@article {pmid40962322,
year = {2025},
author = {Vos-Draper, T and Vinoski Thomas, E and Graybill, E and Morrow, M and Jordan, KA and Manley, PR and Sonenblum, SE},
title = {Stakeholder Perspectives on mHealth Technologies to Prevent Sitting-Acquired Pressure Injuries in Long-Term Care Facilities: Mixed Methods Study.},
journal = {JMIR formative research},
volume = {9},
number = {},
pages = {e59590},
doi = {10.2196/59590},
pmid = {40962322},
issn = {2561-326X},
mesh = {Humans ; *Pressure Ulcer/prevention & control ; *Long-Term Care/methods ; Male ; Female ; *Sitting Position ; *Telemedicine ; *Stakeholder Participation/psychology ; Aged ; Alzheimer Disease/complications ; Dementia/complications ; Surveys and Questionnaires ; Nursing Homes ; Wheelchairs/adverse effects ; Middle Aged ; Qualitative Research ; United States ; },
abstract = {BACKGROUND: Adults with Alzheimer disease (AD) or Alzheimer disease and related dementias (ADRD) who require a wheelchair to accommodate disease-associated decline in mobility are at elevated risk for pressure injuries. More than half of residents in long-term care (LTC) facilities in the United States experience AD or ADRD. In LTC facilities, bed-based technologies exist to facilitate pressure injury prevention efforts, but similar technologies have not yet been widely evaluated to address sitting-related pressure injuries.

OBJECTIVE: This study aimed to determine preliminary design inputs from care providers for technology to address sitting-related pressure injury prevention in LTC settings. Specifically, we sought to (1) understand the types and use of sitting-related equipment used in LTC for residents with AD or ADRD, (2) identify challenges faced by nurses and other caregivers when repositioning seated residents, and (3) understand care provider preferences for features of future sitting-related feedback technologies designed to facilitate effective and timely repositioning.

METHODS: Surveys (n=30) and semistructured interviews (n=9) of administrative and direct care providers in LTC facilities were administered. Survey results were summarized, and we used thematic qualitative analysis of interview responses to develop themes around challenges experienced by care providers and their perceptions about how technologies could facilitate the prevention of sitting-related pressure injuries.

RESULTS: Survey respondents endorsed using many sitting surfaces for LTC residents with memory loss, such as padded reclining chairs, bedside or dining chairs, and wheelchairs with cushions. All indicated that shared equipment is provided by the facility, and 43% of respondents reported having access to a seating specialist at their facility. Sitting time was typically up to 12 hours per day. Themes related to pressure injury prevention in the LTC context, specific to those with memory loss, included (1) barriers to repositioning seated residents vary with the degree of memory loss, (2) care providers are aware of guidelines and policies around the 2-hour repositioning schedule, and (3) care providers are interested in technologies that have relative value over added burden. Care providers expressed interest in mobile health (mHealth) technologies that provide automatic repositioning in later stages of memory loss, delivery of cues for residents with mild memory loss to encourage independent repositioning, and tools to monitor resident sitting and pressure-related outcomes.

CONCLUSIONS: These findings highlight the complexity of addressing the repositioning needs of seated LTC residents with AD or ADRD using mHealth technologies due to changes as the disease progresses. mHealth technologies should encourage more independence by residents experiencing milder memory loss, with increasing automaticity in repositioning residents in later stages. Both approaches could potentially minimize care provider burden in repositioning seated residents throughout the day. Design, development, and implementation of technologies should carefully weigh benefit versus burden to care providers and residents and continue to engage with them for feedback as development progresses.},
}

Humans
*Pressure Ulcer/prevention & control
*Long-Term Care/methods
Male
Female
*Sitting Position
*Telemedicine
*Stakeholder Participation/psychology
Aged
Alzheimer Disease/complications
Dementia/complications
Surveys and Questionnaires
Nursing Homes
Wheelchairs/adverse effects
Middle Aged
Qualitative Research
United States

@article {pmid40962260,
year = {2025},
author = {Swain, S and Metya, AK},
title = {Computational Insights into Dopamine-Mediated Conformational Transitions of Aβ Aggregates in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00456},
pmid = {40962260},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a looming neurological pandemic that affects over 57 million individuals globally and poses a challenge for the healthcare system due to its complex etiology and the fact that it remains incurable despite extensive research efforts. Among the various pathological contributors, dopaminergic dysfunction has emerged as a critical factor implicated in AD, causing apathy, depression, cognitive decline, and hallucinations, which significantly exacerbate disease progression and patient morbidity. Despite dopamine's multifarious role in modulating β-amyloid (Aβ) aggregation and in the pathogenesis of AD, the precise molecular interaction mechanism remains poorly understood. In this study, we employ molecular dynamics (MD) simulations to elucidate dopamine's conformation-specific interactions with Aβ across four hierarchical aggregation states: monomer, trimer, pentamer, and a nine-chain fibrillar assembly. This computational approach reveals that dopamine strongly perturbs the monomeric and trimeric forms, disrupting β-sheet structures and promoting α-helix formation. At the pentameric state, dopamine induces partial α-helix formation while weakening interchain hydrogen bonds and salt bridge interactions, indicating intermediate destabilization. In sharp divergence, the mature fibril exhibits structural rigidity with minimal conformational alteration and no disruption in the β-sheet content. These findings provide an advanced understanding of the conformation-dependent modulation mechanism whereby dopamine selectively interferes with the early nucleation phase rather than fibril elongation; also dopamine exhibits the most pronounced β-sheet disruption in monomers but shows progressively diminished efficacy in higher-order oligomeric and fibrillar assemblies. This selective interaction landscape highlights dopamine's potential as a modulator of early amyloidogenic events and offers novel insights for understanding dopamine-based therapeutic strategies for AD.},
}

@article {pmid40962171,
year = {2025},
author = {Villavicencio-Tejo, F and Olesen, MA and Leonardo Moya, M and Quintanilla, RA},
title = {Disentangling the role of tau pathology in autism spectrum disorders.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111496},
doi = {10.1016/j.pnpbp.2025.111496},
pmid = {40962171},
issn = {1878-4216},
abstract = {Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction, altered communication, and repetitive, stereotyped behaviors. Pathologically, ASD is characterized by abnormal brain development, including dendritic spine and axonal alterations, which are both associated with synaptic plasticity disturbances. Microtubules (MT) and microtubule-associated proteins (MAPs) are critical in regulating brain development by the neuronal cytoskeleton and synaptic formation. Tau is a neuronal MAP protein in which pathological posttranslational modifications (PTMs) are involved in the pathogenesis of neurodegenerative diseases (NDs), including Alzheimer's disease (AD). In this context, accumulative evidence suggests that tau is altered in mouse models and human patients of ASD. Toxic tau modifications like hyperphosphorylation, a disruptor of MTs dynamics, produced alterations in ASD, suggesting that the imbalance of this protein may contribute to neurodevelopmental deficiencies produced during ASD. In this systematic review, we revised essential evidence suggesting that the dysregulation of cytoskeletal components produced by tau pathology could play a crucial role in the pathological and behavioral changes produced in ASD. Finally, we will focus on discussing how the presence of tau pathology in ASD contributes to brain development impairment and whether pathological forms of tau could be suggested as a novel biomedical strategy to support the diagnosis of this disorder.},
}

@article {pmid40962157,
year = {2025},
author = {Xu, G and Angelle, C and Huilgol, D and Sacilotto, P and McFarland, KN and Fromholt, S and Lopez, A and Vo, Q and Rivasplata, A and Brkic, S and Gorski, C and Bali, P and Lu, Q and Borchelt, DR and Chakrabarty, P},
title = {Comparison of the ApoE allelic variants in the formation of intracerebral Aβ deposits.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107105},
doi = {10.1016/j.nbd.2025.107105},
pmid = {40962157},
issn = {1095-953X},
abstract = {The Apolipoprotein E (APOE) isoforms APOE2, APOE3 and APOE4 differentially modulate risk of Alzheimer's disease (AD). Despite established evidence for APOE's impact on Aβ deposition, the differential effects of APOE genotypes on distinct forms of amyloid pathology remain poorly understood. The three primary types of amyloid pathology in the brain are dense-cored fibrillar plaques, diffuse Aβ deposits, and vascular deposits in the form of cerebral amyloid angiopathy (CAA) and their relative distribution is thought to be important in determining the phenotypic outcomes in AD and related dementias. Here, we used different mouse models of AD-amyloidosis to ask two main questions: (1) does human APOE4 promote the deposition of all these subtypes of types of amyloid pathology, and (2) does presence of APOE4 influence the morphological transformation of diffuse Aβ deposits into dense-core neuritic plaques? In the SAA-APP knock-in model of dense-cored Aβ deposits resulting from accumulation of protofibrillar-favoring Aβ42, we observed that crossing in human Apoe reduced amyloid burden. Among the three human APOE alleles, APOE4 produced the highest plaque burden and size, relative to APOE3 and APOE2 in the SAA-APP mice. Though all three human APOE isoforms showed comparable levels of colocalization with individual plaques, focused genomic analysis at early stages of pathology revealed that neural connectivity pathways were affected in mice with human APOE4 compared to human APOE3, implicating mechanisms of early neuronal dysfunction. In the slowly-developing APPsi model, characterized by predominantly diffuse Aβ deposits and cerebral amyloid angiopathy (CAA) emerging at older ages, we also found that mouse Apoe showed the greatest amyloid burden, followed by human APOE4 and APOE3. CAA deposition was noted in aged APPsi mice with mouse Apoe or human APOE4 mice but rarely in APPsi mice with human APOE3. Finally, neonatal Aβ seeding in APPsi mice revealed that APOE4 accelerated parenchymal Aβ deposition compared to APOE3 mice, though seeding in the presence of APOE4 did not alter the inherent diffuse morphology of the Aβ deposits. Collectively, these results demonstrate that APOE genotype influences the deposition of all types of amyloid pathology, including dense-cored, diffuse and vascular pathology. Notably, only the amount of amyloid was modified by APOE variants, while the type of amyloid pathology inherent in each model was not altered. Together these findings implicate a key role for apoE as a modifier of all types of Aβ deposition with limited potential to modify plaque compaction or morphology.},
}

@article {pmid40962154,
year = {2025},
author = {Kedhem, M and Altalbawy, FMA and Baldaniya, L and Jyothi, R and Maharana, L and Chauhan, AS and Joshi, N and Islamova, K and Garg, G and Muzammil, K},
title = {Pharmacological landscape of linarin: From benchside mechanisms to potential bedside applications.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {106876},
doi = {10.1016/j.fitote.2025.106876},
pmid = {40962154},
issn = {1873-6971},
abstract = {Linarin, a glycosylated flavonoid derived from medicinal plants such as Buddleja and Chrysanthemum species, has emerged as a bioactive compound with significant pharmacological potential. This review provides a comprehensive overview of linarin's chemical structure, extraction methods, pharmacokinetics, and therapeutic applications. Linarin exhibits diverse biological activities, including anti-inflammatory, antioxidant, neuroprotective, and anticancer effects, making it a promising candidate for drug development. The flavonoid demonstrates protective effects against hyperuricemia, acute kidney injury, spinal cord injury, ischemic stroke, diabetes, osteoporosis, and inflammatory bowel disease, primarily through modulation of signaling pathways such as Nrf2/Keap1, NF-κB, and MAPK. Additionally, linarin has shown potential in managing neurodegenerative disorders, including Alzheimer's disease, through its acetylcholinesterase inhibitory activity. Its anti-cancer effects have been linked to the inhibition of proliferation, apoptosis induction, and suppression of metastasis-related pathways in lung, prostate, and brain cancers. Moreover, recent studies highlight its potential for ameliorating osteoarthritis, liver injury, and infectious diseases. The mechanisms underlying linarin's therapeutic effects involve its ability to modulate oxidative stress, inflammation, apoptosis, and metabolic pathways. Given its low toxicity, bioavailability, and structural versatility, linarin represents a compelling natural compound for future pharmaceutical applications. However, further preclinical and clinical investigations are warranted to fully elucidate its pharmacokinetics, optimize its bioavailability, and establish its clinical efficacy. This review advances a systems-level perspective that unifies linarin's pleiotropic mechanisms across several diseases. By linking structure-activity relationships with translational bottlenecks such as poor bioavailability and limited clinical validation, we outline a forward-looking roadmap for its development as a multi-target therapeutic scaffold.},
}

@article {pmid40962125,
year = {2025},
author = {Lian, W and Yuan, X and Zhou, F and Tong, Z and Cheng, Y and Zhang, W and He, J and Xu, J},
title = {Cornuside ameliorates LPS induced cognitive dysfunction and microglial NLRP3 inflammasome activation by enhancing Sirt1-mediated autophagy.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120615},
doi = {10.1016/j.jep.2025.120615},
pmid = {40962125},
issn = {1872-7573},
abstract = {Corni fructus are the fruits of Cornus officinalis Sieb. et Zucc. and is widely used in traditional Chinese Medicine for the treatment of dementia. Cornuside, derived from Corni fructus, has been shown to be effective in improving cognition of AD mouse.

AIM: In the present study, we investigated the effect of cornuside on cognitive dysfunction and microglial NLRP3 inflammasome activation, as well as explored the underlying mechanism with respect to Sirt1 and autophagy.

METHODS: AD mice were established and then treated with cornuside (3, 10, and 30 mg/kg) for 2 weeks. A series of behavioral tests were performed to assess cognition, including the Morris water maze, Y maze, nest building, step-down and step-through tests. Nissl staining was used to evaluate neuronal structural damage. LPS-stimulated BV2 cells were used for in vitro experiments. The anti-inflammatory effects of cornuside on cytokines and NLRP3 inflammasome activation were assessed using ELISA, RT-PCR, immunohistochemistry, western blotting, and immunofluorescence assays. To further elucidate the relationship between Sirt1, autophagy, and NLRP3 inflammasome activation, EX527 and 3-MA were used to inhibit Sirt1 and block autophagy flux in vitro, respectively.

RESULTS: Cornuside significantly improved various behavioral performance and inhibited NLRP3 inflammasome activation in LPS-induced mice, as evidenced by decreased levels of NLRP3, ASC, pro-caspase1, caspase1, pro-IL-1β, IL-1β, GSDMD, GSDMD-NT and IL-18. Similar inhibitory effects of cornuside on NLRP3 inflammasome activation was also detected in LPS stimulated BV2 cells. The involvement of Sirt1 and autophagy were further explored in-vivo and in-vitro, revealing that cornuside increased the expression of Sirt1 and enhanced autophagy, with decreased SQSTM1/p62 and increased LC3B II. However, the inhibitory effect of cornuside on NLRP3 inflammasome activation was abrogated by 3-MA, and the effects of cornuside on promoting autophagy and inhibiting NLRP3 inflammasome activation was abolished by EX527.

CONCLUSION: Cornuside exerts therapeutic effects on LPS induce AD mice by inhibiting microglial activation and NLRP3 inflammasome overactivation. And Sirt1 mediated autophagy activation is a vital mechanism by which cornuside degrades NLRP3 inflammasome, thereby alleviating neuroinflammation and improving cognitive function.},
}

@article {pmid40961986,
year = {2025},
author = {Pham, K and Salowe, R and Di Rosa, I and Hamedani, AG and Ying, GS and O'Brien, JM},
title = {The association between glaucoma and dementia in a national cohort of All of Us participants.},
journal = {Ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ophtha.2025.09.007},
pmid = {40961986},
issn = {1549-4713},
abstract = {PURPOSE: To assess the association between glaucoma and its subtypes and incidence of dementia and its subtypes across APOE genotypes in the National Institutes of Health (NIH) All of Us Research Program.

DESIGN: Retrospective longitudinal cohort study.

SUBJECTS: A cohort of individuals with linked electronic health record (EHR) data in the All of Us dataset, with every individual with a glaucoma diagnosis matched with four control participants. Participants diagnosed with dementia prior to glaucoma were excluded.

METHODS: A 1:4 cohort of participants with a glaucoma diagnosis and control participants was created using a propensity score matching design that considered age, race, ethnicity, and sex. Among participants with whole-genome sequencing data, APOE was genotyped to stratify for sub-analyses. Multivariable Cox regression model was used to adjust for residual imbalance in comorbidities: hypertension, obesity, depression, traumatic brain injury, type 2 diabetes, and hearing loss.

MAIN OUTCOME MEASURE: Incidence of dementia and its subtypes.

RESULTS: Among the 393497 All of Us participants with linked EHRs, we identified 9444 individuals (2.40%) with glaucoma diagnoses (excluding participants with diagnoses of dementia before glaucoma) and 37776 matched controls without glaucoma. During the observation period (median: 6.5 years, inter-quartile range: 3.3 to 10.7 years), dementia was diagnosed in 1127 (2.39%) individuals. Glaucoma was associated with a significantly increased risk of all-cause dementia (adjusted HR (aHR): 1.23, 95% CI: 1.08-1.40), Alzheimer's disease (aHR: 1.60, 95% CI: 1.26-2.02), and vascular dementia (aHR: 1.38, 95% CI: 1.04-1.83). Among glaucoma subtypes, primary open-angle glaucoma (POAG, N=5756) and normal-tension glaucoma (NTG, N=1106) was linked to elevated risk of Alzheimer's disease (POAG: aHR: 1.48, 95% CI: 1.11-1.96; NTG: aHR: 1.87, 95% CI: 1.09-3.18), while angle-closure glaucoma (N=3150) showed no significant association (aHR=1.49, 95% CI: 0.91-2.27). Glaucoma was associated with an increased risk of all-cause dementia across the three APOE genotypes assessed, with the greatest increased risk observed in ε2ε3 (N=4965, aHR: 1.76, 95% CI: 1.11-2.79), followed by ε3ε3 (N=23667, aHR: 1.45, 95% CI: 1.19-1.75) and ε3ε4 (N=8544, aHR: 1.43, 95% CI: 1.09-1.87).

CONCLUSIONS: Glaucoma was associated with a higher risk of dementia with varying associations among glaucoma and dementia subtypes across APOE genotypes.},
}

@article {pmid40961977,
year = {2025},
author = {Dolci, G and Cruciani, F and Rahaman, MA and Abrol, A and Chen, J and Fu, Z and Boscolo Galazzo, I and Menegaz, G and Calhoun, V},
title = {An interpretable generative multimodal neuroimaging-genomics framework for decoding Alzheimer's disease.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae087d},
pmid = {40961977},
issn = {1741-2552},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide, encompassing a prodromal stage known as Mild Cognitive Impairment (MCI), where patients may either progress to AD or remain stable. The objective of the work was to capture structural and functional modulations of brain structure and function relying on multimodal MRI data and Single Nucleotide Polymorphisms, also in case of missing views, with the twofold goal of classifying AD patients versus healthy controls and detecting MCI converters.

APPROACH: We propose a multimodal DL-based classification framework where a generative module employing Cycle Generative Adversarial Networks was introduced in the latent space for imputing missing data (a common issue of multimodal approaches). Explainable AI method was then used to extract input features' relevance allowing for post-hoc validation and enhancing the interpretability of the learned representations.

MAIN RESULTS: Experimental results on two tasks, AD detection and MCI conversion, showed that our framework reached competitive performance in the state-of-the-art with an accuracy of 0.926 ± 0.02 (CI [0.90, 0.95]) and 0.711 ± 0.01 (CI [0.70, 0.72]) in the two tasks, respectively. The interpretability analysis revealed gray matter modulations in cortical and subcortical brain areas typically associated with AD. Moreover, impairments in sensory-motor and visual resting state networks along the disease continuum, as well as genetic mutations defining biological processes linked to endocytosis, amyloid-beta, and cholesterol, were identified.

SIGNIFICANCE: Our integrative and interpretable DL approach shows promising performance for AD detection and MCI prediction while shedding light on important biological insights.},
}

@article {pmid40961582,
year = {2025},
author = {Song, X and Shu, K and Yang, P and Zhao, C and Zhou, F and Frangi, AF and Cao, J and Xiao, X and Wang, S and Wang, T and Lei, B and , },
title = {Developing a knowledge-guided federated graph attention learning network with a diffusion module to diagnose Alzheimer's disease.},
journal = {Medical image analysis},
volume = {107},
number = {Pt A},
pages = {103794},
doi = {10.1016/j.media.2025.103794},
pmid = {40961582},
issn = {1361-8423},
abstract = {In studies of Alzheimer's disease (AD), limited sample size considerably hampers the performance of intelligent diagnostic systems. Using multi-site data increases sample size but raises concerns regarding data privacy and inter-site heterogeneity. To address these issues, we developed a knowledge-guided federated graph attention learning network with a diffusion module to facilitate AD diagnosis from multi-site data. We used multiple templates to extract regions-of-interest (ROI)-based volume features from structural magnetic resonance imaging (sMRI) data. These volume features were then combined with previously identified AD features from published studies (prior knowledge) to determine the discriminative features within the images. We then designed an attention-guided diffusion module to synthesize samples by prioritizing these key features. The diffusion module was trained within a federated learning framework, which ensured inter-site data privacy while limiting data heterogeneity. Finally, we designed a federated graph attention learning network as a classifier to capture AD-related deep features and improve the accuracy of diagnosing AD. The efficacy of our approach was validated using three AD datasets. Thus, the classifier developed in this study represents a promising tool for optimizing multi-site neuroimaging data to improving the accuracy of diagnosing AD in the clinic.},
}

@article {pmid40961311,
year = {2025},
author = {Adelman, M and Hull, ML},
title = {Donanemab (Kisunla) for the Slowing of Alzheimer Disease.},
journal = {American family physician},
volume = {112},
number = {3},
pages = {320-321},
pmid = {40961311},
issn = {1532-0650},
}

@article {pmid40961302,
year = {2025},
author = {Qiu, J and Jiang, D},
title = {Galantamine for Dementia due to Alzheimer Disease and Mild Cognitive Impairment.},
journal = {American family physician},
volume = {112},
number = {3},
pages = {258-259},
pmid = {40961302},
issn = {1532-0650},
}

@article {pmid40961174,
year = {2025},
author = {Wang, W and Liu, H and Chen, Y and Xiong, Z and Liu, M and Wang, Z and Ye, W and Li, X},
title = {Identifying differential brain structures and genetic mechanisms between Alzheimer's disease and idiopathic normal pressure hydrocephalus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379046},
doi = {10.1177/13872877251379046},
pmid = {40961174},
issn = {1875-8908},
abstract = {BackgroundIdiopathic normal pressure hydrocephalus (INPH) is a reversible neurological disorder presenting with cognitive decline, urinary incontinence, and gait disturbance, yet it is often misdiagnosed as Alzheimer's disease (AD) due to overlapping features. Magnetic resonance imaging (MRI) highlights structural differences, but their causal links to disease manifestations remain unclear.ObjectiveTo investigate the causal relationships between brain structures and INPH/AD through Mendelian randomization (MR) and to explore genetic mechanisms underlying structural variations.MethodsWe analyzed 83 brain phenotypes from the UK Biobank and INPH/AD data from the FinnGen cohort using bidirectional MR. Differentially expressed genes (DEGs) in MR-identified brain regions were obtained from the Allen Human Brain Atlas and examined via bioinformatics analyses.ResultsMR revealed 12 brain structures associated with INPH and 5 with AD, identifying 13 distinct regions differentiating the two disorders across temporal, frontal, occipital, and parietal lobes, as well as the basal ganglia and limbic system. Genetic analyses identified 205 DEGs linked to these regions, enriched in pathways regulating neurodevelopment, neuronal differentiation, and synaptic plasticity. Notably, the neuroactive ligand-receptor interaction pathway was significantly implicated, suggesting a mechanism contributing to cerebrospinal fluid circulation abnormalities in INPH.ConclusionsThis study integrates MR and bioinformatics to reveal structural and genetic factors distinguishing INPH from AD. These findings provide new insights into the pathogenesis of INPH, improve diagnostic precision, and may inform targeted therapeutic strategies.},
}

@article {pmid40961173,
year = {2025},
author = {Mao, C and Zou, Y and Wang, T and Sha, L and Wu, M and Chu, S and Jin, W and Li, B and Huang, Y and Qiu, Y and Bao, J and Wang, W and Jiang, Y and Dong, L and Feng, F and Huo, L and Teunissen, C and Qiu, L and Gao, J},
title = {Comparison of diagnostic accuracy of Alzheimer's disease cerebrospinal fluid core biomarkers using INNOTEST, Lumipulse G, and Elecsys assays: Insights from the PUMCH dementia cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379084},
doi = {10.1177/13872877251379084},
pmid = {40961173},
issn = {1875-8908},
abstract = {BackgroundCerebrospinal fluid (CSF) core biomarkers play a pivotal role in the biological diagnosis of Alzheimer's disease (AD). While various commercial assays and kits are available for quantifying these biomarkers, their performance across diverse clinical settings remains insufficiently evaluated.ObjectiveThis study aimed to compare the diagnostic accuracy of AD core biomarkers using four measurement methods in a Chinese population and to establish method-specific cutoff values tailored to different clinical scenarios.MethodsA total of 309 participants were enrolled from the PUMCH dementia cohort, comprising 176 AD, 114 non-AD dementia cases, and 19 cognitively normal controls (CN). For biomarker quantification, we employed one manual immunoassay (INNOTEST, conducted in two independent laboratories) and two fully automated immunoassay platforms (Lumipulse G and Roche Elecsys). These methods were used to measure CSF Aβ1-40, Aβ1-42, t-tau, and p-tau181, and to calculate three biomarker ratios (Aβ1-42/Aβ1-40, t-tau/Aβ1-42, and p-tau181/Aβ1-42).ResultsOur findings provide method-specific and clinical context-optimized cutoff values for each application scenario including clinically diagnosed AD versus non-AD dementia, amyloid PET-positive versus PET-negative dementia, and AD versus CN. The accuracy of differential diagnosis was higher using biomarker ratios (Aβ1-42/Aβ1-40, t-tau/Aβ1-42, p-tau181/Aβ1-42) than absolute values. Most of the high accuracy was achieved using automated assays especially Lumipulse G rather than manual assays.ConclusionsIn this first comparative study of three immunoassays in a Chinese cohort, automated assays demonstrated superior performance compared to manual assays. We established assay-specific cutoff values tailored to different clinical contexts in a Chinese population.},
}

@article {pmid40961171,
year = {2025},
author = {Blumen, HM and Delpratt, N and Beauchet, O and Callisaya, ML and Doi, T and Kumar, VP and Lipton, RB and Milman, S and Shimada, H and Srikanth, V and Verghese, J},
title = {Sex-specific brain atrophy patterns associated with the motoric cognitive risk syndrome.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378656},
doi = {10.1177/13872877251378656},
pmid = {40961171},
issn = {1875-8908},
abstract = {BackgroundFemales are twice as likely to be diagnosed with Alzheimer's disease (AD) as males, but the underlying mechanisms of this sex difference are not well-understood. The motoric cognitive risk (MCR) syndrome is characterized by slow gait and subjective cognitive concerns and predicts both AD and vascular dementia (VaD). The prevalence of MCR is typically similar in females and males. We have previously shown that MCR is associated with cortical atrophy in frontal, parietal, and temporal regions.ObjectiveThe current study examined sex-specific, cortical (frontal), and subcortical (hippocampal) atrophy patterns associated with MCR.MethodsFrontal cortical thicknesses (in 11 frontal regions) and hippocampal volumes (in 12 hippocampal subfields) were quantified in 940 females (M Age = 71.03 years) and 1108 males (M Age = 71.07 years). Sex-stratified linear models were used to examine frontal cortical thicknesses and hippocampal volumes as a function of MCR-after adjusting for age, education, total intracranial volume, study site, vascular comorbidities, white matter lesion burden, and multiple comparisons (with the false discovery rate).ResultsMCR-related frontal atrophy was observed (in pars orbitalis and caudal middle frontal) in males but not in females. MCR-related hippocampal atrophy (in CA1, molecular layer, GCMLDG, and Fimbria) was observed in females but not in males.ConclusionsThere are sex-specific patterns of atrophy associated with MCR. Females with MCR display brain atrophy patterns more consistent with early AD, while males with MCR display atrophy patterns more consistent with VaD.},
}

@article {pmid40961168,
year = {2025},
author = {Simon, ZD and McFarland, KN and Golde, TE and Chakrabarty, P and Febo, M},
title = {Sex-dependent effect of amyloidosis on functional network 'hub' topology is associated with downregulated neuronal gene signatures in the APPswe/PSEN1dE9 double transgenic mouse.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378778},
doi = {10.1177/13872877251378778},
pmid = {40961168},
issn = {1875-8908},
abstract = {BackgroundExtracellular amyloid-β (Aβ) impairs brain-wide functional connectivity, although mechanisms linking Aβ to broader functional network connectivity remain elusive.ObjectiveHere, we evaluated the effect of Aβ on fear memory and functional connectome measures in mice.MethodsMiddle-aged (9-11 months of age) double transgenic APP-PS1 mice and age and sex-matched controls were evaluated on a fear conditioning protocol and then imaged at 11.1 Tesla. Brains were harvested and processed for analysis of Aβ plaques and Iba1 immunolabeling in cortex, hippocampus, and basolateral amygdala. Additional RNA sequencing data from separate age, strain, and sex matched mice were analyzed for differentially expressed genes (DEGs) and weighted gene co-expression networks.ResultsIn both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network due to Aβ. Increased functional connectivity within this network was matched by increases in AβPP gene expression, Aβ and Iba1 immunolabeling, and an upregulated cluster of DEGs involved in the immune response. Conversely, the network measure representing node 'hubness', eigenvector centrality, was increased in prefrontal cortical brain regions, but only in female APP-PS1 mice. This female specific-effect of amyloid was associated with downregulation of a cluster of DEGs involved in cortical and striatal GABA transmission, anxiogenic responses, and motor activity, in female APP-PS1 mice, but not males.ConclusionsOur results contribute to a growing literature linking between Aβ, immune activation and functional network connectivity. Furthermore, they reveal effects of Aβ on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.},
}

@article {pmid40961167,
year = {2025},
author = {Bekena, S and Singh, RK and Zhu, Y and Cruchaga, C and Arnold, SE and Ances, BM and Babulal, GM},
title = {Hearing loss, plasma neurodegenerative biomarkers, and cognitive function: Independent and additive effects.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378675},
doi = {10.1177/13872877251378675},
pmid = {40961167},
issn = {1875-8908},
abstract = {BackgroundHearing loss is one of the most prominent modifiable risk factors for dementia, accounting for one of the largest population-attributable risk among midlife exposures according to the Lancet Commission on Dementia. Plasma biomarkers such as neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau-217 (Ptau217) have emerged as promising indicators of neurodegeneration and Alzheimer's disease (AD) pathology.ObjectiveTo evaluate whether hearing loss and plasma biomarker concentrations are independently associated with cognitive function in aging adults, and to examine if these associations vary by age group.MethodsThis cross-sectional study used data from 373 participants in the Aging Adult Brain Connectome (AABC) study. Hearing was assessed using the NIH Toolbox Words-in-Noise test, and cognitive function was measured by a Preclinical Alzheimer's Cognitive Composite (PACC). Plasma biomarkers included NfL, GFAP, total tau (tTau), and Ptau217. General linear models tested associations with cognition, adjusting for demographic, genetic, and cardiometabolic covariates. Interaction terms assessed modification by age and hearing.ResultsHearing loss was independently associated with lower PACC scores (β = -0.03, p < 0.001), after adjusting for covariates. Higher levels of NfL, GFAP, and Ptau217 were each associated with worse cognition. Age significantly moderated these associations, with stronger biomarker-cognition links observed in adults aged 65 and older. No significant interactions were observed between hearing loss and plasma biomarkers.ConclusionsHearing loss and plasma biomarkers reflect distinct, additive pathways of cognitive decline. These findings support integrated dementia risk models and highlight the potential of age- and biomarker-informed cognitive monitoring.},
}

@article {pmid40961163,
year = {2025},
author = {Deng, T and Duan, J and Yu, W and Deng, Z and Tian, Q and Liu, X and Shou, J and Tang, T and Yu, W and Lü, Y},
title = {Education as a domain-specific moderator: Shaping the impact of cerebral structural changes on clinical manifestations in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379078},
doi = {10.1177/13872877251379078},
pmid = {40961163},
issn = {1875-8908},
abstract = {BackgroundGlobal cognitive performance is influenced by change in cerebral structure and educational background. However, little is known about how education moderates the impact of cerebral structural changes on different cognitive domains and other non-cognitive dysfunction across the clinical stages of Alzheimer's disease (AD).ObjectiveTo explore the moderating effect of education on relationship between cerebral structure and various clinical manifestations across the AD continuum, ranging from mild cognitive impairment (MCI) to AD.MethodsThis cross-sectional study included data of 570 patients diagnosed with MCI or AD. The total years of education were used as a moderating variable, and AD-related cerebral structure changes were assessed through visual ratings on magnetic resonance imaging (MRI). Multiple linear regressions were performed to examine whether education moderated the association between cerebral structure and clinical characteristics at different diagnostic stages of AD.ResultsPatients with higher levels of education demonstrated better cognitive ability, enhanced activities of daily living, and milder neuropsychiatric symptoms. The moderating effect of education was most prominent during the MCI or early AD stages, showing cognitive domain-specific effects. In these stage, education alleviated the negative impacts of neurostructural changes on immediate learning but exacerbated the detrimental effects of cerebral structural changes on speed/executive function, language, and episodic memory.ConclusionsEducation serve as a moderator in relationship between cerebral structure and various clinical characteristics. The moderating effect of education is domain-specific and most noticeable in the early stage of AD.},
}

@article {pmid40961135,
year = {2025},
author = {McKay, CE and Deans, M and Connor, J and Saunders, JC and Lloyd, C and Radford, SE and Brockwell, DJ},
title = {Employing deep mutational scanning in the Escherichia coli periplasm to decode the thermodynamic landscape for amyloid formation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {38},
pages = {e2516165122},
doi = {10.1073/pnas.2516165122},
pmid = {40961135},
issn = {1091-6490},
support = {104918MA//Wellcome Trust (WT)/ ; BB/W510403/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; BB/T007222/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; RSRP/R1/211057//Royal Society (The Royal Society)/ ; },
mesh = {*Escherichia coli/genetics/metabolism ; *Amyloid beta-Peptides/genetics/metabolism/chemistry ; Thermodynamics ; *Periplasm/metabolism/genetics ; beta-Lactamases/metabolism/genetics ; *Amyloid/metabolism/genetics/chemistry ; Mutation ; Peptide Fragments/genetics/metabolism/chemistry ; Humans ; Alzheimer Disease/genetics/metabolism ; },
abstract = {Deep mutational scanning (DMS) assays provide a powerful method to generate large-scale datasets essential for advancing AI-driven predictions in biology. The tripartite β-lactamase assay (TPBLA), in which a protein of interest is inserted between two domains of β-lactamase, has previously been reported as capable of detecting and quantitating the aggregation of proteins and biologics in the oxidizing periplasm of Escherichia coli and used as a platform for identifying small molecule inhibitors of aggregation. Here, we repurpose the TPBLA into a high-throughput DMS platform. We validate this format using a single-site saturation library of the intrinsically disordered peptide Aβ42, linked to Alzheimer's disease, demonstrating strong agreement between observed variant fitness scores and variant behavior using our previously reported low-throughput TPBLA. The results of DMS revealed variant fitness scores that correlate with known amyloid-promoting regions. An in silico approach using FoldX-derived per-residue thermodynamic stability confirmed that the TPBLA reports on amyloid fibril stability. In vitro experiments support this finding, showing a strong correlation between variant fitness scores and the critical concentration of amyloid formation. Machine learning using the DMS dataset identified β-sheet propensity and polarity as primary drivers of variant fitness scores. The derived model is also able to predict thermodynamically stabilizing regions in other amyloid systems, underscoring its generalizability. Collectively, our results demonstrate the TPBLA as a versatile platform for generating robust datasets to advance predictive modeling and to inform the design of aggregation-resistant proteins.},
}

*Escherichia coli/genetics/metabolism
*Amyloid beta-Peptides/genetics/metabolism/chemistry
Thermodynamics
*Periplasm/metabolism/genetics
beta-Lactamases/metabolism/genetics
*Amyloid/metabolism/genetics/chemistry
Mutation
Peptide Fragments/genetics/metabolism/chemistry
Humans
Alzheimer Disease/genetics/metabolism

@article {pmid40961133,
year = {2025},
author = {Jehu, DA and Patel, C and Soares, A and Waller, JL and Carrick, RM and Hergott, C and Young, L and Hall, W and Robinson-Johnson, D and Allen, C and Sams, R and Hamrick, M and Huang, Y and Zhu, H and Dong, Y},
title = {The feasibility, acceptability, and effects of the adapted 6-month Otago exercise program on cognitive, physical, and psychological function in people living with dementia in residential care facilities: The ENABLED randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378670},
doi = {10.1177/13872877251378670},
pmid = {40961133},
issn = {1875-8908},
abstract = {BackgroundPeople living with dementia (PWD) have poor executive function, which impacts their independence and fall risk. Exercise is a promising strategy but needs to be adapted for PWD in residential care settings. Thus, the feasibility, acceptability, and efficacy of adapted exercise on executive function need to be established.ObjectiveThe purpose of the 6-month assessor-blinded strENgth And BaLance exercise on Executive function in people living with Dementia (ENABLED) randomized controlled trial was to determine 1) the feasibility and acceptability, and 2) if the adapted physical therapist-led Otago Exercise Program (OEP) plus usual care would improve executive function (primary) and secondary cognitive, physical, and psychological function measures as well as falls compared to usual care only in PWD in residential care facilities.MethodsWe randomized PWD to the exercise (n = 21) or usual care group (n = 21) at two residential care facilities in our parallel, assessor-blinded RCT (1:1) [NCT05488951]. A physical therapist delivered our adapted OEP 3x/week over 6 months. We examined feasibility and acceptability. Participants completed a battery of assessments, with the Color-Word Stroop as our primary outcome.ResultsAttrition (19.0%), exercise adherence (60.2 ± 34.5%; 47/78 sessions), and satisfaction were acceptable (4.2/5 points). We found no differences in the Color-Word Stroop, but better working memory, leg strength, and quality of life following exercise relative to usual care (p < 0.05). No differences in falls emerged.ConclusionsThis feasible and acceptable RCT indicates that exercise improves working memory, leg strength, and quality of life and has implications for the design of therapeutic intervention in PWD.},
}

@article {pmid40961129,
year = {2025},
author = {Liu, Y and Chen, Y and Chen, Z and Wan, H and Wu, C},
title = {Tau seeding activity in Alzheimer's disease: Characteristics, factors, and applications.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378772},
doi = {10.1177/13872877251378772},
pmid = {40961129},
issn = {1875-8908},
abstract = {The prion-like seeding activity (SA) of misfolded microtubule-associated protein tau (MAPT, tau) drives neuropathological progression in Alzheimer's disease (AD), offering a dynamic biomarker beyond static quantitative measures. Recent advances in biomarker research have highlighted the importance of tau seeding activity (TSA), a prion-like propagation mechanism, in the early diagnosis and monitoring of AD. TSA reflects the dynamic process of pathological tau aggregation and spread across brain regions, offering a potential tool for predicting disease progression and differentiating AD from other tauopathies. This article reviews the structural and functional characteristics of tau, the mechanisms underlying its SA, and the impact of post-translational modifications on tau propagation. We also discuss the limitations of current diagnostic methods, which rely on static quantitative measures of tau levels, and propose that tau SA could serve as a more comprehensive biomarker for early diagnosis and risk assessment in asymptomatic individuals. Furthermore, we explore the translational potential of TSA in precision medicine, emphasizing the need for standardized detection methods and clinical validation. By integrating TSA with neuroimaging and fluid biomarkers, a multi-dimensional predictive framework could be established to guide individualized therapeutic strategies and improve diagnostic accuracy in AD and related tauopathies.},
}

@article {pmid40961091,
year = {2025},
author = {Kitayama, Y and Nakano, Y and Hirano, S and Hanayama, S and Chishiki, Y and Izumi, M and Koizumi, Y and Suzuki, Y and Tamura, M and Yamagishi, K and Ishikawa, A and Furukawa, S and Kashiwado, K and Sugiyama, A and Mori, M and Kuwabara, S},
title = {Multimodal neuroimaging related to cerebrospinal fluid biomarkers and cognitive function in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376601},
doi = {10.1177/13872877251376601},
pmid = {40961091},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by amyloid-β (Aβ) and tau protein accumulation, reflected in cerebrospinal fluid (CSF) analysis. However, the interplay among CSF biomarkers, neuroimaging, and cognition remains elusive.ObjectiveTo explore associations among neuroimaging features, CSF biomarkers, and cognitive performance in AD.MethodsSixty patients with clinically diagnosed AD showing Aβ pathology in CSF underwent neuroimaging assessment of gray matter volume using T1-weighted MRI, cerebral blood flow (CBF) using single-photon emission computed tomography, and white matter hyperintensities (WMHs) using T2-weighted or fluid-attenuated inversion recovery images. Partial least square (PLS) regression identified imaging findings related to CSF biomarkers and Mini-Mental State Examination (MMSE) scores. Structural equation modeling (SEM) explored associations between factors with variable importance in projection (VIP) scores above 1.5 in PLS regression.ResultsLateral temporal and occipital gray matter volumes positively correlated with MMSE scores (VIP = 1.95, 1.53), whereas WMHs in parietal and frontal periventricular regions were negatively associated with CSF Aβ42 (VIP = 1.54, 1.58). Lateral temporal CBF was also associated with MMSE scores (VIP = 2.22). SEM analysis showed that reduced CSF Aβ42 was linked to increased WMHs (p = 0.028), which correlated with each region (p < 0.005) and explained the reduced MMSE score (p = 0.013). Lateral temporal CBF correlated with temporo-occipital gray matter volume (p < 0.001) and influenced the MMSE score (p < 0.001).ConclusionsThis study suggests that amyloid pathology via WMHs and neurodegeneration of the lateral temporal lobe independently contribute to cognitive impairment in patients with AD.},
}

@article {pmid40961040,
year = {2025},
author = {Wang, Z and Xiao, S and Wan, M and , },
title = {Association of CSF visinin-like protein 1 levels with cerebral glucose metabolism among older adults.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0329386},
doi = {10.1371/journal.pone.0329386},
pmid = {40961040},
issn = {1932-6203},
mesh = {Humans ; Aged ; Male ; Female ; *Glucose/metabolism ; Positron-Emission Tomography ; *Neurocalcin/cerebrospinal fluid ; Fluorodeoxyglucose F18 ; *Brain/metabolism/diagnostic imaging ; Aged, 80 and over ; Biomarkers/cerebrospinal fluid ; Alzheimer Disease/metabolism/diagnostic imaging ; Cognitive Dysfunction/metabolism/cerebrospinal fluid/diagnostic imaging ; Middle Aged ; },
abstract = {BACKGROUND: CSF visinin-like protein 1 (VILIP-1) levels have exhibited potential utility as a marker of neuronal damage and are increased in Alzheimer's disease (AD). The levels of CSF VILIP-1 have been associated with memory decline and hippocampal atrophy, while no studies have investigated the association between CSF VILIP-1 levels and cerebral glucose metabolism among older adults.

METHODS: Study participants had available baseline CSF VILIP-1 data and more than two assessments of 18-fluorodeoxyglucose positron emission tomography ([18F] FDG-PET) brain imaging. Linear mixed-effects models were used to examine the association between baseline CSF VILIP-1 levels and longitudinal changes in FDG-PET over time. Models were performed separately for the cognitively unimpaired (CU) and cognitively impaired (CI) participants.

RESULTS: Among CU older adults, higher CSF VILIP-1 levels were marginally associated with a faster reduction in cerebral glucose metabolism. In CI older adults, CSF VILIP-1 levels were significantly associated with a faster reduction in cerebral glucose metabolism.

CONCLUSION: These results provide novel insights into the relationship between neuronal injury and cerebral glucose metabolism, highlighting the potential of CSF VILIP-1 as a biomarker for monitoring and predicting the progression of neurodegenerative processes.},
}

Humans
Aged
Male
Female
*Glucose/metabolism
Positron-Emission Tomography
*Neurocalcin/cerebrospinal fluid
Fluorodeoxyglucose F18
*Brain/metabolism/diagnostic imaging
Aged, 80 and over
Biomarkers/cerebrospinal fluid
Alzheimer Disease/metabolism/diagnostic imaging
Cognitive Dysfunction/metabolism/cerebrospinal fluid/diagnostic imaging
Middle Aged

@article {pmid40960941,
year = {2025},
author = {Ward, A and Park, H and Cheng, B and Seeram, D and Thakur, KT and Uhlemann, A-C and Noble, JM and Papapanou, PN},
title = {Cerebrospinal fluid microbiome revisited: no evidence of resident bacteria in archived samples.},
journal = {Microbiology spectrum},
volume = {},
number = {},
pages = {e0130825},
doi = {10.1128/spectrum.01308-25},
pmid = {40960941},
issn = {2165-0497},
abstract = {UNLABELLED: DNA from oral bacteria has been detected in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease and related dementias (AD/ADRD). We hypothesized that examination of archived CSF samples from donors with variable cognitive status would reveal evidence of a resident microbiome. 176 CSF samples harvested from community-dwelling individuals (77% between 61 and 80 years old) were analyzed; 57% originated from donors with impaired cognitive status. DNA was extracted after adding microbial spike-in controls, and libraries were prepared and sequenced on an Illumina-MiSeq platform. 16S rRNA sequences were processed, and a taxonomic classification was performed. Spike-in bacteria were consistently detected, and Streptococcus pneumoniae was found in a positive control sample from a patient with bacterial meningitis. However, very few reads mapping to other bacterial taxa were detected across samples, suggesting a negligible bacterial content consistent with occasional contamination or sequencing errors. CSF is a privileged, sterile environment that does not harbor a resident microbiome in elderly people with various morbidities, including AD/ADRD.

IMPORTANCE: Recent reports have suggested that DNA from oral bacteria has been found in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease and related dementias (AD/ADRD). We hypothesized that examination of archived CSF samples from donors with variable cognitive status would reveal evidence of a resident microbiome. We thus analyzed 176 CSF samples harvested from community-dwelling individuals including donors with impaired cognitive status. While our findings suggested the presence of occasional bacterial contamination, they provided no evidence of a resident microbiome. We thus conclude that the CSF is indeed a privileged, sterile environment that does not harbor a resident microbiome in elderly people with various morbidities including AD/ADRD.},
}

@article {pmid40960513,
year = {2025},
author = {Lee, HJ and Yoo, SW and Kim, M and Kim, HS and Kim, JS},
title = {Co-occurrence of primary familial brain calcification from a likely pathogenic SLC20A2 variant and Alzheimer's disease biology.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/13554794.2025.2562918},
pmid = {40960513},
issn = {1465-3656},
abstract = {Alzheimer's disease (AD) is the leading cause of cognitive decline, whereas primary familial brain calcification (PFBC) is rare. We analyzed the clinical and radiological findings of a 75-year-old man who presented with memory impairment. Brain imaging revealed bilateral basal ganglia calcification, severe white matter hyperintensities, and significant amyloid deposition. Genetic analysis identified a heterozygous c.1711 G > A variant in SLC20A2 and a heterozygous c.166 G > A variant in PSEN2. The patient was diagnosed with genetically confirmed PFBC due to a likely pathogenic SLC20A2 variant, together with AD biology. The PSEN2 variant was classified as a variant of uncertain significance.},
}

@article {pmid40960397,
year = {2025},
author = {Bashyam, VM and Erus, G and Cui, Y and Wu, D and Hwang, G and Getka, A and Singh, A and Aidinis, G and Baik, K and Melhem, R and Mamourian, E and Doshi, J and Davison, A and Nasrallah, IM and Davatzikos, C and , },
title = {DLMUSE: Robust Brain Segmentation in Seconds Using Deep Learning.},
journal = {Radiology. Artificial intelligence},
volume = {},
number = {},
pages = {e240299},
doi = {10.1148/ryai.240299},
pmid = {40960397},
issn = {2638-6100},
abstract = {"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To introduce an open-source deep learning brain segmentation model for fully automated brain MRI segmentation, enabling rapid segmentation and facilitating large-scale neuroimaging research. Materials and Methods In this retrospective study, a deep learning model was developed using a diverse training dataset of 1900 MRI scans (ages 24-93 with a mean of 65 years (SD: 11.5 years) and 1007 females and 893 males) with reference labels generated using a multiatlas segmentation method with human supervision. The final model was validated using 71391 scans from 14 studies. Segmentation quality was assessed using Dice similarity and Pearson correlation coefficients with reference segmentations. Downstream predictive performance for brain age and Alzheimer's disease was evaluated by fitting machine learning models. Statistical significance was assessed using Mann-Whittney U and McNemar's tests. Results The DLMUSE model achieved high correlation (r = 0.93-0.95) and agreement (median Dice scores = 0.84-0.89) with reference segmentations across the testing dataset. Prediction of brain age using DLMUSE features achieved a mean absolute error of 5.08 years, similar to that of the reference method (5.15 years, P = .56). Classification of Alzheimer's disease using DLMUSE features achieved an accuracy of 89% and F1-score of 0.80, which were comparable to values achieved by the reference method (89% and 0.79, respectively). DLMUSE segmentation speed was over 10000 times faster than that of the reference method (3.5 seconds vs 14 hours). Conclusion DLMUSE enabled rapid brain MRI segmentation, with performance comparable to that of state-of-theart methods across diverse datasets. The resulting open-source tools and user-friendly web interface can facilitate large-scale neuroimaging research and wide utilization of advanced segmentation methods. ©RSNA, 2025.},
}

@article {pmid40960201,
year = {2025},
author = {Magalhães, TNC and Hicks, TH and Jackson, TB and Ballard, HK and Herrejon, IA and Bernard, JA},
title = {The Influence of Sex and Sex-Steroid Hormones on Cerebellar Structure and Functional Connectivity Across Adulthood.},
journal = {Human brain mapping},
volume = {46},
number = {14},
pages = {e70356},
doi = {10.1002/hbm.70356},
pmid = {40960201},
issn = {1097-0193},
support = {R01AG065010/NH/NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; Aged ; Middle Aged ; Magnetic Resonance Imaging ; Aged, 80 and over ; Adult ; *Sex Characteristics ; *Cerebellum/diagnostic imaging/physiology/anatomy & histology ; *Aging/physiology ; *Gonadal Steroid Hormones/metabolism ; Estradiol/metabolism ; *Testosterone/metabolism ; Saliva/metabolism/chemistry ; *Progesterone/metabolism ; *Nerve Net/diagnostic imaging/physiology/anatomy & histology ; Neural Pathways/physiology/diagnostic imaging ; *Connectome ; },
abstract = {Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer's, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and sex equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations in the context of sex-steroid hormones. The study included 138 participants (mean age = 57 (13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged (EMA) individuals (mean age = 41 (4.7) years), 48 late middle-aged (LMA) individuals (mean age = 58 (4) years), and 42 older adults (OAs) (mean age = 72 (6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17β-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobules I and IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17β-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobules I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the Right I-IV, Right Crus I, Right V, and Right VI. EMA females showed higher volumes in the Right Lobules V and VI. These results highlight the significant role of sex steroid hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.},
}

Humans
Female
Male
Aged
Middle Aged
Magnetic Resonance Imaging
Aged, 80 and over
Adult
*Sex Characteristics
*Cerebellum/diagnostic imaging/physiology/anatomy & histology
*Aging/physiology
*Gonadal Steroid Hormones/metabolism
Estradiol/metabolism
*Testosterone/metabolism
Saliva/metabolism/chemistry
*Progesterone/metabolism
*Nerve Net/diagnostic imaging/physiology/anatomy & histology
Neural Pathways/physiology/diagnostic imaging
*Connectome

@article {pmid40960191,
year = {2025},
author = {Ak, G and Nilofar, N and Bahadirli, P and Santanatoglia, A and Caprioli, G and Sagratini, G and Koyuncu, I and Kirhan, I and Glamočlija, J and Stojković, D and Uba, AI and Kaya, S and Maslov, MM and Yagi, S and Zengin, G},
title = {Utilizing olive leaves as a rich source of multifunctional bioactive compounds to fight oxidative stress, Alzheimer's disease, diabetes, and cancer using in vitro, in silico, and bioinformatics techniques.},
journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences},
volume = {},
number = {},
pages = {},
pmid = {40960191},
issn = {1865-7125},
abstract = {Olive leaves are of significant interest in traditional medicine and in the development of functional nutraceuticals. In this study, the leaves of four olive varieties (Halhali, arbequina, gemlik, karamani) were utilized to examine and compare the chemical composition and biological activities, particularly their role in enzyme inhibition, cancer prevention, and apoptosis induction. Results showed that among the tested varieties analyzed, Gemlik (77.79 mg gallic acid equivalent (GAE)/g) and halhali (76.03 mg GAE/g) exhibited the phenolic contents while arbequina had the highest flavonoid content (36.51 mg rutin equivalent (RE)/g). Similarly, these two varieties of extracts recorded strong antioxidant activity in several assays. Gemlik (2.70 mg galantamine equivalent (GALAE)/g) and arbequina (2.59 mg GALAE/g) demonstrated the highest acetylcholinesterase (AChE) inhibition. The results of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)) assay showed arbequina provided the highest cytotoxic effect against HeLa cells (IC50 value: 60.59 μg/ml) and annexin-V/PI staining confirmed the inducing of apoptosis by arbequina in HeLa cells. In conclusion, the studied olive varieties of leaf extracts appeared to have more potential as a health supplement rich in natural antioxidants and merit further intensive study.},
}

@article {pmid40960157,
year = {2025},
author = {Wang, J and Dai, L and Zhang, Z},
title = {Protein aggregation in neurodegenerative diseases.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {40960157},
issn = {2542-5641},
abstract = {Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.},
}

@article {pmid40960087,
year = {2025},
author = {Tsui, JSM and Au, DM and Uhm, H and Wong, WW and Lo, RMN and Jiang, Y and Ip, FCF and Mok, KY and Wong, HY and Kwok, TCY and Fu, AKY and Ip, NY},
title = {The TREM2 H157Y variant is associated with more severe neurodegeneration in Alzheimer's disease and altered immune-related processes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70586},
doi = {10.1002/alz.70586},
pmid = {40960087},
issn = {1552-5279},
support = {HKUST16103122//Research Grants Council of Hong Kong (General Research Fund)/ ; HKUST16102824//Research Grants Council of Hong Kong (General Research Fund)/ ; JLFS/M-604/24//SIAT-HKUST Joint Laboratory for Brain Science/ ; 32061160472//NSFC-RGC Joint Research Scheme/ ; CTFCF18SC01//Chow Tai Fook Charity Foundation/ ; ITCPD/17-9//InnoHK Initiative and Grant of the Innovation and Technology Commission of the HKSAR Government/ ; AoE/M-604/16//Area of Excellence Scheme of the University Grants Committee/ ; T13-605/18W//Research Grants Council of Hong Kong (Theme-Based Research Scheme)/ ; C6027-19GF//Research Grants Council of Hong Kong (Collaborative Research Fund)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/immunology ; *Receptors, Immunologic/genetics ; *Membrane Glycoproteins/genetics ; Male ; Female ; Aged ; Disease Progression ; Aged, 80 and over ; Proteomics ; Genetic Predisposition to Disease ; },
abstract = {INTRODUCTION: Multiple TREM2 variants are associated with an increased risk of Alzheimer's disease (AD). TREM2 H157Y is the only variant located at the proteolytic cleavage site that enhances TREM2 protein shedding. While this variant is associated with increased AD risk predominantly in the Chinese population, its impact on AD pathology is largely unknown.

METHODS: We conducted an in-depth study integrating clinical cases, neuroimaging data, and blood proteomic data.

RESULTS: TREM2 H157Y variant carriers with AD exhibit more severe AD pathology, more severe neurodegeneration, and more rapid clinical progression. Cognitively normal individuals carrying the variant show changes in blood proteins that are associated with neurodegeneration and inflammation. Moreover, the TREM2 H157Y variant is associated with altered immune and vascular processes irrespective of disease state.

DISCUSSION: These findings highlight the clinical implications of the TREM2 H157Y variant and the use of blood proteomic data to investigate the effects of genetic variants on disease-related endophenotypes.

HIGHLIGHTS: The TREM2 H157Y variant is associated with more rapid clinical progression of Alzheimer's disease only in the presence of the apolipoprotein E (APOE) ε4 allele. The TREM2 H157Y variant is associated with neurodegeneration, irrespective of disease state. The TREM2 H157Y variant is associated with altered immune and vascular processes, irrespective of disease state. Cognitively normal TREM2 H157Y carriers show altered disease-associated blood proteins related to peripheral immune response. Blood proteomic data can be used to study the impacts of disease-associated genetic variants on disease outcomes and biological processes involved in pathogenesis.},
}

Humans
*Alzheimer Disease/genetics/pathology/immunology
*Receptors, Immunologic/genetics
*Membrane Glycoproteins/genetics
Male
Female
Aged
Disease Progression
Aged, 80 and over
Proteomics
Genetic Predisposition to Disease

@article {pmid40960068,
year = {2025},
author = {Choi, SE and Mukherjee, S and Gibbons, LE and Trittschuh, EH and Lee, M and Scollard, P and Sanders, RE and Snitz, BE and Shaaban, CE and Lopez, OL and Mez, J and Saykin, AJ and Hohman, TJ and Crane, PK},
title = {Beyond NACC's Uniform Data Set for cognition: the impact of additional items on measurement precision.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70694},
doi = {10.1002/alz.70694},
pmid = {40960068},
issn = {1552-5279},
mesh = {Humans ; *Neuropsychological Tests/standards ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Male ; Female ; *Cognition/physiology ; Aged ; Executive Function/physiology ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We sought to determine the implications of integrating additional cognitive test items beyond the items of the Uniform Data Set (UDS) administered by Alzheimer's Disease Research Centers (ADRCs).

METHODS: We considered the UDS 1&2 and UDS 3 cognitive batteries alone ("UDS-only") and compared them to batteries augmented with additional items ("UDS-augmented") administered by the University of Pittsburgh, ADRC. We used confirmatory factor analyses to co-calibrate and harmonize three cognitive domains (memory, executive functioning, and language). Then we compared the UDS-only and UDS-augmented with respect to measurement precision, sample sizes required to detect 25% differences in rates of decline, and association between baseline scores and the hazard of converting from mild cognitive impairment to AD dementia.

RESULTS: UDS-augmented substantially enhanced measurement precision across all cognitive domains for UDS 1&2 and UDS 3.

DISCUSSION: There is substantial value in integrating item content beyond the UDS.

HIGHLIGHTS: We considered items from the UDS 1&2 and UDS 3 cognitive batteries alongside augmented site-specific content for the memory, executive functioning, and language domains. Augmented scales improved measurement precision in each case. As expected, improved measurement precision facilitated better performance for each scale. It would be useful to integrate multiple sources of cognitive data into comprehensive estimates of domain performance.},
}

Humans
*Neuropsychological Tests/standards
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Male
Female
*Cognition/physiology
Aged
Executive Function/physiology
Aged, 80 and over

@article {pmid40960061,
year = {2025},
author = {Cleary, JA and Kumar, A and Su, Y and Singh, S and Hsu, FC and Craft, S and Harrison, W and Keene, CD and Howard, M and Hayden, KM and Espeland, MA and Ding, J and Deep, G},
title = {MicroRNA cargo in neuron-derived vesicles as peripheral biomarkers of brain insulin dysregulation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70597},
doi = {10.1002/alz.70597},
pmid = {40960061},
issn = {1552-5279},
support = {3R01AG058571-02S1/AG/NIA NIH HHS/United States ; 1RF1AG068629/AG/NIA NIH HHS/United States ; R01 AG061805/AG/NIA NIH HHS/United States ; 1R21 AG075611/AG/NIA NIH HHS/United States ; P30AG066509/AG/NIA NIH HHS/United States ; U19AG066567/AG/NIA NIH HHS/United States ; U24AG072458/AG/NIA NIH HHS/United States ; //Nancy and Buster Alvord Endowment/ ; },
mesh = {Humans ; *MicroRNAs/metabolism ; Male ; *Brain/metabolism ; *Insulin Resistance/physiology ; Biomarkers/metabolism ; *Neurons/metabolism ; *Alzheimer Disease/metabolism ; Female ; *Extracellular Vesicles/metabolism ; Aged ; *Insulin/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Amyloid beta-Peptides/blood ; Middle Aged ; },
abstract = {INTRODUCTION: Brain insulin resistance (bIR) is a risk factor for Alzheimer's disease (AD). However, the association between bIR and peripheral insulin resistance and their effects on cognition remains unclear.

METHODS: Here, we analyzed the expression of key genes (n = 84) involved in insulin signaling in brain tissue collected from healthy and AD subjects, as well as regulatory microRNAs (miRNAs) in the brain tissue and tissue-derived small extracellular vesicles (sEV). Subsequently, miRNA expression was analyzed in plasma neuron-derived sEV (NDE) of a second cohort consisting of cognitively normal and adjudicated mixed dementia (aMD) subjects, all with type 2 diabetes.

RESULTS: Analysis of miRNAs in brain tissue and their sEV revealed significant and concordant dysregulation. NDE demonstrated similar changes in specific miRNA expression, with significant upregulation exclusively in male aMD subjects, and showed correlation with cognition and plasma β-amyloid (Aβ) 1-40 and Aβ1-42.

DISCUSSION: NDE may serve as a liquid biopsy to determine sex-specific bIR and cognitive impairment.

HIGHLIGHTS: Insulin signaling is disrupted in brain tissue with Alzheimer's disease (AD). microRNAs (miRNAs) regulate insulin signaling and insulin resistance. miRNAs in neuron-derived small extracellular vesicles (sEV) could serve as biomarkers for brain insulin signaling. Brain insulin signaling biomarkers in neuron-derived sEV (NDE) could predict cognitive impairment. Sex-specific differences exist in brain insulin resistance biomarkers.},
}

Humans
*MicroRNAs/metabolism
Male
*Brain/metabolism
*Insulin Resistance/physiology
Biomarkers/metabolism
*Neurons/metabolism
*Alzheimer Disease/metabolism
Female
*Extracellular Vesicles/metabolism
Aged
*Insulin/metabolism
Diabetes Mellitus, Type 2/metabolism
Amyloid beta-Peptides/blood
Middle Aged

@article {pmid40959955,
year = {2025},
author = {Lai, RH and Chung, RH and Pai, WY and Chen, YC and Lam, KH and Lai, CN and Juang, JL},
title = {Sex- and APOE Genotype-Dependent Pain Susceptibility and Alzheimer's Risk Mediated by the Lipid Metabolism Enzyme LPCAT2.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70234},
doi = {10.1111/acel.70234},
pmid = {40959955},
issn = {1474-9726},
support = {CG-112-GP-08//National Health Research Institutes/ ; MGPP-02-014//National Health Research Institutes/ ; },
abstract = {Neuropathological changes that precede or accompany early cognitive decline in Alzheimer's disease (AD) may also impact pain processing; however, the molecular connection between these domains remains unclear. In this study, we investigated whether a shared causal factor underlies both increased pain susceptibility and AD progression. Analysis of two ethnically distinct cohorts revealed a significant association between pain susceptibility and cognitive decline from cognitively normal (CN) status to mild cognitive impairment (MCI), particularly in non-APOE4 (non-E4) males, an unexpected finding given that APOE4 females exhibited the highest overall pain susceptibility across sex and genotype groups. To explore potential drivers of this APOE genotype- and sex-specific association, blood transcriptomic analysis identified LPCAT2 expression as correlating with both heightened pain susceptibility and progression from MCI to AD, most notably in non-E4 males. This relationship was further supported by elevated LPCAT2 protein levels in the hippocampus of postmortem non-E4 male AD patients. Strengthening this link, our genetic association analysis across four cohorts identified several functional LPCAT2 variants that not only influenced its expression but were also associated with altered pain susceptibility, increased AD risk, and accelerated progression from MCI to AD. To move beyond correlation and assess causality, Mendelian randomization analysis supported a causal role for LPCAT2 in both pain susceptibility and MCI-to-AD progression. Collectively, these findings identify LPCAT2 as a key molecular link between altered pain processing and AD progression, highlighting its potential as both a therapeutic target for genotype- and sex-specific subpopulations and a prognostic biomarker for MCI-to-AD conversion.},
}

@article {pmid40959937,
year = {2025},
author = {Navakkode, S and Kennedy, BK},
title = {Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70235},
doi = {10.1111/acel.70235},
pmid = {40959937},
issn = {1474-9726},
support = {//NUS Medicine/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.},
}

@article {pmid40959898,
year = {2025},
author = {Chun, MY and Jung, SH and Choe, J and Lee, SY and Kim, HR and Son, HJ and Choi, Y and Cho, M and Kim, B and Jang, H and Choi, SH and Jeong, JH and Son, SJ and Hong, CH and Roh, HW and Na, DL and Seo, SW and Won, HH and Seo, J and Kim, HJ},
title = {Polygenic risk score of Alzheimer's disease is associated with cognitive trajectories and phenotypes of cerebral organoids.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70660},
doi = {10.1002/alz.70660},
pmid = {40959898},
issn = {1552-5279},
support = {//Korea Health Technology R&D Project/ ; //Korea Health Industry Development Institute/ ; RS-2021-KH112730//Ministry of Health and Welfare, Republic of Korea/ ; RS-2025-24535069//Ministry of Health and Welfare, Republic of Korea/ ; SMX1250081//Future Medicine 2030 Project of the Samsung Medical Center/ ; RS-2023-00262527//National Research Foundation of Korea/ ; //ICT Creative Consilience Program/ ; //Institute of Information & Communications Technology Planning & Evaluation/ ; RS-2020-II201821//Korea government (MSIT)/ ; RS-2020-NR046866//Basic Science Research Program through the National Research Foundation of Korea (NRF)/ ; //Ministry of Science and ICT, Republic of Korea/ ; //Institute of Medical Sciences, Kangwon National University 2025/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Organoids/pathology/metabolism ; Genome-Wide Association Study ; Phenotype ; *Multifactorial Inheritance/genetics ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Male ; Female ; Aged ; Induced Pluripotent Stem Cells ; *Cognitive Dysfunction/genetics ; Genetic Predisposition to Disease ; Cognition ; Genetic Risk Score ; },
abstract = {INTRODUCTION: Polygenic risk score (PRS) identifies individuals at high genetic risk for Alzheimer's disease (AD), but its utility in predicting cognitive trajectories and AD pathologies remains unclear. We optimized PRS (optPRS) for AD, investigated its association with cognitive trajectories and AD phenotypes of cerebral organoids.

METHODS: Using genome-wide association study (GWAS) summary statistics from a European population, we developed optPRS to predict AD in Korean individuals (n = 1634). We analyzed the association between optPRS and cognitive trajectories (n = 771). We generated induced pluripotent stem cell-derived cerebral organoids from patients with high (n = 3) and low (n = 4) optPRS to evaluate amyloid beta (Aβ) and phosphorylated tau (p-tau) levels.

RESULTS: OptPRS predicted AD dementia and Aβ positivity, independent of apolipoprotein E (APOE). Higher optPRSs correlated with rapid cognitive decline. Cerebral organoids from the high optPRS group exhibited increased Aβ insolubility and p-tau levels.

CONCLUSION: OptPRS predicted cognitive decline and AD phenotypes of cerebral organoids, supporting its use in risk assessments and drug-screening platform.

HIGHLIGHTS: Optimized polygenic risk scores (optPRSs) improve the prediction of Alzheimer's disease (AD) dementia and amyloid beta positivity (Aβ+). High optPRS is associated with faster cognitive decline, particularly in Aβ+. Induced pluripotent stem cell (iPSC)-derived cerebral organoids from high optPRSs show high Aβ insolubility and phosphorylated tau (p-tau). PRS genetic risk stratification provides insight into AD progression and pathology.},
}

Humans
*Alzheimer Disease/genetics/pathology
*Organoids/pathology/metabolism
Genome-Wide Association Study
Phenotype
*Multifactorial Inheritance/genetics
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Male
Female
Aged
Induced Pluripotent Stem Cells
*Cognitive Dysfunction/genetics
Genetic Predisposition to Disease
Cognition
Genetic Risk Score

@article {pmid40959879,
year = {2025},
author = {Miller, ZA and Ossenkoppele, R and Graff-Radford, NR and Allen, IE and Shwe, W and Rosenberg, L and Olguin, DJ and Erkkinen, MG and Butler, PM and Spina, S and Yokoyama, JS and Desikan, RS and Scheltens, P and van der Flier, W and Pijnenburg, Y and Wolters, E and Rademakers, R and Geschwind, DH and Kramer, JH and Rosen, HJ and Rankin, KP and Grinberg, LT and Seeley, WW and Sturm, V and Perry, DC and Miller, BL and Rabinovici, GD and Gorno-Tempini, ML},
title = {Neurodevelopment and neural environment inform Alzheimer's disease age at onset and phenotype.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70668},
doi = {10.1002/alz.70668},
pmid = {40959879},
issn = {1552-5279},
support = {AG048291//National Institutes of Health/ ; AG053435/NH/NIH HHS/United States ; AG019724/NH/NIH HHS/United States ; AG062422/NH/NIH HHS/United States ; AG045611/NH/NIH HHS/United States ; AG062588/NH/NIH HHS/United States ; DC015544/NH/NIH HHS/United States ; NS050915/NH/NIH HHS/United States ; //Hellman Research Scientist Award/ ; //Arking Foundation for Frontotemporal Dementia/ ; //Jon and Gale Love fund/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; Age of Onset ; Female ; Phenotype ; Male ; Aged ; Risk Factors ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Risk factors associated with sporadic non-amnestic and early-onset Alzheimer's disease (AD) remain underexamined.

METHODS: We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non-right-handedness, learning disability, seizures, autoimmune disease).

RESULTS: Early-onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non-right-handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone.

DISCUSSION: Identifying novel factors enriched in early-onset and non-amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment.

HIGHLIGHTS: We identified a suite of novel factors overrepresented in early-onset and non-amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non-right-handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.},
}

Humans
*Alzheimer Disease/epidemiology
Age of Onset
Female
Phenotype
Male
Aged
Risk Factors
Middle Aged
Cohort Studies
Aged, 80 and over

@article {pmid40959862,
year = {2025},
author = {Shi, H and Lipworth, L and Xiao, Q and Han, X and Mumma, M and Keohane, LM and Yu, D and Bolton, CJ and Archer, DB and Hohman, TJ and Full, KM},
title = {Five-year change in sleep duration and incident Alzheimer's Disease and Related Dementias among lower-income older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70678},
doi = {10.1002/alz.70678},
pmid = {40959862},
issn = {1552-5279},
support = {U01CA202979//National Cancer Institute of the National Institutes of Health/ ; K01AG083223-01//National Institute of Aging/ ; 23AARG-1030276/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/epidemiology ; Aged ; *Poverty/statistics & numerical data ; United States/epidemiology ; Incidence ; *Sleep/physiology ; Medicare ; *Dementia/epidemiology ; Cohort Studies ; Aged, 80 and over ; Risk Factors ; Time Factors ; Sleep Duration ; },
abstract = {INTRODUCTION: Little is known about change in sleep duration over time and Alzheimer's Disease and Related Dementias (ADRD) risk.

METHODS: ADRD cases were identified among Southern Community Cohort Study participants enrolled in Medicare. Sleep duration was reported at enrollment and first study follow-up and categorized (short (< 7 hours), recommended (7-9) and long (> 9)), change was calculated between timepoints. Adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs, 95% CIs) for incident ADRD.

RESULTS: We identified 2,093 ADRD cases among 17,945 participants. Compared to maintaining optimal sleep duration (7-9 hours) over 5 years, suboptimal changes were associated with 20-69% greater ADRD risk: adjusted HR (95% CI) was 1.50 (1.23-1.82) for long-recommended, 1.56 (1.21-2.01) for long-long, 1.69 (1.25-2.27) for long-short, 1.49 (1.16-1.91) for short-long, and 1.20 (1.06-1.36) for short-short.

DISCUSSION: Suboptimal 5-year change in sleep durations were associated with ADRD risk among lower-income adults underrepresented in ADRD research.

HIGHLIGHTS: The study calculated 5-year change in sleep duration in a large community-based cohort of predominately lower-income adults. Cases of Alzheimer's Disease and Related Dementias (ADRD) were ascertained from Medicare claims data among 17,945 participants with up to 12 years of follow-up. Compared to maintaining 7-9 hours of sleep, older adults with suboptimal sleep categories were consistently at a greater risk of ADRD.},
}

Humans
Female
Male
*Alzheimer Disease/epidemiology
Aged
*Poverty/statistics & numerical data
United States/epidemiology
Incidence
*Sleep/physiology
Medicare
*Dementia/epidemiology
Cohort Studies
Aged, 80 and over
Risk Factors
Time Factors
Sleep Duration

@article {pmid40959651,
year = {2025},
author = {Gomes, FC and Bertelli, BP and de Souza, CP and Santos, DRO and de Melo-Neto, JS and Pavarino, ÉC and Goloni-Bertollo, EM},
title = {HSPA13 gene and microRNA-155: relationship between Down syndrome and Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {Suppl 1},
pages = {e20240239},
pmid = {40959651},
issn = {1980-5764},
abstract = {UNLABELLED: Gene dysregulation in trisomy 21 can cause disorders of genes that are members of the heat-shock proteins (HSPs) family and contribute to the early onset of Alzheimer's disease (AD) in Down syndrome (DS).

OBJECTIVE: Investigate in silico differently expressed genes (DEGs) of HSPs and the interaction with microRNAs (miRNAs) located in human chromosome 21 (Hsa21).

METHODS: Two transcriptome libraries of human brain samples, datasets GSE5390 (DS) and GSE33000 (DA), were extracted from the Gene Expression Omnibus (GEO) and analyzed via GEO2R. DEGs with p-values (Adj p-values) <0.05 were analyzed via STRING. MiRNAs were identified in the miRbase database and analysis of their potential regulation on DEGs was performed using the DIANA tools.

RESULTS: HSPE1, HSP90B1, HSPB8 and HSPA13 genes showed a different expression pattern in the transcriptomes of DS. The HSPA13 and HSPA2 genes showed an altered expression profile in the DS and AD datasets. In the predicted protein-protein interactions (PPI), we identified the interaction of HSPE1, HSP90B1, HSPB8 and HSPA13 with other HSP proteins. The miRNA encoded by Hsa21 (hsa-miR-155-5p) interacted with the HSPA13 gene.

CONCLUSION: The results suggest that certain genes encoding members of the HSP family, and in particular the interaction between miR-155-5p and HSPA13, may be associated with AD in DS.},
}

@article {pmid40959581,
year = {2025},
author = {Jin, RR and Gu, Y and Lee, TMC and , },
title = {Longitudinal changes in the brain-age gap in mild cognitive impairment and their relationships with neuropsychological functions and Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70180},
pmid = {40959581},
issn = {2352-8729},
abstract = {INTRODUCTION: The discrepancy between biological and modeled brain ages-the brain-age gap (BAG)-could indicate potential neuropsychological changes. This study verified if and how longitudinal BAG changes were associated with neuropsychological functions and Alzheimer's disease-related biomarkers in individuals with mild cognitive impairment (MCI).

METHODS: One hundred thirty-eight individuals with MCI and 103 healthy controls (HCs) with three rounds of magnetic resonance imaging scanning were selected from the Alzheimer's Disease Neuroimaging Initiative. We applied support vector regression on functional connectivity for modeling the brain age and further calculated the BAG.

RESULTS: Longitudinal BAG changes were higher in participants with MCI compared to HCs. Larger BAG fluctuations were correlated with poorer cognitive performance and more severe depressive symptoms in patients with MCI. Neurofilament light chain and phosphorylated tau levels were associated with the longitudinal BAG changes.

DISCUSSION: Present findings demonstrated the necessity of incorporating longitudinal BAG in monitoring the neuropsychological status among cognitively vulnerable populations.

HIGHLIGHTS: Brain-age gap (BAG) changes are sensitive indicators of cognitive vulnerability in aging.BAG changes were larger in patients with mild cognitive impairment than in the controls.Longitudinal BAG changes were associated with worse cognitive-affective states.The plasma neurofilament light chain and cerebrospinal fluid phosphorylated tau levels were associated with the BAG changes.},
}

@article {pmid40959580,
year = {2025},
author = {Amland, R and Selbæk, G and Brækhus, A and Rhodius-Meester, HFM and Strand, BH},
title = {Sex differences in life expectancy in dementia, mild cognitive impairment (MCI), and subjective cognitive decline (SCD).},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70177},
pmid = {40959580},
issn = {2352-8729},
abstract = {INTRODUCTION: It is unclear how dementia affects loss in life expectancy (LE). In this registry-based study, we aimed to study sex differences in LE and loss in LE in dementia, mild cognitive impairment (MCI), and subjective cognitive decline (SCD).

METHODS: A total of 16,358 patients diagnosed with dementia, MCI, or SCD from the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) during 2009-2022 were included and followed up for mortality. Sex differences in LE and loss in LE were predicted using flexible parametric survival models and sex-specific mortality in the general population as reference.

RESULTS: Among dementia patients, women with dementia had the largest loss in LE: 17 years loss at 60 years; correspondingly, men lost 13.5 years. Similar patterns were observed for MCI and dementia subtypes.

DISCUSSION: Women with dementia or MCI had a larger loss in LE compared to men with these diagnoses.

HIGHLIGHTS: Women with dementia had the largest loss in life expectancy compared to the general population.The excess female loss in life expectancy was also evident for all the dementia subtypes and for mild cognitive impairment.The loss in life expectancy was more pronounced in younger patients with dementia, with a loss of 17 years in women at 60 years of age. Men, in comparison, lost 13.5 years at the same age.Subjective cognitive decline was associated with a minor loss in life expectancy in both sexes.},
}

@article {pmid40959537,
year = {2025},
author = {Darabi, S and Gorgich, EA and Rustamzadeh, A and Mohebi, N and Mozhdehipanah, H},
title = {The miR-133b and miR-206 serum levels as a candidate biomarker in Alzheimer's patients with dyslipidemia.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {672-678},
pmid = {40959537},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by cognitive decline. Dyslipidemia, a risk factor for AD, may influence the expression of microRNAs (miRs) involved in AD pathogenesis. Thus, the aim of this study was to investigate the effect of dyslipidemia on the expression levels of miR-133b and miR-206 in AD patients with mild cognitive impairment. This study recruited a total of 45 subjects, who were subsequently divided into three distinct groups: the AD group (n = 15), the AD dyslipidemia group (n = 15), and the dyslipidemia group with normal cognitive status (n = 15). The Aβ42/40 serum ratio was measured using an enzyme-linked immunosorbent assay. miR expression levels were determined by RT-qPCR. Clinicopathological characteristics, including Mini-Mental State Examination (MMSE) scores, Clinical Dementia Rating (CDR), and HDL levels, were also assessed. miR-133b levels were significantly reduced in the AD dyslipidemia group compared to the other two groups (p < 0.001), while miR-206 levels were markedly elevated (p < 0.001). Spearman correlation analysis revealed that miR-133b expression levels were positively associated with the Aβ42/40 ratio (r = 0.799), MMSE scores (r = 0.578), and HDL levels (r = 0.768), while negatively associated with miR-206 levels (r = -0.461), CDR score (r = -0.539), and AD duration (r = -0.569). Conversely, miR-206 levels positively correlated with CDR and disease duration, but were inversely associated with miR-133b, MMSE, Aβ42/40, and HDL. Serum miR-133b and miR-206 levels appear to be associated with AD pathology and clinical parameters in the early stages of the disease. The studied miR expression levels could serve as reliable biomarkers in AD patients with dyslipidemia.},
}

@article {pmid40959450,
year = {2025},
author = {Shi, G and Ni, L and Kong, X and Ren, R and Shi, X and Xu, Y and Qu, Z and Zhou, H and Zhang, X},
title = {Unveiling the therapeutic potential of caudatin: Structural optimization, pharmacological mechanisms, and therapeutic implications.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1640365},
pmid = {40959450},
issn = {1663-9812},
abstract = {Caudatin is a C21 steroidal glycoside isolated from many species of the genus Cynanchum, has been utilized by traditional medicine to treat cancer and inflammation which is increasingly being considered a drug candidate because of the pharmacological activity it displays. This review provides a discussion of caudatin's structure-activity relationship (SAR), pharmacology, and therapeutic uses along with a synthesis of future challenges. Caudatin is a potent anti-cancer therapeutic that has been shown to modulate several important signaling pathways, which include but are not limited to: Wnt/β-catenin, NF-κB, and PI3K/AKT pathway, induce apoptosis through ROS mediated mitochondrial dysfunction, reduce metastatic spread through inhibition of epithelial-mesenchymal transition (EMT), and have an anti-inflammatory effect through inhibition of JNK/AP-1/NF-κB signaling. Caudatin has also displayed neuroprotection in models of Alzheimer's disease by activating TFEB and the autophagosome-lysosomal pathway mechanism of action, while also modulating PPARα. Furthermore, pharmacokinetic studies indicate that caudatin is rapidly absorbed and is able to selectively tail hepatic tissue while having little to no toxicity or significant adverse events in pre- clinical animal studies. Structure-activity studies suggest that modifications on the C-3 hydroxyl position, primarily with nitrogen heterocycles and/or sugars greatly enhance the bioactivity and solubility. With caudatin being such a great scaffold for medicinal chemistry, there is great opportunity to take advantage of caudatin as a building block to generate novel therapies which bridge traditional medicine with modern drug discovery. The future is aimed primarily at a combination strategy of synthetic derivatives, translational studies, and formulations. In further exploring caudatin as a treatment for cancer and neurodegenerative diseases, and inflammation.},
}

@article {pmid40959270,
year = {2025},
author = {Soladogun, AS and Vidal, C and Castro, MDCC and Du, H and Zhang, L},
title = {Altered Heme and Redox Homeostasis Underpin Late-onset Alzheimer's Disease.},
journal = {International journal of biological sciences},
volume = {21},
number = {12},
pages = {5393-5410},
pmid = {40959270},
issn = {1449-2288},
mesh = {*Alzheimer Disease/metabolism/genetics ; Humans ; *Heme/metabolism ; Oxidation-Reduction ; Homeostasis ; Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Early-onset Alzheimer's disease (EOAD) is associated with highly penetrant mutations in genes such as PSEN2, whereas the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) is the APOE4 allele. Despite intense research efforts, how neuronal dysfunction is initiated in LOAD cases and how the initiating events for EOAD and LOAD differ remain to be clarified. Using biochemical measurements of energy metabolism, heme and redox homeostasis, in combination with RNA-Sequencing analysis, we characterized biochemical and transcriptome differences in neurons differentiated from human EOAD and LOAD iPSC-derived neural stem cells, relative to their respective control neurons. Strikingly, we found that LOAD neurons, not EOAD neurons, are defective in heme and redox homeostasis. The levels of multiple proteins and enzymes involved in heme synthesis, degradation, and oxidative phosphorylation are preferentially decreased in LOAD neurons, not EOAD neurons. Likewise, heme transport is decreased in LOAD neurons. ROS generation is strongly increased in LOAD neurons, not EOAD neurons. Further, many genes involved in heme and redox homeostasis, as well as cellular energy generation, are downregulated in LOAD neurons, not EOAD neurons. Together, these results strongly suggest that altered heme and redox homeostasis in LOAD neurons underlie the initiation of neurological deficits.},
}

*Alzheimer Disease/metabolism/genetics
Humans
*Heme/metabolism
Oxidation-Reduction
Homeostasis
Neurons/metabolism
Induced Pluripotent Stem Cells/metabolism
Reactive Oxygen Species/metabolism

@article {pmid40959086,
year = {2025},
author = {Chen, R and Tang, X and Wang, Y and Wang, B and Mao, F},
title = {Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1652741},
pmid = {40959086},
issn = {1664-3224},
mesh = {Humans ; *Lipoylation ; *Signal Transduction ; *Inflammation/metabolism/immunology ; Animals ; *Protein Processing, Post-Translational ; Thiolester Hydrolases ; },
abstract = {Protein palmitoylation is a reversible lipid modification in which palmitoyl esters are covalently attached to cysteine residues of proteins. It controls various cellular physiological processes and alters protein stability, conformation, localization, membrane binding, and interaction with other effector proteins. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), while the acyl-protein thioesterase family mediates depalmitoylation. Emerging evidence suggests that palmitoylation is critical for inflammatory signaling pathways, where palmitoylation is particularly important in the membrane localization of inflammation-associated proteins. Notably, dysregulation of palmitoylation has been associated with a variety of inflammatory diseases. Here, we provide an overview of the regulatory mechanisms of palmitoylation, explore the emerging role of palmitoylation in inflammatory signaling pathways, and examine the link between dysregulated palmitoylation and the pathogenesis of inflammatory diseases, including inflammatory bowel disease, autoimmune diseases, metabolic dysfunction-associated steatohepatitis, sepsis, Alzheimer's disease, Parkinson's disease, and diabetes. Finally, we discuss some of the challenges and opportunities facing the field. Targeting palmitoylation or its associated enzymes serves as a novel therapeutic approach for the treatment of inflammatory diseases.},
}

Humans
*Lipoylation
*Signal Transduction
*Inflammation/metabolism/immunology
Animals
*Protein Processing, Post-Translational
Thiolester Hydrolases

@article {pmid40958945,
year = {2025},
author = {Biafore, F and Docampo, J and Duca, G},
title = {Automated hippocampal volume measurement: agreement analysis between HIPS and volBrain software.},
journal = {Radiologia brasileira},
volume = {58},
number = {},
pages = {e20250003},
pmid = {40958945},
issn = {0100-3984},
abstract = {OBJECTIVE: To perform an agreement analysis between volBrain and HIPS software for measuring hippocampal volume and its associated asymmetry index.

MATERIALS AND METHODS: We evaluated volumetric T1-weighted magnetic resonance imaging scans from radiologically normal subjects (n = 50; age range, 25-75 years). Correlation and Bland-Altman plots were generated. The Pearson correlation coefficient (r) and the intraclass correlation coefficient of absolute agreement between volBrain and HIPS software were calculated for each measurement.

RESULTS: For each hippocampus and its combined volume, a very high correlation was found between the methods (r ≥ 0.96 for absolute values and r ≥ 0.93 for relative values), along with a systematic bias (primarily additive). Consistently, HIPS (with the Kulaga-Yoskovitz protocol) reported smaller volumes than did volBrain. The average difference ranged from 8.2% to 9.1% for absolute values and from 7.9% to 8.7% for relative values. The asymmetry index exhibited a strong correlation (r = 0.82) with no significant bias, although 14% of cases showed opposite signs. The average asymmetry index difference was 32.7%. The intraclass correlation coefficient of absolute agreement ranged from 0.61 to 0.83, reflecting moderate to good agreement overall.

CONCLUSION: Our results indicate that the two methods are not interchangeable for evaluating hippocampal volume and its associated asymmetry index.},
}

@article {pmid40958782,
year = {2025},
author = {Sun, LC and Li, WS and Chen, W and Zhao, DQ and Zhang, X and Li, CX and Ren, Z},
title = {Frontiers and Emerging Trends in Edaravone Research: A Bibliometric Analysis of Molecular Basis and Clinical Studies Using CiteSpace and VOSviewer.},
journal = {Journal of multidisciplinary healthcare},
volume = {18},
number = {},
pages = {5743-5758},
pmid = {40958782},
issn = {1178-2390},
abstract = {PURPOSE: Edaravone is a potent free-radical scavenger and antioxidant that has been widely investigated for its therapeutic potential in neurodegenerative diseases and oxidative stress-related conditions. Although previous studies have explored its molecular structure, pharmacological effects, and clinical applications, a comprehensive bibliometric analysis of its research trends and future directions remains lacking.

METHODS: This study employed bibliometric methods to analyze edaravone-related publications from 2000 to 2024, using the Web of Science Core Collection database. The analysis examined publication trends; contributions by countries, institutions, and authors; and keyword clustering. Data visualization tools, such as CiteSpace and VOSviewer, were utilized to identify research clusters and emerging trends in edaravone research.

RESULTS: The findings revealed a significant increase in edaravone-related publications, with China, Japan, and the United States as the leading contributors. Notable researchers, including Abe K and Yoshino H, have made substantial contributions to this field. Four major research clusters were identified: free radical scavenging, cerebral infarction, amyotrophic lateral sclerosis, and oxidative stress. Emerging trends suggest a growing interest in edaravone dexbornel for acute ischemic stroke treatment, as well as its potential applications in blood-brain barrier interactions and Alzheimer's disease.

CONCLUSION: This bibliometric analysis highlights the growing interest in edaravone and its potential clinical application, particularly in neuroprotection. While this study provides valuable insights into current research trends, future studies should incorporate a broader range of sources and languages to obtain a more comprehensive understanding of the impact and scope of edaravone.},
}

@article {pmid40958778,
year = {2025},
author = {Marongiu, R and Platholi, J and Park, L and Yu, F and Sommer, G and Woods, C and Milner, TA and Glass, MJ},
title = {Correction: Promotion of neuroinflammation in select hippocampal regions in a mouse model of perimenopausal Alzheimer's disease.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1684511},
doi = {10.3389/fmolb.2025.1684511},
pmid = {40958778},
issn = {2296-889X},
abstract = {[This corrects the article DOI: 10.3389/fmolb.2025.1597130.].},
}

@article {pmid40958776,
year = {2025},
author = {Budny, V and Bodenmann, C and Zürcher, KJ and Krüger, M and de Leeuw, SM and Weber, RZ and Rust, R and Ravotto, L and Ruminot, I and Barros, LF and Weber, B and Tackenberg, C},
title = {APOE genotype-dependent differences in human astrocytic energy metabolism.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1603657},
pmid = {40958776},
issn = {1662-5102},
abstract = {INTRODUCTION: The main genetic risk factor for Alzheimer's disease (AD) is the presence of the apolipoprotein E4 (APOE4) allele. While APOE4 increases the risk of developing AD, the APOE2 allele is protective and APOE3 is risk-neutral. In the brain, APOE is primarily expressed by astrocytes and plays a key role in various processes including cholesterol and lipid transport, neuronal growth, synaptic plasticity, immune response and energy metabolism. Disruptions in brain energy metabolism are considered a major contributor to AD pathophysiology, raising a key question about how different APOE isoforms affect the energy metabolism of human astrocytes.

METHODS: In this study, we generated astrocytes (iAstrocytes) from APOE-isogenic human induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE knockout (APOE-KO), and investigated APOE genotype-dependent changes in energy metabolism.

RESULTS: ATP Seahorse assay revealed a reduced mitochondrial and glycolytic ATP production in APOE4 iAstrocytes. In contrast, glycolysis stress tests demonstrated enhanced glycolysis and glycolytic capacity in APOE4 iAstrocytes while genetically encoded nanosensor-based FLIM analysis revealed that APOE does not affect lactate dynamics. In agreement with the increased glycolytic activity, APOE4 iAstrocytes also showed elevated mitochondrial respiration and activity, indicated by proteomic GO enrichment analysis and mitochondrial stress test. This was accompanied by elevated proton leak in APOE4 iAstrocytes while levels of mitochondrial uncoupling proteins (UCPs) were not affected. Mass spectrometry-based metabolomic analysis identified various energy and glucose metabolism-related pathways that were differentially regulated in APOE4 compared to the other genotypes, including mitochondrial electron transport chain (ETC) and glycolysis. In general, APOE2 and APOE-KO iAstrocytes showed a very similar phenotype in all functional assays and differences between APOE2/APOE-KO and APOE4 were stronger than between APOE3 and APOE4.

DISCUSSION: Our study provides evidence for APOE genotype-dependent effects on astrocyte energy metabolism and highlights alterations in the bioenergetic processes of the brain as important pathomechanisms in AD.},
}

@article {pmid40958751,
year = {2025},
author = {Collie, AIM and Nicholson, JS and Phills, CE},
title = {Emerging Adults' Perception of the Typical Dementia Patient Based on Gender and Race.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {40},
number = {},
pages = {15333175251378275},
doi = {10.1177/15333175251378275},
pmid = {40958751},
issn = {1938-2731},
mesh = {Humans ; Female ; Male ; *Dementia/ethnology/psychology ; *Black or African American/psychology/ethnology ; Young Adult ; Sex Factors ; *Social Perception ; Adult ; White People ; White ; },
abstract = {IntroductionThough Black Americans are twice as likely as White Americans to be diagnosed with Alzheimer's Disease, they may be excluded from the mental representation of a person with dementia.MethodsParticipants (N = 143, median age = 19) created visualized mental representations of a person, a man, a woman, a Black man, or a Black woman diagnosed with dementia by repeatedly selecting which among 12 faces looked most like each target category.ResultsThe visualized representation of a person with dementia was more similar to the representation of a man and a Black woman than to a Black man and a woman, respectively.DiscussionThese findings highlight how intersectionality shapes mental representations of dementia, revealing that certain combinations of marginalized identities are perceived differently rather than excluded entirely.},
}

Humans
Female
Male
*Dementia/ethnology/psychology
*Black or African American/psychology/ethnology
Young Adult
Sex Factors
*Social Perception
Adult
White People
White

@article {pmid40958704,
year = {2025},
author = {Vanneste, S and Reynolds, J and De Ridder, D},
title = {Focused transcranial ultrasound stimulation: a breakthrough approach to treating brain disorders.},
journal = {Expert review of medical devices},
volume = {},
number = {},
pages = {},
doi = {10.1080/17434440.2025.2563618},
pmid = {40958704},
issn = {1745-2422},
abstract = {INTRODUCTION: Focused transcranial ultrasound stimulation (fTUS) has emerged as a novel noninvasive technique with promising therapeutic potential for various neurological and psychiatric conditions. The aim of this review is to evaluate current research on fTUS, examining its mechanisms, therapeutic applications, challenges, and future potential in neurological and psychiatric disorders.

AREA COVERED: High intensity fTUS leads to heat-induced thermoablation which has shown efficacy in treating essential tremor and tremor-dominant Parkinson's disease, with promising outcomes in clinical trials. fTUS has been explored for blood-brain barrier opening, facilitating drug delivery for conditions like glioblastoma and Alzheimer's disease. Low intensity fTUS can also be used as a novel neuromodulation tool which has shown potential in alleviating chronic pain, depression, and cognitive decline.

EXPERT OPINION: Challenges remain, including technical refinements, standardization of parameters, and optimization of therapeutic protocols. Emerging approaches like hyperthermia therapy, sonodynamic therapy, and sonothrombolysis hold promise for future applications. With ongoing research and collaboration, the next decade holds immense potential for further advancements in fTUS technology and its clinical integration.},
}

@article {pmid40958408,
year = {2025},
author = {Liu, Y and Song, N and Wang, Q and Cui, P and Min, D},
title = {A Mendelian Randomization Study and Experimental Validation Investigating the Potential Relationship Among Interleukin-6 Receptor Subunit Beta, Obesity, and Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {15},
number = {9},
pages = {e70772},
doi = {10.1002/brb3.70772},
pmid = {40958408},
issn = {2162-3279},
support = {82174114//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism ; *Mendelian Randomization Analysis/methods ; Animals ; *Obesity/genetics/metabolism ; *Receptors, Interleukin-6/genetics/metabolism ; Mice ; Genome-Wide Association Study ; Humans ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Hippocampus/metabolism ; Polymorphism, Single Nucleotide ; },
abstract = {OBJECTIVE: This study employs Mendelian randomization (MR) aimed at systematically evaluating the relationship among interleukin-6 receptor subunit beta, obesity, and Alzheimer's disease (AD). We conducted animal studies to validate the reliability of the MR analytical outcomes.

METHODS: The pooled data for the interleukin-6 receptor subunit beta originated from the genome-wide association study (GWAS) dataset, which included a total of 10,534,735 participants. Obesity pooled data were from the GWAS dataset (case n = 23,971 and control n = 388,084) and AD pooled data from the GWAS database (case n = 39,106 and control n = 46,828). The aforementioned data sets facilitated MR causal analysis. First, utilize the inverse variance weighting (IVW) method for analysis and enhance it with MR-Egger regression and weighted median approaches, and a sensitivity analysis was performed by MR-multiple effect residuals and outliers (MR-Presso), Cochran Q test, and Leave-one (LOO) analysis. We established an obesity model by feeding 6-week-old male ApoE[-/-] mice a high-fat diet for 16 weeks. In contrast, C57BL/6 control mice were fed a normal diet for the same duration. An AD model was established by feeding 3-month-old APP/PS1 mice a normal diet for 24 weeks. We harvested serum and hippocampal tissue from the mice for enzyme-linked immunosorbent assay (ELISA).

RESULTS: MR analysis indicated that a genetically predicted increase in interleukin-6 receptor subunit beta raises the risk of AD (OR = 1.064, 95% CI: 1.021-1.109, p = 0.003). The exposure factor interleukin-6 receptor subunit beta served as a protective element against obesity (OR = 0.9372,95%CI:0.8921-0.9847, p = 0.010). Obesity showed an adverse relationship with AD. As the body mass index (BMI) increased, the risk of developing AD decreased (OR = 0.9299, 95% CI: 0.8939-0.9674, p  ＜0.001). ELISA findings revealed that the levels of interleukin-6 receptor subunit beta (gp130), oncostatin-M (OSM), and IL-6 in serum and hippocampus decreased in obesity, whereas they increased in AD, aligning with the results of the MR Analysis.

CONCLUSION: In summary, our extensive Mendelian randomization data suggest that increased levels of the interleukin-6 receptor subunit beta may be associated with a reduced risk of obesity, and consequently, may increase the risk of AD.},
}

*Alzheimer Disease/genetics/metabolism
*Mendelian Randomization Analysis/methods
Animals
*Obesity/genetics/metabolism
*Receptors, Interleukin-6/genetics/metabolism
Mice
Genome-Wide Association Study
Humans
Male
Disease Models, Animal
Mice, Inbred C57BL
Hippocampus/metabolism
Polymorphism, Single Nucleotide

@article {pmid40958354,
year = {2025},
author = {Fastenau, C and Crisp, R and Keating, M and Ochoa, E and Richardson, TE and Flanagan, ME and Walker, JM and Hopp, SC and Bieniek, KF},
title = {Sialylation patterns in cerebral amyloid angiopathy.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70042},
doi = {10.1111/bpa.70042},
pmid = {40958354},
issn = {1750-3639},
support = {T32AG021890/NH/NIH HHS/United States ; NS082145/NH/NIH HHS/United States ; R21AG072423/NH/NIH HHS/United States ; P30AG013319/NH/NIH HHS/United States ; P30AG066546/NH/NIH HHS/United States ; //Texas Alzheimer's Research and Care Consortium/ ; //Bartell and Mollie Zachry Endowment for Alzheimer's Research and Patient Care/ ; K12 GM111726/GM/NIGMS NIH HHS/United States ; },
abstract = {Glycosylation is the most common form of post-translational modification in the brain and becomes significantly altered in the context of neurodegeneration. One notable alteration is an enrichment of terminal sialic acid (SA) modifications. Previous studies provide evidence of increased sialylation on microglia, the innate immune cell of the brain, in Alzheimer's disease (AD), particularly near amyloid beta plaques. Yet, there is little understanding of the relationship between SA and other amyloid beta-related diseases like Cerebral Amyloid Angiopathy (CAA). Nearly half of all AD cases have CAA; thus, it is critical to understand the relationship between amyloid pathology and SA modifications. The present study aimed to overcome this gap in knowledge by investigating sialylation patterns in AD cases with CAA compared with CAA-negative AD cases and amyloid-negative control cases. The localization of SA modifications was investigated in the frontal cortex of 30 post-mortem cases with or without diagnoses of AD and/or CAA. Quantitative digital pathology analyses were used to determine regional SA differences in parenchymal and leptomeningeal blood vessels. First, we found no difference in intravascular amyloid-beta levels between the parenchymal and leptomeningeal vessels of AD with CAA cases, suggesting no regional differences in this amyloid aggregation. Next, there was a visual increase in microglia sialylation surrounding parenchymal blood vessels in the CAA cases. Notably, there were significant differences in intravascular SA levels across the three comparison groups. AD cases with CAA had significantly greater sialylation levels in both the parenchymal and leptomeningeal vessels compared with the AD-only and control groups. This is a novel finding that supports the consideration of glycosylation changes that contribute to worse pathological outcomes in AD with CAA.},
}

@article {pmid40958224,
year = {2025},
author = {Shen, R and Lyu, Y and Yang, C and Zou, S and Xu, Y},
title = {Genetic association and potential mediators between subjective well-being and cardiovascular events: A bidirectional two-sample, two-step Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {37},
pages = {e44482},
doi = {10.1097/MD.0000000000044482},
pmid = {40958224},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Cardiovascular Diseases/genetics/epidemiology ; Genome-Wide Association Study ; Male ; Female ; Middle Aged ; Polymorphism, Single Nucleotide ; Risk Factors ; },
abstract = {Observational evidence suggests that subjective well-being (SWB) is inversely associated with cardiovascular (CV) events, yet whether this link is causal and through which pathways remains unclear. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis using genetic instruments for SWB (N = 2370,390) and major adverse cardiovascular events (MACE; N = 500,348). All the data were from the largest available genome-wide association studies in populations of European descent. In univariable MR, each 1-standard-deviation increase in genetically predicted SWB reduced the odds of MACE by 39% (odds ratio = 0.61; 95% confidence interval, 0.50-0.74; P = 5.82 × 10[-7]). This association remained after multivariable MR adjustment for general medical conditions - Alzheimer disease, hypothyroidism, hyperthyroidism, multiple sclerosis, Addison disease, Cushing syndrome, Parkinson disease, systemic lupus erythematosus, and epilepsy - which often co-occur with mood symptoms and may also influence CV risk. Two-step MR analysis identified 3 out of 46 candidates as mediators between SWB and MACE: body mass index, diastolic blood pressure and triglycerides, accounting for 13.97% (95% confidence interval, 6.34%-21.60%), 6.05% (95% confidence interval, 0.00%-12.10%) and 10.53% (95% confidence interval, 4.45%-16.60%) of the total effect of SWB on MACE, respectively. Sensitivity analyses were directionally consistent, whereas MR-Egger did not reach statistical significance. Taken together, these results suggest that higher SWB may be associated with a lower risk of CV events, partly through metabolic and hemodynamic pathways. Targeting SWB may therefore complement conventional risk-factor management in CV prevention.},
}

Humans
Mendelian Randomization Analysis
*Cardiovascular Diseases/genetics/epidemiology
Genome-Wide Association Study
Male
Female
Middle Aged
Polymorphism, Single Nucleotide
Risk Factors

@article {pmid40958121,
year = {2025},
author = {Elhady, MM and Zidan, A and Rabea, EM and Farouk, HS and Elattar, MZ and Adel, M and Khalil, MA and Aboali, AA and Zeid, MAA and Shaltout, MA and Abdel-Daim, AM and Alwarraqi, AG and AbuEl-Enien, H and Zaazouee, MS},
title = {The association between H. pylori infection and cognitive deterioration: a systematic review and meta-analysis.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {846},
pmid = {40958121},
issn = {2047-783X},
mesh = {Humans ; *Helicobacter Infections/complications/epidemiology/microbiology ; *Helicobacter pylori/pathogenicity ; *Cognitive Dysfunction/epidemiology/microbiology/etiology ; Prevalence ; },
abstract = {BACKGROUND: The association between cognitive decline and Helicobacter pylori (H. pylori) infection remains controversial, with some evidence suggesting that H. pylori eradication may slow the progression of the disease. This meta-analysis aims to investigate the bidirectional relationship between H. pylori and cognitive decline.

METHODS: We searched PubMed, Web of Science, the Cochrane Library, and Scopus for double-arm studies that reported either the prevalence of cognitive decline in individuals with H. pylori-positive status or the prevalence of H. pylori infection in patients with cognitive decline. A random-effects meta-analysis was conducted using Comprehensive Meta-Analysis software to pool the odds ratios from the included studies. Study quality was assessed using the Newcastle-Ottawa Scale.

RESULTS: Our search identified 1,240 records, with 16 studies meeting the inclusion criteria. Meta-analysis showed that patients with H. pylori had a significantly higher risk of cognitive decline (OR = 1.338, 95% CI 1.046-1.713), with the strongest association seen in studies grouping cognitive dysfunction and dementia (OR: 3.190, 95% CI 1.853-5.490). However, the risk of Alzheimer's disease was insignificant. Cognitive decline cohorts showed a significantly higher prevalence of H. pylori (OR = 1.5, 95% CI 1.131-1.989), with a significant association with Alzheimer's disease (OR: 1.630, 95% CI 1.064-2.497), but not with dementia or cognitive dysfunction. The association varied across study designs, with cross-sectional studies showing no association in both analyses. Heterogeneity was substantial (I[2] > 70% in most analyses), highlighting variability in the findings.

CONCLUSION: This meta-analysis indicates a bidirectional association between H. pylori and cognitive decline. While H. pylori infection increased the overall risk of cognitive decline, no significant link was found with Alzheimer's disease. Conversely, Alzheimer's disease patients had a higher prevalence of H. pylori infection. High heterogeneity underscores the need for further well-designed studies to clarify this relationship.},
}

Humans
*Helicobacter Infections/complications/epidemiology/microbiology
*Helicobacter pylori/pathogenicity
*Cognitive Dysfunction/epidemiology/microbiology/etiology
Prevalence

@article {pmid40958089,
year = {2025},
author = {Zhang, M and Lin, Y and Wei, H and Ju, Q and Gao, T and Zhang, Y and Shen, L and Sun, C},
title = {The membrane receptor CD44: roles in neurodegenerative diseases.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2025.2563243},
pmid = {40958089},
issn = {1744-7631},
abstract = {INTRODUCTION: With the increasing prevalence of aging populations, the incidence of neurodegenerative diseases continues to rise, posing a serious threat to human health and quality of life. Owing to the highly complex pathogenesis of these disorders, the identification of effective therapeutic targets remains a major challenge. CD44, a cell surface glycoprotein, plays a central role in regulating cell proliferation, survival, adhesion, and migration. Emerging evidence further indicates that CD44 contributes to NF-κB activation, thereby amplifying inflammatory responses.

AREAS COVERED: Given its central role in neuroinflammation, CD44 has attracted increasing attention as a potential therapeutic target for neurodegenerative diseases. This review explores the involvement of CD44 in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), with particular emphasis on its contributions to neuroinflammatory processes, neuronal survival, and pathological protein aggregation.

EXPERT OPINION: Chronic low-grade neuroinflammation is a major driver of neurodegenerative diseases, including ALS, AD, and PD. Growing evidence implicates CD44 as a key contributor to disease pathogenesis, with several studies reporting significantly elevated CD44 expression in affected patients. These findings highlight the role of CD44 in disease progression and suggest that targeting CD44-mediated inflammation may offer a promising therapeutic strategy for neurodegenerative disorders.},
}

@article {pmid40957902,
year = {2025},
author = {Ekins, TG and Rybicki-Kler, C and Deng, T and Brooks, IAW and Jedrasiak-Cape, I and Donoho, E and Ahmed, OJ},
title = {Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {40957902},
issn = {1476-5578},
support = {R01MH129282//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R34NS127101//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P50NS123067//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; AARG-NTF-21-846572//Alzheimer's Association/ ; T32DA007268//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; T32DC000011//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; T32DC000011//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; },
abstract = {Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) - important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer's disease - lack 5-HT2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer's disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT2A receptors.},
}

@article {pmid40957712,
year = {2025},
author = {King, KM and Cleveland, EM and Pennington, A and Fuccello, S and Brown, AM},
title = {The Influence of POPC as a Coaggregate in Amyloid-β Oligomer Formation.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00605},
pmid = {40957712},
issn = {1948-7193},
abstract = {Alzheimer's Disease (AD) progresses with the formation of neuronal plaques composed primarily of the 42-residue alloform of amyloid-β (Aβ42), whose oligomeric forms induce cytotoxicity by interacting with neuronal membranes, resulting in permeabilization and calcium ion leakage. In AD, elevated phospholipase activity disrupts lipid homeostasis and may increase the concentration of free lipids, such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), in extracellular environments proximal to the membrane surface, potentially promoting Aβ42 insertion and toxicity. The coaggregation of Aβ42 with free lipids is believed to modulate mechanisms underlying Aβ42-induced cytotoxicity; however, these interactions are poorly understood. Molecular dynamics (MD) simulations were conducted to investigate Aβ42-POPC interactions and study the aggregation and structural morphologies of hexameric, octameric, and decameric Aβ42 in conjunction with free POPC in a 1:1 ratio. Clustering, radius of gyration, and eccentricity analyses revealed that POPC modulates Aβ42 oligomer morphology in a size-dependent manner. POPC increased compactness and sphericity in octameric and decameric systems, but had minimal or variable effects on hexamers. Hydrophobic interactions between Aβ42 and POPC hydrocarbon tails drove co-oligomerization, and increased hydrophobic solvent accessibility of Aβ42 peptides, altering the energetic profiles of hydrophobic and aromatic residues. To this effect, we hypothesize that Aβ42 coaggregation with POPC may nucleate additional oligomerization events through hydrophobic exposure of Aβ42. This work provides a mechanistic basis for early Aβ42 oligomerization events in lipid microenvironments, offering insights into neurodegenerative pathology.},
}

@article {pmid40957222,
year = {2025},
author = {Trushin, S and Nguyen, TKO and Stojakovic, A and Ostroot, M and Deason, JT and Chang, SY and Zhang, L and Macura, SI and Nambara, T and Lu, W and Kanekiyo, T and Trushina, E},
title = {Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease.},
journal = {EBioMedicine},
volume = {120},
number = {},
pages = {105924},
doi = {10.1016/j.ebiom.2025.105924},
pmid = {40957222},
issn = {2352-3964},
abstract = {BACKGROUND: Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed.

METHODS: We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signalling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design and structure‒activity relationship studies yielded mtCI inhibitors profiled in a drug discovery funnel designed to address safety, selectivity, and efficacy.

FINDINGS: The lead compound C458 is highly protective against Aβ toxicity, has favourable pharmacokinetics, and minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted using functional tests, metabolic assessment, in vivo[31]P-NMR spectroscopy, blood cytokine panels, ex vivo electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signalling, and cellular energetics. Efficacy against Aβ and p-Tau was confirmed in human organoids.

INTERPRETATION: These studies provide further evidence that the restoration of mitochondrial function in response to mild energetic stress represents a promising disease-modifying strategy for AD.

FUNDING: This research was supported by grants from NIH AG 5549-06, NS1 07265, AG 062135, UG3/UH3 NS 113776, and ADDF 291204 (all to ET); U19 AG069701 (to TK); the Alzheimer's Association Research Fellowship grant 23AARF-1027342 (to TKON).},
}

@article {pmid40957174,
year = {2025},
author = {Liu, H and Zheng, N and Zhang, Z and Wu, S and Yu, S and Wang, Y and Dong, Z and Zong, S and Wang, X and Lu, Z},
title = {Methionine restriction inhibits the TGF-β1/CCN2/NF-κB pathway to attenuate astrocyte inflammation and cognitive impairment in the APP/PS1 mice.},
journal = {International immunopharmacology},
volume = {166},
number = {},
pages = {115498},
doi = {10.1016/j.intimp.2025.115498},
pmid = {40957174},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterized by cognitive impairment. Astrocytes are involved in AD by clearing amyloid-beta peptide (Aβ) and regulating neuroinflammation. In recent years, methionine restriction (MR) has attracted increasing attention for its benefits in extending lifespan and inhibiting tumor growth. However, the molecular mechanisms underlying the alleviation of astrocyte-mediated neuroinflammation by MR to delay the progression of AD are not well understood. This study determined the existence of the methionine cycle in astrocytes, which was disorganized in AD models. After 4 months of MR dietary intervention, APP/PS1 mice showed improved cognitive function, reduced neuronal loss, decreased Aβ plaque burden, increased dendritic spine density, and lower astrocyte abnormal activation. RNA sequencing of APP/PS1 mouse hippocampal tissue revealed that MR reduced neuroinflammation by downregulating the TGF-β1/CCN2 signaling pathway. Both in vitro and in vivo experiments demonstrated that MR down-regulated CCN2 expression, which in turn reduced the level of neuroinflammation. Moreover, CCN2 downregulation was accompanied by suppression of the NF-κB signaling pathway. This study showed that MR reduced the inflammation mediated by astrocytes and cognitive decline in AD by blocking the TGF-β1/CCN2/NF-κB signaling pathway.},
}

@article {pmid40957103,
year = {2025},
author = {Sanni, A and Bennett, AI and Adeniyi, M and Mechref, Y},
title = {Dysregulated Lipids in Alzheimer's Disease: Insights into Biological Pathways through LC-MS/MS Analysis of Human Brain Tissues.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00230},
pmid = {40957103},
issn = {1948-7193},
abstract = {Alzheimer's Disease (AD), the leading cause of dementia, is characterized by complex pathological mechanisms that extend beyond amyloid-β plaques and tau tangles. This study investigates the dysregulation of lipids with a focus on phospholipids and sphingolipids, in human post-mortem AD brain tissue using lipidomics methodology. By employing a ZIC-HILIC LC-MS/MS platform, the lipidome of AD (N = 18) was compared to the control (N = 18). Out of 45 quantified lipid classes, 16 belonging to phospholipids and sphingolipids group are differentially expressed (p < 0.05; q < 0.05) in AD compared to control. Key findings include the upregulation of phosphatidylcholine (PC), phosphatidylglycerol (PG), ganglioside GD2 (GD2), phosphatidylinositol (PI), phosphatidylserine (PS), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingomyelin (phSM), along with the downregulation of ganglioside GD1a in AD. The targeted analysis revealed that ganglioside GD1b exhibits a higher abundance than ganglioside GD1a across all sample groups. System biology analysis revealed that dysregulated lipids impact critical pathways, including glycerophospholipid biosynthesis and sphingolipid metabolism. Additionally, proteomics analysis on the samples showed that proteins such as Amyloid-β precursor protein, pleckstrin homology and SEC7 domain-containing protein 2 (PSD2), and RAC-gamma serine/threonine-protein kinase (AKT) play a role in phospholipid and sphingolipid dysregulation observed in AD. The dysregulated lipids are predicted to be involved in neuronal cell death, necrosis, and apoptosis, advancing our understanding of AD pathogenesis. The study highlights phospholipids and sphingolipids as promising biomarkers and potential therapeutic targets for AD, paving the way for possible diagnostic tools and personalized treatments.},
}

@article {pmid40956957,
year = {2025},
author = {Quinn, JF},
title = {Targeting the Milieu in Neurodegenerative Disease: Time for "Imprecision Medicine"?.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0966},
pmid = {40956957},
issn = {2152-5250},
abstract = {The possibility of developing precision therapies for neurodegenerative disease is tantalizing, and efforts are under way with several diseases, including Alzheimer's, Parkinson's and Huntington's disease. Despite strong basic neuroscience foundations and excellent clinical trial design, however, these efforts have been disappointing. We present an argument for a complementary approach of targeting the brain milieu in order to achieve disease-modifying effects in patients with or at risk of neurodegenerative disease. We suggest that a milieu-directed "brain health" approach can be applied across a range of at-risk individuals in a specific, quantitative, evidence-based manner. In support of this position, we present data from epidemiologic studies and clinical trials. We propose a program of rigorous research to validate and implement this complement to precision medicine which skeptics might call "imprecision medicine."},
}

@article {pmid40956922,
year = {2025},
author = {Lee, J and Kim, CW and Kim, Y and Lee, S and Choi, JY and Lee, W},
title = {Environmental noise exposure and a new biomarker of Alzheimer's disease: A pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376920},
doi = {10.1177/13872877251376920},
pmid = {40956922},
issn = {1875-8908},
abstract = {BackgroundEnvironmental noise pollution is increasingly recognized as a contributor to neurodegenerative processes, yet its relationship with early Alzheimer's disease biomarkers remains unclear.ObjectiveThis pilot study aimed to assess the feasibility of using gray-to-white matter signal intensity contrast (GWC) as a potential biomarker to explore associations between environmental noise exposure and early neurodegenerative changes.MethodsA total of 106 participants (mean age 35.97 ± 9.21 years, range 20-55), without cognitive impairment or neurological disorders, were included. Environmental noise levels were estimated using spatial interpolation from the National Noise Information System. Based on WHO guidelines (>60 dB daytime or >55 dB nighttime), participants were categorized into high- and low-noise groups. Whole-brain and regional GWC values were derived from 3D T1-weighted MRI using FreeSurfer. Correlations between noise exposure and GWC were analyzed with Pearson's correlation.ResultsThe high-noise group exhibited elevated whole-brain GWC values (20.11 ± 0.93) compared with the low-noise group (19.68 ± 0.96; p = 0.036). Regional analyses revealed higher GWC in the superior frontal gyrus, precentral gyrus, and paracentral lobules (all p < 0.05, FDR corrected). Nighttime noise exposure correlated more strongly with increased GWC (r = 0.203, p = 0.037) than daytime exposure.ConclusionsThis pilot study provides preliminary evidence of an association between environmental noise-particularly nighttime exposure-and subtle structural brain changes, as indicated by elevated GWC values. These findings suggest a potential neurobiological pathway linking noise exposure to early markers of neurodegeneration, warranting validation in larger, longitudinal studies.},
}

@article {pmid40956653,
year = {2025},
author = {Shaker, A and Ljunggren, G and Vossen, LE and Religa, D and Raaschou, P},
title = {Impact of socio-economic and patient-centered characteristics on access to Alzheimer's disease medication in primary care: A population-based study in the Stockholm county, Sweden.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375900},
doi = {10.1177/13872877251375900},
pmid = {40956653},
issn = {1875-8908},
abstract = {BackgroundDespite treatment guidelines for Alzheimer's disease (AD), access to AD medications varies significantly within the same health care setting.ObjectivePredictors influencing access to AD medication were assessed in a retrospective cohort study comprising most individuals diagnosed with AD in Stockholm 2013-2021.Methods14,884 individuals were included, with an incident AD diagnosis between 2013-2021 in Stockholm, Sweden. The primary outcome was the dispensation of AD-specific drugs (cholinesterase inhibitors or memantine) within 90 days before to 180 days after AD diagnosis. We used a generalized linear mixed-effects model (GLMM). Variables included patient-centered characteristics such as age and comorbidities, and characteristics of the primary care centers (PCC) where the individuals were listed, including Care Need Index (CNI).ResultsOverall, 77% of diagnosed patients were dispensed AD medications. Individuals listed at PCCs with high CNI score, indicative of lower socio-economic resources of the area, were less likely to receive a dispensation of any AD medication compared with low CNI score (76.2% versus 84.8%; OR 0.65, 95% CI 0.50-0.86). The association between CNI score and likelihood of receiving AD medication was attenuated in subgroup analysis of individuals living in nursing homes. Also associated with lower likelihood of receiving AD medications were age ≥85 years (OR 0.25, 95% CI 0.21-0.28), nursing home residency (OR 0.37, 95% CI 0.34-0.41), and comorbidity (OR 0.63, 95% CI 0.57-0.70).ConclusionsSocio-economic factors strongly influenced the likelihood of receiving AD medication, in addition to more established factors such as age and comorbidities. Interventions are needed to eliminate barriers to equal drug treatment in AD, particularly those related to socio-economic disadvantages.},
}

@article {pmid40956517,
year = {2025},
author = {Kaur, H and Saikia, B and Choudhary, G and Prajapat, M and Ghosh, K and Ghosh, S and Mondal, P and Prakash, A and Medhi, B},
title = {A novel modulator of the Axin/β-Catenin interaction to restore EAAT2 expression in alzheimer's disease: an in-silico and in-vitro approach.},
journal = {Metabolic brain disease},
volume = {40},
number = {7},
pages = {268},
pmid = {40956517},
issn = {1573-7365},
support = {201610064915//University Grants Commission/ ; },
mesh = {*Axin Protein/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *beta Catenin/metabolism ; *Excitatory Amino Acid Transporter 2/metabolism/biosynthesis ; Animals ; Astrocytes/metabolism/drug effects ; Rats ; Molecular Docking Simulation/methods ; Wnt Signaling Pathway/drug effects ; Humans ; Cell Line, Tumor ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction and neuronal loss, with glutamate excitotoxicity playing a central role in its pathology. The astrocytic glutamate transporter EAAT2, responsible for maintaining synaptic glutamate homeostasis, is significantly downregulated in AD. Restoration of EAAT2 expression presents a promising therapeutic strategy. This study explores the potential of modulating the Wnt/β-catenin signaling pathway to enhance EAAT2 levels by targeting the Axin-1/β-catenin interaction. Through virtual screening of 120,993 compounds from the Asinex-CNS database, five lead candidates were identified based on molecular docking, MMGBSA scores, and drug-likeness parameters. Advanced in-silico analyses-including Principal Component Analysis, Dynamic Cross-Correlation Mapping, molecular dynamics simulations, and MM/PBSA binding free energy calculations-highlighted BAS 04937103 as the most promising compound for disrupting β-catenin degradation. In vitro validation using C6 glioma cells and primary astrocytic cultures demonstrated that BAS 04937103 enhanced β-catenin stabilization and nuclear translocation, reduced Axin-1 expression, and significantly upregulated EAAT2 levels. These molecular effects corresponded with decreased extracellular glutamate concentrations, improved glutamate uptake, and reduced oxidative stress. Collectively, these findings establish BAS 04937103 as a novel modulator of the Axin/β-catenin interaction with therapeutic potential in mitigating glutamate-mediated neurotoxicity in Alzheimer's disease.},
}

*Axin Protein/metabolism
*Alzheimer Disease/metabolism/drug therapy
*beta Catenin/metabolism
*Excitatory Amino Acid Transporter 2/metabolism/biosynthesis
Animals
Astrocytes/metabolism/drug effects
Rats
Molecular Docking Simulation/methods
Wnt Signaling Pathway/drug effects
Humans
Cell Line, Tumor

@article {pmid40956407,
year = {2025},
author = {Guo, S and Wei, F and Chang, Y and Wu, S and Lou, Z and Ma, Y and Huang, Q and He, K and Fu, C and Cao, X and Liang, S and Cheng, W and Yin, Y},
title = {Early astrocyte-targeted intervention guided by [18]F-SMBT-1 imaging attenuates disease progression in 3xTg-AD mice.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {40956407},
issn = {1619-7089},
support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; },
abstract = {PURPOSE: Astrocyte reactivity is a key pathological feature and potential therapeutic target of Alzheimer's disease (AD), however, the optimal timing of its modulation remains unexplored. This study aims to combine [18]F-SMBT-1 based molecular imaging with astrocyte-targeted intervention in 3xTg-AD mice to address this challenge.

METHODS: PET imaging with [18]F-SMBT-1 was conducted in 3xTg-AD mice at 4, 6, 10, and 12 months of age, with age-matched wild-type (WT) mice as controls. The standardized uptake value ratio was calculated using cerebellum as the reference region by PMOD software. Immunofluorescence (IF) analysis was used to assess astrocyte reactivity ex vivo. Astrocyte-targeted intervention via Nrf2 overexpression was performed in 4-month-old 3xTg-AD mice using adeno-associated virus vectors. Following intervention, PET imaging with [18]F-SMBT-1 was performed to assess astrocyte reactivity, open field test and Morris water maze test were performed to evaluate cognitive function, and IF analysis was used to assess pathological feature of AD.

RESULTS: In 3xTg-AD mice of different ages, higher uptake of [18]F-SMBT-1 was observed in the cortex and hippocampus compared to age-matched WT controls. IF analysis further confirmed the presence of reactive astrocytes activation in 3xTg-AD mice. Both in vivo [18]F-SMBT-1 imaging and ex vivo IF analysis identified early-onset astrocyte activation in 3xTg-AD mice. Based on these observations, we implemented early astrocyte-targeted intervention via Nrf2 overexpression at 4 months of age in 3xTg-AD mice. Subsequent in vivo [18]F-SMBT-1 PET imaging demonstrated a significant reduction in astrocyte reactivity following this intervention. Our findings also demonstrated that early astrocyte-targeted intervention might delay AD pathological progression in 3xTg-AD mice, as supported by attenuated anxiety-like behavior and ameliorated neuropathological features.

CONCLUSION: [18]F-SMBT-1 PET imaging served as a diagnostic biomarker for monitoring astrocyte reactivity to guide therapeutic timing decisions, and as a therapeutic response indicator for evaluating treatment efficacy. Early astrocyte-targeted intervention demonstrated significant therapeutic potential. These findings highlighted the translational potential of molecular imaging-guided strategies and astrocyte-targeted therapies in AD.},
}

@article {pmid40956223,
year = {2025},
author = {Madhusoodanan, J},
title = {Prevention Intervention: The evidence is clear that racial discrimination, physical health and the environment contribute to Alzheimer's and other dementias. Now researchers are looking for ways to intervene.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {102},
doi = {10.1038/scientificamerican102025-6qOZmIz2H1y5DlHqxZtdYy},
pmid = {40956223},
issn = {0036-8733},
}

@article {pmid40956221,
year = {2025},
author = {Willyard, C},
title = {Decoding Blood: New biomarkers promise easier and earlier detection of Alzheimer's, but the results aren't always clear.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {96},
doi = {10.1038/scientificamerican102025-40sXDAeTyBigx9YFSG0eGe},
pmid = {40956221},
issn = {0036-8733},
}

@article {pmid40956220,
year = {2025},
author = {Seegert, L},
title = {A Dangerous Silver Bullet: Drugs that hit an Alzheimer's target are gaining traction. Some neurologists remain dubious.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {93},
doi = {10.1038/scientificamerican102025-4pkqWZs4A0HrkVXMH94mN1},
pmid = {40956220},
issn = {0036-8733},
}

@article {pmid40956219,
year = {2025},
author = {Landhuis, E and Christiansen, J and Studios, NM},
title = {A Multipronged Assault: A new understanding of Alzheimer's is leading to a variety of new treatment approaches.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {89},
doi = {10.1038/scientificamerican102025-5T8bP0cW0x69LnvyUGc4td},
pmid = {40956219},
issn = {0036-8733},
}

@article {pmid40956218,
year = {2025},
author = {Harrison, S},
title = {Cultivating Resilience: Early research suggests that Alzheimer's risk can be mitigated through diet, exercise and social stimulation. But definitive studies remain elusive.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {86},
doi = {10.1038/scientificamerican102025-2g8oOmVVXgGO5qSV8D6mRJ},
pmid = {40956218},
issn = {0036-8733},
}

@article {pmid40956217,
year = {2025},
author = {Gravitz, L},
title = {Hope Swells in Alzheimer's Research: Breakthrough therapies, new diagnostics and preventive measures for fighting a devastating disease.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {85},
doi = {10.1038/scientificamerican102025-6WQaHREGezLtKv4MzX4EQr},
pmid = {40956217},
issn = {0036-8733},
}

@article {pmid40956166,
year = {2025},
author = {Li, S and Chen, R and Cao, Z and Zhu, Q and Ma, Y and Zhu, K and Lin, Z and Wu, D and , },
title = {Microstructural Bias in the Assessment of Periventricular Flow as Revealed in Postmortem Brains.},
journal = {Radiology},
volume = {316},
number = {3},
pages = {e250753},
doi = {10.1148/radiol.250753},
pmid = {40956166},
issn = {1527-1315},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/diagnostic imaging/pathology ; *Diffusion Tensor Imaging/methods ; Aged, 80 and over ; Autopsy ; Middle Aged ; *Brain/diagnostic imaging/pathology ; *Glymphatic System/diagnostic imaging/pathology ; },
abstract = {Background Diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS) has been proposed to assess global glymphatic activity in several neurologic diseases. However, it is unclear whether this measurement is biased by fiber microstructure. Purpose To determine the impact of fiber microstructure on DTI-ALPS in postmortem brains with or without Alzheimer disease (AD) and to evaluate the corrected ALPS in living participants. Materials and Methods From June 2021 to August 2023, amyloid β (Aβ)-positive and Aβ-negative postmortem human brains underwent DTI-ALPS. DTI-ALPS and microstructural asymmetries in the postmortem samples were compared between pathologic groups with use of two-way analysis of variance and correlated with age with use of Pearson correlation. The corrected ALPS index, where the age-dependent and pathologic abnormality-related microstructural effect was removed, was applied to in vivo data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and was compared among diagnostic groups with use of analysis of covariance controlling for clinical covariates, with a family-wise error-corrected P < .05 considered indicative of a statistically significant difference. Results Eighteen donors with or without AD (mean age, 69 years ± 13 [SD]; 15 men) and 110 ADNI participants (mean age, 76 years ± 6.8; 65 women) were evaluated. Microstructural asymmetry of the projection fibers was higher in Aβ-negative postmortem specimens than Aβ-positive (Aβ-negative mean, 0.98; Aβ-positive mean, 0.95; P = .045), while asymmetry of the association fibers correlated negatively with age (r = -0.48; P = .044). In the ADNI data, the uncorrected ALPS correlated positively with the Preclinical Alzheimer's Cognitive Composite (PACC) score (r = 0.30; P = .001) and negatively with florbetapir (AV45) PET (r = -0.27; P = .005). For the corrected ALPS, the correlation with AV45 PET was not statistically significant (r = -0.18; P = .059), and the correlation with the PACC score (r = 0.26; P = .006) decreased (Steiger test z = 2.99; P = .003). Conclusion Microstructural asymmetry observed in postmortem DTI-ALPS varied with Aβ pathologic characteristics and age, and after the minimization of microstructural bias, the corrected ALPS correlated less with AD markers in vivo. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Rovira and Pareto in this issue.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/diagnostic imaging/pathology
*Diffusion Tensor Imaging/methods
Aged, 80 and over
Autopsy
Middle Aged
*Brain/diagnostic imaging/pathology
*Glymphatic System/diagnostic imaging/pathology

@article {pmid40956013,
year = {2025},
author = {Sáez, JC and Ocaranza, FJ and Prieto-Villalobos, J and Orellana, JA},
title = {Connexin and Pannexin Hemichannels: Broad-Spectrum Players in Neuroinflammatory Signaling.},
journal = {Journal of neurochemistry},
volume = {169},
number = {9},
pages = {e70237},
doi = {10.1111/jnc.70237},
pmid = {40956013},
issn = {1471-4159},
support = {1231523//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; 1250847//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; },
mesh = {*Connexins/metabolism ; Humans ; Animals ; *Neuroinflammatory Diseases/metabolism ; *Signal Transduction/physiology ; *Nerve Tissue Proteins/metabolism ; },
abstract = {Connexin- and pannexin-formed hemichannels have emerged as pivotal, upstream amplifiers of neuroinflammation. Under physiological stressors-depolarization, Ca[2+] overload, redox shift, or cytokine exposure-these large pores release adenosine triphosphate, glutamate, and other danger signals that activate P2X/P2Y and N-methyl-D-aspartate receptors, ignite NLR family pyrin domain containing (NLRP) 3 inflammasome, and propagate Ca[2+]/reactive oxygen species waves between mast cells, microglia, astrocytes, oligodendrocytes, neurons, and brain endothelium. Evidence across acute (e.g., stroke, trauma, seizure, and sepsis) and chronic (e.g., Alzheimer's, and multiple sclerosis) models shows that genetic ablation or pharmacological blockade of hemichannels shrinks lesions, preserves synaptic plasticity, restores blood-brain barrier integrity, and rescues cognition, often without altering the primary pathogenic trigger. Translational leads include mimetic peptides (e.g., Gap19, [10]panx1), the nanomolar, gap junction-sparing small-molecule D4, and the pleiotropic alkaloid boldine, all of which curb epileptiform activity, neurodegeneration, and depressive-like behavior. Yet key gaps persist, such as the long-term safety of chronic inhibition, which remains poorly defined and will be critical to translate these "gatekeeper" channels into next-generation neuro-anti-inflammatory therapeutics.},
}

*Connexins/metabolism
Humans
Animals
*Neuroinflammatory Diseases/metabolism
*Signal Transduction/physiology
*Nerve Tissue Proteins/metabolism

@article {pmid40955908,
year = {2025},
author = {Atewogboye, O and Taylor, JP and Harrison, JR},
title = {Pharmacological strategies for managing dementia with Lewy Bodies: an expert review of symptom-targeted care.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2025.2562151},
pmid = {40955908},
issn = {1751-2441},
abstract = {INTRODUCTION: Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease, characterized by a complex combination of cognitive, neuropsychiatric, motor, autonomic, and sleep-related symptoms. Symptom fluctuation, polypharmacy risks, and high sensitivity to commonly used drugs present unique challenges in its management.

AREAS COVERED: This review provides a comprehensive overview of the symptomatic management of DLB, organized by clinical domains. It critically evaluates current pharmacological and non-pharmacological treatment strategies for cognitive impairment, hallucinations, parkinsonism, autonomic dysfunction, and sleep disturbances. Evidence is drawn from clinical trials, meta-analyses, and extrapolated findings from related disorders such as Alzheimer's disease and Parkinson's disease.

EXPERT OPINION: Effective DLB management requires an individualized, symptom-prioritized approach that carefully balances therapeutic benefit with potential adverse effects, particularly given the high risk of antipsychotic sensitivity and treatment-induced worsening of symptoms. Despite recent progress, evidence remains sparse for many symptom domains. Greater investment in DLB-specific clinical trials and development of targeted therapies is urgently needed to improve patient outcomes.},
}

@article {pmid40955892,
year = {2025},
author = {Mehndiratta, MM and Singla, M and Dixit, A},
title = {Unlocking the Future of Alzheimer's Disease: Innovations in Diagnosis and Therapy.},
journal = {The Journal of the Association of Physicians of India},
volume = {73},
number = {8},
pages = {92-97},
doi = {10.59556/japi.73.1075},
pmid = {40955892},
issn = {0004-5772},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; Biomarkers/metabolism ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Amyloid beta-Peptides/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is one of the most common forms of dementia, making up around two thirds of all dementia cases globally. Despite its high prevalence, it is estimated to remain undiagnosed in 41 million people with dementia, and with only about 25% of dementia individuals being clinically identified. AD is the major neurodegenerative disorder leading to dementia, characterized by neuronal atrophy and loss. The accumulation of toxic amyloid-beta (Aβ) oligomers, protein aggregates, along with the formation of neurofibrillary tangles (NFTs) within neurons, is the key pathological feature of AD. NFTs are composed of hyperphosphorylated tau protein. These abnormalities contribute to a decline in cerebral glucose metabolism in the brain, synaptic dysfunction, and mitochondrial impairment. The progression of AD occurs in three stages: (1) the presymptomatic stage, (2) mild cognitive impairment (MCI), and (3) the clinical stage of AD. Many biomarkers have been identified for diagnosing AD and differentiating it from atypical AD. It has emerged as a key area of research, offering significant potential for early detection of AD, prognostication, as well as planning drug therapy and monitoring.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
Biomarkers/metabolism
Disease Progression
Cognitive Dysfunction/diagnosis
Amyloid beta-Peptides/metabolism
Neurofibrillary Tangles/pathology/metabolism
tau Proteins/metabolism

@article {pmid40955736,
year = {2025},
author = {Xia, K and Tian, W and Xu, H and Wang, L and Li, X},
title = {Unraveling the structural dynamics of Aβ42 monomer: insights from K16A and K16A + K28A mutations through molecular dynamics simulations.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/07391102.2025.2554351},
pmid = {40955736},
issn = {1538-0254},
abstract = {Alzheimer's disease is a degenerative disease of the central nervous system that pre-dominantly affects the elderly population. The main reason is that amyloid beta 42 has a strong tendency to aggregate, which easily induces the damage to the central nervous system. It was shown that residues 16 and 28 play a key role in the self-assembly process. Moreover, these studies have revealed that substituting alanine for these residues can weaken the toxicity of Aβ. While numerous studies,including molecular dynamics simulations, have emphasized the significance of K16 and K28 in Aβ aggregation and toxicity, the specific impact of their combined mutation(K16A + K28A) on the structural dynamics and toxicity of Aβ remain unclear. Therefore, in this paper, molecular dynamics simulations were used to investigate the structural changes and kinetic properties of Aβ42 protein by the two mutant systems. The results show that both mutant systems inhibit the high flexibility of wild-type Aβ protein during the simulation. By observing the changes in protein structure in different systems, it is found that the K16A system was able to maintain the natural helical conformation of Aβ42 and also inhibit the generation of β-sheet structures. However, for the K16A + K28A system, it not only destroys the helical structure, but also produces more β-sheet structures. The analysis of residue contacts revealed that this phenomenon. The K16A system was able to decrease the interaction between the hp1fragment and the C-terminus in the Aβ42 monomer, whereas the two-point mutation increased this interaction.},
}

@article {pmid40955720,
year = {2025},
author = {Yaari, R and Holdridge, KC and Williamson, M and Wessels, AM and Shcherbinin, S and Kotari, V and Reiman, EM and Tariot, PN and Alexander, R and Langbaum, JB and Sims, JR},
title = {Donanemab in preclinical Alzheimer's disease: Screening and baseline data from TRAILBLAZER-ALZ 3.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70662},
doi = {10.1002/alz.70662},
pmid = {40955720},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/diagnostic imaging ; Aged ; *tau Proteins/blood ; Double-Blind Method ; Male ; Female ; Aged, 80 and over ; Positron-Emission Tomography ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides ; },
abstract = {INTRODUCTION: TRAILBLAZER-ALZ 3 is investigating donanemab in preclinical Alzheimer's disease (AD).

METHODS: This double-blind, placebo-controlled trial used a plasma phosphorylated tau-217 (p-tau217) assay to detect AD pathology for eligibility and a decentralized design to enhance screening and enrollment. After nine monthly infusions, clinical assessments continue every 6 months with a time-to-event primary outcome. A sub-study will evaluate longitudinal changes in amyloid and tau positron emission tomography (PET).

RESULTS: Participants 55-80 years of age were screened (N = 63,124). Plasma p-tau217-eligible participants were enrolled (N = 2196), with Clinical Dementia Rating (CDR) scale-Global score (CDR-GS) of 0 (n = 1202) and 0.5 (n = 664). Plasma p-tau217 eligibility increased with age, differing across races and ethnicities. Mean baseline amyloid levels were 63.2 (CDR-GS: 0) and 70.7 Centiloids (CDR-GS: 0.5). Elevated global tau signal (standardized uptake value ratio ≥1.10) was observed in 15.1% and 26.3% of CDR-GS 0 and 0.5 subgroups, respectively.

DISCUSSION: Utilizing a unique decentralized design, the trial showed baseline data consistent with preclinical AD.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05026866, TRAILBLAZER-ALZ 3 HIGHLIGHTS: TRAILBLAZER-ALZ 3 screened 63,124 participants in the United States and Japan Plasma phosphorylated tau-217 (p-tau217) was used to determine Alzheimer's disease pathology for eligibility A decentralized model was used, including remote raters for clinical testing Randomized participants had Clinical Dementia Rating scale-Global scores of 0 and 0.5.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/diagnostic imaging
Aged
*tau Proteins/blood
Double-Blind Method
Male
Female
Aged, 80 and over
Positron-Emission Tomography
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use
Amyloid beta-Peptides

@article {pmid40955711,
year = {2025},
author = {Tan, A and Wang, Z and Aumont, E and Li, A and Qin, X and Yang, X and Feng, W and Yang, J and Li, X and Xiao, J and Zhou, B and Xing, Y and Yi, Y and Li, J},
title = {Determinants of Treatment Willingness and Willingness-to-Pay for Lecanemab in China: A Network Analysis.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000689},
pmid = {40955711},
issn = {1546-4156},
abstract = {BACKGROUND: Lecanemab is the first disease-modifying therapy for Alzheimer's disease (AD) approved in China. However, the factors affecting patient and caregiver willingness to adopt this novel treatment have not been assessed yet.

OBJECTIVE: To investigate the factors influencing both treatment willingness and willingness-to-pay for lecanemab among Chinese AD patients and their caregivers.

METHODS: We surveyed 195 AD patients and their caregivers using structured questionnaires assessing key factors influencing treatment willingness, including efficacy (Wefficacy), adverse effects (Wadverse), inconvenience (Winconvenience), cost (Wcost), overall willingness to treat (Wtreat), and amount willing to pay (Wamount). Additional variables included income, cognitive and functional assessments, caregiver burden (ZBI), health status (HS), education levels (patient/caregiver: edu, edu.c), psychiatric symptoms (PSY), and satisfaction with conventional treatments (effect). Network analysis mapped variable inter-relationships.

RESULTS: Wtreat showed a strong direct association with Wcost (0.99). Wefficacy and Winconvenience indirectly influenced Wtreat through Wcost (Wefficacy-Winconvenience: 1.5, Winconvenience-Wcost: 1.12, Wcost-Wtreat: 0.99). Income (0.48) and effect (0.51) directly impacted Wtreat. Edu, edu.c, CDR, PSY, ZBI, and HS were indirectly correlated with Wtreat. Wamount was directly associated with Wtreat (0.31), Wcost (0.68), and Wadverse (0.16). Wefficacy and Winconvenience indirectly influenced Wamount through Wcost (Wefficacy- Winconvenience: 1.5, Winconvenience-Wcost: 1.12, Wcost-Wamount: 0.68). Network stability tests (CS >0.50) confirmed robustness.

CONCLUSION: This study demonstrates that reducing payment barriers has a greater impact on real-world adoption of innovative therapies than clinical efficacy alone. Addressing financial constraints also enhances patients' willingness to pay. These findings provide evidence-based insights for developing patient-centered clinical decision pathways.},
}

@article {pmid40955699,
year = {2025},
author = {Guo, J and Zhang, H and Geng, Z and Dai, N and Fu, B and Kong, QX and Fu, X},
title = {Application of Mendelian Randomization Analysis on the Exploration of the Association Between Immune Cell Phenotypes and Alzheimer's disease.},
journal = {The Journal of nervous and mental disease},
volume = {},
number = {},
pages = {},
pmid = {40955699},
issn = {1539-736X},
support = {2023YXNS061//the Key Research and Development Plan of Jining City/ ; },
abstract = {INTRODUCTION: This study explores the correlation between immune inflammation and Alzheimer's disease (AD), focusing on immune-brain interactions impacting neurodevelopment and function.

METHODS: Public genetic data were used to analyze 731 immune cell signals, employing two-sample Mendelian randomization, with multiple testing corrected by the Bonferroni-adjusted false discovery rate (FDR).

RESULTS: Six immune phenotypes were identified as significantly increasing AD risk (effect sizes ranging from OR=1.038 to 1.123), including HLA DR on CD33+ HLA DR+ CD14-, HLA DR on CD14+ monocyte, CD4+ CD8dim T cells (% lymphocytes), CD33 on HLA DR on CD14+ CD16- monocyte, CD33 on CD33+ HLA-DR+ CD14dim cells and CD11c on CD62L+ myeloid dendritic cell.

CONCLUSION: This study confirms the genetic association between specific immune cells and AD, highlighting potential immune-related biomarkers for AD risk.},
}

@article {pmid40955614,
year = {2025},
author = {Baek, MJ and Park, YH and Kim, S},
title = {Comparison Between the Mini-Mental State Examination and the Mini-Mental State Examination-2 in Patients With Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {Journal of Korean medical science},
volume = {40},
number = {36},
pages = {e235},
doi = {10.3346/jkms.2025.40.e235},
pmid = {40955614},
issn = {1598-6357},
support = {//Ministry of Knowledge/Saudi Arabia ; 10035434/KEIT/Korea Evaluation Institute of Industrial Technology/Korea ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Alzheimer Disease/diagnosis/psychology ; Male ; Aged ; Female ; ROC Curve ; *Mental Status and Dementia Tests ; Area Under Curve ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; Sensitivity and Specificity ; Discriminant Analysis ; Republic of Korea ; },
abstract = {BACKGROUND: This study aimed to compare the diagnostic utility of the Mini-Mental State Examination-2 (MMSE-2) and the Korean version of the Mini-Mental State Examination (K-MMSE) in differentiating normal cognitive aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) within a Korean population.

METHODS: A total of 226 individuals with MCI, 97 with AD, and 91 cognitively healthy older adults were recruited. Participants underwent the MMSE-2, K-MMSE, and a comprehensive neuropsychological assessment battery. Discriminant analysis was employed to compare the classification accuracy of each tool, while sensitivity and specificity were evaluated using receiver operating characteristic (ROC) curve analysis.

RESULTS: Discriminant analysis revealed that the MMSE-2 accurately classified 71.1% of participants, including 68.6% of MCI patients, 78.4% of AD patients, and 72.5% of healthy controls. In contrast, the K-MMSE achieved an overall classification accuracy of 67.9%, with 83.6% accuracy for MCI, 68.0% for AD, and 28.6% for healthy controls. ROC analysis indicated that the area under the curve (AUC) values for the MMSE-2: Brief Version (BV) (0.708), Standard Version (SV) (0.720), and Expanded Version (EV) (0.728) surpassed that of the K-MMSE (0.703) in distinguishing healthy controls from MCI patients. However, the K-MMSE (AUC = 0.936) demonstrated superior performance compared to the MMSE-2:BV (0.930), MMSE-2:SV (0.925), and MMSE-2:EV (0.921) in differentiating MCI from AD.

CONCLUSION: The MMSE-2:SV and MMSE-2:EV exhibit greater sensitivity in detecting cognitive impairment between normal aging and MCI. Conversely, the MMSE-2:BV and K-MMSE demonstrate superior sensitivity in distinguishing between MCI and AD. These findings underscore the importance of selecting an appropriate cognitive assessment tool based on specific diagnostic objectives and clinical contexts.},
}

Humans
*Cognitive Dysfunction/diagnosis
*Alzheimer Disease/diagnosis/psychology
Male
Aged
Female
ROC Curve
*Mental Status and Dementia Tests
Area Under Curve
Aged, 80 and over
Neuropsychological Tests
Middle Aged
Sensitivity and Specificity
Discriminant Analysis
Republic of Korea

@article {pmid40955474,
year = {2025},
author = {Edler, MC and Faber, K and Lacy, K and Jackson, J and Foroud, T},
title = {NCRAD: Advancing Alzheimer's research through high-quality biospecimens and data.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70682},
doi = {10.1002/alz.70682},
pmid = {40955474},
issn = {1552-5279},
support = {U24 AG021886/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Biological Specimen Banks ; Biomarkers ; *Biomedical Research ; Specimen Handling ; },
abstract = {The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) was established in 2002 to support research on the genetics of Alzheimer's disease. NCRAD quickly became a central resource, banking samples from numerous studies and distributing them to researchers worldwide. As genetic risk variants were identified, NCRAD prepared for functional studies by expanding its collections to include peripheral blood mononuclear cells (PBMCs), RNA, and biofluids. Over the past decade, NCRAD's extensive repository of plasma, serum, and cerebrospinal fluid was essential to the development of fluid biomarkers. NCRAD's rigorous best practices for sample collection, processing, and distribution ensure biospecimens are of the highest quality for a broad range of experimental approaches. Currently, NCRAD banks samples from 91 studies representing over 135,000 unique, well-characterized participants, and has distributed over 440,000 aliquots to more than 300 researchers. Data from NCRAD-supported studies have contributed to over 1100 publications and numerous key discoveries in Alzheimer's disease and related dementias (ADRD) genetics and biomarkers. HIGHLIGHTS: Centralized Biobanking for ADRD Research: National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) supports over 90 National Institute on Aging (NIA) -funded studies by providing standardized, high-quality biospecimens and longitudinal sample collections, enabling reproducible and scalable research into Alzheimer's disease and related dementias (ADRD). Enabling Genetic Discovery and Functional Genomics: NCRAD partnerships with numerous research initiatives has facilitated major advances in gene discovery, while also supporting downstream functional studies using induced pluripotent stem cells (iPSCs), transcriptomics, and post mortem brain tissue. Rigorous QA/QC and Automation Infrastructure: NCRAD employs comprehensive quality assurance/quality control (QA/QC) systems and cutting-edge automation-including robotic liquid handling, automated nucleic acid extraction, and ultra-low temperature storage-to ensure biospecimen integrity and reduce preanalytical variability. Unique Sample Distribution and Data Sharing Model: NCRAD's blinded sample distribution system and emphasis on returning data to public repositories ensure broad research access, maximize scientific output, and promote transparency and reproducibility. Collaborative, Scalable Repository Ecosystem: As part of Indiana University's integrated biobanking infrastructure, NCRAD supports efficient cross-study and cross-repository research, enabling large-scale multi-omic and biomarker analyses across diverse neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/genetics
*Biological Specimen Banks
Biomarkers
*Biomedical Research
Specimen Handling

@article {pmid40955309,
year = {2025},
author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M},
title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {8135-8159},
pmid = {40955309},
issn = {1177-8881},
mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; },
abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.},
}

Humans
*NF-kappa B/metabolism/antagonists & inhibitors
*Neurodegenerative Diseases/drug therapy/metabolism
*Biological Products/pharmacology/chemistry
*Medicine, Chinese Traditional
Signal Transduction/drug effects
Animals
*Drugs, Chinese Herbal/pharmacology/chemistry

@article {pmid40955230,
year = {2025},
author = {Qasim, H and Khattab, K and Abu Shugaer, M and Varrassi, G},
title = {Epigenetic Dysregulation in Neurodegenerative Disease: Implications for Neuropathology and Therapy.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e90188},
pmid = {40955230},
issn = {2168-8184},
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal dysfunction, yet their underlying mechanisms remain incompletely understood. Emerging evidence implicates epigenetic dysregulation as a central contributor to the pathogenesis of these disorders. A thematic literature review was conducted across major databases using targeted search terms related to epigenetics and neurodegeneration. Studies were selected based on relevance, methodological quality, and contribution to mechanistic understanding, in accordance with Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. Across AD, PD, and HD, distinct yet overlapping patterns of epigenetic alterations were identified. In AD, dysregulated DNA methylation and histone acetylation affect genes linked to amyloid and tau pathology. In PD, hypomethylation of SNCA and altered histone acetylation contribute to α-synuclein overexpression and neuronal loss. In HD, mutant huntingtin protein disrupts chromatin remodeling by sequestering histone acetyltransferases and altering microRNA expression. These changes disrupt neuronal identity, synaptic function, and inflammatory responses, often forming feedback loops that exacerbate disease progression. Epigenetic mechanisms play a pivotal role in neurodegeneration by mediating gene-environment interactions and perpetuating neuropathological changes. Their reversible nature presents opportunities for therapeutic intervention, though challenges related to specificity, delivery, and timing remain. Continued research into epigenetic biomarkers and precision-targeted epigenetic therapies holds promise for advancing early diagnosis and disease modification in NDDs.},
}

@article {pmid40954504,
year = {2025},
author = {Yang, X and Geng, X and Xu, Z and Xu, Y and Han, H and Zhang, Q and Jin, H and Wang, Y and Sun, B and Zhang, M and Zhang, S and Chen, L},
title = {Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer's pathogenesis.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {203},
pmid = {40954504},
issn = {1758-9193},
support = {21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Oxidative Stress/physiology ; *Aging/metabolism/pathology/genetics ; *Brain/metabolism/pathology ; Humans ; Mice ; *Amyloid beta-Peptides/metabolism/toxicity ; *Neurons/metabolism/pathology/drug effects ; Mice, Transgenic ; Disease Models, Animal ; Male ; Aged ; Female ; },
abstract = {Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and memory impairment. Brain aging is indisputably the most significant risk factor for AD. Given that aging is a fundamental driving force behind the onset of AD, identifying the aging - regulated genes that contribute to AD development is of utmost importance. Such genes might hold the key to preventing AD or delaying the transition from normal aging to the disease state. In the present study, a comprehensive bioinformatic analysis was conducted on brain transcriptomic datasets obtained from both aging individuals and those with Alzheimer's disease. Among the shared differentially expressed genes, eight genes were found to be downregulated in both aging and AD datasets. Notably, reduced expression of adaptor protein complex 1 sigma 1 subunit (Ap1s1) was validated across multiple mouse models with varying degree of dementia, including aged mice, senescence-accelerated SAMP8 mice, 5xFAD amyloidosis mice, as well as cellular models, including senescent Neuro-2a (N2a) cells, and Aβ-treated or expressing N2a neurons. Functional studies revealed that Ap1s1 knockdown induced cellular senescence without directly impairing viability. However, Ap1s1 silencing exacerbated neuronal vulnerability to oxidative stress (H2O2) and Aβ toxicity, manifesting as Golgi-dispersion and reduced survival. Proteomic profiling following Ap1s1 depletion implicated dysregulation of rRNA modifications in the nucleus and cytosol, Golgi-associated vesicle biogenesis. These findings position Ap1s1 as a critical aging-related gene at the nexus of brain aging and AD pathogenesis, whose decline may predispose neurons to Alzheimer's-related insults. As such, Ap1s1 may represent a potential therapeutic target for mitigating aging-related cognitive decline and delaying the onset of AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*Oxidative Stress/physiology
*Aging/metabolism/pathology/genetics
*Brain/metabolism/pathology
Humans
Mice
*Amyloid beta-Peptides/metabolism/toxicity
*Neurons/metabolism/pathology/drug effects
Mice, Transgenic
Disease Models, Animal
Male
Aged
Female

@article {pmid40954500,
year = {2025},
author = {Wang, C and Bu, X and Cao, M and Lian, Y and Ling, H and You, M and Yi, J and Gao, X and Wu, D and Li, Y},
title = {Publisher Correction: Mir-199a-3p aggravates neuroinflammation in an Alzheimer's disease transgenic mouse model by promoting M1-polarization microglia.},
journal = {BMC neuroscience},
volume = {26},
number = {1},
pages = {58},
doi = {10.1186/s12868-025-00974-4},
pmid = {40954500},
issn = {1471-2202},
}

@article {pmid40954413,
year = {2025},
author = {Yi, C and Su, Y and Verkhratsky, A},
title = {Targeting Microglial Connexin43 Hemichannels: A Novel Therapeutic Avenue for Alzheimer's Disease.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {40954413},
issn = {1995-8218},
}

@article {pmid40954412,
year = {2025},
author = {Di Stadio, A and Hamiter, MJ and Roccamatisi, D and Lalwani, AK},
title = {Correction to: Hearing Loss and Alzheimer Disease.},
journal = {Current topics in behavioral neurosciences},
volume = {69},
number = {},
pages = {C3},
doi = {10.1007/978-3-031-84920-6_577},
pmid = {40954412},
issn = {1866-3370},
}

@article {pmid40954312,
year = {2025},
author = {Tideman, P and Karlsson, L and Strandberg, O and Calling, S and Smith, R and Midlöv, P and Verghese, PB and Braunstein, JB and Mattsson-Carlgren, N and Stomrud, E and Palmqvist, S and Hansson, O},
title = {Primary care detection of Alzheimer's disease using a self-administered digital cognitive test and blood biomarkers.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40954312},
issn = {1546-170X},
abstract = {After the clinical implementation of amyloid-β-targeting therapies for people with cognitive impairment due to Alzheimer's disease (AD), there is an urgent need to efficiently identify this patient population in primary care. Therefore, we created a brief and self-administered digital cognitive test battery (BioCog). Based on its sub-scores, a logistic regression model was developed in a secondary care cohort (n = 223) and then evaluated in an independent primary care cohort comprising 19 primary care centers (n = 403). In primary care, BioCog had an accuracy of 85% when using a single cutoff to define cognitive impairment, which was significantly better than the assessment of primary care physicians (accuracy 73%). The accuracy increased to 90% when using a two-cutoff approach. BioCog had significantly higher accuracy than standard paper-and-pencil tests (that is, Mini-Mental State Examination, Montreal Cognitive Assessment, Mini-Cog) and another digital cognitive test. Furthermore, BioCog combined with a blood test could detect clinical, biomarker-verified AD with an accuracy of 90% (one cutoff), significantly better than standard-of-care (accuracy 70%) or when using the blood test alone (accuracy 80%). In conclusion, this proof-of-concept study shows that a brief, self-administered digital cognitive test battery can detect cognitive impairment and, when combined with a blood test, accurately identify clinical AD in primary care.},
}

@article {pmid40954136,
year = {2025},
author = {Martínez-García, J and Fernández, B and Artime, E and Álvarez, L and González-Iglesias, H and Clases, D and Pereiro, R},
title = {ICP-MS for Multiplexed Protein Determination in Extracellular Vesicles from APP/PS1 Mice Blood Serum-Application to a Zn Supplementation Pilot Study.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c03630},
pmid = {40954136},
issn = {1520-6882},
abstract = {Neurodegenerative diseases represent a significant challenge due to their complex etiology, late diagnosis, and lack of effective treatments. Extracellular vesicles (EVs) have emerged as promising carriers of disease biomarkers, especially proteins, but their low abundance in biological fluids complicates their detection. Here, we present a novel strategy for the multiplexed quantitative determination of EV-associated proteins in blood serum from APP/PS1 transgenic mice, a model of Alzheimer's disease. The method combines inductively coupled plasma-time-of-flight mass spectrometry (ICP-ToFMS) with competitive immunoassays using metal nanocluster-labeled (AuNCs, PtNCs, IrNCs) antibodies targeting Alpha-Actinin 1 (ACTN), Galectin-3-binding protein (LG3BP), and Moesin (MSN). EVs were isolated using an optimized ultracentrifugation protocol to reduce the level of serum protein contamination. Proteomic screening identified target proteins with a known relevance to neurodegeneration, and the developed assay achieved detection limits in the low femtomolar range. The approach was applied to a pilot study on Zn supplementation in 16-month-old APP/PS1 mice, revealing sex-dependent and genotype-specific differences in protein expression but sex-independent patterns in regulatory mechanisms (especially for MSN and LG3BP). Among the studied markers, MSN levels showed statistically significant differences with Zn treatment in male homozygous mice. This work demonstrates the potential of ICP-MS for sensitive and multiplexed biomarker quantification in EVs, supporting its use in neurodegenerative research and supplementation studies.},
}

@article {pmid40953827,
year = {2025},
author = {Norevik, CS and Huuha, AM and Røsbjørgen, RN and Bergersen, LH and Jacobsen, K and Miguel-Dos-Santos, R and Ryan, L and Skender, B and Moreira, JBN and Kobro-Flatmoen, A and Witter, MP and Scrimgeour, N and Tari, AR},
title = {Corrigendum to "Exercised blood plasma promotes hippocampal neurogenesis in the Alzheimer's disease rat brain" [J Sport Health Sci 13 (2024) 245-255].},
journal = {Journal of sport and health science},
volume = {},
number = {},
pages = {101084},
doi = {10.1016/j.jshs.2025.101084},
pmid = {40953827},
issn = {2213-2961},
}

@article {pmid40953636,
year = {2025},
author = {Crouse, B and Rossom, RC and Crain, AL and O'Connor, PJ and Jaka, MM and Maciosek, MV and Appana, D and Sharma, R and Gustafson, SK and Werner, AM and Svitak, AL and Ekstrom, HL and Borson, S and Rosenbloom, MH and Sperl-Hillen, JM and O'Keefe, LR and Hanson, LR},
title = {Design and protocol of a pragmatic clinical trial to improve cognitive impairment detection in primary care.},
journal = {Contemporary clinical trials},
volume = {},
number = {},
pages = {108080},
doi = {10.1016/j.cct.2025.108080},
pmid = {40953636},
issn = {1559-2030},
abstract = {BACKGROUND: The prevalence of cognitive impairment (CI) including Alzheimer's disease (AD) and related dementias (ADRD) continues to rise worldwide, but often goes undiagnosed leading to increased burden on patients and families. A clinical decision support system (CDSS) could improve care quality by assisting primary care clinicians (PCCs) to recognize, evaluate, diagnose, and manage patients with CI.

METHODS: 38 primary care clinics are randomized to receive the study intervention or usual care (UC). The study intervention consists of a cognitive impairment clinical decision support system (CI-CDSS) and a brief CI-focused training. The CI-CDSS utilizes electronic health record (EHR) data to alert PCCs of patients who may be at high risk for CI, determined by either an abnormal cognitive assessment or identification as high risk using a prototype prediction model developed for this study that estimates likelihood of developing CI in the next 3 years. It also provides tools and resources to evaluate and diagnose CI and gives recommendations for managing care of patients with CI.

ENDPOINTS: The primary outcome is EHR documentation of CI diagnosis up to 18 months after accrual. Secondary outcomes include healthcare costs and PCC confidence in diagnosis and management of patients with CI.

CONCLUSION: This pragmatic, cluster-randomized, Phase III clinical trial aims to assess the effectiveness of a CDSS in increasing detection of CI in primary care. If successful, this system could provide up-to-date personalized recommendations for CI diagnosis and management to improve patient care.},
}

@article {pmid40953390,
year = {2025},
author = {Creapeau, LJ and Airth-Kindree, NM and Goodman, JA},
title = {Brain and Body Fitness Group for Those With Dementia and Their Caregivers Through Community Partnership: A Program Evaluation.},
journal = {WMJ : official publication of the State Medical Society of Wisconsin},
volume = {124},
number = {3},
pages = {265-269},
pmid = {40953390},
issn = {2379-3961},
mesh = {Humans ; *Caregivers/psychology ; Male ; Female ; *Dementia/psychology/therapy ; Quality of Life ; Aged ; Program Evaluation ; Middle Aged ; Aged, 80 and over ; Wisconsin ; },
abstract = {INTRODUCTION: The growing prevalence of dementia calls for nonpharmacological interventions to reduce negative quality of life effects for those living with dementia and their caregivers. Brain and Body Fitness, a community-based collaborative group program, engages people living with dementia and their caregivers through a combination of physical, cognitive, and socialization strategies, to maximize health benefits for sustained functioning.

METHODS: Using an adapted form of the Patient-Reported Outcomes Measurement Information System (PROMIS) Applied Cognition tool, ex post facto data were collected from both participants affected with Alzheimer's disease and related dementias and their caregivers during 12 biweekly sessions of the Brain and Body Fitness program conducted from 2017 through 2021.

RESULTS: Brain and Body Fitness program participants were affected by 4 quality of life indicators: anxiety, sleep, fatigue, and depression. Data reveal significant reductions in anxiety symptoms and significant improvements in fatigue for affected participants. Anecdotally, the program demonstrates nonsignificant trends of overall mood improvement.

CONCLUSIONS: Given the positive outcomes, communities may consider adopting a similar program to provide additional support for participants.},
}

Humans
*Caregivers/psychology
Male
Female
*Dementia/psychology/therapy
Quality of Life
Aged
Program Evaluation
Middle Aged
Aged, 80 and over
Wisconsin

@article {pmid40953372,
year = {2025},
author = {Parkman, S and Larouche, J and Condon, A and Aboueissa, AE},
title = {Enhancing Empathy: A Mixed Methods Exploration of Dementia Simulation in Occupational Therapy and Nursing Education.},
journal = {Journal of gerontological nursing},
volume = {},
number = {},
pages = {1-7},
doi = {10.3928/00989134-20250908-03},
pmid = {40953372},
issn = {0098-9134},
abstract = {PURPOSE: Dementia, including Alzheimer's disease, poses complex challenges requiring health care providers to respond with empathy and skill. The current study examined whether a simulation-based dementia education intervention could enhance empathy in health care students.

METHODS: Using embedded mixed methods, one-group quasi-experimental design, empathy levels in 125 prelicensure nursing and graduate occupational therapy students were measured via the Kiersma-Chen Empathy Scale-Revised (KCES-R) before, immediately after, and 6 weeks post-simulation. In addition, 36 post-debriefing focus groups explored student experiences qualitatively.

RESULTS: Findings showed significant empathy score increases across all time points (F[2,124] = 17.02, p < 0.001). Thematic analysis revealed five themes: The Illusion of Empathy, Developing Empathetic Skills, Confronting Uncomfortable Truths, The Eureka Moment: Transformative Realizations, and Empathy and Power Dynamics.

CONCLUSION: Findings suggest that simulation-based dementia experience improves empathy and motivates students to provide better care. Experiential learning is critical to preparing future health care professionals to meet the growing demands of dementia care.},
}

@article {pmid40953349,
year = {2025},
author = {Pinheiro, A and Ekenze, O and Aparicio, HJ and Beiser, AS and Decarli, CS and Demissie, S and Seshadri, S and Romero, JR},
title = {Multimarker Cerebral Small Vessel Disease Score and Risk of Incident Dementia in the Framingham Heart Study.},
journal = {Neurology},
volume = {105},
number = {7},
pages = {e214113},
doi = {10.1212/WNL.0000000000214113},
pmid = {40953349},
issn = {1526-632X},
mesh = {Humans ; Male ; Female ; *Cerebral Small Vessel Diseases/diagnostic imaging/epidemiology/complications ; Aged ; Magnetic Resonance Imaging ; *Dementia/epidemiology/diagnostic imaging ; Middle Aged ; Biomarkers ; Cohort Studies ; Risk Factors ; Incidence ; Aged, 80 and over ; Risk Assessment ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND AND OBJECTIVES: Individual MRI markers of cerebral small vessel disease (CSVD) are associated with impaired cognition and dementia but may not reflect the overall burden of CSVD. In addition, it is unclear whether these markers provide additional value in dementia risk assessment beyond vascular risk factors alone. Thus, we studied the association between the additive burden of multiple CSVD markers and incident dementia and determined whether this relationship remains independent of the Framingham Stroke Risk Profile (FSRP), a tool used commonly used for stroke risk prediction.

METHODS: A total of 1,152 MRI scans from participants in the Original and Offspring cohorts of the Framingham Heart Study, a large observational cohort study, were included. Participants were older than 55 years and free of prevalent dementia, stroke, or other neurologic conditions at the time of MRI. A multimarker score capturing CSVD burden was defined as the sum of CSVD features detected in the MRI: cerebral microbleeds, covert brain infarcts, extensive white matter hyperintensities, high-burden perivascular spaces, and cortical superficial siderosis. Multivariate Cox regression models examined the association between the multimarker CSVD score and incident all-cause dementia, Alzheimer dementia (AD), and vascular dementia.

RESULTS: The mean age was 70.9 years (SD 8.7) (527 [46%] were male), and 211 (18%) had a CSVD score of ≥2. Over a median follow-up time of 7.4 years (interquartile range 4.6-11.3), participants with a score ≥2 had significantly elevated risk of all-cause dementia compared with those with no CSVD markers after adjustment for the FSRP (hazard ratio [HR] 1.67; 95% CI 1.05-2.66) and vascular risk factors (HR 1.76; 95% CI 1.10-2.81). The multimarker CSVD score demonstrated similar model performance metrics to the FSRP (Harrell c-statistics 0.82-0.83).

DISCUSSION: We found a significant association between all-cause dementia and multimarker CSVD scores, which was independent of the FSRP as well as its individual components. Our results support the use of a multimarker CSVD score as an indicator for incident all-cause dementia risk and suggest that it may be as robust as the FSRP. Further studies are necessary to validate the use of a multimarker CSVD score in dementia risk prediction.},
}

Humans
Male
Female
*Cerebral Small Vessel Diseases/diagnostic imaging/epidemiology/complications
Aged
Magnetic Resonance Imaging
*Dementia/epidemiology/diagnostic imaging
Middle Aged
Biomarkers
Cohort Studies
Risk Factors
Incidence
Aged, 80 and over
Risk Assessment
Brain/diagnostic imaging

@article {pmid40953123,
year = {2025},
author = {Haaland, B and Dickson, SP and Santana, AF and Tanzi, RE and Dubois, B and Peters, O and Grimmer, T and Christensen, J and Mallinckrodt, C and Schneeberger, A and Hendrix, SB},
title = {Efficacy of AD04, an aluminum-based vaccine adjuvant, in patients with early Alzheimer's disease: Post hoc analysis of AFF006 (NCT01117818), a proof-of-concept, phase 2 randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375985},
doi = {10.1177/13872877251375985},
pmid = {40953123},
issn = {1875-8908},
abstract = {BackgroundThe AFF006 trial (NCT01117818) provided unexpected evidence of benefits of the vaccine adjuvant AD04 (aluminum oxyhydroxide) in patients with early Alzheimer's disease (AD), compared with AD02, a vaccine consisting of a peptide that mimics the N-terminal region of human amyloid-β (Aβ) conjugated with keyhole limpet hemocyanin.ObjectiveThe objective of this post hoc analysis was to assess whether this unexpected benefit of AD04 was an artifact of multiple testing (i.e., type I error inflation) or a robust result.MethodsIn this post hoc assessment, we used permutation testing to estimate type I error inflation due to the evaluation of multiple outcomes in AFF006. Efficacy was assessed using a patient-level global statistical test combining composite endpoints of cognition, function, and global AD. In addition, we examined the observed treatment benefits of AD04 in the context of effects observed in trials of aducanumab, donanemab, and lecanemab, monoclonal anti-Aβ antibodies that received regulatory approval for AD.ResultsThe global statistical test suggested a treatment benefit of AD04 versus ineffective AD02 arms, even after accounting for multiplicity (primary methodology p-value, 0.03; permutation test p-value, 0.02). The observed effect estimates for AD04 compared favorably with approved monoclonal antibodies.ConclusionsPost-hoc analyses are hypothesis generating rather than confirmatory. Adjusting for multiplicity using permutation testing can determine whether post-hoc effects are worth pursuing, or unlikely to be confirmed. These analyses have motivated a follow-up prospective randomized controlled trial, ADVANCE (EudraCT 2022-003532-73), in which optimized AD04 dosing will be compared to placebo in early AD.},
}

@article {pmid40953121,
year = {2025},
author = {Gao, M and Chen, J and Zhang, B and Li, J and Lang, J and Zhao, X and Zhang, Q},
title = {Melatonin alleviates cognitive impairment via modulating NLRP3/Caspase 1 pathway in db/db mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375479},
doi = {10.1177/13872877251375479},
pmid = {40953121},
issn = {1875-8908},
abstract = {BackgroundActivation of NLRP3 inflammasome has been implicated in cognitive impairment. Melatonin, known for its anti-inflammatory properties and traditional use in regulating circadian rhythms, is the focus of this study. This study intended to investigate the role of melatonin in diabetic cognitive impairment model.ObjectiveThe present study aimed to investigate the underlying mechanism of melatonin in alleviating diabetic cognitive impairment by suppressing NLRP3/Caspase 1 signaling pathway.MethodsCognitive function was assessed using Morris water maze test and Novel Object Recognition test. Apoptosis rate of hippocampal neurons was evaluated by TUNEL staining. Western blot was used to evaluate NLRP3/Caspase 1 pathway expression. Double immunofluorescence labelling of GFAP, Iba-1 or NeuN with NLRP3 respectively showed the localization of NLRP3 in hippocampus of db/db mice. In vitro, HT-22 cells treated with high glucose as cellular model were transfected with pc-DNA3.1-mNLRP3 or co-cultured with NLRP3 inhibitor MCC950 to elucidate NLRP3/Caspase 1 pathway in neuronal apoptosis regulation.ResultsMelatonin treatment improved cognitive function and morphologic abnormalities of hippocampal neurons. The double immunofluorescence labelling revealed melatonin inhibited NLRP3 inflammasome activation in hippocampal neurons rather than microglia or astrocytes. TUNEL staining and western blot showed melatonin markedly reversed the upregulation of NLRP3/Caspase 1 signaling pathway against neuronal apoptosis.ConclusionsMelatonin attenuates diabetic cognitive impairment in db/db mice with down-regulation of NLRP3/Caspase 1 signaling pathway. In vivo and vitro studies supported that NLRP3 activation in hippocampal neurons was associated with diabetic cognitive impairment progression.},
}

@article {pmid40953110,
year = {2025},
author = {Lohman, T and Sible, I and Kapoor, A and Engstrom, AC and Shenasa, F and Alitin, JPM and Gaubert, A and Rodgers, KE and Bradford, D and Mather, M and Han, SD and Head, E and Sordo, L and Thayer, JF and Nation, DA},
title = {Impaired parasympathetic network function confers susceptibility to neurodegeneration and memory impairment in older adults with elevated beat-to-beat blood pressure variability.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376715},
doi = {10.1177/13872877251376715},
pmid = {40953110},
issn = {1875-8908},
abstract = {BackgroundBlood pressure variability (BPV) is associated with neurodegeneration and cognitive decline independent of average pressure. The effect of parasympathetic central autonomic network (CAN) impairment on this relationship has not been assessed.ObjectiveDetermine whether parasympathetic CAN network function affects the relationship between BPV and neurodegenerative markers.Methods100 independently living older adults (55-89 years) underwent continuous blood pressure monitoring, neuropsychological testing, venipuncture, and brain MRI. Hippocampal volumes and entorhinal cortex thicknesses were assessed. Functional connectivity within a parasympathetic cardiovascular control network was used as a measure of parasympathetic CAN function. Plasma glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were used as measures of glial and neuronal injury, respectively.ResultsElevated BPV was associated with left hippocampal atrophy (p = 0.03) and elevated plasma GFAP (p = 0.005) independent of age, sex, vascular risk factor burden, total intracranial volume (when applicable) and average blood pressure. These relationships were not mediated by parasympathetic central autonomic network impairment. Instead, parasympathetic CAN impairment conferred a vulnerability to elevated BPV. In participants with decreased parasympathetic CAN connectivity elevated BPV was associated with left entorhinal cortex atrophy (p = 0.0001), elevated plasma GFAP (p = 0.0001), elevated plasma NfL (p = 0.001), and memory impairment (p = 0.007).ConclusionsFindings suggest elevated beat-to-beat BPV is directly related to brain injury, and this effect is not mediated by CAN dysfunction. Instead, CAN impairment may confer a susceptibility to glial and neuronal injury in older adults with elevated beat-to-beat blood pressure variability. Mechanisms underlying increased susceptibility to BPV elevation in those with CAN dysfunction warrants further study.},
}

@article {pmid40953107,
year = {2025},
author = {Li, H and Wu, Y and Huang, T and Sun, Y and Lu, Z and Li, M and Wo, H and Shao, F and Tang, S and Zhao, Y and Dai, J and Yi, H},
title = {Development of a risk prediction model for Alzheimer's disease based on the UK Biobank prospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375473},
doi = {10.1177/13872877251375473},
pmid = {40953107},
issn = {1875-8908},
abstract = {BackgroundEarly prevention and intervention for Alzheimer's disease (AD) are critical due to the absence of effective therapeutic treatment. However, a widely accepted risk prediction model for AD has yet to be established.ObjectiveTo develop a novel risk prediction model for AD by leveraging recent advances in identifying risk factors, focusing on multi-omics data.MethodsGenetic data from the UK Biobank were employed to calculate the polygenic risk score (PRS) using the clumping and thresholding (C + T) method. Univariate Cox regression and Elastic Net Cox models were utilized to identify significant predictors in the training cohort. Subsequently, a multivariate Cox regression model was developed to construct the prediction model, which was visualized using a nomogram. The performance of the model was evaluated through calibration curves, receiver operating characteristic (ROC) curves, and the Hosmer-Lemeshow test.ResultsTen risk factors, including age, education, family history of dementia, diabetes, depression, hypertension, anemia, coronary heart disease (CAD), falls and PRS, were identified as significant predictors through Cox regression and Elastic Net Cox model. The model demonstrated strong predictive performance, with area under the curves (AUCs) of 0.864 [95% CI: (0.814, 0.911)], 0.860 [95% CI: (0.842, 0.876)], and 0.842 [95% CI: (0.819, 0.863)] at 5, 10, and 14 years, respectively, in the validation cohort.ConclusionsIncorporating colocalized single nucleotide polymorphisms (SNPs) into the PRS derived using the C + T method significantly enhances predictive accuracy. This study highlights the importance of integrating multimodal patient data, including colocalized genetic information, to refine AD risk prediction.},
}

@article {pmid40953029,
year = {2025},
author = {Park, R and Chevalier, C and Kieser, S and Marizzoni, M and Paquis, A and Armand, S and Scheffler, M and Allali, G and Assal, F and Momjian, S and Frisoni, GB},
title = {Gut microbiome signatures in iNPH: Insights from a shotgun metagenomics study.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0330251},
doi = {10.1371/journal.pone.0330251},
pmid = {40953029},
issn = {1932-6203},
abstract = {Idiopathic normal pressure hydrocephalus (iNPH), a leading cause of reversible dementia in older adults, is marked by ventriculomegaly, gait disturbances, cognitive decline, and urinary incontinence. Emerging evidence suggests that gut dysbiosis (microbial imbalance) may influence neuroinflammation and cerebrospinal fluid dynamics, potentially contributing to glymphatic system dysfunction and ventricular enlargement. This study used shotgun metagenomics to analyze the gut microbiome in iNPH patients (n = 18) compared to healthy controls (n = 50), individuals with ventriculomegaly but no iNPH symptoms (n = 50), and Alzheimer's disease patients (n = 50). Microbiome analysis showed an enrichment of species previously linked to various disease states, such as Enterocloster bolteae and Ruminococcus gnavus, indicating general dysbiosis. In contrast, enrichment of specific taxa, including Evtepia gabavorous and Cuneatibacter sp., were specifically associated with iNPH clinical traits, pointing to possible disease-specific microbial markers. Functional analysis showed enrichment of pathways related to carbohydrate and amino acid metabolism, including the S-adenosyl-L-methionine superpathway, implicating inflammatory and immune processes. These findings suggest distinct gut microbiome signatures in iNPH, offering insights into potential gut-brain interactions that may contribute to the disorder's pathophysiology and highlighting possible targets for future therapeutic strategies.},
}

@article {pmid40953027,
year = {2025},
author = {Casanova, F and Tian, Q and Williamson, DS and Lucas, MR and Zweibaum, D and Ding, J and Atkins, JL and Melzer, D and Ferrucci, L and Pilling, LC},
title = {Predictors of MRI-estimated brain iron deposition in dementia and Parkinson's disease-associated subcortical regions: Genetic and observational analysis in UK Biobank.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375432},
doi = {10.1177/13872877251375432},
pmid = {40953027},
issn = {1875-8908},
abstract = {BackgroundBrain iron in specific subcortical regions increases risk of dementia and Parkinson's disease (PD). Genetic and environmental factors affect iron deposition, but underlying mechanisms are unclear.ObjectiveIdentify risk factors and diseases associated with brain iron; assess causality using genetics.Methods41,581 UK Biobank participants had MRI-estimated brain iron (QSM method) in five dementia or PD-associated subcortical regions (caudate, hippocampus, putamen, substantia nigra, thalamus). We investigated common risk factors (including adiposity, blood pressure, health behaviors, inflammation) and diseases observationally, using covariate-adjusted regression models, and genetically, with Mendelian randomization.ResultsParticipants diagnosed with Alzheimer's disease, PD, or other diseases had higher MRI-estimated brain iron. Anemia, osteoporosis, and hyperparathyroidism were associated with lower brain iron. Higher body mass index and blood pressure, smoking history, and self-reported meat consumption, increased brain iron. Hematological parameters, inflammatory and kidney biomarkers, and calcium, were also associated. Genetics support causal effects of depression, type-2 diabetes, and 7 other diseases with increased iron, but not Alzheimer's disease. Evidence supports a causal effect of osteoporosis on lower iron in the substantia nigra. We found causal associations between adiposity and proteins (including IL-6 receptor and transferrin receptor) on subcortical brain iron.ConclusionsWe identified causal effects for liability to type-2 diabetes, depression, and other conditions, on subcortical MRI-estimated brain iron, but not to Alzheimer's disease, supportive of dementia as a consequence of brain iron deposition, not a cause. The role of adiposity reducing interventions on brain iron should be investigated. Relationships between brain iron, osteoporosis, calcium, and hyperparathyroidism warrant further investigation.},
}

@article {pmid40952998,
year = {2025},
author = {Jeon, S and Alia, AO and Popovic, J and Vassar, R and Cuddy, LK},
title = {ACE1 does not influence cerebral Aβ degradation or amyloid plaque accumulation in 5XFAD mice.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0330193},
doi = {10.1371/journal.pone.0330193},
pmid = {40952998},
issn = {1932-6203},
abstract = {Alzheimer's disease is the most common form of dementia, and multiple lines of evidence support the relevance of Aβ deposition and amyloid plaque accumulation in the neurotoxicity and cognitive decline in AD. Rare mutations in angiotensin-converting-enzyme-1 have been highly associated with late onset AD patients; however, the mechanism for ACE1 mutation in AD pathogenesis is unknown. While numerous studies have shown that ACE1 indeed catabolizes Aβ, majority of these studies were performed in vitro, and conflicting results have been reported in clinical and in vivo systems. Therefore, we further investigated this in vivo by generating and examining a novel mouse model. Specifically, we analyzed 6-month-old 5XFAD mice with ACE1 knockdown restricted to excitatory neurons, achieved by driving Cre recombinase expression under the CamKIIα promoter. These mice were generated by crossing 5XFAD mice to ACE1 conditional knockout mice expressing Cre specifically in excitatory neurons. Our analyses revealed that neuronal ACE1 knockdown does not significantly affect amyloid plaque load and neuroinflammation in the hippocampus and cortex of 5XFAD mice at 6-months of age.},
}