-old 5xFAD mice using RT-qPCR. Separate cohorts of similarly aged 5xFAD and WT mice then received SB290157 and/or methylphenidate for two weeks. Results indicate that increased immune-related genes, including Tyrobp, C3 , C3ar , C1qa , C1qb , and C1qc expression, were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment significantly improved nest-building behavior, reduced C3 and C3ar protein expression, as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.},
}

@article {pmid41377994,
year = {2025},
author = {Bitar, G and Alban, S and Beyene, K and Decourt, B and Harirchian, S and Sabbagh, MN},
title = {Correlations of CSF Biomarkers of Alzheimer's Disease with Cognitive Measures in MCI and AD Dementia: A Cross-Sectional Analysis.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8168314/v1},
pmid = {41377994},
issn = {2693-5015},
abstract = {Background and Objectives: We examined the relationships between cerebrospinal fluid (CSF) amyloid-β, tau, p-tau, and cognition in an Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Studies have examined the longitudinal relationships between CSF biomarkers for Alzheimer's disease (AD) and cognition, but there is discordance in the strength of associations between CSF amyloid-β, t-tau, or p-tau with cognition at different disease stages. Methods: The study included 665 patients from the combined ADNI dataset: 128 cognitively normal (CN), 175 with mild cognitive impairment (MCI), and 362 with AD dementia. All patients were amyloid-β-positive according to established CSF amyloid-β cut-off values. Cognitive assessments, diagnoses, and specimen collection/processing were conducted via published standardized protocols. We examined cross-sectional baseline data and performed correlational and regression analyses to evaluate the associations between CSF biomarkers and assessments of learning, memory, executive function, language, attention, visuospatial skills, and activities of daily living. Results: In the MCI cohort, significant negative correlations were observed between CSF amyloid-β and ADAS-Cog11 (r=-0.164, p=0.02, ADAS-Cog13 (r=-0.181, p=0.01), Trails B (r=0.11, p=0.04), and FAQ (r=-0.131, p=0.01). There were positive correlations between amyloid-β and MMSE (r=0.149, p=0.004) and amyloid-β and WMS-delayed recall (r=0.116, p=0.03). Statistically significant correlations were observed between CSF t-tau and p-tau and CDRSB (t-tau: r=0.105, p=0.047), ADAS-Cog11 (t-tau: r=0.114, p=0.03; p-tau-181: r=0.114, p=0.03), ADAS-Cog13 (t-tau: r=0.165, p=0.002; p-tau-181: r=0.162, p=0.002), RAVLT-forgetting (t-tau: r=0.173, p=0.001; p-tau-181: r=0.167, p=0.001), and WMS-delayed recall (t-tau: r=-0.237, p<0.001 and p-tau-181: r=-0.235, p<0.001). In the AD cohort, no statistically significant relationships were observed between CSF amyloid-β1-42, t-tau, p-tau-181, and any of the cognitive scores. Discussion: The findings suggest that the relationship between CSF biomarkers and cognitive performance is strongest in MCI. The lack of significant correlations in the AD cohort may indicate other pathophysiological changes dominating cognitive dysfunction at this disease stage. Both tau and amyloid showed similar utility in reflecting cognitive impairment, in contrast to some reports in the literature. Further research is warranted to explore biomarker longitudinal impacts and their predictive values across the spectrum of cognitive impairment.},
}

@article {pmid41377971,
year = {2025},
author = {Liu, A and Jiang, R and Li, R and Cao, X and Qi, Z and Feng, R and Sun, H and Fujita, M and Comandante-Lou, N and Lakhani, CM and Empawi, J and Knowles, DA and Zhang, X and Dey, KK and De Jager, P and Bennett, D and Consortium, TADFG and Wang, T and Wang, G},
title = {Distributional genetic effects reveal context-dependent molecular regulation in human brain aging and Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8219833/v1},
pmid = {41377971},
issn = {2693-5015},
abstract = {Molecular QTL studies quantify whether genetic variants affect molecular traits, but non-linear effects including distributional patterns, variance, and interactions provide mechanistic insights beyond mean-level associations. Methods for detecting distributional effects have been developed for eQTL analysis, yet applications have focused on method demonstrations rather than large-scale biological discovery. We comprehensively mapped quantile, variance, and interaction QTLs across 34 data-set from 22 molecular contexts in >2,300 human brain donors, revealing that 48.7% of quantile QTLs (qQTLs) exhibit context-dependent regulation invisible to linear models, with enrichment at phenotypic extremes and in cell-type-specific regulatory elements, chromatin accessibility regions, and long-range chromosomal contacts. qQTL variants explained additional trait heritability beyond linear QTLs for brain-related traits. At Alzheimer's disease (AD) risk loci, qQTL analysis revealed complex regulatory architecture including variance effects at PITRM1 , lower-quantile-specific effects at TMEM106B partially explained by APOE ε4 interactions, and coordinated epigenetic regulation at loci harboring CHRNE / SCIMP / RABEP1 . Quantile-based transcriptome-wide association studies identified 34 AD risk genes and additional aging-related genes beyond standard TWAS, with enrichment in immune regulation and telomere maintenance pathways where distributional effects may reflect threshold-dependent mechanisms. Our non-linear QTL atlas and qTWAS resource enable characterization of context-dependent regulatory effects in complex disease genetics.},
}

@article {pmid41377509,
year = {2025},
author = {Scheel, N and Fernandez, Z and Baker, J and Yanev, P and Keller, JN and Binder, EF and Vidoni, ED and Burns, JM and Stowe, AM and Kerwin, DR and Cullum, CM and Hynan, LS and Vongpatanasin, W and Zhang, R and Zhu, DC},
title = {A Functional Resting-State Network Atlas Based on 420 Older Adults with Hypertension.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.26.690831},
pmid = {41377509},
issn = {2692-8205},
abstract = {The Risk Reduction for Alzheimer's Disease (rrAD) trial included 513 cognitively normal, sedentary, hypertensive older adults (aged 60 to 85 years) with dementia risk factors. We utilized 420 high-quality baseline resting-state functional MRI (rs-fMRI) scans from this cohort to develop a functional atlas tailored for aging populations. Typical rs-fMRI atlases derived from healthy young adults do not account for age-related changes, such as cortical atrophy, enlarged ventricles, and altered connectivity. To address this gap, we created a cohort-specific MNI-adjacent anatomical template, rrAD420, using SPM12's DARTEL registration. In this space, we derived a comprehensive functional atlas using both group independent component analysis (GICA) and probabilistic functional mode decomposition (PROFUMO). The rrAD420 atlas offers detailed representations of Resting-State Network (RSN) connectivity, encompassing unique configurations and overlapping interactions. It features two Default-Mode Network (DMN)-specific seed-based maps (DMN24 with cerebellum, DMN18 without) and data-driven components resembling the major RSNs. Furthermore, PROFUMO allowed for the identification of multimodal and combinatory networks, capturing connections within and between RSNs. While optimized for hypertensive older adults, the rrAD420 atlas serves as a versatile tool for broader aging populations, aiding in the study of neurodegenerative processes and biomarker discovery.},
}

@article {pmid41377453,
year = {2025},
author = {Kumari, A and Kumari, R and Khalid, M and Ria, SG},
title = {Lithium deficiency and Alzheimer's: emerging evidence and therapeutic implications.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {12},
pages = {9111-9112},
pmid = {41377453},
issn = {2049-0801},
}

@article {pmid41377423,
year = {2025},
author = {Kumari, A and Kumari, A and Khalid, M and Ria, SG},
title = {"Omega-3 fatty acids and Alzheimer's disease: current evidence and emerging insights".},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {12},
pages = {9113-9114},
pmid = {41377423},
issn = {2049-0801},
}

@article {pmid41377348,
year = {2025},
author = {Subedi, BK and Gautam, N and Ali, R and Upadhyay, A and Sapkota, P and Subedi, BD},
title = {Comparative risks of mortality, cardiovascular events, and dementia with methotrexate versus hydroxychloroquine in rheumatoid arthritis: a retrospective cohort study.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {12},
pages = {8051-8058},
pmid = {41377348},
issn = {2049-0801},
abstract = {BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder primarily affecting joints. Methotrexate (MTX) and hydroxychloroquine (HCQ) are common disease-modifying antirheumatic drugs, yet more comparative outcome studies are needed. This study aimed to compare associations of HCQ versus MTX initiation with mortality, cardiovascular events, and other major health outcomes in RA patients. This retrospective cohort study utilized the TriNetX database (electronic health records from 142 global health care organizations) to compare selected 10-year outcomes in RA patients starting HCQ or MTX therapy.

METHODS: Patients aged 18-75 years diagnosed with RA (ICD-10 codes) were studied. This retrospective, multi-center cohort study used data from the TriNetX Research Network (analysis: 23 March 2025). Two cohorts, HCQ initiators and MTX initiators, were created. Propensity score matching (PSM) balanced cohorts for age, sex, race, pre-specified comorbidities, and concomitant medications. Primary outcomes were 10-year cumulative incidences of all-cause mortality, non-ST elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI), pulmonary hypertension (PAH), end-stage renal disease (ESRD), interstitial lung disease (ILD), osteoporosis, and Alzheimer's dementia.

RESULTS: After PSM, 56 362 patients were in each cohort. HCQ initiation was associated with significantly higher 10-year relative risks (RR) for NSTEMI (RR: 1.217), ESRD (RR: 2.624), ILD (RR: 1.377), PAH (RR: 1.625), and all-cause mortality (RR: 1.379) compared to MTX. No statistically significant RR differences were observed for Alzheimer's dementia, STEMI, or osteoporosis.

CONCLUSION: In this large, real-world observational study, RA patients initiating HCQ had a higher 10-year risk association for ESRD, ILD, PAH, NSTEMI, and all-cause mortality versus MTX initiators. These findings highlight potential differences in systemic risk profiles and are hypothesis generating. However, the results must be interpreted with significant caution due to major limitations, including the potential for residual confounding from unmeasured variables like disease severity and the absence of adherence data. Further prospective research that addresses these limitations is warranted to confirm these associations and explore underlying mechanisms.},
}

@article {pmid41377300,
year = {2025},
author = {Hamdar, H},
title = {The neuroprotective promise of semaglutide for Alzheimer's disease.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {12},
pages = {9065-9066},
pmid = {41377300},
issn = {2049-0801},
}

@article {pmid41377284,
year = {2025},
author = {Koundinya, S and Chakilam, R and Brahmandam, G and Elkadri, L and Al-Badri, SG and Hannan, A and Khalil, I and Nimmagadda, R},
title = {Long-term proton pump inhibitor use and risk of dementia: a focused review on pantoprazole.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {12},
pages = {8434-8442},
pmid = {41377284},
issn = {2049-0801},
abstract = {BACKGROUND: Proton pump inhibitors (PPIs) are widely prescribed for acid-related disorders, yet concerns about their long-term effects on cognitive function persist. Emerging evidence suggests a possible association between prolonged PPI use and increased dementia risk, though findings remain inconclusive. This narrative review focuses on pantoprazole, a PPI with unique pharmacokinetics, to assess its potential role in dementia development.

METHODS: A systematic search was conducted using PubMed and PubMed Central with keywords including "dementia," "proton pump inhibitors," "Alzheimer's disease," and "adverse effects of PPIs," etc. Studies published from 1 January 2002 to 31 December 2024 were included, focusing on clinical trials, cohort studies, meta-analyses, and systematic reviews. Two independent reviewers assessed eligibility by screening abstracts and full texts, excluding case reports, conference abstracts, and editorial letters.

RESULTS: Thirteen studies investigating the association between PPI use and dementia were included. Observational studies in Asian populations reported an increased risk, whereas Western studies showed inconsistent results. Mechanistic insights suggest PPIs may contribute to dementia through amyloid-β accumulation, vitamin B12 deficiency, and endothelial dysfunction. Mendelian randomization studies and meta-analyses found no statistically significant association. Pantoprazole's prolonged acid suppression may differentially influence dementia risk.

CONCLUSION: Evidence on the link between long-term PPI use and dementia is conflicting, with variability in study populations and methodological limitations. Further prospective studies and randomized controlled trials are needed to clarify causality. Clinicians should exercise caution, reassess long-term PPI necessity, and consider alternatives to mitigate potential risks.},
}

@article {pmid41377219,
year = {2025},
author = {Pandey, P and Rajput, S and Gaur, T and Khandia, R and Gurjar, P},
title = {Animal models in human surgery and implant innovation: ethical considerations and scientific advancements.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {12},
pages = {8291-8303},
pmid = {41377219},
issn = {2049-0801},
abstract = {The main aim of biological research is to bridge the gap between preclinical findings and clinical applications so that human health can be improved. Animal models are beneficial in replicating disease mechanisms, facilitating diagnosis, and assessing treatment efficacy for any disease. They play a vital role in drug discovery, toxicological assessments, dosage determination, and the evaluation of side effects, all while adhering to the ethical guidelines. These models are effectively used to treat a wide range of human diseases, including autoimmune disorders, rheumatoid arthritis, epilepsy, Alzheimer's disease, cardiovascular conditions, atherosclerosis, severe acute respiratory syndrome/Coronavirus disease 2019 (SARS/COVID-19), and diabetes. In disease modeling, they significantly contribute to drug development, medical device testing, tissue engineering, wound healing, and bone and cartilage regeneration. One cannot deny the fact that there are major significances of small and large animal models in scientific studies, apart from various advantages and challenges. Animal Models play an essential role in pharmaceutical research, biomedical research, genome editing, transgenic studies, and surgical applications. These models enable scientists and researchers to perform experiments that would be ethically or practically impossible in humans. In recent years, various animal species have been widely used to study health problems, including the 2019 Coronavirus pandemic, diabetes, and obesity. Mice, pigs, rabbits, rats, murine, primate, porcine, and aquatic models have played a crucial role in understanding the neurological, behavioral, cardiovascular, and oncological disorders while contributing to the development of innovative therapeutic approaches for their treatment. The studies in which pain is inflicted on animals must follow strict ethical standards. Whereas research involving painless animal death is often more accepted because of the fact that animals have limited awareness of their future. This review highlights the use of animal models in indispensable contributions to modern medicine and underscores their relevance in disease research, treatment development, and ethical considerations in experimental studies and their scientific advancements.},
}

@article {pmid41377063,
year = {2026},
author = {Caplash, S and Song, H and Waldman, A and Ying, GS and Kim, BJ},
title = {Characteristics of Study Design and Statistical Analysis in OCT-Based Studies of Neurodegeneration.},
journal = {Ophthalmology science},
volume = {6},
number = {1},
pages = {100961},
pmid = {41377063},
issn = {2666-9145},
abstract = {PURPOSE: To evaluate the design and statistical analysis of recently published clinical studies of retina OCT of neurodegenerative diseases.

DESIGN: Review of 134 publications.

METHODS: Clinical and translational publications from 2013-2023 involving human OCT studies were reviewed. Publications were restricted to the top 10 journals of either ophthalmology or neurology based on the SCImago Journal Rank. Data were extracted and analyzed regarding study design characteristics, disease studied, imaging characteristics, and statistical analysis method.

MAIN OUTCOME MEASURES: Characteristics of study design and statistical analysis.

RESULTS: Of the 134 studies, the most commonly investigated diseases were multiple sclerosis (47.8%), Alzheimer disease (31.3%), and Parkinson disease (14.2%). One hundred three (76.9%) studies were cross-sectional, and 31 (23.1%) studies were longitudinal. Of the 42 Alzheimer disease studies, 19.0% used cerebrospinal fluid biomarkers, 26.2% used positron emission tomography imaging, and 4.8% used genetic data to confirm the diagnosis. The peripapillary retinal nerve fiber layer thickness (95 studies) and macular retina layer thickness (96 studies) were the most commonly studied OCT measurements; 69 studies looked at both of these measurements. For 25 (18.7%) of the studies, no statement of image quality criteria or exclusion of subjects or eyes because of image quality criteria was identified. One hundred seventeen (87.3%) studies performed bilateral eye imaging, but only 89 (66.4%) studies performed bilateral image analysis. Of the 89 studies with bilateral eye image analysis, 53 (59.6%) performed analysis at the eye level by combining data from the left and right eye, making each eye (rather than each subject) the unit of analysis. Of the 53 studies performing analysis at the eye level for data from both eyes, the intereye correlation was adjusted in 38 (71.7%) studies, while 15 (28.3%) studies did not account for the intereye correlation. Thirty-seven (27.6%) studies corrected for multiple comparisons.

CONCLUSION: There may be opportunities for improvement in the study design and statistical analysis of OCT studies of neurodegenerative diseases.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.},
}

@article {pmid41376794,
year = {2026},
author = {Ren, H and Jing, F and Zhou, Y and Luo, Z and Yu, X and Jin, W and Chen, L},
title = {Utilizing multimodal models to forecast Alzheimer's disease progression and clinical subtypes.},
journal = {Health information science and systems},
volume = {14},
number = {1},
pages = {10},
pmid = {41376794},
issn = {2047-2501},
abstract = {BACKGROUND: Alzheimer's disease (AD) exhibits highly heterogeneous clinical courses. Early, accurate prediction and subgroup identification remain challenging due to reliance on single-modality data and coarse subtype schemes.

OBJECTIVE: To develop and validate a multimodal framework that integrates 3D MRI and clinical indicators to (1) stratify patients into clinically meaningful progression subtypes and (2) forecast individual memory/cognitive trajectories at 6, 12, and 48 months.

METHODS: Using ADNI-2 (n = 453), we extracted 3D T1-weighted MRI features via a pre-trained Med3D network and combined them with cognitive, functional, and genetic indicators. Non-negative matrix factorization projected patients into a two-dimensional progression space, and K-means defined three prognostic subgroups ("Low," "Mild," "Fast"). We compared several longitudinal architectures (CNN, Transformer, LSTM variants, ConvLSTM); interpretability was assessed with SHAP.

RESULTS: Clustering metrics (Silhouette peak at k = 3) supported three distinct trajectories. Stacked LSTM led image-only prediction, while standard LSTM favored indicator-only data. Multimodal LSTM with attention achieved the lowest errors-MAE 0.196, 0.203, and 0.261 at 6, 12, and 48 months-alongside accuracies of 0.903, 0.845, and 0.791. SHAP highlighted memory- and language-related features as dominant contributors.

CONCLUSION: An interpretable, fully automated multimodal framework enables robust subgroup stratification and individualized cognitive forecasting up to four years, supporting personalized prognosis and targeted clinical decision-making.},
}

@article {pmid41376786,
year = {2025},
author = {Miller, SJ and Logan, R and Zhang, C and Hafler, BP},
title = {The amyloid-beta wave hypothesis of Alzheimer's disease.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1723095},
pmid = {41376786},
issn = {2235-2988},
mesh = {*Alzheimer Disease/pathology/immunology/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism/immunology ; Immunity, Innate ; Plaque, Amyloid ; Neurons/metabolism ; Animals ; Central Nervous System/immunology/pathology ; },
abstract = {Alzheimer's disease (AD) is a complex and multifactorial disorder that affects all races and genders. Genetic traits influenced by lifestyle and environment lead to a tremendous amount of heterogeneity in Alzheimer's disease onset and severity. Regardless of these unique contributing factors, Alzheimer's disease is traditionally met with amyloid-beta plaque formation in the central nervous system. In this commentary, we shed light on the growing literature surrounding amyloid-beta's ability to act as an antimicrobial peptide in the central nervous system's innate immune response to pathogenic infections. We hypothesize that there are, "amyloid-beta waves" that are created by the responses of neuroglia and neurons to microbial pathogens. The improper clearance and residual buildup of amyloid-beta waves throughout life increases the likelihood of developing Alzheimer's disease. In conclusion, we suggest that anti-amyloid therapies during pathogenic infections or flare-ups may slow the development of Alzheimer's disease by reducing amyloid-beta waves throughout the aging of individuals.},
}

*Alzheimer Disease/pathology/immunology/metabolism
Humans
*Amyloid beta-Peptides/metabolism/immunology
Immunity, Innate
Plaque, Amyloid
Neurons/metabolism
Animals
Central Nervous System/immunology/pathology

@article {pmid41376658,
year = {2025},
author = {Wang, L and Ambekar, A and Eloyan, A},
title = {Geometric Modeling of Hippocampal Tau Deposition: A Surface-Based Framework for Covariate Analysis and Off-Target Contamination Detection.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41376658},
issn = {2331-8422},
abstract = {We introduce a framework combining geometric modeling with disease progression analysis to investigate tau deposition in Alzheimer's disease (AD) using positron emission tomography (PET) data. Focusing on the hippocampus, we construct a principal surface that captures the spatial distribution and morphological changes of tau pathology. By projecting voxels onto this surface, we quantify tau coverage, intensity, and thickness through bidirectional projection distances and interpolated standardized uptake value ratios (SUVR). This low-dimensional embedding preserves spatial specificity while mitigating multiple comparison issues. Covariate effects are analyzed using a two-stage regression model with inverse probability weighting to adjust for signal sparsity and selection bias. Using the SuStaIn model, we identify subtypes and stages of AD, revealing distinct tau dynamics: the limbic-predominant subtype shows age-related nonlinear accumulation in coverage and thickness, whereas the posterior subtype exhibits uniform SUVR increases across disease progression. Model-based predictions show that hippocampal tau deposition follows a structured spatial trajectory expanding bidirectionally with increasing thickness, while subtype differences highlight posterior hippocampal involvement consistent with whole-brain patterns. Finally, directional signal patterns on the principal surface reveal contamination from the choroid plexus, demonstrating the broader applicability of the proposed framework across modalities including amyloid PET.},
}

@article {pmid41376656,
year = {2025},
author = {He, Z and Sun, J},
title = {Clearance mechanisms of the glymphatic/lymphatic system in the brain: new therapeutic perspectives for cognitive impairment.},
journal = {Cognitive neurodynamics},
volume = {19},
number = {1},
pages = {111},
pmid = {41376656},
issn = {1871-4080},
abstract = {The glymphatic/lymphatic system of the brain has been an important discovery in the field of neuroscience in recent years. As the "waste clearance network" of the central nervous system, it clears metabolic products and neurotoxic substances through the cerebrospinal fluid-interstitial fluid circulation, which is crucial for maintaining the homeostasis of the intracerebral environment and plays important roles in learning, memory and other advanced cognitive functions. The glymphatic/lymphatic system is crucial for the clearance of beta-amyloid and tau proteins, and thus the abnormal function of this system has been confirmed to be closely related to the pathological mechanisms of various diseases associated with cognitive impairment, such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia. The physiological function of this system is influenced by a variety of factors, especially when it is relatively active during sleep. The application of noninvasive imaging techniques to assess glymphatic/lymphatic system function has facilitated the development of clinical research. Therefore, a focus on the role of the cerebral glymphatic/lymphatic system in cognitive impairment and an understanding of its relationship with cognitive impairment from a new perspective are of great scientific and clinical importance.},
}

@article {pmid41376376,
year = {2025},
author = {Shi, Y and Zhao, T and Peng, L and Wang, P and Huang, X and Xu, F and Tan, Y and Peng, S and Xiong, T and Bai, Y and Liu, X and Wei, C and Zhang, W and Ding, H},
title = {Investigating the shared genetic architecture between post-traumatic stress disorder and neurodegenerative diseases: a large-scale genomewide cross-trait analysis.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000004347},
pmid = {41376376},
issn = {1743-9159},
abstract = {BACKGROUND: Post-traumatic stress disorder (PTSD), the most prevalent psychopathological consequence following traumatic events, profoundly impacts human life amidst global societal pressures. Emerging twin and family studies suggest that individuals with stress-related disorders face an elevated risk of neurodegenerative diseases, yet the genetic underpinnings of this association remain poorly understood.

METHODS: Here, we present a comprehensive framework elucidating this genetic basis. Using bivariate causal mixture models (MiXeR), we quantified polygenic overlap between PTSD (N = 1,280,933) and four neurodegenerative phenotypes (N = 115,803- 487,511), leveraging summary statistics from the largest PTSD genome-wide association study to date. Conditional/conjunction false discovery rate (FDR) analysis identified shared genomic loci.

RESULTS: MiXeR revealed considerable genetic variant sharing between neurodegenerative diseases and PTSD. Subsequent conjunction FDR analysis pinpointed 15 distinct shared loci. ρ-HESS local genetic correlation analysis identified seven significant local genetic correlations, with Chr6: 61,880,512-63,552,888 emerging as the most significant shared locus between PTSD and Alzheimer's disease. Cross-trait analyses using MTAG and CPASSOC identified 174 PTSD risk loci associated with at least one psychiatric disorder. Protein-coding genes mapped to known and novel shared loci exhibited specific spatial developmental trajectories. Through a framework incorporating five fundamental TWAS algorithm models, we identified 27 novel susceptibility genes that passed rigorous screening. Polygenic risk score (PRS) stratification in the UK Biobank cohort revealed dose-dependent relationships between PRS and risks of Alzheimer's disease, multiple sclerosis, and Parkinson's disease, with limited support for ALS and PTSD.

CONCLUSIONS: These findings illuminate the shared genetic architecture between PTSD and neurodegenerative phenotypes, advancing our understanding of their neurobiological interconnections. And enhance statistical power for detecting shared loci, thereby refining the characterization of common genetic mechanisms underlying PTSD and neurodegenerative pathologies.},
}

@article {pmid41376208,
year = {2025},
author = {Li, X and Gao, W and Ye, Q and Li, H},
title = {The Role and Therapeutic Potential of the cGAS-STING Signaling Pathway in Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {15},
number = {12},
pages = {e71130},
doi = {10.1002/brb3.71130},
pmid = {41376208},
issn = {2162-3279},
support = {LH2023H064// Natural Science Foundation of Heilongjiang Province of China/ ; 82105035//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Nucleotidyltransferases/metabolism ; *Signal Transduction/physiology ; *Membrane Proteins/metabolism ; Animals ; Autophagy/physiology ; },
abstract = {PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, posing a significant challenge to global public health. As a core signaling pathway in the mammalian innate immune system, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in maintaining intracellular homeostasis. This review aims to systematically elucidate the role and therapeutic potential of the cGAS-STING signaling pathway in AD, focusing on its involvement in key pathological processes and its relevance to AD risk factors.

METHOD: Through literature search, we summarized the molecular mechanisms of the cGAS-STING pathway and its dysregulation in AD, emphasizing the integrated evidence linking cGAS-STING to neuroinflammation, autophagy impairment, and neuronal death, as well as its interactions with aging, obesity, cardiovascular disease, and diabetes.

FINDINGS: The cGAS-STING pathway is critically involved in AD pathogenesis, contributing to neuroinflammation, defective autophagy, and neuronal loss. Its activation is associated with multiple AD risk factors, suggesting a broad influence on disease progression. Pharmacological inhibition of cGAS-STING shows promise in attenuating these pathological features in preclinical models.

CONCLUSION: The cGAS-STING signaling pathway plays a central regulatory role in the central nervous system, and its dysregulation promotes neuroinflammation and is closely associated with AD. This pathway forms a vicious cycle by integrating multiple pathological signals, including mitochondrial dysfunction and endoplasmic reticulum stress. Small-molecule inhibitors and natural products targeting this pathway have demonstrated significant efficacy in preclinical studies, providing a basis for developing disease-modifying therapies for AD. Future efforts should focus on multi-target combination strategies (e.g., STING inhibitors co-administered with Aβ/tau drugs) and dynamically deciphering pathway alterations across AD stages to advance personalized treatment approaches.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Nucleotidyltransferases/metabolism
*Signal Transduction/physiology
*Membrane Proteins/metabolism
Animals
Autophagy/physiology

@article {pmid41376207,
year = {2025},
author = {Zhang, R and Li, B and Miao, Y},
title = {Alcohol consumption and risk of dementia: a systematic review and meta-analysis.},
journal = {Internal medicine journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/imj.70288},
pmid = {41376207},
issn = {1445-5994},
support = {82074530//National Natural Science Foundation of China/ ; },
abstract = {To examine the relationship between alcohol intake and the risk of developing dementia, we conducted a comprehensive search of PubMed, Embase, Cochrane Library and Web of Science databases for relevant studies up to July 22, 2024. The quality of the original studies was appraised utilising the Newcastle-Ottawa Scale (NOS). The link between alcohol intake and the risk of dementia was presented using relative risks (RRs) and their corresponding 95% confidence intervals (CIs). Subgroup analyses were implemented based on the level of alcohol consumption, geographic region and age. All statistical analyses were executed utilising Stata 15.0. The meta-analysis unveiled no significant link between alcohol exposure and the risk of developing dementia, including all-cause dementia (ACD) (RR = 1.03, 95% CI: 0.84-1.27), Alzheimer disease (AD) (RR = 0.97, 95% CI: 0.86-1.08), vascular dementia (VD) (RR = 1.09, 95% CI: 0.95-1.26) and other dementia (RR = 0.62, 95% CI: 0.33-1.15). In the subgroup analysis by drinking levels, light to moderate alcohol intake was linked to a decreased risk of ACD and AD (RR = 0.88, 95% CI: 0.81-0.96; RR = 0.88, 95% CI: 0.79-0.97, respectively). Nonetheless, heavy alcohol consumption significantly increased the risk of developing all types of dementia (ACD, RR = 1.18, 95% CI: 1.02-1.36; AD, RR = 1.29, 95% CI: 1.21-1.36; VD, RR = 1.25, 95% CI: 1.11-1.40). Further subgroup analyses indicated that light to moderate drinking's protective effect was stronger in Europe and among individuals aged 60 to 69 years. Light to moderate drinking may protect against dementia, while heavy drinking or alcohol use disorders raises dementia risk.},
}

@article {pmid41376134,
year = {2025},
author = {Pan, FF and Huang, L and Wang, Y and Huang, Q and Guan, YH and Li, YH and Xie, F and Guo, QH},
title = {Plasma P-tau217, GFAP, and NfL as biomarkers for Alzheimer's disease: role in disease stratification, pathological progression, and cognitive decline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70987},
doi = {10.1002/alz.70987},
pmid = {41376134},
issn = {1552-5279},
support = {82171198//National Natural Science Foundation of China/ ; 202440010//Shanghai Municipal Commission of Health Research Project/ ; 202440009//Shanghai Municipal Commission of Health Research Project/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/pathology/diagnosis ; *Neurofilament Proteins/blood ; Biomarkers/blood ; *Glial Fibrillary Acidic Protein/blood ; Male ; Female ; Disease Progression ; *Cognitive Dysfunction/blood/pathology ; Aged ; Amyloid beta-Peptides ; Hippocampus/pathology ; Phosphorylation ; Atrophy/pathology ; Cohort Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Blood-based phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) show promise for Alzheimer's disease (AD), while their links to brain amyloid beta (Aβ)/tau, hippocampal atrophy, and cognitive decline need further investigation.

METHODS: A cohort of 1275 participants, representing various cognitive stages, was recruited to examine the links between plasma biomarkers and brain Aβ/tau stages, tau progression, hippocampal atrophy, and cognitive decline.

RESULTS: Plasma p-tau217 effectively distinguished A-T-/A-T+ individuals and A+T+Braak III-VI patients, though it identified early A+T-/A+T+Braak I-II stages only in Aβ+ subjects. Plasma GFAP levels plateau beyond a certain tau threshold, while Aβ-induced tau progression occurred only in those with high GFAP. Plasma NfL showed a weak link to brain Aβ and tau pathology, hippocampal atrophy, and typical AD cognitive decline.

DISCUSSION: Plasma p-tau217 aids in disease stratification, and GFAP promotes tau progression, while NfL is inadequate as a neuronal injury biomarker for AD.

HIGHLIGHTS: Plasma p-tau217 is strongly linked to brain Aβ/tau burdens and effectively differentiates between various Aβ/tau stages. Elevated plasma levels of GFAP consistently contributed to the Aβ-induced tau progression across various Braak stages. Plasma NfL exhibits limited associations with Aβ/tau pathology, AD-specific hippocampal atrophy, and cognitive decline.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/pathology/diagnosis
*Neurofilament Proteins/blood
Biomarkers/blood
*Glial Fibrillary Acidic Protein/blood
Male
Female
Disease Progression
*Cognitive Dysfunction/blood/pathology
Aged
Amyloid beta-Peptides
Hippocampus/pathology
Phosphorylation
Atrophy/pathology
Cohort Studies
Aged, 80 and over

@article {pmid41376120,
year = {2025},
author = {Kemna, RE and Kueck, PJ and Blankenship, A and John, CS and Johnson, CN and Green, ZD and Mayfield, H and Yoksh, L and Johnson, L and Thyfault, JP and Mahnken, JD and Miller, BF and Morris, JK},
title = {Acute effects of lactate infusion on metabolism, AD biomarkers, and cognition: The LEAN study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70984},
doi = {10.1002/alz.70984},
pmid = {41376120},
issn = {1552-5279},
support = {R01AG081421/NH/NIH HHS/United States ; R01AG080589/NH/NIH HHS/United States ; F31AG091982/NH/NIH HHS/United States ; F30AG076278/NH/NIH HHS/United States ; T32AG078114/NH/NIH HHS/United States ; P30AG072973/NH/NIH HHS/United States ; P20GM148326//the CNS Metabolism COBRE/ ; /ALZ/Alzheimer's Association/United States ; T32AG078114//The Margaret "Peg" McLaughlin and Lydia A. Walker Opportunity Fund/ ; P30AG072973//The University of Kansas Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/metabolism ; Aged ; *Lactic Acid/administration & dosage/metabolism ; *Cognition/drug effects ; tau Proteins/blood ; *Cognitive Dysfunction/metabolism/drug therapy ; Glial Fibrillary Acidic Protein/blood ; Neuropsychological Tests ; Brain-Derived Neurotrophic Factor/blood ; },
abstract = {BACKGROUND: Impaired cerebral glucose metabolism is a hallmark of Alzheimer's disease (AD). Lactate is an alternative brain fuel; however, whole-body lactate metabolism has not been measured in AD.

METHODS: The Lactate for Energy and Neurocognition Trial (NCT05207397) was a single-arm trial that enrolled 24 cognitively healthy (CH) older adults and 12 cognitively impaired (CI) participants. Subjects underwent a stable isotope lactate infusion to evaluate lactate metabolism, cognitive testing, and blood biomarker analyses. pTau217, brain-derived tau (BD-tau), pTau181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total tau, and brain-derived neurotrophic factor (BDNF) were analyzed by Simoa HD-X (Quanterix).

RESULTS: Lactate metabolic clearance rate did not differ between CH and CI subjects (p = 0.988). After infusion, global cognition was improved (p < 0.001) and plasma pTau217 (-33.8%, p < 0.001), BD-tau (-32.6%, p < 0.001), pTau181 (-21.4%, p < 0.001), GFAP (-39.7%, p < 0.001), and NfL (-19.5%, p < 0.001) were reduced.

CONCLUSIONS: Lactate turnover was not different between diagnosis groups. Lactate infusion improved cognition and reduced AD fluid biomarkers.

HIGHLIGHTS: Individuals with Alzheimer's disease (AD) can metabolize lactate as well as healthy controls. Lactate infusion might improve global cognition and processing speed. Lactate infusion results in significant decrease of AD fluid biomarkers.},
}

Humans
Biomarkers/blood
Male
Female
*Alzheimer Disease/metabolism
Aged
*Lactic Acid/administration & dosage/metabolism
*Cognition/drug effects
tau Proteins/blood
*Cognitive Dysfunction/metabolism/drug therapy
Glial Fibrillary Acidic Protein/blood
Neuropsychological Tests
Brain-Derived Neurotrophic Factor/blood

@article {pmid41375975,
year = {2025},
author = {Song, Y and Pan, W and Meng, L and Wu, H and Li, B and Han, X and Fu, T and Liang, W and Zhou, S and Ma, W},
title = {A Novel Probiotic Limosilactobacillus fermentum IOB802 and Its Postbiotic Alleviate Cognitive Impairment Induced by Scopolamine in Mice.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {23},
pages = {},
doi = {10.3390/foods14234037},
pmid = {41375975},
issn = {2304-8158},
support = {24YFZCSN00320//Tianjin Key Research and Development Program/ ; ZR2022MH126//Natural Science Foundation of Shandong Province/ ; },
abstract = {Cognitive impairment is acknowledged as an early stage between normal aging and Alzheimer's disease, emphasizing the need for prompt intervention. There is growing evidence that the gut-brain axis plays a role in regulating cognitive function, indicating that probiotics and their derivatives may impact cognitive functions through the brain-gut axis. In this study, we isolated and identified a novel bacterial strain Limosilactobacillus fermentum IOB802 (IOB802) from traditionally fermented pickles. This strain showed promising probiotic properties, and its postbiotic was also prepared. Both the probiotic IOB802 and its postbiotic preparation significantly improved memory and learning abilities by using a mouse model with cognitive impairment induced by scopolamine. In comparison to the scopolamine group, IOB802 and IOB802 postbiotic administration decreased acetylcholinesterase activity by 59.2% and 29.51%, increased antioxidant enzyme activity by 44.45% and 29.43%, and lowered lipid peroxidation by 44.19% and 32.53%, respectively. Moreover, IOB802 postbiotic notably boosted acetylcholine levels by 72.08%. In addition, the treatments preserved the integrity of neurons in specific regions of the hippocampus, as shown by histological analysis. The IOB802 postbiotic increased the expression of neurotrophic factors BDNF and NGF by 1.36- and 1.73-fold, while reducing the expression of inflammatory cytokines TNF-α, IL-6, and IL-1β by 2.05-, 1.85-, and 2.46-fold, respectively. Compared to the scopolamine group, IL-6 and IL-1β expression decreased by 1.32- and 2.37-fold in the IOB802 group. Additionally, IOB802, especially its postbiotic, was found to restore disrupted intestinal flora caused by scopolamine. These findings suggest that IOB802 and its postbiotic can improve cognitive function through enhancing cholinergic activity, reducing oxidative stress, providing neuroprotection, and restoring gut microbiota composition. Postbiotics, in particular, may represent a promising alternative to live probiotics for supporting cognitive health.},
}

@article {pmid41375768,
year = {2025},
author = {Eckert, M and Ostermann, T and Ehlers, JP and Hohenberg, G},
title = {Immersive, Open-World Virtual Reality for Dementia Care: NeuroVRX Pilot Study.},
journal = {Journal of clinical medicine},
volume = {14},
number = {23},
pages = {},
doi = {10.3390/jcm14238465},
pmid = {41375768},
issn = {2077-0383},
abstract = {Background: The increasing prevalence of Alzheimer's disease and related dementia are a global problem generating social and economic burdens. Cognitive Stimulation Therapy is a non-pharmaceutical aid for people with dementia. In this context, digital and virtual reality approaches are underinvestigated, especially with respect to explorable open-world environments. The pilot aims to evaluate the feasibility, acceptability, and safety of an immersive, open-world virtual reality application for people with dementia. Methods: We conducted a single-arm, unrandomised study with three male participants diagnosed with dementia. The intervention consisted of a single virtual reality session in an immersive, open-world environment, where participants were able to explore freely while seated, using arm movements and head control to navigate an avatar. Results: All three participants finished the session without the occurrence of adverse events. The mean session time was 28 min, and the average walking distance was 0.9 km, with 1210 steps on average. Questionnaire results indicate acceptance and a positive attitude toward the usability of the intervention. We measured minimal changes in mood. Anecdotal reports indicate high immersion and autobiographical stimulation. We detected no adverse events or occurrences of cybersickness. Conclusions: Immersive, open-world virtual reality proved to be feasible, safe, and well accepted by the participants. The combination of state-of-the-art hardware and exploration-based software design enabled cognitive and motoric stimulation. The results indicate strong feasibility for the application of exploratory three dimensional virtual reality applications and further support the execution of controlled trials to assess therapeutic outcomes.},
}

@article {pmid41375604,
year = {2025},
author = {Chen, SS and Chang, YC and Yu, CY and Hsieh, TY and Sung, WW},
title = {Differential Risks of Dementia, Depression, and Injury Among Common α-Blockers, with Tamsulosin as the Reference Drug: A Real-World Cohort Study in Men with Lower Urinary Tract Symptoms.},
journal = {Journal of clinical medicine},
volume = {14},
number = {23},
pages = {},
doi = {10.3390/jcm14238302},
pmid = {41375604},
issn = {2077-0383},
support = {NSTC 113-2314-B-040-023//National Science and Technology Council/ ; CSH-2025-D-004//Chung Shan Medical University Hospital/ ; },
abstract = {Background/Objectives: Although α-blockers are commonly used to treat lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH), their differential neuropsychiatric safety profiles remain underexplored. Some studies have suggested an increased risk of cognitive decline, mood disorders, and falls, but the results remain inconclusive. Methods: We conducted a large retrospective cohort study using the TriNetX global network, identifying over 264,000 men treated with a single α-blocker between 2005 and 2023. Patients were grouped by α-blocker type-tamsulosin, doxazosin, terazosin, alfuzosin, silodosin, or prazosin-and matched 1:1 using propensity scores to adjust for demographic, clinical, and psychosocial variables. The primary outcomes were new-onset dementia, depression, and unintentional injuries, assessed at 1-, 3-, and 10-year intervals. The median follow-up duration was approximately 5.5 years, ranging from 1824 to 2200 days across cohorts, indicating balanced observation periods among the six α-blocker groups. Results: Among the included patients, tamsulosin (n = 213,690) and prazosin (n = 1184) were associated with significantly higher risks of neurodegenerative, psychiatric, and injury-related outcomes. Alfuzosin (n = 10,138) exhibited the most favorable safety profile across all endpoints. The findings remained robust in sensitivity analyses, excluding patients with prior malignancy or other α-blocker exposure. Conclusions: Substantial differences in long-term neuropsychiatric safety exist among α-blockers. Given its favorable profile, alfuzosin may be the preferred agent in patients at elevated risk of cognitive or psychiatric disorders. These findings highlight the need for individualized α-blocker selection and long-term pharmacovigilance in BPH management.},
}

@article {pmid41375579,
year = {2025},
author = {O'Donnell, AJ and Zhao, X and Parr, A and Aspinall, S and Anderson, TS},
title = {Early Outcomes of Lecanemab for Alzheimer's Disease in the Veterans Health Administration.},
journal = {Journal of clinical medicine},
volume = {14},
number = {23},
pages = {},
doi = {10.3390/jcm14238277},
pmid = {41375579},
issn = {2077-0383},
support = {N/A//Technology Enhancing Cognition and Health - Geriatric Research Education and Clinical Center (TECH-GRECC), VA Pittsburgh Healthcare System/ ; },
abstract = {Background/Objectives: While lecanemab (Leqembi) and several amyloid targeting therapies were approved for Alzheimer's disease, questions remain on real-world implementation, safety, and effectiveness. The objective of this study was to describe the uptake and early outcomes of Veterans initiating lecanemab. Methods: This retrospective cohort study included Veterans who initiated lecanemab in the Veteran's Health Administration (VHA) between October 2023 and July 2024. Treatment persistence and monitoring, change in Montreal Cognitive Assessment (MoCA) score, incidence of adverse events, including amyloid-related imaging abnormalities (ARIA), and healthcare utilization were analyzed at 7 months. Results: Overall, 32 Veterans (mean [SD] age 75.3 [6.0] years, 100% male, 97% white, 84% urban dwelling) initiated lecanemab. Seventeen patients (53%) had mild cognitive impairment, 15 (47%) had mild dementia; mean baseline MoCA score was 21.3 (SD 3.4). At 7 months following treatment initiation, we assessed process, safety, and effectiveness outcomes. Process outcomes: In all, 25 patients (78%) were persistent with treatment. Safety outcomes: Three patients (9%) experienced a stroke, and 7 (22%) experienced ARIA. Effectiveness outcomes: Only 12 (38%) patients had a MoCA completed by 7 months, and the mean change in MoCA was 0.0 (SD 3.7, p = 1.0). A follow-up amyloid positron emission tomography (PET) scan was completed by 9 (28%) patients, and 5 had reductions in amyloid. Conclusions: Initial observations in a small VHA cohort suggest that uptake of lecanemab was limited, and the finding that nearly 30% of patients experienced ARIA or stroke within 7 months of initiation underscores the importance of monitoring the lecanemab safety and effectiveness long-term. These early findings should be interpreted cautiously given the limited sample size and very limited follow-up MoCA data.},
}

@article {pmid41375185,
year = {2025},
author = {Vieira, RC and Nascimento, LA and Nascimento, AA and Alves, NRM and Nascimento, ÉCM and Martins, JBL},
title = {NCIVISION: A Siamese Neural Network for Molecular Similarity Prediction MEP and RDG Images.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {23},
pages = {},
doi = {10.3390/molecules30234589},
pmid = {41375185},
issn = {1420-3049},
support = {306682/2021-4 and 308419/2025-1//National Council for Scientific and Technological Development/ ; 00193-00000869/2021-31//Foundation for Research Support of the Federal District/ ; },
mesh = {*Neural Networks, Computer ; Static Electricity ; *Drug Discovery/methods ; Humans ; Cholinesterase Inhibitors/chemistry/pharmacology ; Protein Kinase Inhibitors/chemistry/pharmacology ; },
abstract = {Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer's disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates.},
}

*Neural Networks, Computer
Static Electricity
*Drug Discovery/methods
Humans
Cholinesterase Inhibitors/chemistry/pharmacology
Protein Kinase Inhibitors/chemistry/pharmacology

@article {pmid41375178,
year = {2025},
author = {Tsopka, IC and Pontiki, E and Sigala, I and Nikolakaki, E and Prousis, KC and Hadjipavlou-Litina, D},
title = {Design, Synthesis, Biological Evaluation, and In Silico Studies of Novel Multitarget Cinnamic Acid Hybrids.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {23},
pages = {},
doi = {10.3390/molecules30234582},
pmid = {41375178},
issn = {1420-3049},
mesh = {*Cinnamates/chemistry/pharmacology/chemical synthesis ; Humans ; *Drug Design ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; Lipoxygenase Inhibitors/pharmacology/chemical synthesis/chemistry ; Lipid Peroxidation/drug effects ; Molecular Docking Simulation ; Cyclooxygenase Inhibitors/pharmacology/chemical synthesis/chemistry ; Computer Simulation ; Structure-Activity Relationship ; Nitric Oxide Donors/chemistry/pharmacology/chemical synthesis ; Nitric Oxide ; Lipoxygenase/metabolism ; Molecular Structure ; Cell Line, Tumor ; Cyclooxygenase 2/metabolism/chemistry ; },
abstract = {Chronic inflammation is implicated in the development of various multifactorial diseases, including cancer, diabetes, arthritis, cardiovascular disorders, Alzheimer's disease, and autoimmune diseases. The enzymes that play a key role in the onset of the inflammation are cyclooxygenases (COXs) and lipoxygenases (LOXs). In recent years, cinnamic acid hybrid molecules, particularly those incorporating a nitric oxide (NO) donor moiety, have attracted considerable attention as potential pharmacological agents for the treatment of multifactorial diseases. In the present study, novel cinnamic acid-nitric oxide (NO) donor hybrids were synthesized as multitarget agents and evaluated for their antioxidant, anti-inflammatory, and cytotoxic properties. In particular, hybrids 5a-i, 6a-i, 9a-i, and 11 were synthesized and evaluated as lipid peroxidation and LOX inhibitors, while selected molecules were further tested as COX-1 and COX-2 inhibitors. Hybrids 6a-i, 9a-i, and 11 that contain a NO donor moiety, were additionally tested as albumin denaturation inhibitors and for their ability to release NO. The results indicated that compound 9a is a promising multitarget agent, exhibiting the lowest IC50 for LOX inhibition, significant antioxidant activity, and the highest NO donor potency. Furthermore, compound 9e demonstrated significant inhibitory activity against both COX-2 and LOX, suggesting its potential as a dual COX-LOX inhibitor. Additionally, compound 6i exhibited the strongest cytotoxic activity among the tested compounds, with EC50 values ranging from 36 to 45 μM across multiple cancer cell lines. All synthesized compounds were also evaluated through in silico studies.},
}

*Cinnamates/chemistry/pharmacology/chemical synthesis
Humans
*Drug Design
Antioxidants/pharmacology/chemistry/chemical synthesis
Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry
Lipoxygenase Inhibitors/pharmacology/chemical synthesis/chemistry
Lipid Peroxidation/drug effects
Molecular Docking Simulation
Cyclooxygenase Inhibitors/pharmacology/chemical synthesis/chemistry
Computer Simulation
Structure-Activity Relationship
Nitric Oxide Donors/chemistry/pharmacology/chemical synthesis
Nitric Oxide
Lipoxygenase/metabolism
Molecular Structure
Cell Line, Tumor
Cyclooxygenase 2/metabolism/chemistry