@article {pmid40902885,
year = {2025},
author = {Lu, H and Meng, C},
title = {Letter to the editor: Persistent depressive-symptom trajectories predict conversion from mild cognitive impairment to Alzheimer's disease: A longitudinal ADNI study.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120186},
doi = {10.1016/j.jad.2025.120186},
pmid = {40902885},
issn = {1573-2517},
}

@article {pmid40902868,
year = {2025},
author = {Shi, J and Yang, X and Wu, H and Ye, W and Li, Z and Zhang, T and Gao, J},
title = {Mesenchymal stem cell membrane functionalized vesicles for Baicalein targeted delivery in Alzheimer's disease.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126133},
doi = {10.1016/j.ijpharm.2025.126133},
pmid = {40902868},
issn = {1873-3476},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. The lack of effective therapeutic strategies underscores the urgent need for disease-modifying therapies. Baicalein (Bai), a natural compound, exhibits multi-target properties and diverse pharmacological activities, positioning it as a promising candidate. However, its therapeutic potential in AD is limited by low bioavailability and inadequate brain accumulation. To overcome these challenges, we developed mesenchymal stem cell membrane-functionalized vesicles for targeted Bai delivery (MSC-Bai-Lipo). Using Box-Behnken response surface methodology, we optimized preparation parameters to achieve high encapsulation efficiency. In AD model mice, MSC-Bai-Lipo demonstrated targeted delivery to lesions, exhibiting superior therapeutic effects by mitigating AD-associated neuronal damage and neuroinflammatory processes.},
}

@article {pmid40902672,
year = {2025},
author = {Sharma, S and Bashir, B and Kolekar, KA and Acharya, A and Gupta, M and Jena, R and Vishwas, S and Kaur, J and Gupta, G and Kumbhar, PS and Patle, D and Chaitanya, M and Gulati, M and Singh, SK},
title = {Tailoring the biomarkers of Alzheimer's disease using a gut microbiome-centric approach: Preclinical, clinical, and regulatory perspectives.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102888},
doi = {10.1016/j.arr.2025.102888},
pmid = {40902672},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to its complex etiology and limited treatment options. Traditional pharmacotherapies targeting amyloid-β (Aβ) and cholinergic pathways offer modest benefits and are often associated with adverse effects. Emerging evidence implicates gut dysbiosis and the gut-brain axis in the pathogenesis and progression of AD. This review explores the multifactorial pathophysiology of AD and evaluates the therapeutic potential of gut-based interventions such as probiotics, prebiotics, synbiotics, metabiotics, postbiotics, and fecal microbiota transplantation (FMT) in mitigating disease pathology. Emphasis has also been given on role of miRNA released from FMT in management of AD. Preclinical and clinical studies demonstrate that these strategies can restore microbial homeostasis, reduce neuroinflammation, enhance gut barrier integrity, and improve cognitive outcomes. The regulatory aspects with use of probiotics based products and FMT is also highlighted. The modulation of neuroimmune, neuroendocrine, and neural pathways through microbiota-derived metabolites offers a promising avenue for AD management. Despite encouraging findings, further research is needed to address interindividual microbiome variability, delivery challenges, and the requirement for large-scale, randomized trials. Personalized gut-targeted approaches may open new horizons for the prevention and treatment of AD.},
}

@article {pmid40902589,
year = {2025},
author = {Hirota, Y and Sakakibara, Y and Morishima, M and Sano, T and Hara, M and Arakawa, A and Takao, M and Murayama, S and Saito, Y and Sekiya, M and Iijima, KM},
title = {Biomarker-related phospho-tau217 appears in synapses around Aβ plaques prior to tau tangle in cerebral cortex of preclinical Alzheimer's disease.},
journal = {Cell reports},
volume = {},
number = {},
pages = {116203},
doi = {10.1016/j.celrep.2025.116203},
pmid = {40902589},
issn = {2211-1247},
abstract = {Phospho-tau protein p-tau181 is a cerebrospinal fluid biomarker for Alzheimer's disease (AD), while p-tau217 is the most sensitive plasma biomarker for cerebral amyloid β (Aβ) load prior to tau pathology in preclinical AD. Diagnostic and prognostic use of these p-tau biomarkers requires neuropathological interpretation. Here, we analyzed the cellular localization of biomarker p-tau species in postmortem human brains harboring different extents of Aβ plaque and tau pathology. Signals for p-tau217 were absent in normal brains but present in pre- and post-synapses surrounding Aβ plaques in preclinical AD brains. p-Tau217 colocalized with tau pathology markers p-tau202/205, p-tau231, and p-tau262, while p-tau181 was normally present in glutamatergic and GABAergic axons, which were distorted around Aβ plaques, where p-tau217 and p-tau181 colocalized. p-tau217-containing pre-synapses were enriched with active tau kinases and were not preferentially engulfed by glial cells. Emergence of p-tau217 represents a neuronal/synaptic reaction to Aβ plaques in preclinical AD brains.},
}

@article {pmid40902587,
year = {2025},
author = {Song, Z and Xie, X and Chen, Y and Zhang, B and Li, X and Yang, Y and Mo, W and Zhang, J and Xu, D},
title = {Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease.},
journal = {Immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.immuni.2025.07.024},
pmid = {40902587},
issn = {1097-4180},
abstract = {Neuroinflammation drives Alzheimer's disease (AD) pathogenesis. Z-DNA, a non-canonical left-handed DNA structure, activates innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated Z-DNA detection in AD remains undefined. Here, we found that ZBP1 is amplified in AD microglia, driving innate immune responses and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that oxidized mtDNA, generated by amyloid-β (Aβ)-induced oxidative stress, was fragmented and released into the cytoplasm, forming Z-DNA. Z-DNA-activated ZBP1 engaged receptor-interacting protein kinase 1 (RIPK1), promoting its kinase activation and inducing transcription of pro-inflammatory molecules and inflammatory signaling mediators. Genetic deletion of Zbp1 or inhibition of RIPK1 attenuated neuroinflammation, Aβ pathology, and behavioral deficits in an AD mouse model. Our findings reveal that oxidation induces the Z conformer in mtDNA and establish the ZBP1-RIPK1 axis as a key driver of AD neuroinflammation, providing insights into the immune mechanisms underlying AD pathogenesis and identifying a potential therapeutic target.},
}

@article {pmid40902468,
year = {2025},
author = {Shen, M and Wen, P and Song, B and Li, Y},
title = {Muti-band Morlet mutual information functional connectivity for classifying Alzheimer's disease and frontotemporal dementia with a deep learning technique.},
journal = {Computers in biology and medicine},
volume = {197},
number = {Pt A},
pages = {111041},
doi = {10.1016/j.compbiomed.2025.111041},
pmid = {40902468},
issn = {1879-0534},
abstract = {Accurate differentiation of Alzheimer's disease (AD), frontotemporal dementia (FTD), and healthy control (HC) is critical for early diagnosis and intervention of brain disorders. This study introduces a deep learning framework that leverages electroencephalography (EEG)-derived multiband functional connectivity (FC) features. Multiband Morlet wavelet mutual information (MMMIFC) was utilized to generate high-resolution FC matrices across 1-20 Hz, which were subsequently processed by a 3D convolutional neural network (3D-CNN) based on a modified VGG architecture. The proposed model achieved classification accuracies of 90.77 % for AD vs HC and 90.38 % for FTD vs HC, with sensitivity and specificity of 88.89 % and 93.10 % for AD vs HC, and 86.96 % and 93.10 % for FTD vs HC, respectively. Beyond classification performance, the analysis identified distinct EEG-based biomarkers within the default mode network. In AD analysis, global efficiency, diffusion efficiency, and clustering coefficient were consistently reduced in the delta and theta bands, reflecting disrupted low-frequency network integration and the theta band presents the most prominent group differences between AD and HC. In FTD analysis, graph theory metrics were also reduced in the delta and theta bands, with the delta band showing the most pronounced group differences compared to HC.},
}

@article {pmid40902465,
year = {2025},
author = {Basanta-Torres, S and Rivas-Fernández, MÁ and Galdo-Alvarez, S},
title = {Artificial Intelligence for Alzheimer's disease diagnosis through T1-weighted MRI: A systematic review.},
journal = {Computers in biology and medicine},
volume = {197},
number = {Pt A},
pages = {111028},
doi = {10.1016/j.compbiomed.2025.111028},
pmid = {40902465},
issn = {1879-0534},
abstract = {Alzheimer's disease (AD) is a leading cause of dementia worldwide, characterized by heterogeneous neuropathological changes and progressive cognitive decline. Despite the numerous studies, there are still no effective treatments beyond those that aim to slow progression and compensate the impairment. Neuroimaging techniques provide a comprehensive view of brain changes, with magnetic resonance imaging (MRI) playing a key role due to its non-invasive nature and wide availability. The T1-weighted MRI sequence is frequently used due to its prevalence in most MRI protocols, generating large datasets, ideal for artificial intelligence (AI) applications. AI, particularly machine learning (ML) and deep learning (DL) techniques, has been increasingly utilized to model these datasets and classify individuals along the AD continuum. This systematic review evaluates studies using AI to classify more than two stages of AD based on T1-weighted MRI data. Convolutional neural networks (CNNs) are the most widely applied, achieving an average classification accuracy of 85.93 % (range: 51.80-100 %; median: 87.70 %). These good results are due to CNNs' ability to extract hierarchical features directly from raw imaging data, reducing the need for extensive preprocessing. Non-convolutional neural networks and traditional ML approaches also demonstrated strong performance, with mean accuracies of 82.50 % (range: 57.61-99.38 %; median: 86.67 %) and 84.22 % (range: 33-99.10 %; median: 87.75 %), respectively, underscoring importance of input data selection. Despite promising outcomes, challenges remain, including methodological heterogeneity, overfitting risks, and a reliance on the ADNI database, which limits dataset diversity. Addressing these limitations is critical to advancing AI's clinical application for early detection, improved classification, and enhanced patient outcomes.},
}

@article {pmid40902363,
year = {2025},
author = {Ospondpant, D and Yang, M and Gao, J and Dong, TT and Tsim, KWK},
title = {The extracts of Ardisia elliptica fruit attenuate inflammation in LPS-activated BV2 microglia via JNK, ERK1/2, p38, and NF-κB signaling inhibition.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {147},
number = {},
pages = {157211},
doi = {10.1016/j.phymed.2025.157211},
pmid = {40902363},
issn = {1618-095X},
abstract = {BACKGROUND: Neuroinflammation is a pivotal defense mechanism against brain infections and injury; the dysregulation contributes to neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. Ardisia elliptica Thunb. (Primulaceae), known as Ram Yai or Pilangkasa in Thai traditional medicine, has been used to treat diarrhea with fever. However, the potential of A. elliptica fruit to modulate neuroinflammation remains unexplored.

PURPOSE: This study aimed to investigate the anti-neuroinflammatory properties of A. elliptica fruit extracts in activated microglia as well as their anti-amyloidogenic effects in vitro.

METHODS: Lipopolysaccharide (LPS), a potent inflammatory stimulus, was used to activate both BV2 microglia, a well-established model of neuroinflammation, and RAW264.7 macrophages. In the inflammatory studies, assays including qRT-PCR, Western blotting, and phagocytic activity were performed. In the amyloidogenic study, thioflavin T and atomic force microscopy assays were conducted.

RESULTS: A. elliptica fruit was extracted using ethanol and water. The extracts significantly reduced the mRNA and protein expression of IL-1β, TNF-α, and iNOS in LPS-activated BV2 cells and RAW264.7 cells. The 90 % ethanol extract of A. elliptica fruit exhibited greater efficacy compared to 50 % ethanol or water extracts. In addition, A. elliptica fruit extract significantly decreased the phosphorylation of JNK, ERK1/2, p38, and NF-κB, while markedly attenuating excessive phagocytic activity by reducing uptake of fluorescent beads and Aβ1-42 fibrils in LPS-activated BV2 cells. Notably, the extracts inhibited Aβ1-42 fibril formation and disassembled preformed fibril aggregates. Embelin was identified as a major bioactive constituent of the extracts, accounting for part of the identified activities.

CONCLUSION: Our study elucidates the mechanisms by which A. elliptica fruit extract suppresses inflammation through inhibition of JNK, ERK1/2, p38, and NF-kB pathways in LPS-activated microglia. A. elliptica fruit extracts exhibit both anti-inflammatory and anti-amyloidogenic activities, suggesting the potential as a promising multi-target candidate natural product for neuroinflammatory disorders such as AD.},
}

@article {pmid40902261,
year = {2025},
author = {Lefèvre-Arbogast, S and Scala, P and Zorilla, A and Helmer, C and Chaker, J and David, A and Mercier, F and Samieri, C},
title = {Associations of plasma persistent organic pollutants with brain atrophy, cognitive decline and risk of dementia in older adults.},
journal = {Environment international},
volume = {203},
number = {},
pages = {109756},
doi = {10.1016/j.envint.2025.109756},
pmid = {40902261},
issn = {1873-6750},
abstract = {BACKGROUND: Persistent Organic Pollutants (POP), including polychlorinated biphenyls (PCBs) and organochlorine pesticides, are established neurotoxicants in experimental models; yet it remains uncertain whether exposures in the general population increase the risk to develop brain aging pathologies. We assessed the prospective associations of plasma POP concentrations with three dementia-related outcomes in a population-based cohort of older adults.

METHODS: Analyses included 515 participants from the Three-City Study, free of dementia at baseline at the time of blood measurements (1999-2000, mean age 72.5), who underwent up to 8 repeated assessments of cognitive function and dementia over 17 years and up to 3 neuroimaging examinations over 10 years. Plasma concentrations of 15 PCBs, 12 organochlorine pesticides and 1 brominated flame retardant were measured by gas chromatography coupled with tandem mass spectrometry (detection rate ≥5 %), and a POP score summarizing overall exposure was derived via factorial analysis. Associations with dementia risk, longitudinal changes in cognitive function (composite measure of four tests) and in brain volume (medial temporal lobe) were analyzed using Cox and linear mixed models, adjusted for baseline age, sex, education, apolipoprotein E (APOE) genotype, body mass index and total lipid concentrations.

RESULTS: In multivariable-adjusted models, neither individual POPs nor the total POP score were significantly and consistently associated with dementia-related outcomes. Significant interactions were observed between APOE genotype and highly-chlorinated PCBs (congeners 180, 194, and 196-203) across all outcomes (p for interaction ≤0.05), whereby adverse associations were seen in carriers of the APOE-ɛ4 allele, whereas opposing trends were observed in non-carriers.

CONCLUSION: Overall, this prospective study does not provide robust evidence to support an adverse association between exposure to POPs in the general population and the risk of all-cause dementia, cognitive decline, or brain atrophy in older adults.},
}

@article {pmid40902155,
year = {2025},
author = {Hill, JR and Gardner, B and Rodriguez, MJ and Golzarri-Arroyo, L and Zoh, RS and Boustani, Z and Burnell, J and Jordan, EJ and Boustani, MA and Holden, RJ},
title = {Mobile Telehealth Intervention to Support Care Partners of Patients With Alzheimer Disease and Related Dementias (I-CARE 2): Protocol for a Randomized Effectiveness Clinical Trial.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e73387},
doi = {10.2196/73387},
pmid = {40902155},
issn = {1929-0748},
mesh = {Humans ; *Telemedicine ; *Alzheimer Disease/psychology/therapy ; *Caregivers/psychology ; *Mobile Applications ; *Dementia/therapy/psychology ; Male ; Randomized Controlled Trials as Topic ; Female ; Indiana ; },
abstract = {BACKGROUND: Nearly all individuals with Alzheimer disease and related dementias (ADRD) experience behavioral and psychological symptoms of dementia (BPSD), which include symptoms such as agitation, wandering, delusions, and hallucinations. Care partners (a person, often a family member, who provides care and support to someone with ADRD) struggle to manage BPSD, making symptom management a critical focus of intervention research. Our team has developed a mobile telehealth intervention (Brain CareNotes) to help care partners manage BPSD.

OBJECTIVE: This paper outlines a protocol for a randomized controlled trial of 160 care partners of patients with ADRD to test the effect of Brain CareNotes on care partner burden and patients' BPSD.

METHODS: Participants will be recruited from partner health systems in Indiana, United States, by word of mouth, and through community outreach efforts. They will be randomly assigned to use either the Brain CareNotes mobile app intervention-which helps care partners manage BPSD through the support of a care coach, written and visual materials on developing care skills, and BPSD measurement and tracking-or an education-only mobile app control for 12 months. Data will be collected over the phone at baseline, 6 months, and 12 months. Primary outcomes assessed for this trial are (1) care partner burden and (2) patients' BPSD. Secondary and exploratory outcomes assessed include care partner depressive symptoms, patient and care partner acute care use, intervention usability and acceptability, and intervention use. The trial will also collect patient and care partner demographics and measure care partner self-efficacy, care partner social support, patients' ADRD severity, and patients' functional abilities.

RESULTS: As of March 2025, we have enrolled 159 participants, and 42 have successfully completed the study.

CONCLUSIONS: Brain CareNotes is a unique mobile app intervention to support care partners in managing BPSD. Due to the scalability of mobile health interventions, if Brain CareNotes is shown to be effective in reducing caregiver burden and patients' BPSD, it has the potential for widespread adoption to support many ADRD care partners.

DERR1-10.2196/73387.},
}

Humans
*Telemedicine
*Alzheimer Disease/psychology/therapy
*Caregivers/psychology
*Mobile Applications
*Dementia/therapy/psychology
Male
Randomized Controlled Trials as Topic
Female
Indiana

@article {pmid40902032,
year = {2025},
author = {Watson, BE and Waugh, ML and Foreman, NJ and Moss, MA},
title = {Influence of Alzheimer's associated Aβ oligomers and oxidative stress on blood-brain barrier dysfunction.},
journal = {Tissue barriers},
volume = {},
number = {},
pages = {2553927},
doi = {10.1080/21688370.2025.2553927},
pmid = {40902032},
issn = {2168-8370},
abstract = {Blood-brain barrier (BBB) dysfunction is an early event observed in Alzheimer's disease (AD). Two characteristics of AD brain and brain vasculature contribute to BBB dysfunction: the accumulation of aggregated amyloid-β protein (Aβ) and an increase in oxidative stress. This work uses a BBB model of primary human brain microvascular endothelial cells to investigate the individual and synergistic influence of both pathogenic Aβ oligomers and oxidative stress on BBB transendothelial electrical resistance (TEER), an indicator of barrier integrity. Results indicate that nontoxic, physiological concentrations of Aβ oligomers reduce TEER, while Aβ monomer remains inert. Moreover, introducing mild oxidative stress, which alone does not influence monolayer integrity, exacerbates the effect of Aβ oligomers on TEER within this BBB model. These findings advance the understanding of BBB dysfunction in AD and point toward therapeutic strategies targeting this early event that contributes to a currently irreversible disease.},
}

@article {pmid40901987,
year = {2025},
author = {Sun, Z and Li, C and Leitner, D and Wu, M and Zhang, J and Wisniewski, T and Ge, Y},
title = {Age-related Vascular Alterations in the Choroid Plexus: Novel Insights from Pathophysiology and Imaging Studies.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0735},
pmid = {40901987},
issn = {2152-5250},
abstract = {The choroid plexus (ChP), a highly vascularized brain structure responsible for cerebrospinal fluid (CSF) production, undergoes significant age-related changes that may contribute to neurodegenerative diseases involving disrupted immune regulation, fluid homeostasis and waste clearance. Compared to other brain regions, vascular research on the ChP remains limited despite its critical role as a central interface between the blood and CSF. This review focuses on age-related vascular and structural alterations in the ChP from both histopathological and neuroimaging perspectives, and explores their impact on CSF dynamics, immune regulation, and the integrity of the blood-CSF barrier (BCSFB). Rather than shrinking, the aging ChP often enlarges due to dystrophic changes, as shown in volumetric MRI studies. Histological studies reveal epithelial degeneration, basement membrane thickening, and stromal fibrosis in the normal aging process. In dementia such as Alzheimer's disease (AD), proteomic studies have identified upregulation of AD- and immune-related proteins, along with downregulation of proteins linked to CSF clearance and metabolic support. Emerging high-resolution contrast-enhanced MRI techniques now allow in vivo visualization of microvascular changes within the ChP, shedding light on its normal and abnormal aging processes. Understanding these alterations is critical, as they may influence the onset and progression of various neurological diseases such as AD, Parkinson's disease (PD), normal pressure hydrocephalus, and amyotrophic lateral sclerosis (ALS). The recent advancements and challenges described in this study underscore the need for deeper investigation into ChP aging to inform future diagnostic and therapeutic strategies of neurodegenerative diseases.},
}

@article {pmid40901983,
year = {2025},
author = {Gellrich, J and Ruhnau, J and Köslich, L and Gross, S and Flöel, A and Schulze, J and Vogelgesang, A},
title = {Antigen-Specifically Activated CD8+ and Double-Negative T Cells Accumulate in the Brain of Alzheimer's Disease Mice.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0452},
pmid = {40901983},
issn = {2152-5250},
abstract = {Emerging evidence suggests adaptive immunity plays a key role in cognitive function and neurodegenerative diseases. However, the specific contribution of T cells in Alzheimer's disease (AD) remains poorly understood. Despite successful T cell modulation in other neurological conditions, similar strategies in AD remain underexplored due to gaps in our understanding of antigen-specific T cell activity and antigen-unspecific bystander activation in the diseased brain. In this study, we used flow cytometry to characterize T cell populations and their activation mode in an AD mouse model. By assessing GFP expression in C57BL/6J-Tg(Nr4a1-EGFP/cre)820Khog; Tg(APPswe,PSEN1dE9)85Dbo/Mmjax mice, we distinguished antigen-dependent from antigen-independent activation in CD4[+], CD8[+], and double-negative T cells (DNTs). This approach allows analysis of the full repertoire of antigen-specifically activated T cells in a physiological immune system without prior knowledge of target antigens. AD-like amyloid pathology progression was monitored by monthly scoring until mice reached 2, 6, 10-12 or 15-18 months of age and Aβ-quantification via thioflavine S staining. Antigen-specific activation during AD development was assessed by comparing AD mice with wild-type littermates. At 15-18 months, AD mice exhibited elevated numbers of activated, highly differentiated DNTs, along with increased antigen-specific CD8[+] and DNT cells relative to controls. These results indicate a significant role for antigen-dependent immune activity in AD, highlighting CD8[+] T cells and DNTs as potential therapeutic targets.},
}

@article {pmid40901978,
year = {2025},
author = {Zhao, T and Pan, P and Jia, Y and Zhou, Y and Zhang, X and Guan, H and Li, Q and Zhou, Y},
title = {Crossing Pathological Boundaries: Multi-Target Restoration of the Neurovascular Unit in Alzheimer's and Vascular Dementia-From Modern Therapeutics to Traditional Chinese Medicine.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0801},
pmid = {40901978},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) and vascular dementia (VD) are the two most common forms of dementia, and they share common mechanisms, especially in regard to neurovascular dysfunction. There has been increasing evidence that the disruption of the neurovascular unit (NVU), which consists of endothelial cells, pericytes, astrocytes, microglia, neurons, and basement membrane, is one of the key early events in both AD and VD. The objective of this review is to summarize the structure and physiological function of the NVU, then discuss the pathological remodeling of the NVU in AD and VD and finally, show emerging evidence of multi-target approaches that restore the NVU and neurovascular protection. We begin with a description of the structure, and dietary regulatory roles of the NVU in cerebral homeostasis, especially related to Aβ, the blood-brain barrier (BBB), and neurovascular coupling (NVC). The NVU is then related to the pathological events that cause AD and VD, specifically to impaired Aβ clearance, inflammatory cascades, oxidative stress, and neurovascular uncoupling. Finally, the discussion focuses on a multi-target approach involving exercise, estrogen therapy, mesenchymal stem cells/exosomes, remote ischemic conditioning (RIC), and mindfulness meditation, and analyzes its implications for recovering NVU structure and function. We also discuss the concept of traditional Chinese medicine (TCM) approaches associated with NVU modulation with herbal formulas, traditional Chinese exercises and acupuncture, which has integrative pathways for MVU modulation. NVU dysfunction has a significant and converging impact on the development of both AD and VD. There is considerable support for multi-pathway neurovascular unit targeting, which should show a significant delay in cognitive decline. Incorporating multi-modal evidence from contemporary and traditional medical systems could offer new insights for individualized, neurovascular-targeted therapy for dementia.},
}

@article {pmid40901947,
year = {2025},
author = {Segen, V and Kabir, MR and Streck, A and Slavik, J and Glanz, W and Butryn, M and Newman, E and Tiganj, Z and Wolbers, T},
title = {Path integration impairments reveal early cognitive changes in subjective cognitive decline.},
journal = {Science advances},
volume = {11},
number = {36},
pages = {eadw6404},
doi = {10.1126/sciadv.adw6404},
pmid = {40901947},
issn = {2375-2548},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis ; Male ; Female ; Aged ; Bayes Theorem ; Alzheimer Disease/physiopathology ; *Cognition ; Entorhinal Cortex/physiopathology ; Middle Aged ; Virtual Reality ; Case-Control Studies ; },
abstract = {Path integration, the ability to track one's position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimer's disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimer's disease, and healthy controls using an immersive virtual reality task. We developed a Bayesian computational model to decompose path integration errors into distinct components. SCD participants exhibited significantly higher path integration error, primarily driven by increased memory leak, while other modeling-derived error sources, such as velocity gain, sensory, and reporting noise, remained comparable across groups. Our findings suggest that path integration deficits, specifically memory leak, may serve as an early marker of neurodegeneration in SCD and highlight the potential of self-motion-based navigation tasks for detecting presymptomatic Alzheimer's disease-related cognitive changes.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnosis
Male
Female
Aged
Bayes Theorem
Alzheimer Disease/physiopathology
*Cognition
Entorhinal Cortex/physiopathology
Middle Aged
Virtual Reality
Case-Control Studies

@article {pmid40901891,
year = {2025},
author = {de Graaff, MLA and Bijnsdorp, FM and Rademakers, JJDJM and Francke, AL and van Valkengoed, IGM and van den Buuse, S and van der Heide, I},
title = {Care Experiences of Family Caregivers of People with Dementia: A Nationwide Survey Study Comparing Caregivers with Migrant and Native Backgrounds.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012251375251},
doi = {10.1177/14713012251375251},
pmid = {40901891},
issn = {1741-2684},
abstract = {Introduction: Having a migration background might be associated with the care experiences of family caregivers of people with dementia. For example, caregivers with a migration background often face additional challenges in accessing professional care. The aim of this study was to provide insight into differences in care experiences between family caregivers with a native Dutch and a European or a non-European migration background. Methods: Data were used from a large-scale Dutch survey among family caregivers of relatives with dementia. The sample consisted of 170 caregivers with a European migration background, 199 caregivers with a non-European migration background and 4,158 caregivers with a native Dutch background. Linear and multinomial logistic regression analyses were used to analyse the survey data. The results were adjusted for background characteristics such as sex and age. Results: No differences were found between the two migrant groups and the native Dutch group in the perceived care burden and the caregiving intensity. Family caregivers with a European migration background were less likely to feel prepared for future changes in the dementia trajectory of their relative with dementia than caregivers with a native Dutch background. In addition, caregivers with a European migration background gave a lower score for their appreciation of the overall supply of care and support. Discussion: Caregivers with a European migration background, but not caregivers with a non-European migration background, were less likely to feel prepared for future changes than caregivers with a native Dutch background. In addition, they had lower appreciation for the overall supply of care and support. Offering a good supply of professional care and support, tailored to the individual situation and support needs, is important for caregivers in general, and those with a European migration background in particular.},
}

@article {pmid40901808,
year = {2025},
author = {Campanelli, L and Sendoya, JM and Brody, S and Galeano, P and Do Carmo, S and Cuello, AC and Castaño, EM and Gonzalés-Jimenez, A and Verheul, J and Medina-Vera, D and de Fonseca, FR and Wernersson, R and Morelli, L},
title = {New insights into the molecular biology of Alzheimer's-like cerebral amyloidosis achieved through multi-omics approaches.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0330859},
doi = {10.1371/journal.pone.0330859},
pmid = {40901808},
issn = {1932-6203},
mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; Animals ; *Metabolomics/methods ; *Amyloidosis/metabolism/genetics/pathology ; Rats ; Rats, Transgenic ; Feces/microbiology ; Amyloid beta-Peptides/metabolism ; Protein Interaction Maps ; Male ; Disease Models, Animal ; Humans ; Metabolome ; Gastrointestinal Microbiome ; Multiomics ; },
abstract = {BACKGROUND: One of the neuropathologic hallmarks of Alzheimer's disease (AD) is amyloid plaques composed of fibrillar amyloid beta (Aβ) that accumulate in the hippocampus and cerebral cortex. The identification of molecular changes and interactions associated with Aβ-dependent cerebral amyloidosis is a need in the field. We hypothesize that structured datasets linking proteins to differentially abundant metabolites may provide an indirect but effective means of elucidating the processes and functions in which these metabolites are involved. The goal of this study was to identify core network modules related to AD-like cerebral amyloidosis to provide new insights into the molecular underpinnings of this brain disorder potentially associated with diet and microbiota modulation.

METHODS: We performed fecal bacterial genotyping and untargeted metabolomic analysis of plasma and feces from wild-type and McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like cerebral amyloidosis, that were exposed to a high-fat diet protocol. To identify relevant proteins associated with the discriminant metabolites, we used several structured databases. Protein-metabolite associations (both physical and functional) were retrieved, and a collection of AD-associated protein-protein interaction (PPI) networks were built using a near-neighborhood approach.

RESULTS: A total of 44 bacterial genera and 636 plasma and 576 fecal metabolites were analyzed. From the discriminating metabolites of the Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) models, 657 networks were collected and a subset of the top 20 exploratory networks was defined. The first ranked network in terms of seed protein enrichment and number of participating metabolites showed strong biological signals of innate and adaptive immunity processes, with CD36 emerging as a central hub, orchestrating immunity, metabolic pathways, and fatty acid trafficking.

CONCLUSIONS: The network biology approach enabled a precise definition of the metabolic pathways underlying the disease biology highlighting the role of immune system in the complex interaction of the brain-gut axis.},
}

*Alzheimer Disease/metabolism/genetics/pathology
Animals
*Metabolomics/methods
*Amyloidosis/metabolism/genetics/pathology
Rats
Rats, Transgenic
Feces/microbiology
Amyloid beta-Peptides/metabolism
Protein Interaction Maps
Male
Disease Models, Animal
Humans
Metabolome
Gastrointestinal Microbiome
Multiomics

@article {pmid40901302,
year = {2025},
author = {Stothart, G and Alderman, S and Hermann, O and Creavin, S and Coulthard, EJ},
title = {A passive and objective measure of recognition memory in mild cognitive impairment using Fastball memory assessment.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf279},
doi = {10.1093/braincomms/fcaf279},
pmid = {40901302},
issn = {2632-1297},
abstract = {As viable pharmacotherapies and blood biomarkers emerge for dementia treatment and screening, there remains a great need for accurate, sensitive biomarkers of cognitive function. We have previously demonstrated that Fastball, a new Electroencephalography (EEG) method for the passive and objective measurement of recognition memory that requires no behavioural memory response or task comprehension, is sensitive to cognitive dysfunction in Alzheimer's disease. Here we present new evidence that Fastball is sensitive to amnestic dysfunction in an earlier stage of the dementia lifecourse, Mild Cognitive Impairment (MCI). 53 MCI patients and 54 healthy older adult (HOA) controls completed a 3-min Fastball task in which they passively viewed rapidly presented images while EEG captured their automatic ability to differentiate between images based on previous exposure. They also completed neuropsychological assessments of memory (Delayed Match to Sample-48), sustained attention (Psychomotor Vigilance Task), and general cognitive function (Addenbrookes Cognitive Exam-iii). Participants were re-tested after 1 year to establish the test-retest reliability of Fastball in HOAs, and the sensitivity of Fastball to cognitive decline in MCI patients, over a 1 year period. Amnestic MCI patients showed significantly reduced Fastball responses compared with non-amnestic MCI patients (P = 0.001, Cohen's d = 0.98) and HOA controls (P = 0.005, Cohen's d = 0.64). Regression analyses showed that Fastball EEG responses were selectively predictive of neuropsychological measures of recognition memory and not attention. Between baseline and year one follow-up Fastball showed moderate to good test-retest reliability in HOA controls, and the six MCI-dementia converters showed a trend for lower Fastball responses at baseline which will be confirmed with further longitudinal assessment. Fastball is further validated as a viable method for testing recognition memory in cognitively impaired populations. We have demonstrated that it is selectively predictive of memory dysfunction and not attention or other cognitive functions. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball is a viable functional biomarker that can help to advance cognitive assessment in MCI.},
}

@article {pmid40901300,
year = {2025},
author = {Umair, M and Khan, MS and Hanif, M and Ghaban, W and Nafea, I and Qasem, SN and Saeed, F},
title = {Privacy-preserving dementia classification from EEG via hybrid-fusion EEGNetv4 and federated learning.},
journal = {Frontiers in computational neuroscience},
volume = {19},
number = {},
pages = {1617883},
doi = {10.3389/fncom.2025.1617883},
pmid = {40901300},
issn = {1662-5188},
abstract = {As global life expectancy rises, a growing proportion of the population is affected by dementia, particularly Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Electroencephalography (EEG) based diagnosis presents a non-invasive, cost effective alternative for early detection, yet existing methods are challenged by data scarcity, inter-subject variability, and privacy concerns. This study proposes lightweight and privacy-preserving EEG classification framework combining deep learning and Federated Learning (FL). Five convolutional neural networks (EEGNetv1, EEGNetv4, EEGITNet, EEGInception, EEGInceptionERP) have been evaluated on resting-state EEG dataset comprising 88 subjects. EEG signals are preprocessed using band-pass (1-45 Hz) and notch filtering, followed by exponential standardization and 4-second windowing. EEGNetv4 outperformed among other EEG tailored models, and upon utilizing the hybrid fusion techniques it achieves 97.1% accuracy using only 1,609 parameters and less than 1 MB of memory, demonstrating high efficiency. Moreover, FL using FedAvg is implemented across five stratified clients, achieving 96.9% accuracy on the hybrid fused EEGNetV4 model while preserving data privacy. This work establishes a scalable, resource-efficient, and privacy-compliant framework for EEG-based dementia diagnosis, suitable for deployment in real-world clinical and edge-device settings.},
}

@article {pmid40900994,
year = {2025},
author = {Xu, J and Doig, AJ and Michopoulou, S and Proitsi, P and Costen, F and , },
title = {Accurate and robust prediction of Amyloid-β brain deposition from plasma biomarkers and clinical information using machine learning.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1559459},
doi = {10.3389/fnagi.2025.1559459},
pmid = {40900994},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) greatly affects the daily functioning and life quality of patients and is prevalent in the elderly population. Amyloid-β (Aβ) accumulation in the brain is the main hallmark of AD pathophysiology. Positron Emission Tomography (PET) imaging is the most accurate method to identify Aβ deposits in the brain, but it is expensive and not widely available. The development of a low-cost method to detect Aβ deposition in the brain, as an alternative to PET, would therefore be of great value. This study aims to develop and validate machine learning algorithms for accurately predicting brain Aβ positivity using plasma biomarkers, genetic information, and clinical data as a cost-effective alternative to PET imaging.

METHODS: We analyzed 1,043 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and validated our models on 127 patients from the Center for Neurodegeneration and Translational Neuroscience (CNTN) dataset. Brain Aβ status was determined using plasma biomarkers [Aβ42, Aβ40, Phosphorylated tau (pTau) 181, Neurofilament light chain (NfL)], Apolipoprotein E (APOE) genotype, and clinical information [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), age, education year, and gender]. Decision tree, random forest, support vector machine, and multilayer perceptron machine learning methods were used to combine all this information. We introduced a feature selection method to balance the performance and the number of features. We conducted a feature matching technique to enable our model to be tested on the external dataset without retraining.

RESULTS: Our system achieved a value of 0.95 for the Area Under the ROC curve (AUC) using the ADNI dataset (n = 340) and the full set of 11 features. Our architecture was also tested on an external dataset (CNTN, n = 127) and achieved an AUC of 0.90. When using only five features (pTau 181, Aβ42/40, Aβ42, APOE ɛ4 count, and MMSE) on 341 ADNI patients, we achieved an AUC of 0.87.

CONCLUSION: The random forest, support vector machine and multilayer perceptron methods can accurately predict brain Aβ status using plasma biomarkers, genotype, and clinical information. The method generalizes well to an independent dataset and can be reduced to using only five features without losing much accuracy, thus providing an inexpensive alternative to PET imaging.},
}

@article {pmid40900992,
year = {2025},
author = {Wang, T and Mao, Z and Shang, Y and Merlini, S and Vitali, F and Wiegand, JP and Brinton, RD},
title = {Accelerated midlife endocrine and bioenergetic brain aging in APOE4 females.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1632877},
doi = {10.3389/fnagi.2025.1632877},
pmid = {40900992},
issn = {1663-4365},
abstract = {Female sex, age, and APOE4 genotype are the greatest risk factors for Alzheimer's disease. Using a translational perimenopause mouse model based on human Stages of Reproductive Aging Works (STRAW) criteria, we investigated the impact of APOE genotype on female midlife endocrine aging, peripheral metabolic indicators, brain bioenergetic pathways, mitochondrial function, neuroimmune activation, and myelination. Compared to APOE3 females, APOE4 females exhibited accelerated endocrine aging that was coincident with failure to mount adaptive bioenergetic reprogramming and significant decline in mitochondrial function that were coupled with increased immune activation and demyelination in brain. In women, APOE4 was associated with early menopause. Further, APOE4 women experiencing early menopause exhibited the highest risk of Alzheimer's. These results provide plausible mechanistic pathways underlying the earlier emergence and greater risk of Alzheimer's in APOE4 postmenopausal females. Collectively, these findings support midlife as a critical window for intervention to prevent or delay the onset of the prodromal stage of Alzheimer's disease in APOE4 carriers.},
}

@article {pmid40900876,
year = {2025},
author = {Das, N and Gade, KR and Addanki, PK},
title = {Artificial intelligence for early diagnosis and risk prediction of periodontal-systemic interactions: Clinical utility and future directions.},
journal = {World journal of methodology},
volume = {15},
number = {4},
pages = {105516},
doi = {10.5662/wjm.v15.i4.105516},
pmid = {40900876},
issn = {2222-0682},
abstract = {BACKGROUND: Artificial intelligence (AI) is transforming healthcare by improving diagnostic accuracy and predictive analytics. Periodontal diseases are recognized as risk factors for systemic conditions, including type 2 diabetes mellitus, cardiovascular disease, Alzheimer's disease, polycystic ovary syndrome, thyroid dysfunction, and post-coronavirus disease 2019 complications. These conditions exhibit complex bidirectional interactions, underscoring the importance of early detection and risk stratification. Current diagnostic tools often fail to capture these interactions at an early stage, limiting timely intervention. This study hypothesizes that AI-driven approaches can significantly improve early diagnosis and risk prediction of periodontal-systemic interactions, enhancing clinical outcomes.

AIM: To evaluate AI's role in diagnosing and predicting periodontal-systemic interactions in studies from 2010 to 2024.

METHODS: This systematic review followed PRISMA guidelines (2009) and included peer-reviewed articles from PubMed, Scopus, and Embase. Studies with large sample sizes (≥ 500 participants) were selected, focusing on AI models integrating multi-omics data and advanced imaging techniques such as cone beam computed tomography and magnetic resonance imaging. Machine learning models processed structured clinical data, deep learning models combined imaging and clinical data, and natural language processing models extracted insights from clinical notes.

RESULTS: AI applications significantly enhanced diagnostic and predictive accuracy, reducing diagnostic time by 40% and improving predictive accuracy by 25% in periodontal patients with type 2 diabetes mellitus. Studies with sample sizes of 1000-1500 participants reported diagnostic accuracy improvements up to 92%, with specificity and sensitivity rates of 94% and 90%, respectively. Increasing sample sizes over the years reflected advancements in AI, data collection, and model training, reinforcing model reliability.

CONCLUSION: AI's integration of multi-omics and imaging data has transformed early diagnosis and risk prediction in periodontal-systemic interactions, improving clinical outcomes and decision-making.},
}

@article {pmid40900875,
year = {2025},
author = {Kaur, R and Morya, AK and Gupta, PC and Aggarwal, S and Menia, NK and Kaur, A and Kaur, S and Sinha, S},
title = {Artificial intelligence-based apps for screening and diagnosing diabetic retinopathy and common ocular disorders.},
journal = {World journal of methodology},
volume = {15},
number = {4},
pages = {107166},
doi = {10.5662/wjm.v15.i4.107166},
pmid = {40900875},
issn = {2222-0682},
abstract = {Artificial intelligence (AI), encompassing machine learning and deep learning, is being extensively used in medical sciences. It is slated to positively impact the diagnosis and prognostication of various diseases. Deep learning, a subset of AI, has been instrumental in diagnosing diabetic retinopathy (DR), diabetic macular edema, glaucoma, age-related macular degeneration, and numerous other ocular diseases. AI performs equally well in the early prediction of glaucoma and age-related macular degeneration. Integrating AI with telemedicine promises to improve healthcare delivery, although challenges persist in implementing AI algorithms, especially in developing countries. This review provides a comprehensive summary of AI, its applications in ophthalmology, particularly DR, the diverse algorithms utilized for different ocular conditions, and prospects for the future integration of AI in eye care.},
}

@article {pmid40900744,
year = {2025},
author = {Mani, S and Wasnik, S and Shandilya, C and Srivastava, V and Khan, S and Singh, KK},
title = {Pathogenic synergy: dysfunctional mitochondria and neuroinflammation in neurodegenerative diseases associated with aging.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1615764},
pmid = {40900744},
issn = {2673-6217},
abstract = {The term "neurodegenerative diseases" (NDDs) refers to a range of aging-associated conditions, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Unique clinical symptoms and underlying pathological mechanisms distinguish each of these illnesses. Although these conditions vary, they share chronic neuroinflammation as a defining characteristic. Protein aggregation and mitochondrial dysfunction are believed to play a role in initiating the neuroinflammatory response and, subsequently, the development and course of these illnesses. Apart from providing energy to the cells, mitochondria are involved in the immunoinflammatory response associated with neurological disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy. This involvement is attributed to controlling processes such as inflammasome activation and cell death. Under inflammatory conditions, the underlying regulatory mechanisms for these aging-associated disorders may include calcium homeostasis imbalance, mitochondrial oxidative stress, mitochondrial dynamics, and epigenetics. Various NDDs are linked to neuroinflammation and mitochondrial dysfunction. The linkages between these occurrences are becoming more apparent, but the etiology of these pathologic lesions is yet to be elucidated. This review examines the role of neuroinflammation and mitochondrial dysfunction in the growth and course of NDDs, emphasizing the possibility of identifying novel therapeutic targets to address aging-related neurodegenerative processes and retard the progression of these illnesses.},
}

@article {pmid40900487,
year = {2025},
author = {Castro-Suarez, S and Zegarra-Valdivia, JA and Meza-Vega, M and Guevara-Silva, EA},
title = {Clinical profile of early-onset Alzheimer's disease in Peru: case series from a neurological care center.},
journal = {Revista peruana de medicina experimental y salud publica},
volume = {42},
number = {2},
pages = {196-202},
doi = {10.17843/rpmesp.2025.422.14413},
pmid = {40900487},
issn = {1726-4642},
mesh = {Humans ; *Alzheimer Disease/diagnosis/epidemiology ; Female ; Male ; Retrospective Studies ; Peru ; Age of Onset ; Middle Aged ; Aged ; Sex Factors ; Aged, 80 and over ; },
abstract = {BACKGROUND: Motivation for the study. To describe the clinical characteristics of early-onset Alzheimer's disease (EOAD) and compare them according to gender. This condition is considered a rare disease, whose manifestations are still poorly understood. Main findings. The most common clinical presentation of EOAD is the amnestic variant, which mainly affects episodic memory and executive function and is often accompanied by neuropsychiatric symptoms such as depression and irritability. Women tend to have more impairments in calculus, constructive apraxia, and visuospatial functions than men. Implications for public health. By identifying the clinical characteristics of EOAD, healthcare professionals can recognize patients early on. Furthermore, it is essential to broaden the concept of dementia, avoiding limiting it exclusively to the population over 65 years of age.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) accounts for between 5 and 10% of all cases of Alzheimer's disease and is a rare and devastating form of the disease. This retrospective study analyzed the medical records of patients diagnosed with EOAD between 2022 and 2023 at a tertiary neurological center in Lima, Peru. Of 547 cases of dementia, 60 met the criteria for EOAD. Most were women (73.3%), and 71% had more than six years of education. The mean MMSE score was 11.92 ± 7.5, and the mean CDR score was 2, indicating severe cognitive impairment and moderate dementia. The amnestic variant was the most common clinical form, highlighting the involvement of episodic memory and executive function. The most common psychological and behavioral symptoms were depression and irritability. Atypical features such as myoclonus (5%) and epilepsy (10%) were also identified. These findings highlight the importance of healthcare professionals recognizing dementia in young adults at an early stage and offering comprehensive management to improve the quality of life of patients and their families.

BACKGROUND: Motivation for the study. To describe the clinical characteristics of early-onset Alzheimer's disease (EOAD) and compare them according to gender. This condition is considered a rare disease, whose manifestations are still poorly understood. Main findings. The most common clinical presentation of EOAD is the amnestic variant, which mainly affects episodic memory and executive function and is often accompanied by neuropsychiatric symptoms such as depression and irritability. Women tend to have more impairments in calculus, constructive apraxia, and visuospatial functions than men. Implications for public health. By identifying the clinical characteristics of EOAD, healthcare professionals can recognize patients early on. Furthermore, it is essential to broaden the concept of dementia, avoiding limiting it exclusively to the population over 65 years of age.},
}

Humans
*Alzheimer Disease/diagnosis/epidemiology
Female
Male
Retrospective Studies
Peru
Age of Onset
Middle Aged
Aged
Sex Factors
Aged, 80 and over

@article {pmid40899979,
year = {2025},
author = {Liao, M and Long, X and Wang, M and Zhou, W and Chen, Y and Guo, J and Solé-Guardia, G and Tuladhar, AM and Li, H and Fan, Y},
title = {Disruptions of deep medullary veins and MRI indices of glymphatic function in cerebral small vessel disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372926},
doi = {10.1177/13872877251372926},
pmid = {40899979},
issn = {1875-8908},
abstract = {BackgroundDisruptions of deep medullary veins (DMV) have been associated with the radiological severity and cognitive impairment observed in cerebral small vessel disease (SVD). Glymphatic dysfunction may serve as a potential mechanism underlying these associations.ObjectiveWe aimed to clarify the associations between DMV disruptions, MRI indices previously hypothesized as related to glymphatic function, white matter hyperintensities (WMH), and cognitive impairment in SVD.MethodsThis cross-sectional study included 133 SVD participants. DMV disruptions were visually rated on susceptibility-weighted imaging (SWI). Five MRI indices related to glymphatic function were measured: the diffusion tensor imaging along the perivascular space (DTI-ALPS), free water (FW) fraction, choroid plexus (Cp) volumes, perivascular spaces in basal ganglia (BG-PVS) and white matter (WM-PVS).ResultsHigher DMV scores were associated with higher WMH volumes (β = 0.55, p < 0.001) and lower Montreal Cognitive Assessment (MoCA) scores (β = -0.24, p = 0.003). Higher DMV scores were correlated with lower DTI-ALPS values, higher FW fraction, higher volumes in Cp, BG-PVS, and WM-PVS (all p < 0.001). DTI-ALPS values and BG-PVS volumes mediated the associations between DMV scores and WMH volumes, with only BG-PVS volumes mediating the associations between DMV scores and MoCA scores.ConclusionsOur results suggested that DMV disruptions contribute to WMH burden and cognitive impairment in SVD. This effect could be mediated by MRI markers indicative of glymphatic dysfunction, particularly the enlargement of BG-PVS.},
}

@article {pmid40899976,
year = {2025},
author = {Liu, G and Sun, Y},
title = {Harnessing nanoparticles for Alzheimer's disease: Innovations in drug delivery and pathology-specific treatments.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251374149},
doi = {10.1177/13872877251374149},
pmid = {40899976},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and the accumulation of amyloid-β plaques and tau tangles in the brain. Current treatments are predominantly symptomatic and do not alter the underlying pathological processes, which include amyloid aggregation, tau hyperphosphorylation, synaptic dysfunction, and neuroinflammation. Nanoparticle-based drug delivery systems have emerged as a promising strategy to address these challenges by facilitating the targeted delivery of therapeutics across the blood-brain barrier, enhancing drug bioavailability, and minimizing systemic toxicity and immunogenicity through biomimetic surface modifications, optimized physicochemical properties, and targeted delivery approaches. This review examines the multifaceted role of nanoparticles in AD therapy under various pathological mechanisms. Additionally, the review explores the diagnostic potential of nanoparticles in improving the detection of AD biomarkers, offering early diagnosis and real-time monitoring of disease progression. Despite these promising developments, the clinical translation of nanoparticle-based approaches faces challenges related to biocompatibility, long-term safety, and regulatory barriers. Ongoing research and innovation are essential to optimize nanoparticle formulations, ensure their safety, and bring these advanced technologies into clinical practice. Nanotechnology represents a paradigm shift in AD management, offering the potential for more effective treatments and improved patient outcomes.},
}

@article {pmid40899972,
year = {2025},
author = {Tyler, SL and Paterson, KB and Hutchinson, CV},
title = {Carers' recognition of concurrent visual impairment in dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372971},
doi = {10.1177/13872877251372971},
pmid = {40899972},
issn = {1875-8908},
abstract = {Background40-60% of people with dementia live with visual impairment. Those with mild-moderate dementia reliably report reduced vision-related quality of life across several visual domains with associated effects on vision-related social functioning. Despite the marked impact on concurrent dementia and visual impairment, no studies have investigated whether the impact of visual impairment on the lived experiences of people with dementia is recognised by their carers.ObjectiveThe present study investigated whether: (1) problems related to vision and vision-related quality of life reported by people with dementia are recognised and acknowledged by their carers and (2) whether currently validated vision-related quality of life measures for mild-moderate dementia are appropriate as proxy measures of vision-related quality of life in this group.MethodsThe 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and the Visual Activities Questionnaire (VAQ) were completed by 48 participants with mild-moderate dementia and 48 carers. Participants with dementia completed the questionnaires based on their own experiences and carers completed them by proxy (i.e., on behalf of the person with dementia for whom they cared).ResultsThere was good agreement between people with dementia and their carers on both measures overall and on the majority of subscales, with no significant differences between carer and dementia reports.ConclusionsThis provides further support that people with mild-moderate dementia can accurately report their visual experiences, and that carers could provide a valid proxy of the existence and impact of visual impairment on people living with dementia.},
}

@article {pmid40899970,
year = {2025},
author = {Lu, Y and Liu, Y and Zhou, X and Wu, H and Zhou, Y and Hu, L and Zhang, H and Long, Y and Pang, C and Xi, J and Wang, D and Chen, J and Zhang, Z and Xu, J and Chen, S},
title = {Progressive structural alterations in the cerebral small vessel disease with cognitive impairment and vascular dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372953},
doi = {10.1177/13872877251372953},
pmid = {40899970},
issn = {1875-8908},
abstract = {BackgroundThe progression of cerebral small vessel disease (CSVD) leads to cognitive decline, which can be categorized into subcortical vascular mild cognitive impairment (svMCI) and vascular dementia (VaD).ObjectiveThis research aimed to examine the structural changes in gray (GM) and white matter (WM) in the brain across the disease spectrum.MethodsA total of 30 healthy controls (HC), 26 individuals with svMCI, and 29 individuals with VaD were included in study. All participants underwent MRI scans and clinical evaluations. Voxel-based morphometry (VBM), voxel-based analysis of diffusion tensor imaging (VBA-DTI), and fixel-based analysis (FBA) were utilized to examine progressive structural changes, with correlation analyses conducted to explore their relationship with clinical measures.ResultsVBM analysis revealed progressive GM atrophy in right dorsal cingulate gyrus, and right hippocampus in svMCI and VaD compared to HC. VBA-DTI results demonstrated alterations in fractional anisotropy (FA) values in the inferior longitudinal fasciculus, along with changes in mean diffusivity (MD) values in the inferior longitudinal fasciculus. FBA results identified significant WM alterations in superior corona radiata, and posterior corona radiata. As disease progressed, those with VaD showed more severe cognitive impairments and more pronounced changes in GM and WM of various brain regions. The correlation results indicated that structural changes in GM and WM, identified through VBM, FA, and MD analyses, were significantly associated with severity of cognitive and motor deficits.ConclusionsOur study reveals notable alterations in GM and WM in brains of individuals with cognitive impairments associated with svMCI and VaD. These results provide a foundation for clinical observation of CSVD-related alterations and offer strong support for further in-depth exploration of neuropathological changes.Clinical Trial RegistrationChiCTR2400093373.},
}

@article {pmid40899953,
year = {2025},
author = {Zhu, Y and Chen, Q and Chen, F and Lu, J and Long, C and Ge, D and Xu, X and Lei, Y and Wu, X and Du, S and Bai, Y and Liu, D and Chen, Y and Fan, S and Yang, H and Zhu, Z and Zhang, X and Yang, QX and Zhang, B},
title = {Functional connectivity signatures of olfactory networks linked to cognitive risk: A functional MRI study in subjective cognitive decline at risk for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251373017},
doi = {10.1177/13872877251373017},
pmid = {40899953},
issn = {1875-8908},
abstract = {BackgroundIndividuals with subjective cognitive decline (SCD) are at high risk of preclinical Alzheimer's disease (AD). While olfactory dysfunction is evident in AD and mild cognitive impairment (MCI), its presence and neural mechanism in SCD remain unclear.ObjectiveThis study examined functional connectivity (FC) alterations across olfactory networks and their mediating role between olfactory and cognitive functions in SCD and MCI.MethodsEighty SCD, 51 MCI, and 80 normal controls underwent cognitive and olfactory tests and resting-state functional magnetic resonance imaging scanning. Two olfactory networks (primary and advanced), each with six selected spherical regions, were defined. We compared FCs within and between networks, examined correlations with olfactory and cognitive functions, performed mediation analysis, and evaluated classification via receiver operating characteristic curves.ResultsSCD participants presented increased FCs in key regions with normal olfactory scores, while MCI patients exhibited reduced FCs and olfactory scores. Altered FCs correlated with olfactory performance and mediated the relationship between olfactory and cognitive functions. FC features effectively distinguished SCD from normal controls.ConclusionsIncreased FCs in SCD indicated a significant compensatory neural mechanism for the disrupted FCs in MCI, leading to an apparent normal olfactory function in SCD participants. Moreover, the findings suggest that olfactory deficits may be associated with cognitive decline rather than solely impaired olfactory sensory processing. As such olfactory deficits could be a proxy for cognitive decline in AD and the altered FCs could aid in the early detection of individuals at high risk for preclinical AD.},
}

@article {pmid40899951,
year = {2025},
author = {Shoushtari, SI and Liaw, E and Alluri, S and Sheikh, Z and Kumar, S and Huynh, C and Schmidt, IM and Ness, S and Chen, X and Siegel, NH and Waikar, SS and Stein, TD and Lu, W and Subramanian, ML},
title = {The association between SLIT2 in human vitreous humor and plasma and neurocognitive test scores.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251374287},
doi = {10.1177/13872877251374287},
pmid = {40899951},
issn = {1875-8908},
abstract = {BackgroundSlit Guidance Ligand 2 (SLIT2) binds Roundabout (ROBO) guidance receptors to direct axon pathfinding and neuron migration during nervous system development. SLIT2 expression has previously been linked to dementia risk.ObjectiveTo study the association between SLIT2 expression in human vitreous humor and plasma samples and neurocognitive test scores in a cross-sectional cohort study utilizing a novel, highly-sensitive Meso Scale Discovery (MSD) assay for SLIT2 detection.MethodsSeventy-nine individuals with a mean age of 55.79 ± 12.03 years underwent eye surgery with collection of vitreous humor, blood (plasma) collection, and neurocognitive assessment. Vitreous humor and plasma samples were analyzed by SLIT2 MSD electrochemiluminescence immunoassay. Associations between SLIT2 levels in vitreous humor and plasma were analyzed using GraphPad Prism.ResultsWe found up to a 7-fold higher level of SLIT2 in human vitreous humor compared to plasma. Lower vitreous SLIT2 levels were associated with a lower Montreal Cognitive Assessment (MoCA) score and Immediate Recall Verbatim (IRV) z-score, and higher plasma SLIT2 was associated with a lower MoCA score. In multivariate analysis using single and multiple predictor models, the same significant associations were found when adjusted for age, sex, race, diabetic status, diabetic retinopathy status, glaucoma status, and Apolipoprotein E (APOE) genotype.ConclusionsSLIT2 protein levels are significantly associated with MoCA score and IRV z-score in middle-aged individuals. The relationship remained significant when adjusted for demographics, co-morbidity, and APOE genotype, suggesting SLIT2 may be a sensitive biomarker for detection of mild cognitive impairment and early dementia, and warrants further studies.},
}

@article {pmid40899950,
year = {2025},
author = {Jiang, X and Liu, Y and Lu, Q and Liu, J and Huang, Y and Liang, Z},
title = {Identification of exosome-related genes in Alzheimer's disease: Evidence from transcriptomic and Mendelian randomization analyses.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372065},
doi = {10.1177/13872877251372065},
pmid = {40899950},
issn = {1875-8908},
abstract = {BackgroundEmerging evidence implicates exosomes in the pathogenesis of Alzheimer's disease (AD).ObjectiveThis study aimed to investigate the role of exosome-related genes in AD pathogenesis and evaluate their potential as diagnostic biomarkers.MethodsWe analyzed AD transcriptomic datasets (GSE5281, GSE138260, GSE29378) from the Gene Expression Omnibus database. Exosome-related differentially expressed genes (DEGs) were identified by intersecting the DEGs with exosome-related genes derived from GeneCards. The most AD-relevant exosome-related DEGs were screened using the least absolute shrinkage and selection operator regression and random forest algorithms. We then performed a two-sample Mendelian randomization (MR) analysis to evaluate potential causal effects of these candidate genes on AD risk, with the inverse-variance weighted method as the primary approach. Underlying molecular mechanisms were investigated through gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). The diagnostic potential of candidate genes was assessed via external validation.ResultsFour core exosome-related DEGs (TGFBR3, CXCR4, PSMB3, CD44) were identified. MR analysis demonstrated a significant causal effect of elevated TGFBR3 expression on AD risk (OR = 1.885, 95% CI 1.091-3.255, p = 0.023). Integrated GSEA and GSVA linked high TGFBR3 expression to synaptic impairment. Notably, TGFBR3 exhibited robust diagnostic accuracy across multiple external validation cohorts.ConclusionsTGFBR3, an exosome-related gene, may contribute to AD pathogenesis via synaptic dysfunction. Our findings support its potential as a diagnostic biomarker for AD.},
}

@article {pmid40899946,
year = {2025},
author = {Streiber, AM and Neitzel, J and Yaqub, A and Vernooij, MW and Bos, D},
title = {Arteriosclerosis in the heart-brain axis and Alzheimer's disease plasma markers in the Rotterdam Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372641},
doi = {10.1177/13872877251372641},
pmid = {40899946},
issn = {1875-8908},
abstract = {BackgroundArteriosclerosis in the heart-brain axis has emerged as an important area of study in Alzheimer's disease (AD) dementia research. While previous research primarily focused on structural brain changes, the relationship between arteriosclerosis and blood-based markers for AD dementia remains understudied.ObjectiveTo comprehensively assess arteriosclerosis in the heart-brain axis and investigate its link to AD dementia plasma markers.MethodsAnalyses are based on 2238 community-dwelling elderly from the population-based Rotterdam Study (52% female, mean age 69.5 ± 6.8 years) who underwent a non-contrast CT scan to quantify arteriosclerosis in the heart-brain axis. Coronary artery calcification, aortic arch calcification, extracranial carotid artery calcification, intracranial carotid artery calcification, and vertebrobasilar artery calcification were measured as proxies for arteriosclerosis. Participants had available total tau, neurofilament light chain (NfL), and amyloid-β (Aβ40, Aβ42, and Aβ42/40 ratio) plasma measures (median time difference between CT scan and plasma measurement 3.2 months). Using linear regression, we studied the relationship of calcification presence and burden in the abovementioned arteries with plasma markers.ResultsA higher arteriosclerosis burden correlated with higher plasma marker concentrations, especially for NfL (e.g., βintracranial carotid: 0.15, [95% Confidence interval (CI): 0.04, 0.26]) and Aβ40 (e.g., βintracranial carotid: 0.18, [95% CI: 0.05, 0.30]). Additionally, vertebrobasilar artery calcification was most consistently associated with elevated levels of AD dementia plasma markers (e.g., total tau; β: 0.06. [95% CI: 0.01, 0.10]).ConclusionsOur findings emphasize the critical role of vascular health in neurodegenerative processes and underscore the importance of monitoring and managing arteriosclerosis.},
}

@article {pmid40899945,
year = {2025},
author = {Saido, TC and Iwata, N},
title = {The tale of donanemab: God is in the details.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251371240},
doi = {10.1177/13872877251371240},
pmid = {40899945},
issn = {1875-8908},
abstract = {Alzheimer's disease is a major cause of dementia, that affects approximately 7-8% of people aged 65 years and older (according to WHO & Alzheimer's Disease International) and thus is a major concern in public health world-wide. This review chronicles the foundational research and translational trajectory leading to the development of donanemab, a monoclonal antibody targeting pyroglutamyl amyloid-β (Aβ3pE-X) peptides, recently approved for the treatment of early Alzheimer's disease (AD). We trace a 30-year arc from the biochemical identification of Aβ species to the recognition of Aβ3pE-42 as a predominant pathological isoform in AD and Down syndrome brains-a fact still underrecognized among clinicians and researchers. We highlight key breakthroughs in antibody generation, Aβ peptide biochemistry, and resistance to enzymatic degradation. Mechanistic distinctions between donanemab (Kisunla[®]), and lecanemab (Leqembi[®]) are also explored, along with therapeutic implications for targeting specific Aβ species at preclinical stages of disease. The review emphasizes how persistent biochemical research, fueled by intellectual curiosity, serendipity, and rigorous experimentation, has culminated in clinical proof-of-concept for the amyloid hypothesis. In addition to its molecular specificity, donanemab's development underscores a critical shift toward precision medicine in Alzheimer's care. Its clinical validation, though limited in scope, reinforces the need for scalable and affordable interventions that can address the growing global burden of dementia. We expect these therapeutic antibodies to contribute to reducing the global burden by ceasing the disease progression in a preclinical stage now that new methods for fluid biomarkers are becoming available. As the global population ages, understanding and addressing AD has become a top priority in neuroscience and public health.},
}

@article {pmid40899930,
year = {2025},
author = {Špeh, A and Boada, M and Jessen, F and Visser, PJ and Winblad, B and Wimo, A and Sannemann, L and Stopar, N and Zwan, M and Rodriguez-Gomez, O and Johansson, G and Alegret, M and Rodríguez, I and Gurrutxaga, M and Sotolongo, O and Ruiz, A and Cantero-Fortiz, Y and Kramberger, MG},
title = {Cardiovascular health and cognition in older adults: Variations across recruitment models and European countries in the MOPEAD project.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251371729},
doi = {10.1177/13872877251371729},
pmid = {40899930},
issn = {1875-8908},
abstract = {BackgroundThe Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project aimed to identify the most effective and cost-efficient recruitment model for detecting prodromal and mild Alzheimer's disease (AD) across five European countries.ObjectiveTo examine differences in cardiovascular risk factors and cognitive performance among countries and recruitment models using MOPEAD data.MethodsIndividuals aged 65-85 with a high risk for prodromal or mild AD were included. Four recruitment models were used: a web-based screening tool, an open house initiative (OHI), a primary care-based protocol for early detection of cognitive decline, and a tertiary care-based screening at a diabetologist clinic. Participants from Germany, Spain, the Netherlands, Sweden, and Slovenia were recruited. Cardiovascular risk factors were self-reported, and cognition was assessed using The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).ResultsA total of 414 individuals (mean age 71.9, SD = 5.0) were included. Significant differences were observed in physical activity (p < 0.001), with individuals from Sweden and Slovenia being the most active. Dutch participants scored highest on most cognitive measures. Individuals recruited via web-based survey were youngest, most active (61.7%), and had the lowest rates of diabetes (12.0%) and heart disease (6.4%), as well as the best cognitive scores. Those recruited via diabetologist clinics displayed the highest cardiovascular risk and the lowest cognitive performance.ConclusionsThis study unveils significant disparities in cardiovascular health and cognition across recruitment strategies and European countries. The OHI shows promise for future recruitment in the context of disease-modifying AD treatments.},
}

@article {pmid40899929,
year = {2025},
author = {Walters, ME and Small, BJ and Andel, R and Lerch, O and Horakova, H and Molinari, VA and Salemi, JL and Vyhnalek, M and Nedelska, Z and Hort, J and , },
title = {Differential MRI atrophy profiles and incident dementia: A cross-national comparison.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251371734},
doi = {10.1177/13872877251371734},
pmid = {40899929},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder with extensive neuropathological and clinical heterogeneity.ObjectiveWe assessed empirically derived brain atrophy profiles in relation to incident AD dementia.MethodsA secondary data analysis of two prospective cohort studies was conducted, including participants without dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1703) and the Czech Brain Aging Study (CBAS; n = 385). Latent profile analysis identified profiles across 10 pre-selected, AD-related brain regions derived from structural magnetic resonance imaging (hippocampus, middle temporal, superior temporal, precuneus, anterior cingulate, medial orbitofrontal, pericalcarine, precentral, lingual, caudate regions). Cox proportional hazards regression assessed how profiles related to incident AD dementia.ResultsFour profiles emerged in ADNI: Minimal (n = 192), Mild (n = 691), Moderate (n = 567), and Severe (n = 253) Atrophy. Two profiles emerged in CBAS: Mild (n = 208) and Severe (n = 177) Atrophy. In ADNI, participants with Mild (HR = 3.11, 95% CI [1.43, 6.78]), Moderate (HR = 7.58, 95% CI [3.45, 16.68]), and Severe (HR = 16.95, 95% CI [7.39, 39.86]) Atrophy (versus Minimal) had increased incident AD dementia risk. In CBAS, participants with Severe Atrophy (versus Mild) had increased incident AD dementia risk (HR = 3.51, 95% CI [2.14, 5.77]). Controlling for baseline cognition attenuated effects for Mild (ADNI) and Severe (CBAS) Atrophy to non-significance.ConclusionsIn two geographically and culturally distinct samples, magnitude of atrophy, not pattern across regions, determined classification into profiles, which predicted incident AD dementia. Findings highlight generalized, rather than region-specific, atrophy patterns associated with AD, and underscore the clinical utility of brain volumetry in identifying those with elevated incident AD dementia risk.},
}

@article {pmid40899927,
year = {2025},
author = {Mulligan, M and Beiser, AS and O'Donnell, A and Banerjee, A and Ghosh, S and Thibault, E and El Fakhri, G and Johnson, KA and Seshadri, S and McGrath, ER},
title = {A steep decline in diastolic blood pressure over early to mid-life is associated with tau-PET burden in dementia-free adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372561},
doi = {10.1177/13872877251372561},
pmid = {40899927},
issn = {1875-8908},
abstract = {BackgroundThe relationship between blood pressure (BP) trajectories across early (∼40 years) into mid-life (∼55 years) and preclinical dementia has not previously been well studied using positron emission tomography (PET) imaging outcomes.ObjectiveTo examine the association between BP trajectories across early mid-life into mid mid-life and amyloid- and tau-PET burden in adults without clinical dementia.MethodsThis prospective cohort study included dementia-free Framingham Heart Study 3[rd] generation participants with data on remote BP (2002-2005) and recent BP (2016-2019) who participated in [11]C-Pittsburgh Compound-B (PiB)-PET and/or [18]F-Flortaucipir (FTP)-PET scans between 2016 to 2022. Outcomes included global amyloid deposition (in the frontal, lateral temporal, parietal and retrosplenial cortices, FLR region) and entorhinal tau deposition.ResultsIn 410 participants (mean age 40 ± 8 years at remote exam, 56 ± 8 years recent exam), the mean time between the remote exam BP measurement and PET was 16 ± 2 years. A steep change (slope of ≥0.5 or ≤-0.5 mmHg/year) in DBP over early to mid-life was associated with increased entorhinal tau-PET deposition (β = 0.02; 95% CI = 0.01, 0.04; p = 0.047), driven by a steep decline in DBP (β = 0.04; 95% CI = 0.01, 0.07; p = 0.01). Persistent hypertension, new-onset hypertension, resolved hypertension or a steep change in SBP were not associated with amyloid or tau burden.ConclusionsIn adults without clinical dementia, a steep DBP decline from early mid-life into mid-life was associated with tau deposition in the entorhinal cortex, one of the earliest affected regions in Alzheimer's disease. Maintaining normotension across the ∼15-16 years mid-life period may reduce the future risk of tau-PET burden in the brain.},
}

@article {pmid40899597,
year = {2025},
author = {Kolli, D and Rout, SK and Riek, R and Chapman, MR},
title = {The Evolution of Functional Amyloids and Their Impact on Host-Microbe Interactions.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10109},
doi = {10.1002/advs.202510109},
pmid = {40899597},
issn = {2198-3844},
support = {R01 GM118651/NH/NIH HHS/United States ; NIH T32 AI007528/NH/NIH HHS/United States ; /SNSF_/Swiss National Science Foundation/Switzerland ; //ETH Zurich/ ; },
abstract = {Amyloids are highly ordered β-sheet-rich structures that are well conserved across the domains of life. Amyloids have a unique repetitive structure that enables autocatalytic self-replication. This property is most well-known in the context of neurodegeneration, in which proteins misfold into amyloid and begin an amyloid cascade resulting in the deposition of large amyloid aggregates characteristic of various diseases such as Alzheimer's disease and Parkinson's disease. The amyloid fold, however, can be pathological or functional. The repetitive nature of amyloids positions self-replicating amyloids as a potential key player in the origin of life. This may explain why, despite the pathogenic potential of amyloids, the amyloid fold is readily found. Many amyloids are not pathogenic and instead they contribute positively to the overall fitness of the cell. Bacteria, for example, use functional amyloids to facilitate biofilm formation, dissemination, storage, adhesion to cells or surfaces, and virulence. Interestingly, the high conservation of the amyloid fold and its ability to self-replicate enables bacterial functional amyloids to accelerate amyloid-associated disease in a human host. Here, the structure, conservation, and biology of the bacterial functional amyloids, as well as their impact on human health, are discussed.},
}

@article {pmid40899490,
year = {2025},
author = {Araújo, PL and Araújo, EDS and Barreto, EMA and Alves, JLB and Souza, KM and Freire, MOL and Souza, RMP and Pereira, FO},
title = {Pleurotus Mushrooms in Nutrition and Health: Clinical and Preclinical Insights for Nutraceutical Development.},
journal = {Comprehensive reviews in food science and food safety},
volume = {24},
number = {5},
pages = {e70279},
doi = {10.1111/1541-4337.70279},
pmid = {40899490},
issn = {1541-4337},
mesh = {*Pleurotus/chemistry ; Humans ; *Dietary Supplements/analysis ; Animals ; Nutritive Value ; },
abstract = {Pleurotus mushrooms are fungi widely consumed due to their high nutritional value and potential applications as nutraceuticals. Their sustainable cultivation and rich composition of bioactive compounds provide significant health benefits. This review examines the scientific evidence regarding the safety, efficacy, and nutraceutical potential of Pleurotus species, focusing on their effects on various human diseases. The review incorporates findings from preclinical, clinical studies, and nutraceutical formulations related to innovative Pleurotus-based products. Preclinical studies have shown that Pleurotus species can reduce inflammatory markers, modulate gut microbiota, and improve lipid and glucose metabolism. As a result, these mushrooms exhibit potential hypoglycemic, anti-obesity, hepatoprotective, neuroprotective, anti-atherogenic, and anticancer properties, along with possible benefits for preventing Alzheimer's disease. Clinical trials suggest that consuming Pleurotus has a positive effect on metabolic parameters in healthy individuals and patients with chronic conditions. However, the variability among studies and the absence of standardized nutraceutical formulations hinder definitive conclusions about their therapeutic efficacy. Despite the promising potential of Pleurotus mushrooms in the nutraceutical sector, future research should focus on developing standardized formulations, optimizing bioavailability, expanding clinical trials, exploring the diversity of native species, and uncovering the underlying mechanisms of action to establish their practical application as nutraceuticals.},
}

*Pleurotus/chemistry
Humans
*Dietary Supplements/analysis
Animals
Nutritive Value

@article {pmid40899340,
year = {2025},
author = {Zamanian, MY and Khachatryan, LG and Heidari, M and Darabi, R and Golmohammadi, M and Al-Aouadi, RFA and Akkol, EK},
title = {The Therapeutic Potential of Flavonols in Alzheimer's Disease: Inhibiting Amyloid-β, Oxidative Stress, and Neuroinflammation.},
journal = {BioFactors (Oxford, England)},
volume = {51},
number = {5},
pages = {e70047},
doi = {10.1002/biof.70047},
pmid = {40899340},
issn = {1872-8081},
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics ; *Flavonols/pharmacology/therapeutic use ; Animals ; Kaempferols/pharmacology ; Flavonoids/pharmacology ; *Neuroprotective Agents/pharmacology ; Quercetin/pharmacology ; Mice ; Humans ; Male ; Mitochondria/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Signal Transduction/drug effects ; Amyloid Precursor Protein Secretases/genetics/metabolism ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, oxidative stress, and neuroinflammation, remains a significant global health challenge. This study investigates the therapeutic potential of flavonols-quercetin, kaempferol, myricetin, and fisetin-in targeting Aβ aggregation and mitigating AD pathology through diverse molecular mechanisms. Our findings reveal that flavonols effectively inhibit Aβ oligomerization and fibril formation, reduce oxidative stress via Nrf2/HO-1 pathway activation, and suppress neuroinflammation by modulating microglial polarization. Additionally, these compounds enhance mitochondrial function, promote autophagy-mediated clearance of Aβ aggregates, and regulate key enzymes such as β-secretase (BACE1) and α-secretases (ADAM10/17), favoring non-amyloidogenic pathways. Quercetin demonstrated neuroprotective effects by activating TrkB signaling, reducing tau phosphorylation, and enhancing synaptic plasticity. Kaempferol prevented Aβ-induced apoptosis via the ER/ERK/MAPK pathway and inhibited acetylcholinesterase activity, improving cognitive outcomes. Myricetin ameliorated mitochondrial dysfunction and oxidative damage through GSK3β/ERK2 signaling modulation and showed enhanced brain bioavailability when delivered via nanostructured lipid carriers. Fisetin reduced Aβ burden by upregulating neprilysin expression, suppressed neuroinflammation, and improved synaptic function by restoring synaptic protein levels. Overall, flavonols exhibit multi-targeted therapeutic potential against AD by addressing its complex pathogenesis. Their ability to cross the blood-brain barrier and low toxicity profiles position them as promising candidates for further clinical development. This study underscores the potential of flavonols as natural agents for AD treatment and highlights their role in advancing multi-mechanistic therapeutic strategies.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology/genetics
Oxidative Stress/drug effects
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics
*Flavonols/pharmacology/therapeutic use
Animals
Kaempferols/pharmacology
Flavonoids/pharmacology
*Neuroprotective Agents/pharmacology
Quercetin/pharmacology
Mice
Humans
Male
Mitochondria/drug effects
*Neuroinflammatory Diseases/drug therapy
Signal Transduction/drug effects
Amyloid Precursor Protein Secretases/genetics/metabolism

@article {pmid40899305,
year = {2025},
author = {Townsend, DL and Properzi, MJ and Betthauser, TJ and Klinger, HM and Boyle, R and Coughlan, G and Hanseeuw, BJ and Yang, HS and Cody, KA and Amariglio, RE and Farrell, M and Jacobs, HIL and Shirzadi, Z and Yau, WY and Price, JC and Chhatwal, J and Rentz, DM and Johnson, KA and Sperling, RA and Schultz, AP and Buckley, RF},
title = {Estimating the preclinical Alzheimer's disease course with multimodal data.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70658},
doi = {10.1002/alz.70658},
pmid = {40899305},
issn = {1552-5279},
support = {AARG-22-920434/ALZ/Alzheimer's Association/United States ; R01 AG080766/AG/NIA NIH HHS/United States ; P01 AG036694/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; Positron-Emission Tomography ; Male ; Female ; Aged ; Amyloid beta-Peptides/metabolism ; *Disease Progression ; Longitudinal Studies ; *Brain/pathology/diagnostic imaging ; tau Proteins/metabolism ; Prodromal Symptoms ; Aged, 80 and over ; Middle Aged ; },
abstract = {INTRODUCTION: In observational studies of preclinical AD, an arbitrary "baseline" can obscure where an individual is located along a theoretical continuum. Optimizing longitudinal trajectories can distill multiple, non-linearly distributed observations into a single metric and inform where an individual may be along the disease course.

METHODS: We developed a cognitive time (c-time) metric based on longitudinal cognitive data (mean = 7.4 years, range = 1.7-11.6) from 316 participants from the Harvard Aging Brain Study using non-linear least-squares optimization. We examined path analyses between a published time-to-amyloid beta (Aβ)+ metric (longitudinal Aβ positron emission tomography [PET]: mean = 6.3 years, range = 4.2-9.7) and c-time, including demographics, brain volume, cortical thickness, tau PET, and cardiovascular risk.

RESULTS: Time-to-Aβ+ and c-time were positively correlated, with time-to-Aβ+ possessing direct and indirect associations with c-time through regional tau PET, hippocampal volume, and cortical thickness.

DISCUSSION: Optimizing longitudinal multimodal data to estimate a theoretical continuum can provide unique and age-independent information about the distance an individual might be from disease-related events.

HIGHLIGHTS: Cognitive time (c-time) represents an individual's distance from a hinge point of cognitive decline. C-time and time-to-amyloid beta (Aβ)+ were moderately positively correlated. Inferior temporal tau and cortical thickness mediated the effect between c-time and time-to-Aβ+. C-time more closely associates with tau, brain atrophy, and cortical thickness.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
Positron-Emission Tomography
Male
Female
Aged
Amyloid beta-Peptides/metabolism
*Disease Progression
Longitudinal Studies
*Brain/pathology/diagnostic imaging
tau Proteins/metabolism
Prodromal Symptoms
Aged, 80 and over
Middle Aged

@article {pmid40898925,
year = {2025},
author = {Park, HA and Amjad, E and Burnett, G and Ferdous, KA and Scott, M and Jansen, J and Bannerman, S and Scott, M and Correll, RN and Ciesla, L and Ellis, A},
title = {Oral Supplementation of Fucoxanthin Regulates Gene Expression in the Brain of Middle-aged Rats.},
journal = {The British journal of nutrition},
volume = {},
number = {},
pages = {1-31},
doi = {10.1017/S0007114525104996},
pmid = {40898925},
issn = {1475-2662},
abstract = {Age is the main risk factor for many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. Despite our limited understanding of cellular mechanisms of aging-associated neuronal loss, an increasing number of studies demonstrate that oxidative stress and inflammation are key drivers. Epidemiological studies indicate that diet during middle adulthood can influence the risk of developing neurodegenerative diseases later in life, so it is important to investigate dietary interventions to combat oxidative stress and inflammation. In this study, we hypothesized that treatment with fucoxanthin, a marine carotenoid with strong antioxidant properties, prevents aging-associated oxidative stress that is known to be related to natural brain aging. Treatment with fucoxanthin protected rat primary hippocampal neurons against oxidative stress and aging in vitro. In our in vivo study, middle-aged male Sprague-Dawley rats were gavaged with fucoxanthin (1 mg/kg, 5 days/week, n=6) or vehicle (n=6) for 4 weeks. After supplementation was completed, brain samples were harvested and subjected to quantitative and bioinformatic analyses. Fucoxanthin was detected and shown to decrease lipid peroxidation in the brains of the animals supplemented with fucoxanthin. Microarray analysis showed that treatment with fucoxanthin changed 5602 genes. Together, our results suggest that treatment with fucoxanthin prevents aging-associated oxidative stress and is capable of regulating genes that potentially ameliorate age-related changes to the brain.},
}

@article {pmid40898829,
year = {2025},
author = {Radmard, M and Gad, M and Sheikhy, A and Dagher, R and Yedavalli, V and Luna, LP},
title = {Functional Imaging in Alzheimer's Disease: A Systematic Review and Meta-Analysis of ASL-MRI and FDG-PET.},
journal = {Journal of neuroimaging : official journal of the American Society of Neuroimaging},
volume = {35},
number = {5},
pages = {e70080},
doi = {10.1111/jon.70080},
pmid = {40898829},
issn = {1552-6569},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Positron-Emission Tomography/methods ; *Fluorodeoxyglucose F18 ; *Magnetic Resonance Imaging/methods ; Radiopharmaceuticals ; *Cognitive Dysfunction/diagnostic imaging ; Brain/diagnostic imaging ; Sensitivity and Specificity ; Reproducibility of Results ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are two common conditions associated with cognitive decline. With global dementia cases rising, identifying the most accurate imaging method for diagnosis is essential.

METHODS: Following Preferred Reporting Items for Systematic review and Meta-Analysis Protocols, we systematically reviewed studies utilizing arterial spin labeling magnetic resonance imaging (ASL-MRI) and [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for neurodegenerative disorders. Searches in PubMed/MEDLINE, Scopus, and Embase led to 17 studies directly comparing these modalities for MCI/AD diagnosis. Seven studies met criteria for meta-analysis based on interreader agreement and area under the curve (AUC) data. Meta-analysis was performed using the R "Mada" package, with study heterogeneity assessed via the Zhou and Dendukuri approach.

RESULTS: Meta-analysis of seven studies showed FDG-PET had a slightly higher AUC (0.864, sensitivity 0.81, specificity 0.80) compared to ASL-MRI (AUC 0.836, sensitivity 0.73, specificity 0.80), but no statistically significant difference. Low heterogeneity was observed (I[2]: 9.4% for FDG-PET, 6.5% for ASL-MRI). In MCI subgroup analysis, FDG-PET outperformed ASL-MRI with significantly higher sensitivity (0.90 vs. 0.75), specificity (0.91 vs. 0.73), and AUC (0.92 vs. 0.80, p < 0.001).

CONCLUSION: FDG-PET and ASL-MRI demonstrate comparable diagnostic accuracy for AD and MCI. Selection between modalities may depend on availability, cost, and safety considerations.

Both FDG-PET and MRI-ASL are effective at identifying MCI and AD, enabling accurate diagnosis. The choice of which modality to use may be addressed by cost, availability, and consideration of other potential diagnoses.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Positron-Emission Tomography/methods
*Fluorodeoxyglucose F18
*Magnetic Resonance Imaging/methods
Radiopharmaceuticals
*Cognitive Dysfunction/diagnostic imaging
Brain/diagnostic imaging
Sensitivity and Specificity
Reproducibility of Results

@article {pmid40898750,
year = {2025},
author = {Flanagan, B and Lynch, J and Kakar, S and McGuinness, B and Patterson, K and Passmore, AP and Cunningham, EL},
title = {Most Patients Attending a Geriatrician-Led Memory Clinic are Not Eligible for Alzheimer's Disease-Modifying Drugs.},
journal = {International journal of geriatric psychiatry},
volume = {40},
number = {9},
pages = {e70149},
doi = {10.1002/gps.70149},
pmid = {40898750},
issn = {1099-1166},
}

@article {pmid40898616,
year = {2025},
author = {Hogestyn, JM and Wischhof, E and Chen, Y and Chan, T and Richards, B and Mahendran, T and Adams, J and Dubreuil, D and Bu, J and Jackson, R and Goulet, M and Mueller, C and Ramachandran, S and Elmer, B},
title = {AAV delivery of artificial miRNA targeting MAPT for the reduction of tau pathology in Alzheimer's disease.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2025.08.052},
pmid = {40898616},
issn = {1525-0024},
abstract = {Tau reduction is a promising therapeutic approach with the potential to slow the progression of Alzheimer's disease. Here, we propose adeno-associated viral (AAV) delivery of an artificial miRNA (amiRNA) targeting the microtubule-associated protein tau (MAPT) mRNA for sustained tau reduction with a single therapeutic injection. Out of 22 initial designs, we identified potent, accurately processed, and highly specific amiRNA candidates. Our lead, amiR[Tau01], significantly reduced pathological forms of phosphorylated tau in the brain and spinal cord of the Tau22 tauopathy mouse model. In a nonhuman primate study using the novel capsid AAV.GMU01, we demonstrated clear amiR[Tau01]-mediated MAPT knockdown in individual neurons, however, vector biodistribution in the NHP brain was insufficient to drive MAPT reduction in bulk tissue. Our findings support amiR[Tau01] as a potent therapeutic amiRNA, warranting development of new capsids with improved brain biodistribution to facilitate clinical development for Alzheimer's disease.},
}

@article {pmid40898457,
year = {2025},
author = {Peng, S and Ouyang, J and Liu, Y and Wang, L and Liu, R},
title = {Causal effect of infectious mononucleosis on neurodegenerative diseases: A Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {35},
pages = {e44145},
doi = {10.1097/MD.0000000000044145},
pmid = {40898457},
issn = {1536-5964},
support = {2019YFE0117100//the National key research and development program of China/ ; 82104603//the National Natural Science Foundation of China/ ; 82074174//the National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Infectious Mononucleosis/complications/genetics/epidemiology/virology ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/virology/etiology/epidemiology ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics ; Parkinson Disease/genetics ; Multiple Sclerosis/genetics ; },
abstract = {Neurodegenerative diseases (NDs) are common chronic diseases with unknown etiology, and the association between virus and its pathogenesis is not clear. The aim of this study is to explore the role of virus in the pathogenesis of NDs by analyzing the causal effect between infectious mononucleosis (IM) mainly caused by Epstein-Barr virus and NDs. Based on the summary statistics of a large-scale genome-wide association study, we analyzed the causal effects of IM and NDs by Mendelian randomization (MR) using genetic variants as instrumental variables, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. The reliability and stability of the MR analysis results were assessed by the MR-Egger intercept test, MR-PRESSO test, and heterogeneity test. Twenty-two single nucleotide polymorphisms that were significantly and strongly associated with IM were used as instrumental variables in the MR analysis. Inverse variance weighted as the main method of MR analysis shows that there were significant causal effects between IM and Alzheimer disease (OR: 1.037, 95% CI: 1.006-1.070) and Parkinson disease (OR: 0.964, 95% CI: 0.930-1.000), while IM was not significantly associated with amyotrophic lateral sclerosis (P = .269) and multiple sclerosis (P = .182). Sensitivity analyses showed that the results were robust. This study suggests that EB virus may contribute to the pathogenesis of NDs, and more research is needed to explore the specific mechanism of virus action on NDs.},
}

Humans
*Infectious Mononucleosis/complications/genetics/epidemiology/virology
Mendelian Randomization Analysis
*Neurodegenerative Diseases/genetics/virology/etiology/epidemiology
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Alzheimer Disease/genetics
Parkinson Disease/genetics
Multiple Sclerosis/genetics

@article {pmid40898417,
year = {2025},
author = {Pishva, E and Bertram, L and Lunnon, K},
title = {Delineating blood DNA methylation biomarkers for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70646},
doi = {10.1002/alz.70646},
pmid = {40898417},
issn = {1552-5279},
mesh = {*Alzheimer Disease/blood/genetics/cerebrospinal fluid/diagnosis ; Humans ; *DNA Methylation ; Biomarkers/blood/cerebrospinal fluid ; *Chitinase-3-Like Protein 1/genetics/blood ; Epigenesis, Genetic ; Neurofilament Proteins/cerebrospinal fluid ; },
abstract = {Epigenetic mechanisms act as mediators of genetic and environmental influences. In Alzheimer's disease, blood-based DNA methylation signatures are increasingly being explored as minimally invasive peripheral biomarkers. We previously reported associations between blood DNA methylation in the CHI3L1 gene (encoding YKL-40) and cerebrospinal fluid (CSF) levels of YKL-40, a marker of neuroinflammation. These findings have now been replicated in an independent study (Kaleck et al. 2025), reinforcing their robustness and biological relevance. We also reported associations between DNA methylation and CSF neurofilament light chain levels, a marker of axonal damage, which were not independently replicated in the analyses by Kaleck et al. Several factors may have contributed to this inconsistency in results, which we discuss in detail as they are relevant to future DNA methylation-based studies in the field. Together, these findings highlight both the potential and the complexity of identifying consistent blood-based epigenomic signatures for neurodegenerative processes. They also underscore the importance of harmonizing methodologies across studies to improve reproducibility and, eventually, to yield meaningful biomarkers allowing an early detection of this devastating disease.},
}

*Alzheimer Disease/blood/genetics/cerebrospinal fluid/diagnosis
Humans
*DNA Methylation
Biomarkers/blood/cerebrospinal fluid
*Chitinase-3-Like Protein 1/genetics/blood
Epigenesis, Genetic
Neurofilament Proteins/cerebrospinal fluid

@article {pmid40898416,
year = {2025},
author = {Kaleck, T and Campos-Martin, R and Cano, A and Fernández, MV and Martino-Adami, P and Kleineidam, L and Fuentes, VMA and Tripathi, KP and Parveen, K and Puerta, R and de Rojas, I and Ravichandran, KA and Peters, O and Hellmann-Regen, J and Priller, J and Gemenetzi, M and Schneider, A and Wiltfang, J and Düzel, E and Buerger, K and Perneczky, R and Teipel, S and Laske, C and Brosseron, F and Marquié, M and van den Hove, D and Boada, M and Heneka, MT and Wagner, M and Marchant, N and Lambert, JC and Frikke-Schmidt, R and Jessen, F and Ruiz, A and Ramirez, A},
title = {Replication of blood DNA methylomic signatures associated with cerebrospinal fluid levels of YKL-40 and NfL biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70647},
doi = {10.1002/alz.70647},
pmid = {40898416},
issn = {1552-5279},
support = {01ED2007A//German Federal Ministry of Education and Research (BMBF)/ ; 01ED1614B//German Federal Ministry of Education and Research (BMBF)/ ; 01EK2102A//German Federal Ministry of Education and Research (BMBF)/ ; MR/T046171/1/MRC_/Medical Research Council/United Kingdom ; PR067/21//Agency for Innovation and Entrepreneurship/ ; PID2021-122473OA-I00//Spanish Ministry of Science and Innovation, Proyectos de Generación de Conocimiento/ ; PID2021-123462OB-I00//Spanish Ministry of Science and Innovation, Proyectos de Generación de Conocimiento/ ; PID2019-106625RB-I00//Spanish Ministry of Science and Innovation, Proyectos de Generación de Conocimiento/ ; //University of Texas System/ ; //National Institute of Aging/ ; P30AG066546/NH/NIH HHS/United States ; N°AC19/00097//Instituto de Salud Carlos III/ ; 115975//Innovative Medicines Initiative/ ; PR067/21//Flander Innovation and Entrepreneurship (VLAIO)/ ; RA1971/7-1//Deutsche Forschungsgemeinschaft/ ; },
}

@article {pmid40898408,
year = {2025},
author = {Zhang, P and Mao, C and Sun, A and Yang, Y and Hou, Y and Fu, Z and Babak, T and Leverenz, JB and Pieper, AA and Luo, Y and Cummings, J and Cheng, F},
title = {Real-world observations of GLP-1 receptor agonists and SGLT-2 inhibitors as potential treatments for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70639},
doi = {10.1002/alz.70639},
pmid = {40898408},
issn = {1552-5279},
support = {R01AG092591/AG/NIA NIH HHS/United States ; R01AG066707/AG/NIA NIH HHS/United States ; U01AG073323/AG/NIA NIH HHS/United States ; R01AG084250/AG/NIA NIH HHS/United States ; R01AG076448/AG/NIA NIH HHS/United States ; R01AG082118/AG/NIA NIH HHS/United States ; RF1AG082211/AG/NIA NIH HHS/United States ; R56AG074001/AG/NIA NIH HHS/United States ; R21AG083003/AG/NIA NIH HHS/United States ; R01AG053798/AG/NIA NIH HHS/United States ; R35AG071476/AG/NIA NIH HHS/United States ; RF1NS133812/NS/NINDS NIH HHS/United States ; U01NS093334/NS/NINDS NIH HHS/United States ; P30AG072959//Cleveland Alzheimer's Disease Research Center/ ; //Case Western Reserve University/ ; //University Hospitals Morley-Mather Chair in Neuropsychiatry/ ; //Valour Foundation/ ; //AHA/Allen Initiative in Brain Health and Cognitive Impairment/ ; //Louis Stokes/ ; //Keep Memory Alive (KMA)/ ; P20GM109025/GM/NIGMS NIH HHS/United States ; //Alzheimer's Disease Drug Discovery Foundation (ADDF)/ ; ALZDISCOVERY-1051936/ALZ/Alzheimer's Association/United States ; R01LM013771/LM/NLM NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Male ; Aged ; Female ; Pharmacoepidemiology ; *Hypoglycemic Agents/therapeutic use ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors have potential beneficial effects in Alzheimer's disease (AD).

METHODS: We conducted pharmacoepidemiologic studies using two large-scale real-world databases. We fitted covariate-adjusted Cox models to compare the risks of AD among initiators of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors.

RESULTS: We identified GLP-1 receptor agonist initiation compared to DPP-4 inhibitors initiation was associated with a reduced risk of AD (hazard ratio [HR] ≤ 0.69 and P value < 0.001) and SGLT-2 inhibitor initiation compared to DPP-4 inhibitor initiation was associated with a reduced risk of AD (HR ≤ 0.67 and P value < 0.001).

DISCUSSION: GLP-1 receptor agonist initiation and SGLT-2 inhibitor initiation are associated with a reduced risk of AD. Randomized clinical trials are warranted to validate the causal beneficial effects of GLP-1 receptor agonists and SGLT-2 inhibitors in AD.

HIGHLIGHTS: Glucagon-like peptide-1 (GLP-1) receptor agonists are significantly associated with a reduced risk of Alzheimer's disease (AD) compared to dipeptidyl peptidase-4 (DPP-4) inhibitors. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are significantly associated with a reduced risk of AD compared to dipeptidyl peptidase-4 (DPP-4) inhibitors. Two GLP-1 receptor agonists (liraglutide and semaglutide) and three SGLT-2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) are associated with a reduced risk of AD in drug-specific sensitivity analyses.},
}

Humans
*Alzheimer Disease/drug therapy/epidemiology
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
*Glucagon-Like Peptide-1 Receptor Agonists
*Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
Male
Aged
Female
Pharmacoepidemiology
*Hypoglycemic Agents/therapeutic use
Aged, 80 and over

@article {pmid40898377,
year = {2025},
author = {Borkowski, K and Liang, N and Zhao, N and Arnold, M and Huynh, K and Karu, N and Mahmoudiandehkordi, S and Kueider-Paisley, A and Kanekiyo, T and Bu, G and Kaddurah-Daouk, R and , },
title = {APOE genotype influences on the brain metabolome of aging mice - role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {97},
pmid = {40898377},
issn = {1750-1326},
support = {R01AG069901/AG/NIA NIH HHS/United States ; RF1AG051504/AG/NIA NIH HHS/United States ; R01AG081322/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00888-z.},
}

@article {pmid40898372,
year = {2025},
author = {Augur, ZM and Fogo, GM and Arbery, MR and Stern, AM and Benoit, CR and Hsieh, YC and Young-Pearse, TL},
title = {Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {188},
pmid = {40898372},
issn = {2051-5960},
support = {F31AG082393-03//NIA Ruth L. Kirschstein Predoctoral Individual National Research Service Award/ ; K00AG079793//NIA Pathway to Independence Award/ ; R01AG055909//NIH Grant/ ; },
mesh = {Humans ; *Neurons/metabolism/pathology ; *Membrane Transport Proteins/deficiency ; *Cell Cycle Proteins/deficiency ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics ; *Clusterin/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Proteostasis/physiology ; Phosphorylation ; *Transcription Factor TFIIIA/deficiency/genetics ; Female ; Autophagy ; Male ; Brain/metabolism/pathology ; Astrocytes/metabolism ; Aged ; },
abstract = {Optineurin (OPTN) is an autophagy adaptor protein involved in selective autophagy, including aggrephagy and mitophagy. Pathogenic mutations in OPTN have also been linked to amyotrophic lateral sclerosis, frontotemporal dementia, and glaucoma, supporting its role in the etiology of neurodegenerative diseases. Despite its established biological roles, knowledge about its potential contribution to Alzheimer's disease (AD) pathology and neuronal functioning is lacking. AD is characterized by the accumulation of extracellular amyloid-β plaques and intracellular phosphorylated tau (pTau) tangles, with dysfunction in the autophagy-lysosomal pathway exacerbating tau pathology and impairing proteostasis. To investigate the role of OPTN in neuronal proteostasis and AD, we utilized induced pluripotent stem cell-derived neuron (iN) and astrocyte (iA) models. Analyses revealed a significant negative correlation between OPTN and specific pTau epitopes in neurons, as well as a decrease in OPTN protein abundance in brain tissues of individuals with AD. Given these findings, we generated OPTN knockout (KO), heterozygous, and wildtype iNs and iAs using CRISPR/Cas9 editing of iPSCs in two genetic backgrounds. Loss of OPTN in iNs increased specific pTau proteoforms without substantially affecting autophagy processes or mitochondrial respiration. Despite no clear effect on mitochondrial function, several mitochondrial proteins, including OXCT1, were enriched in an unbiased analysis of the OPTN interactome in iNs, as well as proteins involved in intracellular trafficking. Proteomic analyses further identified intracellular clusterin, an AD risk gene, as significantly upregulated in OPTN KO iNs, suggesting OPTN may influence its intracellular processing. Our model system demonstrates modest roles for OPTN in certain neuronal biological processes and potential implications for AD pathogenesis. These findings also suggest that OPTN may exhibit functional redundancy with other autophagy adaptor proteins in human neurons, leading to relatively mild phenotypic changes with complete loss of OPTN.},
}

Humans
*Neurons/metabolism/pathology
*Membrane Transport Proteins/deficiency
*Cell Cycle Proteins/deficiency
*tau Proteins/metabolism
*Alzheimer Disease/metabolism/pathology/genetics
*Clusterin/metabolism
Induced Pluripotent Stem Cells/metabolism
*Proteostasis/physiology
Phosphorylation
*Transcription Factor TFIIIA/deficiency/genetics
Female
Autophagy
Male
Brain/metabolism/pathology
Astrocytes/metabolism
Aged

@article {pmid40898366,
year = {2025},
author = {Loffredo, G and D'Amelio, M},
title = {Disarming COX-1 to disrupt Alzheimer's inflammatory trajectory: preclinical insights and translational promise.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {46},
pmid = {40898366},
issn = {2047-9158},
support = {AARG-21-851219/ALZ/Alzheimer's Association/United States ; RF-2018-12365527//Ministero della Salute/ ; },
}

@article {pmid40898264,
year = {2025},
author = {Drinkall, NJ and Siersma, V and Lathe, R and Waldemar, G and Janbek, J},
title = {Herpesviruses, antiviral treatment, and the risk of dementia - systematic review and meta-analysis.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {201},
pmid = {40898264},
issn = {1758-9193},
mesh = {Humans ; *Antiviral Agents/therapeutic use ; *Dementia/epidemiology/virology ; *Herpesviridae Infections/drug therapy/complications/epidemiology ; *Herpesviridae ; Risk Factors ; },
abstract = {INTRODUCTION: The aim of this systematic review and meta-analysis was to synthesize the evidence on the association between herpesviruses, antiviral treatment, and the risk of dementia. We also aimed to explore the impact of time between herpesviruses and dementia on the reported associations.

METHODS: PubMed and Web of Science were searched along with reference lists of the included studies. We included studies that looked at clinical episodes or serology (IgG/IgM) of herpes simplex virus type 1/2 (HSV1/2) and/or varicella zoster virus (VZV), antiviral treatment and incident dementia (all-cause dementia, Alzheimer's disease, and vascular dementia). Study results were pooled with random effect meta-analyses.

RESULTS: We included 32 studies. The pooled hazard ratio for all-cause dementia was 1.36 [95% CI: 1.01, 1.83] following a clinical episode of HSV1/2, and 1.12 [95% CI: 1.00, 1.25] following a clinical episode of VZV. The pooled estimate for all-cause dementia following antiviral treatment and VZV was 0.88 [95% CI: 0.81, 0.96].

CONCLUSIONS: The present review of the scientific literature generally shows little evidence of an association between herpesviruses and risk of dementia. However, the review shows evidence of an association between antiviral treatment and a decreased risk of dementia. Because of considerable heterogeneity, future investigations could advantageously target certain subgroups.},
}

Humans
*Antiviral Agents/therapeutic use
*Dementia/epidemiology/virology
*Herpesviridae Infections/drug therapy/complications/epidemiology
*Herpesviridae
Risk Factors

@article {pmid40898257,
year = {2025},
author = {Yeh, TS and Huang, YC and Ho, SC and Siow, CY and Lee, HC and Recio-Rodriguez, JI and Sung, JY and Tani, J},
title = {Combined effect of cognitive dysfunction and sleep disturbance on mortality risk: NHANES 2011-2014.},
journal = {Annals of general psychiatry},
volume = {24},
number = {1},
pages = {52},
pmid = {40898257},
issn = {1744-859X},
abstract = {BACKGROUND: Both cognitive dysfunction and sleep disturbances are individually linked to heightened risks of chronic illnesses and mortality. However, their combined impact on all-cause and cardiovascular mortality remains underexplored.

METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014, focusing on participants aged ≥ 60 years who completed cognitive tests and sleep-related questionnaires. Cognitive function was evaluated using three standardized tests: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), the Animal Fluency Test, and the Digit Symbol Substitution Test. Participants with global cognitive z-scores below - 1 were classified as having low cognitive function. Sleep disturbance was identified based on self-reported diagnoses of sleep disorders or complaints of trouble sleeping. Mortality data were sourced from the National Death Index. Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHR) for all-cause and cardiovascular mortality, with adjustments for potential confounders.

RESULTS: A total of 3,170 participants ≥ 60 years of age were included for analysis. Participants with low cognitive function alone had an adjusted hazard ratio (aHR) of 1.59 (95% CI: 1.12-2.26) for all-cause mortality. The risk increased to an aHR of 1.73 (95% CI: 1.07-2.79) when both low cognitive function and sleep disturbances were present. Stratified analyses revealed that the associations between cognitive function, sleep disturbance, and mortality risks varied across sex, BMI, and chronic kidney disease status.

CONCLUSIONS: The combination of low cognitive function and sleep disturbances is associated with a higher risk of all-cause and cardiovascular mortality, exceeding the risk of either condition alone. These findings emphasize the need to consider both factors together when assessing mortality risk in older adults.},
}

@article {pmid40897975,
year = {2025},
author = {Ali, M and Erabadda, B and Chen, Y and Xu, Y and Gong, K and Liu, M and Pichet Binette, A and Timsina, J and Western, D and Yang, C and Heo, G and Vogel, JW and Tijms, BM and Krish, V and Imam, F and , and Hansson, O and Winchester, L and Cruchaga, C},
title = {Author Correction: Shared and disease-specific pathways in frontotemporal dementia and Alzheimer's and Parkinson's diseases.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41591-025-03970-7},
pmid = {40897975},
issn = {1546-170X},
}

@article {pmid40897785,
year = {2025},
author = {Espis, A and Marzi, C and Diciotti, S},
title = {Comparative analysis of supervised and self-supervised learning with small and imbalanced medical imaging datasets.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {32345},
pmid = {40897785},
issn = {2045-2322},
support = {PNRR - M4C2-I1.3 Project PE_00000019 "HEAL ITALIA", CUP J33C22002920006//NextGenerationEU/ ; },
mesh = {Humans ; *Supervised Machine Learning ; Alzheimer Disease/diagnostic imaging/diagnosis ; Magnetic Resonance Imaging ; Tomography, Optical Coherence ; Aged ; *Image Processing, Computer-Assisted/methods ; Brain/diagnostic imaging ; Retinal Diseases/diagnostic imaging ; },
abstract = {Self-supervised learning (SSL) in computer vision has shown its potential to reduce reliance on labeled data. However, most studies focused on balanced, large, broad-domain datasets like ImageNet, whereas, in real-world medical applications, dataset size is typically limited. This study compares the performance of SSL versus supervised learning (SL) on small, imbalanced medical imaging datasets. We experimented with four binary classification tasks: age prediction and diagnosis of Alzheimer's disease from brain magnetic resonance imaging scans, pneumonia from chest radiograms, and retinal diseases associated with choroidal neovascularization from optical coherence tomography with a mean size of training sets of 843 images, 771 images, 1,214 images, and 33,484 images, respectively. We tested various combinations of label availability and class frequency distribution, repeating the training with different random seeds to assess result uncertainty. In most experiments involving small training sets, SL outperformed the selected SSL paradigms, even when a limited portion of labeled data was available. Our findings highlight the importance of carefully selecting learning paradigms based on specific application requirements, which are influenced by factors such as training set size, label availability, and class frequency distribution.},
}

Humans
*Supervised Machine Learning
Alzheimer Disease/diagnostic imaging/diagnosis
Magnetic Resonance Imaging
Tomography, Optical Coherence
Aged
*Image Processing, Computer-Assisted/methods
Brain/diagnostic imaging
Retinal Diseases/diagnostic imaging

@article {pmid40897759,
year = {2025},
author = {Zhang, J and Cao, Q and Chen, W and Yang, S and Yang, S and Du, X and Wu, Y and Wu, X and Gu, W and Zhong, J and Xu, X and Yan, P and Liu, Q and Wu, T},
title = {Compensatory retinal blood flow enhancement in cognitively normal ApoE ε4 carriers.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {32349},
pmid = {40897759},
issn = {2045-2322},
support = {81971237//the National Natural Science Foundation of China/ ; BE2017734//he Jiangsu Municipal Science and Technology Bureau/ ; BE2023023-2//the Key Project of Jiangsu Province's Key Research and Development Program/ ; },
mesh = {Humans ; Male ; Female ; *Apolipoprotein E4/genetics ; *Retinal Vessels/diagnostic imaging/physiology ; Middle Aged ; Tomography, Optical Coherence ; Heterozygote ; Adult ; *Regional Blood Flow ; *Retina/diagnostic imaging/physiology ; *Cognition/physiology ; Aged ; Fovea Centralis/blood supply ; },
abstract = {This study aims to compare retinal vascular characteristics between ApoE ε4 carriers and non-carriers in healthy individuals. A total of 84 cognitively healthy subjects-64 non-carriers and 20 carriers of the ApoE ε4 allele-were analyzed using swept-source optical coherence tomography angiography (SS-OCTA). In the retinal vascular layer of OCTA images, parameters such as foveal avascular zone (FAZ) area, vessel perimeter, acircularity index (AI), and vascular density (FD) were quantified. Additionally, blood flow areas in the outer retina and choroidal capillaries, as well as the area without perfusion in the superficial vascular complex (SVC), were measured. Compared to non-carriers, carriers of ApoE ε4 exhibited significant reductions in the FAZ area, as well as increased foveal vessel density in both the deep and superficial vascular complexes. No significant differences were observed in AI, FD, blood perfusion area, or perifoveal blood vessel density between the groups. These findings suggest that reduced FAZ area and increased foveal blood flow density in ApoE ε4 carriers may indicate a compensatory mechanism in retinal blood flow, potentially serving as early indicators of Alzheimer's disease (AD).},
}

Humans
Male
Female
*Apolipoprotein E4/genetics
*Retinal Vessels/diagnostic imaging/physiology
Middle Aged
Tomography, Optical Coherence
Heterozygote
Adult
*Regional Blood Flow
*Retina/diagnostic imaging/physiology
*Cognition/physiology
Aged
Fovea Centralis/blood supply

@article {pmid40897577,
year = {2025},
author = {Huyghe, L and Salman, Y and Colmant, L and Gérard, T and Malotaux, V and Besson, G and Delhaye, E and Bastin, C and Dessain, Q and Dricot, L and Lhommel, R and Ivanoiu, A and Quenon, L and Hanseeuw, B},
title = {Preclinical detection of Alzheimer's disease pathology using conceptual discrimination abilities.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100332},
doi = {10.1016/j.tjpad.2025.100332},
pmid = {40897577},
issn = {2426-0266},
abstract = {BACKGROUND: Performance on the Conceptual Matching Task (CMT), a measure of discrimination between conceptually confusable items, has been suggested as a cognitive marker of rhinal cortex atrophy, one of the first brain regions affected by Alzheimer's disease (AD) pathology.

OBJECTIVES: We aimed to determine whether CMT can detect preclinical AD, and whether CMT performance is related to regional deposition of tau protein or other AD-associated lesions including amyloid (Aβ) accumulation and white matter hyperintensities (WMH).

This cross-sectional study include 101 participants from the UCL2016-121 cohorts in Brussels, Belgium, classified as 56 Aβ-negative cognitively unimpaired (Aβ-CU), 25 Aβ-positive CU (Aβ+CU, preclinical AD), and 20 Aβ-positive mildly cognitively impaired (Aβ+MCI, prodromal AD) individuals.

MEASUREMENTS: Participants underwent CMT and a standard neuropsychological assessment that included the Preclinical Alzheimer Cognitive Composite (PACC5), an Aβ status examination, a 3D-T1 MRI and a [[18]F]MK-6240 tau-PET scan.

RESULTS: CMT performance was lower among Aβ+MCI and Aβ+CU than Aβ-CU individuals. The effect of Aβ on CMT performance was stronger in the presence of WMH, but rhinal tau burden did not explain CMT performance beyond the effects of Aβ and WMH. CMT performance correlated with executive, memory, and language performance. Finally, CMT was more sensitive than PACC5 to detect CU individuals with Aβ or tau pathology.

CONCLUSION: Given that impaired performance is observed earlier in the CMT than in standard neuropsychological tests, this test shows promise as an early diagnostic tool for AD and may offer significant utility in the context of clinical trials.},
}

@article {pmid40897213,
year = {2025},
author = {Jooshin, MJ and Koohkansaadi, G and Hassanzadeh-Khanmiri, M and Fazilat, A and Ahmadalipour, A and Mobed, A and Charsouei, S},
title = {Amyloid beta biosensors in neurodegenerative disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120582},
doi = {10.1016/j.cca.2025.120582},
pmid = {40897213},
issn = {1873-3492},
abstract = {The accumulation of amyloid beta (Aβ) peptides in the brain is a hallmark of several neurodegenerative diseases, particularly Alzheimer's disease. Early and accurate detection of Aβ is crucial for timely intervention and effective management of these conditions. This paper explores the role of biosensors in detecting amyloid beta, highlighting recent advancements in sensor technology that enhance sensitivity, specificity, and real-time monitoring capabilities. We discuss various biosensor platforms, including electrochemical, optical, and nanomaterial-based sensors, and their applications in both research and clinical settings. Furthermore, we examine the challenges faced in the development and implementation of these biosensors, such as biocompatibility, integration with existing diagnostic tools, and regulatory considerations. By providing a comprehensive overview of the current state of biosensor technology for Aβ detection, this study aims to underscore the potential of these innovative tools in improving neurodegenerative disease management and facilitating the development of targeted therapeutic strategies.},
}

@article {pmid40897157,
year = {2025},
author = {Zhang, B and Zhang, X and Treebupachatsakul, W and Pantan, R and Kampan, N and Phatsara, M and Shi, C and Narakornsak, S},
title = {Neuroprotective effect of Urolithin A via downregulating VDAC1-mediated autophagy in Alzheimer's disease.},
journal = {Acta histochemica},
volume = {127},
number = {4},
pages = {152290},
doi = {10.1016/j.acthis.2025.152290},
pmid = {40897157},
issn = {1618-0372},
abstract = {BACKGROUND: Amyloid β (Aβ) accumulation in the brains of patients with Alzheimer's disease (AD) contributes to cognitive impairment and neuronal damage. Urolithin A (UA), a gut microbiota-derived metabolite of ellagic acid, has been reported to cross the blood-brain barrier to exert anti-inflammatory and anti-oxidation effects in the brain. However, the molecular mechanisms of UA in AD were still unclear. This study aims to explore the neuroprotective effect and mechanism of UA on APP/PS1 mice and Aβ1-42-injured N2a and PC12 cells.

METHODS: In this study, Morris water maze was used to detect the cognitive function. Immunofluorescence was used to detect the deposition of Aβ and the expression of voltage-dependent anion channel 1 (VDAC1) in the brains of APP/PS1 mice. Western blotting was used to detect the expression of VDAC1, AMPK pathway, PI3K pathway and autophagy-related proteins. CCK8 was used to detect the viability of Aβ1-42-injured cells.

RESULTS: In this research, we found that UA improved cognitive dysfunction and reduced Aβ deposition in APP/PS1 mice. Furthermore, UA activated autophagy and upregulated the levels of autophagy-related proteins in both APP/PS1 mice and Aβ1-42-injured N2a and PC12 cells. At the same time, UA down-regulated the phosphorylation level of PI3K/AKT/mTOR and up-regulated the phosphorylation level of AMPK in APP/PS1 mice and Aβ1-42-injured N2a cells and PC12 cells. In addition, UA down-regulated VDAC1, consistent with the effect of VDAC1 antagonist DIDS (4'-diisothiocyano-2,2'-disulfonic acid stilbene). Importantly, the UA-induced activation of autophagy and modulation of the PI3K and AMPK pathways were reversed by VDAC1 overexpression.

CONCLUSION: These findings demonstrated that UA down-regulated VDAC1 played a key neuroprotective role on AD by inhibiting the PI3K/AKT/mTOR pathway and activating the AMPK pathway to promote autophagy.},
}

@article {pmid40897039,
year = {2025},
author = {Musaeus, CS and Gleerup, HS and Clemmensen, FK and Sellebjerg, F and Hansen, MB and Søndergaard, HB and Waldemar, G and Hasselbalch, SG and Simonsen, AH},
title = {Serum neurofilament light chain levels are associated with cognitive decline in a consecutive cohort of patients with Alzheimer's disease.},
journal = {Journal of the neurological sciences},
volume = {477},
number = {},
pages = {123679},
doi = {10.1016/j.jns.2025.123679},
pmid = {40897039},
issn = {1878-5883},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive decline, but the individual progression rates vary. One type of blood-based biomarker that has been widely investigated is neurofilament light chain (NfL), as it reflects measures neuronal damage.

AIM: The aim of the current study was to investigate whether NfL could determine the rate of progression in patients with AD.

METHODS: A total of 274 patients with dementia due to AD in the mild to moderate stage were included in the study, during the initial diagnostic evaluation at a memory clinic. At the initial evaluation, blood samples were collected, and the serum was analyzed for NfL. Follow-up by a clinician was performed in accordance with the workflow in the clinic.

RESULTS: A significant negative association was found between short-term progression (days, mean (SD): 365 ± 224) and NfL (estimate (log-transformed): -1.2792, p-value: 0.003). No significant association was found between long-term progression (days, mean (SD): 611 (323) and NfL. NfL could not separate whether a patient was going to progress more than two points on the Mini-Mental Status Examination (MMSE) between the baseline visit and the first follow-up.

CONCLUSIONS: Although serum levels of NfL were associated with changes in MMSE, they do not alone provide sufficient utility for long term monitoring of cognitive decline in patients with AD. To achieve the desired sensitivity for this purpose, a combination of blood-based biomarkers, validated in clinical cohorts, may be necessary.

SIGNIFICANCE STATEMENT: This study suggests that serum levels of neurofilament light chain cannot predict cognitive decline in individual patients with Alzheimer's Disease.},
}

@article {pmid40896959,
year = {2025},
author = {Yun, J and Moon, M and Yang, J and Yeom, HD and Lee, MH and Lee, G and Lee, JH},
title = {Molecular regulation and subtype-specific effects of naringenin and naringin on nicotinic acetylcholine receptors expressed in Xenopus oocytes.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {191},
number = {},
pages = {118494},
doi = {10.1016/j.biopha.2025.118494},
pmid = {40896959},
issn = {1950-6007},
abstract = {Naringenin and naringin, bioactive flavonoids from citrus fruits, exhibit neuroprotective effects, showing promise for neurodegenerative diseases like Alzheimer's and Parkinson's. Additionally, they demonstrate significant anticancer potential, modulating key signaling pathways involved in tumor growth, apoptosis, and metastasis, thus expanding their therapeutic applications in cancer treatment. These compounds interact with nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels critical for modulating neurotransmission within the central nervous system. In this study, naringenin and naringin were found to selectively inhibit specific subtypes of nAChRs in a concentration-dependent, reversible, and noncompetitive manner. These effects were examined using two-electrode voltage-clamp recordings in Xenopus laevis oocytes heterologously expressing various human nAChR subtypes, and further analyzed by site-directed mutagenesis and molecular docking simulations to identify key binding residues. Mutational analyses, supported by molecular docking, revealed that certain mutations in nAChRs eliminate naringin's inhibitory effect, highlighting a selective binding affinity. This inhibition was observed selectively in α3β2 and α3β4 nAChR subtypes, which are significant within the autonomic nervous system, while α7 and α4β2 nAChRs, often implicated in neurodegenerative processes, remained unaffected. These findings suggest that naringenin and naringin could be developed as targeted modulators of nAChRs, offering therapeutic potential.},
}

@article {pmid40896796,
year = {2025},
author = {Dirir, AM and Ali, A and Hachem, M},
title = {Recent Advancements in Lipid Nanoparticles-Based Phytoactives Delivery Systems for Neurodegenerative Diseases.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {10279-10300},
doi = {10.2147/IJN.S537566},
pmid = {40896796},
issn = {1178-2013},
abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, pose a significant and continuous burden on the healthcare system, urging the search for innovative therapeutical approaches targeting the central nervous system. Nowadays, no definitive treatment can effectively modulate the neuronal degeneration associated with such diseases. The current line of therapies is primarily symptomatic and suffers several drawbacks. Among these, phytochemicals are emerging for their potential in the management of neurodegenerative disorders. Indeed, plants produce secondary metabolites that provide defensive functions against abiotic and biotic stresses. These metabolites can target the neurons and represent a promising therapeutic intervention for neurological disorders. However, the polar nature of phytochemicals and their large size hinder their passage through the blood-brain barrier, a selective barrier separating blood and the brain. Emerging studies have shown that the therapeutic efficiency of phytochemicals has been enhanced following their encapsulation with engineered nanocarriers such as lipid nanoparticles. Recent research indicates that delivering phytochemicals through lipid nanoparticles improves their physiological stability, promotes their passage across the blood-brain barrier, and enhances their accumulation in brain tissue-resulting in more effective neuroprotective effects than their free, unencapsulated form. Hence, the aim of the present review is to highlight the application of lipid nanoparticles as carriers for phytoactives with neuroprotective properties, discuss the current challenges associated with such nanocarriers, and provide insights into potential future research work.},
}

@article {pmid40896732,
year = {2025},
author = {Elci, MP and Ören, S and Miser-Salihoglu, E and Yardim-Akaydin, S},
title = {Examination of the effects of polyunsaturated fatty acids on the alzheimer model caused by amiloid β1-42 toxicity in human SHSY5Y cells by in vitro methods.},
journal = {Toxicology research},
volume = {14},
number = {4},
pages = {tfaf130},
doi = {10.1093/toxres/tfaf130},
pmid = {40896732},
issn = {2045-452X},
abstract = {Alzheimer's disease (AD) is a progressive, chronic disease characterized by impaired cognitive function. Currently, there is no complete cure for ad; current treatments are aimed at reducing symptoms and slowing the progression of the disease. It is thought that the amount of fatty acid consumption and the balance between them may be protective against neurological diseases. In this study, it was aimed to determine the protective effects of Ω3/Ω6 polyunsaturated fatty acids ratios in Aβ1-42-induced ad model in human neuroblastoma (SH-SY5Y) cells. The viability of cells was determined by MTT assay. The percentage of apoptotic cells was determined by FITC-conjugated Annexin-V/PI. ROS, MMP and cell cycle analysis were performed by flow cytometry. The amount of acetylcholinesterase enzyme was measured with a commercial kit. 48 h after the application, a statistically significant decrease was observed in the MTT test in the 1/1, 1/2 and 1/8 groups and in the amount of AChE in the 1/4, 1/8 and 1/16 groups. According to apoptosis findings, all ratios were observed to reduce cell viability compared to the control group. ROS and MMP levels were detected to decrease in all groups compared to the control group. The highest neuroprotective effect against oxidative stress was observed at 1/1 dose. Aβ1-42 induced blockade of the cell cycle was observed to be partially corrected by 1/8 dose. As a result, it can be said that Ω6 and Ω3 fatty acids, when used in 1/4 and 1/8 doses can provide a protective effect against Alzheimer's disease.},
}

@article {pmid40896725,
year = {2025},
author = {Bannerjee, A and Elkins, W and Resnick, SM and Bilgel, M},
title = {Alzheimer's disease neuropathology and longitudinal change in subjective cognitive complaints.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70176},
doi = {10.1002/dad2.70176},
pmid = {40896725},
issn = {2352-8729},
abstract = {INTRODUCTION: Subjective cognitive complaints often precede declines in objective measures of cognitive performance. Associations of incipient Alzheimer's disease (AD) neuropathology with subjective cognitive complaints may be detectable earlier than associations with neuropsychological testing among cognitively normal individuals.

METHODS: We examined the independent associations of positron emission tomography measures of amyloid beta and tau pathologies with longitudinal subjective complaints and memory among 91 cognitively normal Baltimore Longitudinal Study of Aging participants using linear mixed effects models. Subjective complaints and memory performance were assessed with the Cognitive Failures Questionnaire and the California Verbal Learning Test, respectively.

RESULTS: Greater parahippocampal tau, independent of amyloid, was associated with higher subjective complaints (estimate = 0.25, standard error [SE] = 0.1, P = 0.015), while greater entorhinal tau corresponded to an attenuated increase in complaints over time (estimate = -0.06, SE = 0.03, P = 0.047). Hippocampal tau was associated with steeper memory decline (estimate = -0.03, SE = 0.01, P = 0.040).

CONCLUSION: Subjective cognitive complaints may be a reflection of early cerebral tau pathology in cognitively normal individuals.

HIGHLIGHTS: Greater parahippocampal tau was linked with higher subjective cognitive complaints.Entorhinal tau was associated with slower increases in cognitive complaints over time.Subjective complaints may reflect early amyloid and tau in cognitively normal adults.},
}

@article {pmid40896555,
year = {2025},
author = {Huang, HH and Zhu, Z and Booppasiri, S and Chen, Z and Pang, S and Kao, CM},
title = {A statistical reconstruction algorithm for positronium lifetime imaging using time-of-flight positron emission tomography.},
journal = {IEEE transactions on radiation and plasma medical sciences},
volume = {9},
number = {4},
pages = {478-486},
doi = {10.1109/trpms.2025.3531225},
pmid = {40896555},
issn = {2469-7311},
abstract = {Positron emission tomography (PET) is an important modality for diagnosing diseases such as cancer and Alzheimer's disease, capable of revealing the uptake of radiolabeled molecules that target specific pathological markers of the diseases. Recently, positronium lifetime imaging (PLI) that adds to traditional PET the ability to explore properties of the tissue microenvironment beyond tracer uptake has been demonstrated with time-of-flight (TOF) PET and the use of non-pure positron emitters. However, achieving accurate reconstruction of lifetime images from data acquired by systems having a finite TOF resolution still presents a challenge. This paper focuses on the two-dimensional PLI, introducing a maximum likelihood estimation (MLE) method that employs an exponentially modified Gaussian (EMG) probability distribution that describes the positronium lifetime data produced by TOF PET. We evaluate the performance of our EMG-based MLE method against approaches using exponential likelihood functions and penalized surrogate methods. Results from computer-simulated data reveal that the proposed EMG-MLE method can yield quantitatively accurate lifetime images. We also demonstrate that the proposed MLE formulation can be extended to handle PLI data containing multiple positron populations.},
}

@article {pmid40896275,
year = {2025},
author = {Sohrabei, S and Zolfaghari, V and Ehsanzadeh, SJ},
title = {The Effect of Immersion Technology on the Quality of Life in Older Adults: A Systematic Review.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {8},
number = {4},
pages = {324-346},
doi = {10.1002/agm2.70024},
pmid = {40896275},
issn = {2475-0360},
abstract = {OBJECTIVES: In physical reality, mobility limitations often hinder the ability of older individuals to fully interact with the world. Aging increases the likelihood of a decline in social activities. New technologies, including immersion technologies, are increasingly gaining attention as society grapples with the challenges of an aging population. The metaverse offers a compelling opportunity to reimagine the perspective of empowering older individuals.

METHODS: A systematic review was conducted on the PubMed, IEEE, Scopus, and Web of Science databases in December 2024 using a search strategy composed of the keywords "elderly," "metaverse," "augmented reality" and "virtual reality," along with their synonyms in the titles of the articles. Descriptive, qualitative, review, and non-English studies were excluded. The quality assessment of the articles and their bias evaluation were performed based on the JBI index and PRISMA guidelines.

RESULTS: The search yielded 1153 articles, 37 of which met the study entry conditions. Thirty studies utilized virtual reality technology for the rehabilitation of elderly people. Most studies aimed to improve symptoms of Alzheimer's disease, physical activity, and cognitive impairment. Seven studies focused on the design and use of immersive technologies to improve Parkinson's symptoms and motor impairments resulting from strokes. Four studies focused on designing environments and games that could help elderly people engage in physical activity and exercise using immersive technologies. The quality of life of elderly people improved in line with the use of these technologies, and symptom weakness improved.

CONCLUSIONS: The metaverse can serve as a comprehensive and supportive platform for elderly people. The development of various digital applications or applications covering health, banking, financial affairs, shopping, and social media for performing daily activities from home via an online mode can assist elderly people. The metaverse offers innovative solutions to inspire and support elderly people in staying active. VR and AR technologies provide a dynamic platform for participation in exercise programs, recreational activities, and personalized health programs for elderly people.},
}

@article {pmid40896260,
year = {2025},
author = {Budson, AE and Paller, KA},
title = {Memory, Sleep, Dreams, and Consciousness: A Perspective Based on the Memory Theory of Consciousness.},
journal = {Nature and science of sleep},
volume = {17},
number = {},
pages = {1957-1972},
doi = {10.2147/NSS.S522975},
pmid = {40896260},
issn = {1179-1608},
abstract = {Insights into the mysteries of dreaming and waking conscious experience can be gained by considering fundamental concepts in memory research. To support this assertion, we first provide an overview of the conscious/nonconscious distinction in memory research and then summarize the memory theory of consciousness (MToC). According to the MToC, the brain system responsible for explicit memory is also responsible for all our conscious experiences-perceptions, thoughts, memories, imaginings, and dreams. Ordinarily, we experience a continuity of consciousness, even when we wake from a period of sleep. On the other hand, memory dysfunction can disrupt this continuity across sleep and lead to disorientation upon awakening. The relationship between sleep and consciousness comes into sharper focus when considering the proposition that most sleep-based memory processing is below the surface of what we can experience. During sleep, stored information is reactivated in the service of memory consolidation and, unlike dreams, this memory processing remains in the realm of implicit memory. We further propose that many multifarious memories can be simultaneously reactivated through this sleep-based processing, engaging both the hippocampus and cerebral cortex. At the same time, fragments of information from a subset of reactivated memories may be strung together to create a consciously experienced storyline or dream. In keeping with the MToC, we emphasize that conscious experiences, both while awake and while dreaming, are not read-outs of external reality even though they are typically experienced as such. Sensory experiences seem direct and instantaneous, but they are indirect and delayed because they require sensory processing to reach the explicit-memory system. Furthermore, because we remain oblivious to the unconscious memory processing that pervades our sleep, people generally underestimate the impact of sleep on our subsequent recollections and habits in the wake state. In sum, memory research enriches our understanding of consciousness in many ways.},
}

@article {pmid40896259,
year = {2025},
author = {Xu, J and Jin, H and Li, X and Jiang, Z and Meng, F and Wang, W and Li, WY},
title = {ADAM17 Inhibition Protects Cognition in Intermittent Hypoxia: The Role of TREM2.},
journal = {Nature and science of sleep},
volume = {17},
number = {},
pages = {1915-1928},
doi = {10.2147/NSS.S513304},
pmid = {40896259},
issn = {1179-1608},
abstract = {PURPOSE: The triggering receptor expressed on myeloid cells 2 (TREM2) is a new therapeutic target in Alzheimer's disease. However, its role in obstructive sleep apnea (OSA)-related cognitive impairment is still unclear. This study aimed to investigate the effect and regulatory mechanism of TREM2 on cognitive impairment related to OSA.

METHODS: Since intermittent hypoxia (IH) is the primary pathophysiologic characteristic of OSA, we conducted IH animal and BV2 cell model to investigate the mechanism. Trem2 knockdown and Trem2 overexpression cells were created by Lentivirus transfection. A disintegrin and metalloprotease 17 (ADAM17) is the primary enzyme for TREM2 shedding, we used TAPI-1 to inhibit its activity. Morris water maze, Nissl staining, real-time PCR, immunofluorescence, Western blotting, fluorometric assay kit, and enzyme-linked immunosorbent assay were used to explore the molecular mechanism.

RESULTS: The TREM2 levels were decreased in BV2 cells exposed to IH for 24 hours. IH elevated the levels of IL-1β, TNF-α and CD86 in BV2 cells, as well as the levels of p-Tau in conditioned media-cultured HT-22 cells. Conversely, IH reduced the levels of IL-10 and CD206 in BV2 cells. However, these effects were exacerbated in BV2 cells with Trem2 knockdown, whereas they were mitigated in those with Trem2 overexpression. Additionally, the ADAM17 activity and soluble TREM2 (sTREM2) levels were increased in BV2 cells subjected to IH. Treatment with TAPI-1, suppressed ADAM17 activity and restored TREM2 expression both in vitro and in vivo. Inhibition of ADAM17 led to a reduction in the expression of CD86, IL-1β, TNF-α and p-Tau levels, while enhancing the expression of CD206, IL10 and cognitive functions.

CONCLUSION: TREM2 played a protective role in IH-induced neuroinflammation and neuronal injury by promoting microglia M2 polarization. IH caused excessive activation of ADAM17 and resulted in augmented degradation of TREM2. Restoring TREM2 expression by inhibiting ADAM17 indicates a potentially promising therapeutic strategy for cognitive impairment in OSA.},
}

@article {pmid40896206,
year = {2025},
author = {Belz, M and Gmeinwieser, S and Abdel-Hamid, M and Kühler, R and Blum, J and Hessmann, P and Strenzke, N and Bartels, C},
title = {Results from AD-HEARING (ADherence to and adjustment of HEARING aids in clinical routine care as preventive dementia strategy): a prospective 6-month follow-up study on cognition and psychological well-being.},
journal = {Frontiers in psychiatry},
volume = {16},
number = {},
pages = {1494197},
doi = {10.3389/fpsyt.2025.1494197},
pmid = {40896206},
issn = {1664-0640},
abstract = {BACKGROUND: Age-related hearing loss (ARHL) is a modifiable dementia risk factor and often associated with psychological symptoms. Hearing aid use might reduce this risk by preserving cognitive and psychological functions.

OBJECTIVE: This study aims to investigate the influence of ARHL and hearing aid use on cognition and different aspects of psychological well-being.

METHODS: During 05/2021 and 05/2023, 31 subjects with audiometrically confirmed ARHL were included and 28 underwent follow-up 6 months later (final analysis sample). Successful hearing aid adjustment was controlled by fitting protocols, and hearing aid use was self-reported (IOI-SH). The following primary outcomes were analyzed by general linear models (GLM) for repeated measures and compared between hearing aid users (>8 h of daily use) vs. non-users (≤8 h of daily use) at baseline and follow-up: (1) cognition: Consortium To Establish a Registry for Alzheimer's Disease (CERAD-plus, Chandler score), (2) depression: Geriatric Depression Scale, 15-item short form (GDS-SF), (3) social isolation: Lubben Social Network Scale-6-item form (LSNS-6), (4) psychological burden: Symptom Checklist-90[®]-Standard General Symptom Index (SCL-90[®]-S GSI), and (5) health-related quality of life: visual analogue scale of the EQ-5D.

RESULTS: Mild cognitive impairment was diagnosed in 11 participants with ARHL at baseline (39.3%). Only a minority exhibited psychological symptoms (n = 1-2, 3.6%-10.7% with pathological values in psychological outcomes). All primary outcomes failed to differentiate between hearing aid users vs. non-users over time (all interaction effects ns). At follow-up, between-group differences in psychological burden and quality of life were more pronounced in favor of hearing aid users vs. non-users.

CONCLUSION: ARHL has a considerable impact on cognition. Whether hearing aid use is able to substantially attenuate cognitive impairment in a short term remains unclear. Further large-scale and long-term follow-up studies are needed to additionally address specific subgroups who might have more benefit from hearing aid use.

CLINICAL TRIAL REGISTRATION: https://drks.de/search/de/trial/DRKS00025111, identifier DRKS00025111.},
}

@article {pmid40896066,
year = {2025},
author = {Maeshima, S and Takeda, A and Sakurai, K and Osawa, A and Arai, H},
title = {Aphasia Leading to the Diagnosis of Myotonic Dystrophy Type 1: A Case Report.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e89002},
doi = {10.7759/cureus.89002},
pmid = {40896066},
issn = {2168-8184},
abstract = {Myotonic dystrophy type 1 (DM1) is a multisystem autosomal dominant disorder primarily characterized by myotonia and distal muscle weakness. Central nervous system (CNS) involvement, including cognitive, executive, and emotional dysfunctions, is increasingly being recognized; however, language impairment as an initial presentation is rare. A 50-year-old right-handed woman with a six-month history of progressive word-finding difficulty, vague speech, and social withdrawal was referred for evaluation. Neurological examination revealed distal muscle atrophy (grip strength: 5 kg right, 8 kg left) without overt dysarthria or dysphagia, and intact reflexes and coordination. Neuropsychological testing revealed fluent spontaneous speech with anomia, semantic paraphasia, impaired comprehension of longer sentences, and surface dyslexia/agraphia (Mini-Mental State Examination-Japanese: 22/30, Frontal Assessment Battery: 8/18, Raven's Colored Progressive Matrices: 28/36, Montreal Cognitive Assessment-Japanese: 21/30). Brain magnetic resonance imaging revealed left-sided frontotemporal and limbic atrophy, and [99m]Tc-ethyl cysteinate dimer single-photon emission computed tomography showed a corresponding left-dominant hypoperfusion. Amyloid positron emission tomography (PET) scan results were negative. Two weeks later, percussion and grip myotonia emerged. Genetic analysis revealed a cytosine-thymine-guanine repeat expansion (~1500 repeats) in the myotonic protein kinase 1 gene, confirming the diagnosis of DM1. The patient's semantic-variant primary progressive aphasia-like profile (impaired semantic processing with preserved fluency) and frontotemporal imaging findings were consistent with rare CNS phenotypes reported in DM1. Previous studies have described frontotemporal atrophy, hypoperfusion, and cognitive/emotional changes in DM1. Negative amyloid PET excluded Alzheimer-related primary progressive aphasia. The subsequent detection of myotonia and a positive family history were key to diagnosis. We conclude that this case expands the clinical spectrum of DM1 to include progressive aphasia as an initial manifestation. Clinicians should maintain a high suspicion of neuromuscular disorders and actively pursue targeted genetic testing when atypical aphasia symptoms are accompanied by distal muscle atrophy.},
}

@article {pmid40896041,
year = {2025},
author = {Estil-Las, AA and Grace, M and Arsene, C and Gonzalez La Rosa, J},
title = {Blinded Minds: The Role of Cataracts in Cognitive Decline and Dementia.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e89166},
doi = {10.7759/cureus.89166},
pmid = {40896041},
issn = {2168-8184},
abstract = {Dementia and cataracts are two leading causes of disability among the elderly population throughout the world. The relationship between both pathologies remains underrecognized. This paper explores the emerging evidence linking cataracts to cognitive decline and dementia, proposing that visual impairment may contribute to neurodegeneration. Popular hypotheses supporting these claims include circadian rhythm disruption, sensory deprivation, reduced social engagement, and increased cognitive load. Epidemiological data supports the co-prevalence of cataracts and dementia. Patients undergoing cataract removal have shown improved performance on cognitive assessments, suggesting that vision correction may enhance neural efficiency and quality of life; moreover, interventional studies demonstrate that cataract surgery not only improves visual impairment but may also slow cognitive deterioration. This paper also elucidates the clinical and public health implications of the integration of vision care into cognitive health strategies. The global dementia burden is projected to rise sharply in the coming decades; we propose that early intervention through cataract surgery may offer a cost-effective method to preserve cognitive function. Ultimately, identifying and treating visual impairment may serve as a crucial step toward delaying the progression of dementing illnesses.},
}

@article {pmid40895811,
year = {2025},
author = {Tysinger, B and Wei, Y and Heun-Johnson, H and Zissimopoulos, JM},
title = {Long-term value of lecanemab to individuals and families.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70151},
doi = {10.1002/trc2.70151},
pmid = {40895811},
issn = {2352-8737},
abstract = {INTRODUCTION: An assessment of the value of lecanemab for patients living with Alzheimer's disease (AD) and their care partners provides them and their health-care providers important information for deciding treatment initiation.

METHODS: We used data from a nationally representative sample of middle aged and older Americans combined with data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) on AD progression and data on lecanemab treatment effects from Clarity AD clinical trials. We use dynamic microsimulation modeling to quantify the long-term health and economic value of lecanemab for persons living with AD and their care partners.

RESULTS: We quantified five measures of value: quality of life of the persons living with AD and their care partners, medical costs, caregiving costs, and earnings, and estimated that lecanemab had a value of $21,398 relative to no treatment after 4 years and $37,943 after 10 years. Extending the treatment to 48 months resulted in a value of $42,821 relative to no treatment after 4 years and $95,311 after 10 years. Forty-eight months of a similar next-generation therapy but with 50% efficacy in slowing cognitive and functional decline resulted in a value of $82,116 relative to no treatment after 4 years and $189,691 after 10 years.

DISCUSSION: Over time, lecanemab treatment reduced medical costs, hours of care required from care partners, and improved quality of life. There is much value to be gained with next-generation treatments that have a larger impact on slowing decline. Considering a wider range of outcomes in future assessments will provide a more complete understanding of value to support decision making about treatment initiation and about reimbursement for payers.

HIGHLIGHTS: There is significant value of lecanemab for persons with mild cognitive impairment or mild dementia.Over time, lecanemab reduces medical costs, caregiver hours, and improves the quality of life of persons living with Alzheimer's disease (AD) and their care partners.A next-generation treatment for AD with similar features to lecanemab but higher efficacy, more than doubles the value.Assessing therapy value supports decision making by patients and their health-care providers.},
}

@article {pmid40895800,
year = {2025},
author = {D'Arrigo, C and Labbate, S and Galante, D},
title = {Boosting the Therapeutic Potential of Extracellular Vesicles Derived From Mesenchymal Stem Cells via Advanced Preconditioning for Neurodegenerative Disorders.},
journal = {Stem cells international},
volume = {2025},
number = {},
pages = {2616653},
doi = {10.1155/sci/2616653},
pmid = {40895800},
issn = {1687-966X},
abstract = {Acute and chronic neurodegenerative conditions (NDs) are major causes of disability and mortality worldwide. Acute NDs encompass conditions such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). On the other hand, chronic NDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Currently, no definitive cure exists for these diseases, and available therapies focus primarily on slowing the progression of symptoms. Mesenchymal stem cells (MSCs), due to their multilineage differentiation capacity, immunomodulatory abilities, and regenerative properties, have gained attention in regenerative medicine. In recent years, extracellular vesicles (EVs) derived from MSCs have shown great promise as a cell-free therapeutic approach, eliminating the risks associated with direct MSCs use, such as tumorigenicity and poor cell survival after transplantation. EVs have emerged as powerful mediators of intercellular communication and tissue repair, exhibiting immunomodulatory, anti-inflammatory, and proregenerative properties. However, limitations such as low EVs yield and reduced efficacy due to MSCs replicative senescence restrict their therapeutic potential. Preconditioning strategies, including hypoxia, 3D cultures, and biochemical priming, have been explored in other fields to enhance EVs properties, yet their specific application to NDs remains under-reported. This review aims to address this gap by analyzing the preconditioning methods used to boost the therapeutic potential of MSCs-derived EVs for neurodegenerative diseases. These preconditioning strategies may enhance EVs yield, functional cargo, and targeted therapeutic efficacy for treating acute and chronic NDs.},
}

@article {pmid40895582,
year = {2025},
author = {Natarajan, A and Vadrevu, LR and Kora, AJ and Rangan, K},
title = {Amyloid formation of mutated Alzheimer's Aβ 16-36 residues peptide and application in toxic lead and uranium ion binding.},
journal = {Nanoscale advances},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5na00228a},
pmid = {40895582},
issn = {2516-0230},
abstract = {Amyloid nanostructures are gaining attention as bio-compatible materials with diverse potential applications. The formation/self-assembly of amyloid fibrils, though implicated in the prognosis of several neurodegenerative diseases, contrastingly can also be explored for their functional properties owing to their unique stability and strength. The physicochemical environment and amino-acid composition are characteristic and specifically crucial for a protein/peptide to form amyloid fibrils. The Aβ peptide involved in the Alzheimer's disease prognosis consists of two central hydrophobic core regions and a central polar region forming a β-hairpin. In this study, a 21 amino acid containing peptide KLVFFAEDVESNRGAIIGLMV is designed introducing point mutations to the original 16-36 residues of the Aβ peptide (G → E at position 25 and K → R at position 28), resulting in a modified Aβ peptide variant. The self-assembling nature of this modified peptide has been explored, and ThT fluorescence and circular dichroism spectroscopy exhibit β-sheet structures. Detailed morphological analysis using SEM, AFM, and confocal microscopy revealed a progression from initial blob-like spongy forms to protofibrils, culminating in branched amyloid fibrils. These strategic mutations enable binding of toxic metals such as uranium and lead, as demonstrated via UV-visible spectroscopy, XPS, AAS and fluorescence spectroscopy, highlighting its promise for environmental remediation.},
}

@article {pmid40895150,
year = {2025},
author = {Chen, G and Su, Y and Chen, S and Lin, T and Lin, X},
title = {Polyphenols and Alzheimer's Disease: A Review on Molecular and Therapeutic Insights With In Silico Support.},
journal = {Food science & nutrition},
volume = {13},
number = {9},
pages = {e70496},
doi = {10.1002/fsn3.70496},
pmid = {40895150},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation resulted the cognitive memory loss. Despite extensive research, effective therapeutic treatment remains elusive. Polyphenols, naturally occurring bioactive compounds, have emerged as promising neuroprotective agents due to their potent antioxidant, anti-inflammatory, and amyloid-modulating properties. Research indicated that these bioactive compounds have potent antioxidant and anti-inflammatory properties, have garnered significant attention for their potential role in combating AD by targeting its key pathological mechanisms. Preclinical studies highlight the efficacy of various polyphenols, such as resveratrol, curcumin, and epigallocatechin gallate, in improving cognitive function and reducing neurodegeneration. Moreover, in silico approaches, displayed polyphenols mechanistic interactions with key AD targets to reduce pathogenesis. These computational models accelerate drug discovery by predicting binding affinities, optimizing structural modifications, and identifying novel polyphenol derivatives with enhanced therapeutic potential. This review explores the multifaceted role of polyphenols in AD mitigation, emphasizing their impact on oxidative stress and neuroinflammation while integrating in silico evidence to reinforce their therapeutic relevance. Convincingly, through the suppression of key mediators of AD, including oxidative stress, neuroinflammation, amyloid-beta and tau proteins, polyphenols exhibited outstanding therapeutic potential to treat AD.},
}

@article {pmid40895100,
year = {2025},
author = {Yang, Y and Koo, MS and Kwak, YT},
title = {Efficacy of Ginkgo biloba extract in amyloid PET-positive patients with mild cognitive impairment.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1639924},
doi = {10.3389/fneur.2025.1639924},
pmid = {40895100},
issn = {1664-2295},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) with amyloid PET positivity represents a prodromal stage of Alzheimer's disease (AD), yet no disease-modifying therapies are currently approved. Ginkgo biloba, traditionally used in East Asian and European ethnomedicine as an oral decoction or standardized extract to support memory and cognitive function, is commonly utilized, however, its efficacy as monotherapy in biomarker-confirmed MCI remains uncertain. Aβ oligomers, produced by abnormal cleavage of amyloid precursor protein, disrupt synaptic function and contribute to cognitive decline.

OBJECTIVE: This study evaluated whether Ginkgo biloba alone, without adjunctive anti-dementia medication, could provide clinical and biomarker benefits in amyloid PET-positive MCI patients. Plasma MDS-Oaβ (Multimer Detection System-Oligomeric Aβ), a dynamic biomarker reflecting Aβ oligomerization tendency, was used to explore mechanistic relevance.

METHODS: In this retrospective cohort study, 64 amyloid PET-positive MCI patients were followed for 12 months. Participants received either oral Ginkgo biloba monotherapy (240 mg/day, n = 42) or standard cognitive enhancers (n = 22). Clinical outcomes included the Korean version of the Mini-Mental State Examination (K-MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Korean Instrumental Activities of Daily Living (K-IADL), and Neuropsychiatric Inventory (NPI). Plasma MDS-Oaβ levels were assessed at baseline and at 12 months.

RESULTS: At 12 months, the Ginkgo group showed significantly higher responder rates (100% vs. 59.1%, p < 0.001), no conversion to AD dementia (0% vs. 13.6%, p = 0.037), and greater improvement in K-MMSE and K-IADL scores. MDS-Oaβ levels decreased significantly in the Ginkgo group (p < 0.001) but not in the control group. No significant between-group differences were observed in CDR-SB or NPI scores.

CONCLUSION: Ginkgo biloba monotherapy was associated with preserved cognition, improved daily functioning, and reduced plasma Aβ oligomerization in amyloid PET-positive MCI patients. These findings suggest potential disease-modifying effects and warrant further validation in prospective, biomarker-based clinical trials.},
}

@article {pmid40895094,
year = {2025},
author = {Musso, G and Fiorenzato, E and Misenti, V and Cauzzo, S and Biundo, R and Fogliano, CA and Bonato, G and Meissner, WG and Campagnolo, M and Carecchio, M and Vianello, F and Guerra, A and Cosma, C and Cagnin, A and Cecchin, D and Montagnana, M and Antonini, A},
title = {Detecting amyloid and tau pathology in Parkinson's disease, 4R-tauopathies and control subjects with plasma pTau217.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1638852},
doi = {10.3389/fneur.2025.1638852},
pmid = {40895094},
issn = {1664-2295},
abstract = {INTRODUCTION: Plasma phospho-tau 217 (pTau217) is a biomarker for Alzheimer's disease (AD) pathology, reflecting amyloid (Aβ) and tau burden, but its role in Parkinson disease (PD) and 4-repeat(4R)-tauopathies remains incompletely understood. We measured plasma pTau217 across the cognitive spectrum of Lewy body diseases (PD, Dementia with Lewy bodies [DLB]) and in 4R-tauopathies, comparing these groups to cognitively unimpaired (CU) and mild cognitive impairment (MCI) individuals.

METHODS: Participants included 18 cognitively normal PD (PD-NC), 32 PD with MCI, and 7 PD with dementia (PDD), alongside 4 DLB patients, grouped as PDD/DLB. The 4R-tauopathy group included 28 Progressive Supranuclear Palsy (PSP) and 4 corticobasal syndrome (CBS) patients, compared to 51 CU and 26 MCI individuals. Ptau217 was measured using the fully automated Lumipulse platform, with values adjusted for creatinine levels. Further, the presence of AD-pathology was defined using a validated cut-off based on Aβ-PET.

RESULTS: PTau217 levels were significantly lower in PD-NC and CU individuals compared to those with greater cognitive impairment (PD-MCI, PDD/DLB, and PSP/CBS), and MCI individuals. AD co-pathology was identified in 28% of PDD/DLB and PSP/CBS patients, 16% of PD-MCI, and none of PD-NC. MCI showed the highest pTau217 positivity (35%), while 8% of CU individuals were positive despite normal cognition. In PD, pTau217 negatively correlated with cognitive performance, as assessed by Montreal Cognitive Assessment (MoCA: rs = -0.38, p = 0.004) and Mini-Mental State Examination (MMSE: rs = -0.37, p = 0.006).

DISCUSSION: Plasma pTau217 levels serve as a scalable, non-invasive marker of AD-pathology across Lewy body diseases, PSP/CBS, and MCI/CU populations. AD co-pathology independently contributes to cognitive deficits in PD, but not in PSP/CBS.},
}

@article {pmid40894925,
year = {2025},
author = {He, G and Huang, J and Zeng, Z and Sun, H and Wu, C and Xu, Q and Hu, C and Jin, B and Tong, M and Wang, C},
title = {Stem cell therapy offers new hope for the treatment of Alzheimer's disease.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1650885},
doi = {10.3389/fcell.2025.1650885},
pmid = {40894925},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment and cognitive decline, for which no curative treatment is currently available. Existing therapeutic strategies, such as cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, can only provide limited symptomatic relief and fail to halt disease progression. In recent years, stem cell therapy has emerged as a promising approach for AD due to its multifaceted mechanisms of action. The therapeutic effects of stem cells in AD are mainly attributed to their ability to differentiate into functional neurons or glial cells, thereby replacing damaged cells and repairing neural networks. In addition, stem cells secrete neurotrophic and anti-inflammatory factors that contribute to the improvement of the brain microenvironment. Furthermore, they can regulate neuroinflammation, promote the clearance of β-amyloid (Aβ) deposits, and suppress neuroinflammation, thus potentially slowing disease progression. However, several challenges remain, including low cell survival rates, immune rejection, tumorigenic risks, and difficulties in crossing the blood-brain barrier. Looking ahead, the integration of advanced technologies such as organoid models, gene editing, artificial intelligence, and multi-omics approaches may drive substantial progress in the clinical translation of stem cell therapies for AD. Although still in its early stages, the future of this therapeutic strategy holds great promise.},
}

@article {pmid40894788,
year = {2025},
author = {Feng, Y and Shuai, Y and Villalón-Reina, JE and Chandio, BQ and Thomopoulos, SI and Nir, TM and Jahanshad, N and Thompson, PM},
title = {Streamline Density Normalization: A Robust Approach to Mitigate Bundle Variability in Multi-Site Diffusion MRI.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.18.670965},
pmid = {40894788},
issn = {2692-8205},
abstract = {Tractometry enables quantitative analysis of tissue microstructure is sensitive to variability introduced during tractography and bundle segmentation. Differences in processing parameters and bundle geometry can lead to inconsistent streamline reconstructions and sampling, ultimately affecting the reproducibility of tractometry analysis. In this study, we introduce Streamline Density Normalization (SDNorm), a supervised two-step method designed to reduce variability in bundle reconstructions. SDNorm first computes streamline weights using linear regression to match a subject's bundle to a template streamline density map, then iteratively prunes streamlines to achieve a target density using a novel metric called effective Streamline Point Density (eSPD). We evaluate SDNorm across multiple bundles and acquisition protocols in dMRI data from a subset of subjects from Alzheimer's Disease Neuroimaging Initiative and demonstrate that it can significantly reduce variability in streamline density, improve consistency in along-tract microstructure profiles, and provide useful metrics for automated bundle quality control. These results suggest that SDNorm can help enhance the reproducibility and robustness of bundle reconstruction across heterogeneous image acquisition protocols and tractography settings, making it well-suited for large-scale and multi-site neuroimaging studies.},
}

@article {pmid40894768,
year = {2025},
author = {Roe, JM and Jagust, WJ and Landau, SM and Harrison, TM and Grydeland, H and Slivka, M and Alatorre-Warren, JL and Garrido, PF and Sørensen, Ø and Grødem, EOS and Ward, TJ and Leonardsen, EH and Fladby, T and Bjørnerud, A and Walhovd, KB and Fjell, AM and Vidal-Piñeiro, D and Wang, Y},
title = {Cortical thickness changes precede high levels of amyloid by at least seven years.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.14.670398},
pmid = {40894768},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is now defined based on its underlying brain pathology [1] , with the presence of amyloid (Aβ) plaques at high enough levels sufficient to warrant a diagnosis in the absence of cognitive symptoms. High levels of PET-detectable Aβ are widely thought to be the first imaging marker, with structural brain changes detectable on MRI scans thought to occur later. We combined 4570 longitudinal MRIs and 1684 Aβ PET scans from three cognitively healthy cohorts to test the difference in cortical thickness and its change between those that subsequently converted to be Aβ-positive or stayed Aβ-negative, using MRIs acquired exclusively in the years before conversion. We found those that subsequently developed elevated Aβ levels show both thicker cortex and less cortical thinning, even when the last MRI used to estimate their thickness trajectories was acquired at least seven years before conversion. Many effects remained when accounting for quantitative Aβ levels, suggesting some cortical thickness effects may be partly independent of Aβ. Differences in cortical thickness and its change between converters and Aβ-negative individuals showed moderate alignment with patterns of Aβ deposition, and the timing of thickness changes tracked the temporal progression of Aβ accumulation. Thus, if amyloid is AD [1] , we show that high levels of PET-detectable amyloid are not the first imaging marker of AD, as cortical thickness changes can be traced years before pathological amyloid. This has implications for understanding the sequence of events leading up to the earliest stages of AD.},
}

@article {pmid40894731,
year = {2025},
author = {Xu, W and Wang, L and Lu, L and Liu, X and Rajabli, F and Celis, K and Gearing, M and Bennett, DA and Flanagan, M and Weintraub, S and Geula, C and Schuck, T and Scott, WK and Dykxhoorn, DM and Griswold, AJ and Pericak-Vance, MA and Young, JI and Jin, F and Vance, JM},
title = {Finding ancestry-specific chromatin architecture in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.19.671054},
pmid = {40894731},
issn = {2692-8205},
abstract = {Genetic risk for Alzheimer's Disease (AD) varies across populations. We hypothesized that three-dimensional (3D) genome architecture variations could offer novel epigenetic understanding of ancestry-specific genetic risk. Herein, we performed Hi-C analyses of frontal cortex from APOE ε4/ε4 individuals with African (AF) or European (EU) ancestry who also had single nuclei ATAC-seq and RNA-seq data available. Ancestry-specific 3D genome architecture was found at both compartment and chromatin loop levels. EU genomes have more active compartments than AF genomes, consistent with our previous report of higher chromatin accessibility in EU than AF genome. Of the over one million chromatin loops identified by the DeepLoop pipeline, we called 12,082 putative EU-specific and 2885 putative AF- specific loops. The AF-specific loops are smaller (median size =158 kb) and likely represent promoter-enhancer interactions, while EU-specific loops are larger (median size = 496 kb) and enriched for CTCF loops. We found that differently expressed genes between AF and EU ancestries were significantly enriched at the putative ancestry-specific loop loci (Fisher-test; p<2.2×10 [-16] ; OR=5.13). High confidence HiC-QTLs (N=38) were identified after filtering with CTCF consensus sequence and chromatin accessibility-QTLs. Our study demonstrates variations in 3D genome structure between ancestries, which may contribute to the ancestry-specific genetic risk.},
}

@article {pmid40894712,
year = {2025},
author = {Alarcón-Espósito, J and Nagiri, RK and Wang, S and Larson, C and Carvallo-Torres, L and Singh, VK and Glickman, F and Gan, L and Sinha, SC},
title = {High-Throughput Screening and Initial SAR Studies Identify a Novel Sub-micromolar Potent Human cGAS Inhibitor.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.18.670979},
pmid = {40894712},
issn = {2692-8205},
abstract = {Cyclic GMP-AMP synthase (cGAS) has emerged as a promising therapeutic target of several human diseases, including Alzheimer's disease (AD) and other neurodegenerative disorders. As a cytosolic DNA sensor, cGAS generates an innate immune response to promote neuroinflammation by producing an endogenous agonist of the stimulator of interferon genes (STING), 2'3'-cyclic GMP-AMP (cGAMP), which activates the cGAS-STING pathway. We have performed a high-throughput screening of a chemical library containing over 300K small molecules at the Fisher Drug Discovery Resource Center (DDRC), Rockefeller University (RU), to identify multiple hit inhibitors of human (h)-cGAS. We used a modified Kinase Glo® Luminescent Kinase assay, which was earlier developed at RU and later used by multiple groups, including ours, to perform primary screening of the library using h-cGAS. The hit candidates bearing novel scaffolds are structurally diverse and exhibited in vitro activity in the low micromolar range. RU-0610270 or compound (cpd) 1 , a sulfonamide derivative, is one of the most potent hits (IC 50 =1.88 µM), selected for hit expansion and structure-activity relationship (SAR) analysis. We synthesized new analogs of cpd 1 and evaluated them in vitro against h-cGAS to identify cpd 6 (IC 50 =0.66 µM) as the most potent hit analog. We further profiled cpd 6 and found that it modestly inhibited cGAMP levels by 29% at 30 µM in THP1 cells without detectable toxicity, and by 76% at 100 µM, albeit with a moderate decrease (∼20%) in cell viability. These results highlight a novel chemical series with promising in vitro activity, providing a starting point for the development of selective and potent human cGAS inhibitors for clinical use.},
}

@article {pmid40894695,
year = {2025},
author = {Huang, Y and Xie, X and Chen, R and Huang, Z and Gangal, H and Wang, X and Wang, J},
title = {Pathology-Specific Modulation of Corticostriatal Circuitry by Chronic Alcohol Consumption in Alzheimer's Disease Mouse Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.15.670607},
pmid = {40894695},
issn = {2692-8205},
abstract = {UNLABELLED: Chronic alcohol use is a major modifiable risk factor for Alzheimer's disease (AD), yet the mechanisms by which it modulates AD pathophysiology remain unclear. Here, we examined circuit-level and pathological changes in two distinct AD mouse models, humanized Aβ knock-in (hAPP-KI) (Aβ-driven) and PS19 (tau-driven), subjected to a chronic intermittent alcohol exposure paradigm. In hAPP-KI mice, alcohol increased Aβ accumulation and excitatory transmission in the medial prefrontal cortex (mPFC) while reducing corticostriatal transmission and striatal cholinergic output. These alterations were accompanied by enhanced recruitment of microglia around Aβ plaques. In contrast, alcohol-exposed PS19 mice displayed elevated mPFC-to-dorsomedial striatum (DMS) glutamatergic transmission and increased tau phosphorylation without significant changes in microglial activation or local mPFC excitatory drive. In wild-type mice, microglial depletion enhanced glutamatergic transmission onto cortical neurons, suggesting a homeostatic role for microglia in maintaining excitatory balance. Together, these findings reveal pathology-specific effects of alcohol on circuit dysfunction and propose microglia as an important modulator of alcohol-induced synaptic remodeling in the early stage of AD.

HIGHLIGHTS: Chronic alcohol exposure modulates glutamatergic transmission and neuroimmune responses in pathology-specific manners across Aβ- and tau-driven Alzheimer's disease mouse models.In hAPP-KI mice, alcohol increases mPFC excitatory input, Aβ plaque burden, and microglial activation, while impairing corticostriatal transmission and striatal cholinergic signaling.In PS19 mice, alcohol enhances mPFC-to-striatum excitatory transmission and tau phosphorylation without altering local microglial activation or mPFC excitability.Microglial depletion in wild-type mice recapitulates alcohol-induced glutamatergic changes in hAPP-KI mice, revealing a homeostatic role for microglia in regulating cortical excitatory balance.},
}

@article {pmid40894647,
year = {2025},
author = {Cuní-López, C and Root, JT and Hao, Y and Kowal, I and Blomberg, N and Ghirlando, R and Yang, LG and Koppes-den Hertog, SJ and Cookson, MR and van der Kant, R and Giera, M and Qi, YA and Narayan, PS},
title = {APOE genotypes differentially remodel the astrocytic lipid droplet-associated proteome to shape lipid droplet dynamics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.19.669163},
pmid = {40894647},
issn = {2692-8205},
abstract = {The lipids and proteins that comprise lipid droplets regulate several cellular functions including lipid storage, stress responses, and inflammation. Glial lipid droplets have been implicated in the pathogenesis and progression of Alzheimer's disease (AD), yet the mechanisms linking genetic risk to lipid droplet biology remain unclear. Here we examined how APOE, the strongest genetic modulator of late-onset AD, impacts lipid droplet composition and dynamics. We defined the lipid droplet-associated proteome and lipidome in human induced pluripotent stem cell-derived astrocytes harboring the three common APOE genotypes: APOE2 (protective), APOE3 (neutral), and APOE4 (risk). Each APOE variant displays distinct lipid droplet-associated proteins and lipids. These molecular changes yield differences in lipophagy; lipid droplets in APOE2 astrocytes undergo autophagic turnover, whereas those in APOE4 astrocytes are resistant to degradation. These findings suggest that impaired lipid droplet clearance, rather than accumulation, distinguishes APOE4-associated AD risk, and may present a new metabolic node for modulating risk.},
}

@article {pmid40894617,
year = {2025},
author = {Chandio, BQ and Nir, TM and Villalon-Reina, JE and Thomopoulos, SI and Feng, Y and Reid, RI and Jack, CR and Weiner, MW and Garyfallidis, E and Jahanshad, N and Braskie, MN and O'Bryant, S and Thompson, PM and , and , },
title = {White Matter Tract Vulnerability to Amyloid Pathology on the Alzheimer's Disease Continuum.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.18.670970},
pmid = {40894617},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is marked by progressive cognitive decline and memory loss, due to the abnormal accumulation of amyloid-beta (Aβ) plaques, followed by tau pathology, and a gradually spreading pattern of neuronal loss. Understanding how amyloid positivity affects the brain's neural pathways is critical for understanding how the brain changes with AD pathology. Tractometry offers a powerful approach for the in vivo , 3D quantitative assessment of white matter tracts, enabling the localization of microstructural abnormalities in diseased populations and those at risk. In this study, we applied BUAN (Bundle Analytics) tractometry to multi-cohort diffusion MRI data from a total of 1,908 participants: 606 participants in ADNI3 (Alzheimer's Disease Neuroimaging Initiative Phase 3) and 1,302 participants from the HABS-HD (Health and Aging Brain Study-Healthy Diversity). Using BUAN and along-tract statistical analysis, we assessed the localized effects of amyloid positivity, potentially mediated by tau, on white matter pathways, with amyloid positivity quantified via amyloid-sensitive positron emission tomography (PET). BUAN enables tract-specific quantification of white matter microstructure and supports statistical testing along the full length of fiber bundles to detect subtle, spatially localized associations. We present 3D visualizations of tract-wise amyloid associations, highlighting distinct patterns of white matter degeneration in AD.},
}

@article {pmid40894614,
year = {2025},
author = {Cullen, AE and Reeve, EH and Winder, NR and Henson, GD and Arora, N and Leonhardt, T and Hogan, AP and Kumaran, SK and Setthavonsack, N and Krajbich, V and Alkayed, NJ and Pike, MM and Woltjer, RL and Walker, AE},
title = {Cerebral blood flow in elastin haploinsufficient and 3xTg-AD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.18.670895},
pmid = {40894614},
issn = {2692-8205},
abstract = {Artery structural properties and Alzheimer's disease (AD) pathology are individually associated with impaired cerebrovascular function; however, the interaction of these factors is unclear. Furthermore, while elastin haploinsufficient (Eln+/-) mice are known to have impaired cerebrovascular function, sex differences for this effect have not been previously studied. To answer these questions, we crossed middle-aged and old Eln+/-mice with 3xTg-AD mice. We measured cerebral blood flow (CBF) using arterial spin labeling MRI at rest and during hypercapnia to calculate cerebrovascular reactivity (CVR). We also assessed neuroinflammation by microglia and astrocyte cell counts. We found that Eln+/- mice had lower resting blood flow rate in the cerebral cortex compared with Eln+/+ mice, but Eln+/- mice had an intact hypercapnic response, resulting in better CVR compared with Eln+/+ in hippocampus. Sex did not impact resting blood flow or CVR. 3xTg-AD mice had a lower resting CBF than non-AD mice, and there was an interaction between Eln genotype and AD mutations on CVR, such that Eln+/-x 3xTg-AD mice had the poorest hippocampal CVR of all groups. Glia cell counts were highly dependent on brain region, with Eln+/- having more microglia but fewer astrocytes, while 3xTg-AD having higher both microglia and astrocytes. While sex also impacted glial cell counts, we found no interactions between sex and Eln genotype. Our results demonstrate that elastin haploinsufficiency and AD mutations individually result in lower resting CBF, and the combination of these leads to impaired CVR.},
}

@article {pmid40894612,
year = {2025},
author = {Desel, T and Walker, MP and Brown, C and Chen, C and Chadwick, TA and Jagust, WJ and Sharon, O},
title = {REM Sleep Misfires: Intruding Delta Waves Forecast Tau, Amyloid, and Forgetting in Aging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.18.670879},
pmid = {40894612},
issn = {2692-8205},
abstract = {Rapid Eye Movement (REM) sleep degrades with age, and more severely in Alzheimer's disease (AD). REM sleep comprises about twenty percent of adult sleep, alternates between phasic and tonic periods, and includes delta waves (1-4Hz) in two forms: fast sawtooth waves and slower, NREM-like waves, whose expression dynamically varies across REM periods. Yet, the functional relevance of these REM sleep delta waves remains unknown. Here, using two independent cohorts, we show that aging is associated with a shift from fast sawtooth to slow NREM-like delta waves, particularly during phasic REM sleep-a period typically marked by high cortical activation. Beyond chronological age, this shift is associated with amyloid-beta and tau burden, suggesting that AD pathology disrupts REM-specific oscillatory patterns. Furthermore, this shift in REM oscillations is linked to impaired overnight memory consolidation, independent of NREM sleep quality. Moreover, variation in ApoE alleles, a major genetic risk factor for AD, was independently associated with a reduction in fast sawtooth wave density, thereby linking a genetic predisposition for AD to these specific REM microstructural changes. These findings identify a novel signature of memory decline in aging and implicate REM sleep as a distinct vulnerable substrate through which AD pathology may impair brain function.},
}

@article {pmid40894600,
year = {2025},
author = {Baral, R and van Deventer, R and Lyubchenko, YL},
title = {Amyloid β interaction with membranes: Removal of cholesterol from the membranes to catalyze aggregation and amyloid pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.20.671368},
pmid = {40894600},
issn = {2692-8205},
abstract = {The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42- residue form of the amyloid-β peptide) peptides in pathological aggregates is considered as one of the major molecular mechanisms in development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that the high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability of monomeric Aβ42. Extracted cholesterol interacts with Aβ42 and accelerates its on- membrane aggregation. We propose a model of interaction of Aβ42 with membranes based on the ability of Aβ42 to extract cholesterol, which explains several AD associated observations related to cholesterol interplay with Aβ42 aggregation resulting in the AD onset and progression.},
}

@article {pmid40894542,
year = {2025},
author = {Shuai, Y and Chandio, BQ and Feng, Y and Villalon-Reina, JE and Nir, TM and Ching, CRK and Ba Gari, I and Thomopoulos, SI and Alibrando, JD and John, JP and Venkatasubramanian, G and Jahanshad, N and Thompson, PM},
title = {Deterministic versus Probabilistic Tractography: Impact on White Matter Bundle Shape.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.19.669949},
pmid = {40894542},
issn = {2692-8205},
abstract = {In diffusion MRI-based tractography, deterministic and probabilistic algorithms reconstruct white matter using distinct strategies, yet their impact on bundle morphology remains uncertain. Using bundle shape similarity analysis, we compared both methods for the left arcuate fasciculus (AF L) (The left arcuate fasciculus is a critical white matter tract that connects language comprehension and production areas in the human brain, enabling fluent language processing) across four datasets: Alzheimer's Disease Neuroimaging Initiative (ADNI), Human Connectome Project-Aging (HCP-A), National Institute of Mental Health and Neurosciences (NIMHANS), and Pediatric Imaging, Neurocognition, and Genetics (PING). Probabilistic tractography consistently produced higher inter-subject shape similarity, by capturing broader anatomical trajectories and enhancing reproducibility. However, this extensive coverage may obscure subtle pathological variations critical for clinical detection. Bundle shape similarity analysis with atlas corroborated these findings, showing stronger alignment for probabilistic tracking and highlighting its utility in quantitative quality control. These results emphasize the need to balance morphological consistency with sensitivity to neuroanatomical variation when selecting tractography methods for research and clinical applications.},
}

@article {pmid40894526,
year = {2025},
author = {Jiang, J and Petrella, JR and Hao, W and , },
title = {Identifiability-Guided Assessment of Digital Twins in Alzheimer's Disease Clinical Research and Care.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.17.670697},
pmid = {40894526},
issn = {2692-8205},
abstract = {Digital twins - personalized, data-driven computational models - are emerging as a powerful paradigm for representing and predicting disease trajectories at the individual level. These models have the potential to support diagnosis, monitor disease evolution, and evaluate therapeutic interventions in virtual settings in the context of clinical trials and patient care. Rigorous model assessment is thus critical for its implementation, but medical data are often sparse, noisy, and vary significantly across individuals, making it challenging to determine whether a digital twin optimized on such data is valid. In such settings, identifiability analysis becomes essential for evaluating whether model parameters can be reliably estimated and interpreted. To address this, we investigate how identifiability can support the clinical application of a computational causal digital twin model for Alzheimer's Disease (AD), where data sparsity and variability are particularly pronounced. Our results show that the magnitude and distribution of biomarker data influence the parameter practical identifiability, and that constraints on the model structure and parameters can significantly affect identifiability. We also observe differences in identifiability across diagnostic groups, with several parameters showing significantly different values between individuals with AD, mild cognitive impairment (MCI), and cognitively normal (CN) subjects. Uncertainty quantification for identifiable parameters and their corresponding model trajectories provides visual insight into variability in disease progression and reveals mild trends related to biomarker data spread. This study represents a first step toward incorporating identifiability techniques into clinical digital twin frameworks, using a data-driven, interpretable example based on a previously published AD model.},
}

@article {pmid40894445,
year = {2025},
author = {Eksioglu, M and Azapoglu Kaymak, B and Unal Akoglu, E and Akyıldız, SF and Sivil, R and Cimilli Ozturk, T},
title = {Comparative Prognostic Accuracy of Clinical and Inflammation- or Nutrition-Based Scores in Older Adults with Community-Acquired Pneumonia.},
journal = {International journal of general medicine},
volume = {18},
number = {},
pages = {4811-4824},
doi = {10.2147/IJGM.S540730},
pmid = {40894445},
issn = {1178-7074},
abstract = {PURPOSE: This study aimed to assess the prognostic accuracy of the Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), and C-reactive protein/albumin ratio (CAR) in predicting 30-day mortality and intensive care unit (ICU) admission compared with the Pneumonia Severity Index (PSI) and CURB-65 in older adults with community-acquired pneumonia (CAP).

PATIENTS AND METHODS: This retrospective, single-center cohort study was conducted in a tertiary emergency department. Patients aged ≥65 years with CAP were included. Exclusion criteria were hospital- or ventilator-associated pneumonia, pneumonia mimics, and immunocompromised status. GPS and mGPS were calculated using CRP >10 mg/L and albumin <35 g/L. ROC and logistic regression analyses were performed.

RESULTS: A total of 349 patients (mean age: 77.96 ± 8.42 years; 52.7% men) were included. The 30-day mortality and ICU admission rates were 19.5% and 27.2%, respectively. For predicting mortality, the GPS showed an AUC of 0.753 (95% CI: 0.690-0.816), sensitivity of 75.0%, specificity of 73.3%, PPV of 43.9%, and NPV of 92.4%. mGPS had an AUC of 0.747 (95% CI: 0.679-0.814), sensitivity 77.9%, specificity 73.3%, PPV 45.2%, and NPV 93.2%. The CAR yielded an AUC of 0.677 (95% CI: 0.604-0.751), sensitivity of 82.4%, specificity of 45.6%, PPV of 29.5%, and NPV of 91.4%. For ICU admission, the AUCs were 0.770 (GPS), 0.757 (mGPS), and 0.676 (CAR). The PSI demonstrated the highest predictive accuracy (AUC: 0.884 for mortality, 0.919 for ICU admission), followed by CURB-65 (AUC: 0.848 and 0.879, respectively). Independent predictors of 30-day mortality included acute confusion, lower PaO2/FiO2 ratio, low systolic blood pressure, reduced hemoglobin levels, and Alzheimer's disease or dementia.

CONCLUSION: The PSI and CURB-65 demonstrated superior prognostic accuracy. GPS and mGPS showed moderate performance, whereas CAR exhibited the lowest overall discriminative ability for both outcomes.},
}

@article {pmid40894255,
year = {2025},
author = {Hu, N and Chen, L and Hu, G and Ma, R},
title = {Advancements in extracellular vesicle therapy for neurodegenerative diseases.},
journal = {Exploration of neuroprotective therapy},
volume = {5},
number = {},
pages = {},
doi = {10.37349/ent.2025.1004104},
pmid = {40894255},
issn = {2769-6510},
abstract = {Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.},
}

@article {pmid40894164,
year = {2025},
author = {Lyu, X and Mundada, NS and Brown, CA and Sadeghpour, N and McGrew, E and Xie, L and Li, Y and Wuestefeld, A and Duong, MT and Cook, P and Gee, J and Nasrallah, IM and Chen-Plotkin, AS and Shaw, LM and Mechanic-Hamilton, D and Wisse, LEM and Yushkevich, PA and Das, SR and Wolk, DA and , },
title = {Medial temporal lobe Tau-Neurodegeneration mismatch from MRI and plasma biomarkers identifies vulnerable and resilient phenotypes with AD.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.17.25333859},
pmid = {40894164},
abstract = {While tau pathology is closely associated with neurodegeneration in Alzheimer's disease (AD), our prior work using multi-modality imaging revealed that mismatch between tau (T) and neurodegeneration (N) may reflect contributions from non-AD processes. The medial temporal lobe (MTL), an early site of AD pathology, is also a common target of co-pathologies such as limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), often following an anterior-posterior atrophy gradient. Given the susceptibility of MTL to co-pathologies, here we explored T-N mismatch specifically within MTL using plasma ptau 217 and MTL morphometry for identifying vulnerabilities and resilience in cognitively impaired or unimpaired AD patients. We parcellated the MTL into 100 spatially contiguous segments and calculated their T-N mismatch using plasma ptau 217 as a measure for T and thickness as a marker of N. Based on these mismatch profiles, we clustered 447 amyloid-positive individuals from ADNI cohort into data-driven T-N phenotypes. We characterized the T-N phenotypes by examining their cross-sectional and longitudinal atrophy both within the MTL and across the whole brain, as well as cognitive trajectories. This framework was replicated in an independent cohort and finally translated to a real-world clinical sample of 50 patients undergoing anti-amyloid therapy. Clustering identified three T-N phenotypes with different MTL T-N mismatch profiles, atrophy patterns, and cognitive outcomes, despite comparable AD severity. The "canonical" group, characterized by low T-N residuals (N ∼ T), showed AD-like neurodegeneration patterns. The "vulnerable" group, characterized by disproportionately greater neurodegeneration than tau (N > T), showed atrophy primarily in the anterior MTL that extended into temporal-limbic regions, both in cross-sectional and longitudinal analyses. This group also exhibited neurodegeneration that preceded estimated tau onset and experienced faster cognitive decline across multiple domains, aligning with the typical characteristics of mixed LATE-NC with AD. In contrast, the "resilient" group (N < T) showed minimal atrophy and preserved cognitive function. These phenotypes were reproducible in an independent research cohort. Importantly, in a feasibility study applying the model developed from ADNI to a clinical cohort of patients receiving lecanemab, we identified vulnerable individuals with LATE-like atrophy patterns. This highlights its potential utility for identifying individuals with co-pathology in clinical settings. Our findings demonstrate that T-N mismatch within MTL using MRI and plasma biomarkers can reveal AD groups with varying vulnerability/resilience, with the vulnerable group displaying structural and cognitive outcomes suggestive of LATE-NC. This approach offers a cost-effective strategy for clinical trial stratification and precision medicine for AD therapeutics.},
}

@article {pmid40894158,
year = {2025},
author = {Cousins, KAQ and Boyle, R and Morse, C and Verma, A and Brown, CA and O'Brien, KS and Serper, M and Dehghani, N and , and McMillan, CT and Lee, EB and Shaw, LM and Wolk, DA},
title = {Electronic health records to test multimorbidity influences to plasma biomarker interpretation for Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.16.25333799},
pmid = {40894158},
abstract = {OBJECTIVE: Plasma biomarkers of Alzheimer's disease (AD) pathology are frequently tested in specialized research settings, limiting generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers - phosphorylated tau 217 (p-tau217), β-amyloid 1-42/1-40 (Aβ42/Aβ40) and p-tau217/Aβ42 - in a real-world, diverse clinical population with multimorbidities.

METHODS: Participants (n=617; 44% Black/African American; 41% female) were selected from the University of Pennsylvania Medicine BioBank with plasma assayed using Fujirebio Lumipulse. International Classification of Diseases (ICD) Ninth and Tenth Revision codes determined AD dementia (ADD; n=43), mild-cognitive impairment (MCI; n=140), unspecified/non-AD cognitive impairment (CI; n=106), and cognitively normal cases (n=328), and other medical histories. APOE ε4, body mass index (BMI), metrics of kidney function (e.g., eGFR), and liver disease were derived from electronic health records. Multivariable models identified factors related to plasma levels. Previously established cutpoints classified AD status ("AD+", "AD-", or "Intermediate").

RESULTS: Plasma p-tau217/Aβ42 had the strongest association with known AD-related factors - MCI, ADD, future progression to MCI/ADD, age, and APOE ε4 - compared to p-tau217 and Aβ42/Aβ40. Plasma p-tau217/Aβ42 was also associated with eGFR, diabetes, and history of hearing loss. Importantly, AD-related factors were most frequent/severe for AD+ classification by p-tau217/Aβ42, while medical morbidities were most frequent/severe for Intermediate classification. Exploratory analyses test p-tau217/Aβ42 adjusted for eGFR to eliminate its influence on plamsa levels.

INTERPRETATION: In this real-world dataset, we identified effects of multimorbidities on plasma biomarkers, especially kidney function. The p-tau217/Aβ42 ratio had low rates of Intermediate classification and may help to account for multimorbidity effects on plasma levels.},
}

@article {pmid40894157,
year = {2025},
author = {Wang, X and Bakulski, KM and Walker, E and Mukherjee, B and Dodge, H and Albin, RL and Paulson, HL and Park, SK},
title = {Exposure to Lead and Incidence of Alzheimer Disease and All-Cause Dementia in the United States.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.15.25333790},
pmid = {40894157},
abstract = {INTRODUCTION: Growing evidence suggests lead exposure may increase dementia risk, but evidence from human studies is limited. We investigated associations between lead exposure and incident Alzheimer disease (AD) and all-cause dementia in a nationally-representative, prospective cohort.

METHODS: We examined over 14,000 individuals with baseline measured blood lead and estimated patella and tibia lead from the National Health and Nutrition Examination Survey (NHANES)-III (1988-1994) and continuous NHANES (1999-2016), linked to Medicare and the National Death Index for incident AD and all-cause dementia, with up to 30 years of follow-up. Survey-weighted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: In continuous NHANES, estimated patella lead was positively associated with AD (HR=2.96, 95% CI: 1.37-6.39) and all-cause dementia (HR=2.15, 95% CI: 1.33-3.46), comparing quartile-4 vs. quartile-1. We observed weaker associations in NHANES-III. Blood lead showed no association.

DISCUSSION: These findings suggest cumulative lead as a potential dementia risk factor.},
}

@article {pmid40894034,
year = {2025},
author = {Cheng, F and Qiu, Y and Hou, Y and Wetzel, LW and Caldwell, J and Zhu, X and Liu, T and Pieper, A},
title = {Systematic characterization of cell type-specific master metabolic regulators in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7207381/v1},
pmid = {40894034},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) exhibits metabolic heterogeneity; yet, the consequences on metabolic dynamics in a cell-type-specific manner and the underlying metabolite-sensor network basis remain unclear. Here, we show that neurons exhibit a striking decrease in energy and lipid-related metabolic activity, contrasted by an increase in microglial metabolism associated with neuroinflammation. To identify brain cell-type specific master metabolic regulators underlying the metabolic alterations of AD, we introduce scFUMES (single cell FUnctional MEtabolite-Sensor), an algorithm integrating single-cell RNA sequencing, interactomics (protein-protein interactions), genomics, transcriptomics, and metabolomics from large human brain biobanks. Applied to two AD-vulnerable regions (middle temporal gyrus and dorsolateral prefrontal cortex), scFUMES uncovers hundreds of AD-associated regulators, with neurons and microglia showing the most interactions. Particularly, scFUMES pinpoints genetics-informed master metabolic regulators across AD severity, sex and APOE genotype (e.g., PPARD-glycerol in microglia). Experimental testing reveals that two interaction pairs predicted by scFUMES, neuronal palmitic acid bound fatty acid binding protein 3 and gut metabolite indole-3-propionic acid binding to kynurenine aminotransferase 1, both lower pathological tau species in AD. In summary, scFUMES identifies cell type-specific master metabolic regulators, offering insights into cellular metabolic heterogeneity and metabolism-targeted therapeutic strategies for AD and neurodegenerative diseases if broadly applied.},
}

@article {pmid40894028,
year = {2025},
author = {Deng, HW and Gong, Y and Zhang, QL and Wu, D and Liu, A and Li, T and Xiao, Z and Li, Y and Haeri, M and Swerdlow, R and Chen, Y and Yan, X and Shen, H and Xiao, HM},
title = {Novel Pathological Mechanisms Revealed by Spatial Transcriptomic Analysis of Hippocampus in Aged Control, Primary Age-Related Tauopathy, and Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7303622/v1},
pmid = {40894028},
issn = {2693-5015},
abstract = {While both Primary Age-Related Tauopathy (PART) and Alzheimer's Disease (AD) involve the accumulation of hyperphosphorylated tau (pTau)-positive neurofibrillary tangles (NFTs) in the hippocampus, PART is distinguished by the absence of β-amyloid (Aβ) deposition and is generally associated with milder cognitive impairment than AD. To delineate cellular and molecular mechanisms that are common or uniquely linked to disease progression in PART and AD, we constructed a transcriptome-wide, high-resolution atlas of the human hippocampus using samples from six individuals spanning the aged control (AC), PART, and AD groups. Our results supported that PART represent a precursor stage of AD, as evidenced by the altered transcriptional profiles of excitatory neurons (Exc) in the PART group, which exhibited a markedly increased capacity to promote Aβ production compared to both AC and AD groups. While the microglia (Mic) were reactivated in the PART group, this response was reduced in AD samples despite the presence of Aβ deposition, and appeared to further induce NFTs formation as a loop consequently driving the progression from PART to AD. Furthermore, subregion interactions in the signalling pathways related to neuronal survival and the maintenance of blood-brain-barrier (BBB) integrity were decreasing in the PART and disrupted in the AD groups, compared to the AC group. Additionally, we found a P53 signalling-related gene, TP53INP2 , was uniquely upregulated in astrocytes near large vessels in AD. This suggests a potential mechanism of vessel-induced neuronal apoptosis in AD, a feature absent in AC and PART. In summary, our study offers new insights into the relationship between PART and AD, along with the molecular mechanisms driving the transition from PART to AD. Furthermore, we identified key molecular pathways associated with BBB disruption and vascular-associated neuronal degradation in AD which were absent in PART. These findings deepen our understanding of AD pathogenesis and may inform the development of targeted therapeutic strategies.},
}

@article {pmid40894003,
year = {2025},
author = {Kridawati, A and Indrawati, L and Hadisaputra, S and Adawiyah, AR},
title = {The preventive role of tempeh isoflavones on menopausal women's cognitive function: A multiple mechanism pathway.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251371284},
doi = {10.1177/25424823251371284},
pmid = {40894003},
issn = {2542-4823},
abstract = {Cognitive dysfunction in the elderly is not only a disease but also could be considered a preclinical condition of Alzheimer's disease (AD), one of the most common types of dementia in the elderly. Therefore, treatment such as early detection and management of risk factors that could slow and prevent the onset of dementia is necessary for the elderly. Estrogen reduces the risk of AD in postmenopausal women. It has also been shown to reduce amyloid-β (Aβ) pathology in animal models of AD and suppress Aβ secretion from neuronal tissue. Estrogen receptors are involved in cognitive processes such as learning and memory, the formation of the hippocampus, the amygdala, and the cerebral cortex. Hormone replacement therapy (HRT) could improve cognition and thus delay the development of AD. Giving HRT after 9 years has been shown to increase the risk of breast cancer two-fold and cardiovascular disease. Phytoestrogens are hormones found in plants that can be an alternative to HRT. One of the foods that contains phytoestrogens and is widely consumed in Indonesia is tempeh. Isoflavone is a dominant phytoestrogen, structurally an estrogen-like substance, and functionally similar to 17β-estradiol. In this review article, we will discuss the role of tempeh isoflavones in a mechanism pathway on cognition.},
}

@article {pmid40894002,
year = {2025},
author = {Ramezannezhad, E and , },
title = {Longitudinal impact of cholinesterase inhibitors on cholinergic white matter integrity in mild cognitive impairment: A diffusion MRI study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251374681},
doi = {10.1177/25424823251374681},
pmid = {40894002},
issn = {2542-4823},
abstract = {BACKGROUND: Early degeneration of the cholinergic nucleus basalis of Meynert contributes to cognitive decline in Alzheimer's disease (AD). Microstructural damage in downstream cholinergic tracts-the cingulum bundle (CGC), entorhinal cortex (EC), and uncinate fasciculus (UNC)-often precedes volumetric atrophy. While cholinesterase inhibitors (ChEIs) can preserve cortical and hippocampal volume, their influence on white-matter integrity is unclear.

OBJECTIVE: To determine whether ChEIs slow microstructural decline in four cholinergic tracts (CGC, EC, UNC, posterior thalamic radiation [PTR]) in mild cognitive impairment (MCI), and whether baseline cognitive status modulates this effect.

METHODS: Diffusion-tensor imaging from the Alzheimer's Disease Neuroimaging Initiative was analyzed in 46 MCI participants receiving donepezil or rivastigmine and 62 untreated MCI controls, each scanned serially over two years. Fractional anisotropy (FA) and mean diffusivity (MD) indexed tract integrity. Linear mixed-effects models tested time × medication × baseline cognition (ADAS-Cog13) interactions, adjusting for age, sex, APOE ε4, and white-matter hyperintensity burden.

RESULTS: Across groups, CGC showed progressive degeneration (FA↓, MD↑; p < 0.001). Significant three-way interactions emerged for MD in bilateral CGC, FA in right EC, and MD in left PTR (all p < 0.01). ChEI users with milder baseline impairment (lower ADAS-Cog13) exhibited attenuated FA loss and MD increase, indicating slower microstructural decline; those with greater initial impairment derived minimal benefit. No medication effect was detected in UNC.

CONCLUSIONS: ChEIs confer tract-specific, stage-dependent protection of cholinergic white matter, particularly in early MCI. The findings underscore the value of initiating ChEI therapy before substantial cognitive deterioration and highlight the need for stage-tailored interventions aimed at preserving white-matter integrity in prodromal AD.},
}