@article {pmid41394741,
year = {2025},
author = {Tung, TH and Babu, S and Tang, X and Sciutto, A and Romer, M and Racha, P and Fisler, V and Saha, A and Saito, T and Saido, TC and Grinspan, JB and Mathys, H and Kozai, TDY and Cambi, F},
title = {Fus depleted oligodendrocytes reduce neuronal damage and attenuate AD progression in the App [NL-G-F] mouse.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.24.689041},
pmid = {41394741},
issn = {2692-8205},
abstract = {Oligodendrocytes (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of Alzheimer's Disease (AD). OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. To gain insight on how OL and myelin may improve neuronal deficits associated with AD, we have generated a novel mouse model (AD/cKO) by crossing the App [NL-G-F] mouse which carries three human AD mutations in the mouse App gene with the Fus [OL] cKO, which has thicker myelin associated with greater cholesterol biosynthesis. The spatial working memory deficits manifested by the aged AD mouse were fully rescued by the Fus [OL] cKO. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the plaque niches and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Single cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in protecting neurons and affecting microglia state in AD pathology.},
}

@article {pmid41394728,
year = {2025},
author = {Wang, Z and Veerareddy, V and Eberts, PM and Azarin, SM and Kandimalla, KK},
title = {Endothelial-pericyte interactions activate insulin signaling and its implications for blood-brain barrier dysfunction in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.24.690270},
pmid = {41394728},
issn = {2692-8205},
abstract = {PURPOSE: This study aimed to investigate how pericyte degeneration contributes to BBB disruption in Alzheimer's disease, focusing on the roles of insulin signaling and the imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs).

METHODS: We employed an in vitro BBB model by co-culturing brain-specific microvascular endothelial-like cells (iBMECs) differentiated from human induced pluripotent stem cells (hiPSCs) and primary human brain vasculature pericytes (hBVPs). Protein expression under solo- versus co-culture conditions was assessed by western blot. MMP enzymatic activity in the culture media was measured by fluorometric assay. Exosomes were isolated from conditioned media and brain derived neurotrophic growth factor (BDNF) concentrations were determined using ELISA assays.

RESULTS: TIMP1 and collagen-IV expression was significantly increased in co-cultured BBB endothelial cells and pericytes compared to solo-cultures. However, a greater effect was observed in cells co-cultured for 2 days than 7 days. Elevated TIMP1 in co-culture media significantly inhibited MMP activity. The AKT and ERK pathways were activated in both cell types after 7 days of co-culture, and the ERK signaling mediated TIMP1 upregulation in endothelial cells. BDNF was significantly enriched in exosomes isolated from co-culture media on the abluminal side compared to the solo-cultures. Endothelial cells also protected pericytes from accumulation of toxic amyloid-beta 42 by downregulating low density lipoprotein receptor-related protein 1 (LRP1) expression.

CONCLUSIONS: These findings provide mechanistic insights into BBB disruption due to pericyte degeneration and highlight the important role of BBB insulin resistance in causing cerebrovascular dysfunction in AD.},
}

@article {pmid41394696,
year = {2025},
author = {Houmam, S and Siodlak, D and Seshadri, M and Hallum, GB and Pezant, NP and Stanford, DR and Salinas-Salinas, C and Thomason, YM and Montgomery, CG and Rice, HC},
title = {Oligodendrocytes show enriched expression of amyloid precursor protein and GABA B receptor isoform 1a.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690528},
pmid = {41394696},
issn = {2692-8205},
abstract = {Amyloid precursor protein (APP) is a type I transmembrane protein that undergoes proteolytic processing to generate amyloid-β, the main component of amyloid plaques found in brains with Alzheimer's disease. The proteolytic processing of APP also generates soluble APP alpha (sAPPα) which can modulate synaptic transmission and neurite outgrowth through the γ-aminobutyric acid type B receptor (GABA B R). Whether GABA B R mediates functions of sAPPα in other neural cell types such as glia remains unknown. sAPPα binds the R1a subunit isoform of GABA B R1 which contains two sushi domains absent in R1b. It is unclear whether both GABA B R1 isoforms are expressed equally across brain cell types. We determined relative RNA levels of the GABA B R1a and 1b isoforms in oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons in adult mice using two approaches. We developed a GABA B R1 isoform-specific RNAseq analysis workflow to probe a publicly available dataset. We also isolated five cell types from a single mouse brain and performed RT-qPCR. We show that the GABA B R1a and 1b isoforms are differentially expressed among cell types. GABA B R1a expression was highest in oligodendrocytes and GABA B R1b expression was highest in astrocytes, suggesting that sAPPα-mediated GABA B R signaling may be most prominent in oligodendrocytes. We also confirmed that APP is expressed in all five cell types and showed that APP RNA levels are highest in oligodendrocytes. Together, our findings uncover cell type-specific expression of GABA B R isoforms and highlight oligodendrocytes as a principal cell type for GABA B R1a-mediated APP signaling, providing a foundation for future mechanistic studies.},
}

@article {pmid41394684,
year = {2025},
author = {Montesinos, J and Yun, TD and Salomón-Cruz, ID and Agudelo-Castrillón, SC and Uceda, M and Ferre, AC and Anton-Barros, C and Gomez-Lopez, N and Agrawal, RR and Larrea, D and Velasco, KR and Fernàndez-Bernal, A and Benitez, E and Zhu, X and Schon, EA and Lopera, F and Cardona-Gomez, GP and Area-Gomez, E},
title = {Upregulation of MAM by C99 disrupts ACSL4 activity and phospholipid homeostasis in Alzheimer's disease models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690197},
pmid = {41394684},
issn = {2692-8205},
abstract = {The structure and function of cellular and intracellular membranes are critically governed by the fatty acid (FA) composition of phospholipids (PLs), which is dynamically regulated by a network of enzymes that fine-tune lipid species according to cellular demands. In this study, we identify a mechanism through which the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) modulates the activity of the acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that channels polyunsaturated fatty acids (PUFAs) into phosphatidylcholine (PC) via the Lands cycle. Through integrated biochemical, proteomic, and lipidomic analyses in both cellular and animal models, we demonstrate that MAM formation enhances ACSL4 activity, promoting arachidonic acid (AA) activation and its preferential incorporation into PC in concert with the MAM-localized lysophospholipid acyltransferase 4 (LPCAT4). Our findings further uncover an unexpected link between this pathway and the pathogenesis of Alzheimer's disease (AD). We show that elevated levels of C99-the β-secretase cleavage product of amyloid precursor protein (APP)-induce MAM remodeling through cholesterol clustering, which in turn activates ACSL4 and alters PC composition. This effect is mirrored in AD models as well as in fibroblasts, neurons, and immune cells derived from both familial and sporadic AD patients, all of which exhibit chronically increased C99 levels, heightened ACSL4 activity, and enrichment of PUFA-containing PC species, leading to lipid imbalance and membrane dysfunction. Together, these results establish MAMs as dynamic lipid-regulatory hubs that coordinate ACSL4-dependent membrane remodeling and highlight the contribution of MAM dysregulation to lipid abnormalities observed in AD.},
}

@article {pmid41394664,
year = {2025},
author = {Philippe, TJ and Avey, DR and Kearns, NA and Vyas, H and Tissera, S and Xu, J and Ng, B and Saunders, DM and Lagrimas, AK and Duong, D and Seyfried, NT and Bennett, DA and Wang, Y},
title = {A Multi-omic Atlas of Human Choroid Plexus in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.23.690014},
pmid = {41394664},
issn = {2692-8205},
abstract = {The choroid plexus (CP) regulates barrier integrity, cerebrospinal-fluid (CSF) dynamics, and immune surveillance, yet its role in Alzheimer's disease (AD) remains poorly defined. We performed snRNA-seq on CP samples from 69 ROSMAP participants spanning normal cognition, mild cognitive impairment, and AD dementia, and integrated these data with spatial transcriptomics, snATAC-seq, and proteomics from CP tissue and CSF. We identified 17 CP cell states and uncovered widespread disease-associated transitions that converged into three major phenotypic axes. Along the inflammatory axis, epithelial cells and border-associated macrophages (BAMs) showed progressive immune activation, with BAMs shifting from inflammatory to stress-dominant states. In the barrier axis, epithelial cells, fibroblasts, and endothelial cells exhibited reduced junction-related gene expression and broad alterations in transport pathways. Epithelial cells also showed late-stage cilia loss and CSF-regulatory pathway impairment, indicating a breakdown in epithelial polarity and CSF sensing, consistent with abnormal CSF proteomic signatures. Along the remodeling axis, fibroblasts showed bidirectional ECM alterations, while epithelial and stromal cells demonstrated aberrant cell-matrix adhesion pathways. Spatial neighborhood analysis revealed a multicellular signaling hub, with epithelial-rich niches showing the strongest dysregulation in AD. Together, these findings define a unified model of CP dysfunction in AD and position the CP as an active, multicellular contributor to AD pathophysiology.},
}

@article {pmid41394641,
year = {2025},
author = {Blumenfeld, J and Li, Y and Kim, MJ and Yip, O and Yao, L and De Leon, S and Fulthorpe, R and Shostak, D and Platow, Z and Suan, K and Hao, Y and Koutsodendris, N and Ellis, C and Nguyen, J and Huang, Y},
title = {Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690488},
pmid = {41394641},
issn = {2692-8205},
abstract = {Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target.},
}

@article {pmid41394599,
year = {2025},
author = {Deshpande, A and Bei, Z and Ma, J and Krieger, S},
title = {MIMYR: Generative modeling of missing tissue in spatial transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.24.690239},
pmid = {41394599},
issn = {2692-8205},
abstract = {Spatial transcriptomics enables the study of how gene expression is organized across tissues, revealing how cells interact within their native microenvironments in health and disease. However, tissue damage during sectioning and the allocation of intermediate slices to other assays often result in regions or entire planes missing from the data, limiting downstream analysis. Here, we introduce MIMYR, a generative framework for reconstructing realistic spatial transcriptomics data in unmeasured tissue regions. MIMYR addresses this challenge through three coupled components: predicting cell locations via guided diffusion, assigning cell types through supervised classification, and generating gene expression profiles with a transformer conditioned on spatial and cellular context. MIMYR accurately reconstructs held-out regions in mouse brain data and generalizes across experimental conditions, including variations in gene panels and slicing orientations. After finetuning on limited Alzheimer's disease data, MIMYR captures disease-associated transcriptional changes in unmeasured brain regions. By enabling high-fidelity spatial imputation from limited training data, MIMYR extends the utility of spatial transcriptomics, allowing researchers to recover unmeasured tissue states and deepen investigations into tissue spatial organization and dynamics.},
}

@article {pmid41394596,
year = {2025},
author = {Liu, A and De Jager, PL and Bennett, D and , and Wang, G and Denault, WRP},
title = {mfSuSiE enables multi-cell-type fine-mapping and multi-omic integration of chromatin accessibility QTLs in aging brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690439},
pmid = {41394596},
issn = {2692-8205},
abstract = {Molecular quantitative trait locus (QTL) studies increasingly profile chromatin accessibility, histone modifications, DNA methylation, RNA modifications such as N6-methyladenosine (m6A), and transcription across multiple cell types using high-throughput sequencing, generating dense base-pairresolved measurements. The conventional approach of testing each variant against each molecular feature independently suffers from severe multiple testing burden and ignores linkage disequilibrium and spatial correlation. Existing fine-mapping methods only partially address these challenges and are suboptimal for analyzing such datasets: multivariate approaches such as mvSuSiE jointly analyze multiple molecular contexts but are designed for a single trait value per context and cannot accommodate thousands of base-resolution measurements per context, while functional approaches such as fSuSiE model spatial structure across thousands of measurements but analyze each context separately. Here, we introduce mfSuSiE , which integrates multivariate analysis with wavelet-based functional regression to jointly fine-map thousands of base-resolution traits across multiple cell types. In simulations, mfSuSiE identified causal variants and affected molecular features more accurately than fSuSiE , while mvSuSiE cannot be applied to this type of data. Applied to single-nucleus chromatin accessibility data from six brain cell types from postmortem aging human brains, mfSuSiE substantially increased discovery and resolution, with substantial power gains for cell types with limited samples. Multi-cell-type analysis revealed extensive sharing of regulatory effects on chromatin accessibility (caQTL). Importantly, mfSuSiE produces Bayesian inference compatible with the SuSiE framework, enabling systematic multi-omic integration. Applied to Alzheimer's disease loci, we integrated caQTL with expression QTLs, epigenomic QTLs, and GWAS, observing regulatory patterns suggesting complex mechanisms at loci including EARS2, CHRNE, SCIMP , and RABEP1 .},
}

@article {pmid41394565,
year = {2025},
author = {Cardona-Gómez, GP and Salomón-Cruz, ID and Lozano-Trujillo, LA and Galvis-Garrido, ND and Agudelo-Castrillon, SC and Barbosa-Carvajal, JP and Ríos, MH and Trujillo-Chacón, LM and Henao, E and Fernandez, GJ and Osorio, E and Quiroz, YT and Schon, E and Lopera, F and Villegas, A and Aguirre-Acevedo, DC and Arias-Londoño, JD and Aguillón, D and Area-Gómez, E},
title = {Serum Lipidome as an Early Peripheral Indicator in Familial Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690392},
pmid = {41394565},
issn = {2692-8205},
abstract = {Protein biomarkers in biofluids are highly sensitive indicators of prodromal cognitive impairment yet remain limited for primary prevention. Lipids, essential to brain structure and function, offer untapped prognostic value. Here, we identify a lipidomic signature in serum from asymptomatic PSEN1-E280A mutation carriers aged 6-40 years, that differentiate carriers from non-carriers with an AUC 80-90%. Similarly, to symptomatic carriers (≥41 years; 93%) and sporadic AD cases (85%), using high-resolution mass spectrometry. Latent profile analysis revealed lipid-based signatures of dementia risk and resilience, shaped by genotype, sex, and APOE isoform, and supported by SIMOA protein biomarkers. Age-dependent dysregulation in sphingolipid and glycolipid metabolism was validated by enzymatic activity (TLC), glial phenotyping (flow cytometry), and gene expression (snRNAseq) in postmortem brain. Ganglioside clearance deficits emerged by age 6-12, followed by proinflammatory shifts from age 13 and p-tau217 elevation by age 20, with greater burden in females and APOE4 carriers. APOE3Ch individuals showed differential salvage pathways of ceramides and gangliosides. These findings position early lipid pathway dysregulation as a biological contributor to Alzheimer's pathogenesis and a potential therapeutic target for primary prevention.},
}

@article {pmid41394556,
year = {2025},
author = {Seto, M and Klinger, HM and Clifton, M and Janve, VA and Brown, JA and Birkenbihl, C and Coughlan, G and Townsend, DL and Wang, TC and Properzi, M and Hanseeuw, B and Chhatwal, J and Yang, HS and Rissman, RA and Aisen, P and Cuppels, M and Donohue, MC and Raman, R and Johnson, KA and Sperling, RA and Dumitrescu, L and Hohman, TJ and Buckley, RF},
title = {Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.21.689770},
pmid = {41394556},
issn = {2692-8205},
abstract = {Plasma pTau217, an emerging Alzheimer's disease (AD) biomarker, may reflect a synaptic response to β-amyloid (Aβ) plaques before cortical tangle formation, but the broader biological processes at play remain unclear. Using whole blood RNAseq, we sought to identify gene expression associated with plasma pTau217 and to determine whether APOE ε4, sex, and neocortical Aβ-PET burden further amplify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Studies. 1,540 genes were moderated by Aβ-PET, and 772 genes were moderated by both Aβ-PET and sex. Our findings include genes previously associated with AD (e.g., TREML2) and implicate biological functions such as chromatin remodeling, lipid signaling, and RNA processing that interact with Aβ-PET and sex to impact plasma pTau217. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated Aβ-PET.},
}

@article {pmid41394343,
year = {2025},
author = {Schweitzer, N and Cover, C and Aizenstein, H and Wu, M and Vazquez, A and Iordanova, B},
title = {Near-lifespan mesoscopic optical imaging of cerebrovascular function reveals age and sex differences in preclinical Alzheimer's disease model.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf472},
pmid = {41394343},
issn = {2632-1297},
abstract = {Growing evidence suggests vascular dysfunction plays a critical role in the early stages of Alzheimer's disease, commonly associated with amyloid-β deposition. This vascular dysfunction is particularly relevant in the context of cerebral amyloid angiopathy, where amyloid-β accumulates within cerebral vessel walls. Notably, sex differences impact progression of both Alzheimer's disease and cerebrovascular dysfunction, with post-menopausal females displaying increased small vessel disease burden and diminished carbon dioxide reactivity compared to older males and pre-menopausal females. Moreover, the cerebrovasculature is a target of sex hormones where they exert influence in numerous vascular functions and pathologies across lifespan. Combined, cerebrovascular dysfunction along with amyloid-β deposition may have differential effects on sex. Despite observational studies in humans, preclinical mechanistic and functional research on sex-specific vascular differences in Alzheimer's disease has been limited. In this near-lifespan longitudinal study, we investigated age and sex-specific neurovascular coupling and carbon dioxide reactivity in a transgenic mouse model expressing chimeric mouse/human amyloid precursor and mutant human presenilin 1 (APP/PS1) and control mice using widefield optical imaging. Neurovascular coupling was probed via whisker stimulation and then vascular reactivity was measured using hypercapnic challenge. During whisker stimulation, neuronal activity was measured through GCaMP6f fluorescence change, while vascular response was quantified via haemoglobin-based optical intrinsic signal. Carbon dioxide reactivity was evaluated by measuring dilatory changes of vessel diameters across the cerebrovascular tree. In vivo two-photon microscopy was used to longitudinally measure cerebral amyloid angiopathy vessel coverage and amyloid-β tissue plaque volume. We observed that APP/PS1 mice exhibited attenuated neurovascular coupling during whisker stimulation and this response worsened through lifespan compared to controls. Compared to controls, APP/PS1 mice exhibited decreased carbon dioxide reactivity with age. No sex differences between control mice were observed in the neurovascular response to whisker, whereas during hypercapnia, control females had higher carbon dioxide reactivity than control males. While both APP/PS1 males and females showed reduced dilatory responses with age, APP/PS1 females exhibited this decrease in small arteries, whereas APP/PS1 males experienced decreased dilation in larger arteries. Diminished vascular reactivity in APP/PS1 mice was associated with increased cerebral amyloid angiopathy and amyloid-plaque burden. This study highlights sex-specific pathophysiology's of vascular dysfunction across the lifespan. Our findings underscore needs to incorporate sex differences in preclinical Alzheimer's disease research, given the rising importance of vascular contributions to cognitive impairment and dementia. Our findings have important implications for developing targeted, age and sex-specific biomarkers and therapeutics for cerebrovascular health in Alzheimer's disease.},
}

@article {pmid41394158,
year = {2025},
author = {Li, Y and Zhang, Y and Liu, M and Dawuti, T and Chen, X and Xiao, H},
title = {Polyphenol-rich Morus nigra L. extract mitigates neuroinflammation and cognitive impairment through gut-brain axis modulation in an Alzheimer's disease rat model.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1695768},
pmid = {41394158},
issn = {1663-9812},
abstract = {BACKGROUND: The gut-brain axis (GBA) has emerged as a critical pathway in the pathogenesis of Alzheimer's disease (AD), offering a potential target for dietary interventions. This study aimed to explore the neuroprotective effects of a polyphenol-enriched extract from Morus nigra L. fruits (MMF) in an AD rat model, focusing on gut-brain communication.

METHODS: AD-like pathology was induced in rats using a combination of D-galactose and aluminum chloride, followed by a 10-week MMF treatment. Cognitive performance was evaluated using the Morris water maze, and brain Aβ1-42 accumulation and neuroinflammation (Iba1, GFAP) were assessed. Multi-omics approaches, including 16S rDNA sequencing and untargeted colonic metabolomics, were applied.

RESULTS: MMF treatment significantly enhanced spatial memory, reduced hippocampal Aβ burden, and attenuated glial activation. Furthermore, MMF restored gut microbial diversity and increased the abundance of short-chain fatty acid-producing Firmicutes taxa, which were inversely correlated with inflammation. Metabolomics analysis revealed that MMF modulated bile acid and lipid metabolic pathways, with β-muricholic acid, DHA, and ergosterol identified as key effectors.

CONCLUSION: MMF alleviates AD pathology through modulation of the gut microbiota and metabolic reprogramming, suggesting a promising microbiota-targeted strategy for AD prevention.},
}

@article {pmid41394066,
year = {2025},
author = {Rubiño-Díaz, JÁ and Zapata-Moreno, M},
title = {Highly sensitive early-onset Alzheimer's disease: a case report.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1688924},
pmid = {41394066},
issn = {1664-1078},
abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD) is an atypical syndrome that can be confused with other neurodegenerative diseases. This disease presents before the age of 65, with symptoms that generally affect executive functions, praxis, and visuoperceptual abilities, as opposed to episodic memory. Highly sensitive individuals present the temperament trait of sensory processing sensitivity, which is characterized by a differential susceptibility compared to other individuals. Neuropsychological evaluation should involve a holistic and integrative person-centered care approach for optimal treatment and disease progression.

CASE SUMMARY: A highly sensitive 54-year-old individual was diagnosed with EOAD at age 47 in 2017. Neuropsychological follow-up was conducted for 6 years. Initial neuropsychological testing revealed a cognitive pattern with impairments in executive functions, attention, and visual perception, the advancement of which led to a progressive deterioration in daily, occupational, and social functioning. During this period, he received psychotherapy from a psychologist specializing in neuropsychology and high sensitivity, using a holistic and integrative approach. Initially, sessions were held twice a week throughout the first year of consultation and, subsequently, continued at the patient's home and in his usual context, using a completely ecological perspective and consisting of person-centered care. In 2022, the patient, aged 59, was admitted to a nursing home. This situation, outside his usual environment, without autobiographical references and his own life story, led to accelerated deterioration, with the patient ultimately dying at age 60, in 2023.

CONCLUSION: The patient with highly sensitive EOAD was followed for 6 years by a psychologist specializing in neuropsychology and high sensitivity. Neuropsychological intervention was maintained with a holistic and integrative person-centered approach using the unmet needs model to address cognitive, psychological, and functional levels. Follow-up with this approach could be key to slowing the disease and ensuring patient satisfaction throughout the entire progression of the illness. Greater visibility into unusual cases like this will enable psychology professionals to be vigilant for timely differential and diagnostic testing, which will significantly impact the treatment and progression of the illness, ultimately influencing quality of life and well-being through an optimal neuropsychological approach.},
}

@article {pmid41393998,
year = {2025},
author = {Wang, Y and Zhou, J and Zhou, Q and Wang, H},
title = {New progress on the role and mechanism of tau protein in Alzheimer's disease and depression.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1551273},
pmid = {41393998},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by two major pathological hallmarks: (1) the formation of extracellular β-amyloid (Aβ) plaques; (2) the accumulation of intracellular neurofibrillary tangles (NFTs) composed of phosphorylated tau. The number of NFTs is positively correlated with the severity of AD. However, there are still no effective strategies to treat or slow AD progression. Despite recent approvals of anti-Aβ therapies, their limited clinical benefit has shifted increasing attention toward tau pathology as a parallel driver of AD progression. In recent years, the importance of tau in the pathogenesis of Alzheimer's disease increasingly recognized. The transmission of pathogenic tau proteins in the brain, known as prion-like seeding, is considered a key driving factor for AD. Post-translational modifications of tau-such as hyperphosphorylation, acetylation, glycosylation, ubiquitination, and truncation-promote the onset and progression of Alzheimer's disease. Consequently, tau-targeting therapies have become a major focus in anti-AD research, though most remain at the pre-clinical stage. Furthermore, depression is highly prevalent in AD patients, representing both a potential risk factor and a consequence of the disease. Depression is a risk factor of AD, it is also a consequence of AD. Researchers have found that tau is closely related to depression, not Aβ. This review will focus on tau, tau and AD, post-translational modification of tau, tau targeting strategies, and the role of tau in depression. Since tau pathology not only disrupts synaptic and neuronal networks but also affects limbic and cortical circuits involved in emotion regulation, its dysfunction may underlie depressive symptoms frequently observed in AD. Therefore, understanding tau's neural impact provides a mechanistic bridge between AD pathology and depression.},
}

@article {pmid41393958,
year = {2025},
author = {Nacer, M and Kalla, A and Tamfu, AN and Boudiba, S and Hanini, K and Hioun, S and Messaoudi, M and Atoki, AV and Kucukaydin, S and Latifa, K and Ceylan, O and Boudiba, L},
title = {Phenolic profile of different solvent extracts of Reseda alba L. and evaluation of anti-quorum sensing, antioxidant, and enzyme inhibition activities.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1699534},
pmid = {41393958},
issn = {2296-861X},
abstract = {BACKGROUND: Reseda alba (white mignonette) is a wild, edible, and medicinal plant native to the Mediterranean region, with limited studies on its chemical composition and bioactivities.

METHODS: The phenolic profile and bioassays of antioxidant, anti-swarming, quorum sensing (QS), and enzyme inhibitory activities of different solvent extracts of R. alba are investigated using high-performance liquid chromatography with diode-array detection (HPLC-DAD).

RESULTS: Rosmarinic acid was identified as the predominant phenolic compound in the ethyl acetate extract (197.5 ± 0.25 μg/g) and n-butanol extract (205.4 ± 0.47 μg/g). Minimal inhibitory concentrations (MICs) ranged from 0.3125 to 2.5 mg/mL against Chromobacterium violaceum and Pseudomonas aeruginosa PA01. These extracts demonstrated significant inhibition of quorum sensing and swarming motility against C. violaceum and P. aeruginosa PA01 at MIC and sub-MIC. Extracts exhibited inhibition of enzymes, especially cholinesterases implicated in neurodegenerative diseases. The extracts demonstrated antioxidant activity, as determined through six assays, with the dichloromethane extract (DCME) exhibiting higher antioxidant activity compared to the standards α-tocopherol and ascorbic acid in the ferric-reducing antioxidant power (FRAP) assay.

CONCLUSION: The results demonstrate that R. alba extracts (RAEs) possess significant inhibitory effects on enzymes implicated in neurodegenerative disorders, such as Alzheimer's disease, particularly through butyrylcholinesterase inhibition. Additionally, the extracts show promising anti-quorum sensing and anti-swarming activities, which could reduce microbial virulence and biofilm formation, suggesting potential as alternative antimicrobial agents. The moderate antioxidant activity further supports its therapeutic potential. Overall, R. alba could be developed as a natural source for managing enzyme-related diseases and controlling bacterial infections by targeting microbial communication mechanisms.},
}

@article {pmid41393957,
year = {2025},
author = {Wei, L and Li, Z and Shi, M and Song, W and Teng, Z and Zhang, C},
title = {Neuroprotective properties of extra virgin olive oil polyphenols in Alzheimer's disease: a multi-target mechanistic review.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1736633},
pmid = {41393957},
issn = {2296-861X},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated tau protein, neuroinflammation, and mitochondrial dysfunction. The limited efficacy of single-target pharmacological strategies has spurred interest in multi-target therapeutic approaches. Extra virgin olive oil (EVOO), rich in diverse polyphenolic compounds, has emerged as a promising source of such multi-target neuroprotective agents. This review systematically elucidates the mechanisms of key EVOO polyphenols-hydroxytyrosol, oleuropein, tyrosol, verbascoside, oleocanthal, and ligustroside-in combating AD pathology. We highlight the growing body of evidence demonstrating that these polyphenols can synergistically inhibit the aggregation of Aβ and tau, mitigate neuroinflammation, restore mitochondrial function, reduce oxidative stress, and promote neurogenesis. Preclinical studies in cellular and animal models of AD consistently show that EVOO polyphenols can ameliorate cognitive deficits and pathological hallmarks. Future research should focus on validating these benefits in animals and clinical trials and developing optimized formulations for clinical application. In conclusion, the bioactive polyphenols in EVOO present a compelling multi-targeted therapeutic strategy with significant potential to delay the progression of AD by concurrently modulating multiple key pathological pathways.},
}

@article {pmid41393939,
year = {2025},
author = {Li, L and Wang, K},
title = {Integrative effects of saffron and physical activity on endurance performance, quality of life, cognitive, emotional, and metabolic outcomes in age-related and neurodegenerative diseases.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1698135},
pmid = {41393939},
issn = {2296-861X},
abstract = {Age-related diseases, including cardiovascular disorders, type 2 diabetes, neurodegenerative conditions such as Alzheimer's and Parkinson's disease, and age-related eye diseases, represent leading causes of disability and mortality worldwide. Growing evidence highlights the therapeutic promise of non-pharmacological interventions, notably saffron (Crocus sativus L.) and structured exercise, both of which exert pleiotropic effects through antioxidant, anti-inflammatory, and neuroprotective pathways. In this review, we summarize current experimental and clinical data on saffron's bioactive compounds, crocin, crocetin, and safranal, and their capacity to modulate lipid metabolism, insulin sensitivity, mitochondrial function, and protein aggregation. Parallel findings from exercise research demonstrate improvements in cardiovascular function, glycemic control, neuroplasticity, and ocular health. Importantly, emerging studies reveal synergistic benefits when saffron supplementation is combined with physical activity, resulting in amplified improvements in vascular remodeling, glycemic regulation, neurotrophic signaling, and behavioral outcomes. These complementary interventions target shared molecular pathways, including PI3K/Akt/mTOR signaling, SIRT1-PGC-1α activation, Nrf2-mediated antioxidant defense, and modulation of inflammatory cytokines. Taken together, saffron and exercise represent safe, accessible, and multi-target strategies that may delay or attenuate the progression of aging-related diseases. Future large-scale, long-term clinical trials are warranted to establish optimal protocols and to integrate these interventions into preventive and therapeutic frameworks for healthy aging.},
}

@article {pmid41393862,
year = {2025},
author = {Stein, RG and Falck, RS and Tai, D and Crockett, RA and Davis, JC and Hsiung, GYR and Eng, JJ and Middleton, LE and Hall, PA and Liu-Ambrose, T},
title = {The interaction effect of physical activity and sleep on cognitive function in stroke.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70185},
pmid = {41393862},
issn = {2352-8737},
abstract = {INTRODUCTION: Having a stroke increases risk for dementia two-fold. Poor sleep quality and quantity are common after a stroke and are associated with cognitive impairment. Physical activity benefits cognitive function. Whether there is an interaction effect of physical activity and sleep on cognitive function among persons living with chronic stroke is unknown.

METHODS: A cross-sectional study used baseline data acquired from 97 community-dwelling adults aged ≥55 years, living with chronic stroke (71±9 years; n = 38, female), and enrolled in a 6-month randomized controlled trial. We measured physical activity (i.e., moderate to vigorous physical activity [MVPA] and light physical activity [PA]) and sleep quality and quantity (i.e., efficiency, latency, duration) using wrist-worn accelerometry. Global cognitive function was measured with the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-13). We assessed whether the interaction of physical activity (MVPA and light PA) with sleep quality and quantity (interaction term: physical activity * sleep) was associated with ADAS-Cog-13 score: (1) in the full sample and (2) among males and females separately (i.e., sex-stratified). Significant moderations were plotted as continuous simple slopes.

RESULTS: In the full sample, there was a significant interaction effect between MVPA and sleep duration on the ADAS-COG-13 score (ß = 1.636 ± 0.787; p = 0.041). Specifically, among individuals with shorter sleep duration (i.e., one standard deviation below mean sleep duration), those with greater MVPA had better ADAS-Cog-13 performance. In the sex-stratified analysis, the interaction effect of MVPA and sleep duration on cognitive function was significant in males (ß = 3.417 ± 1.374; p = 0.016) but not females.

DISCUSSION: Moderate to vigerous physical activity may mitigate the negative impact of shorter sleep on cognitive function among persons living with stroke, particularly males.

HIGHLIGHTS: Physical activity and sleep are associated with cognitive function following stroke.Physical activity may ameliorate the negative effects of poor sleep on cognitive function.Females suffer greater health consequences of sleep dysregulation than males.Physical activity moderates the association of sleep duration and cognitive function.Physical activity may promote cognitive function in males with short sleep duration.},
}

@article {pmid41393810,
year = {2025},
author = {Terao, CM and Erani, F and Weigand, AJ and Gross, AL and Edmonds, EC and Bangen, KJ and An, Y and Walker, KA and Resnick, SM and Thomas, KR},
title = {Data-driven neuropsychological phenotypes in the Baltimore Longitudinal Study of Aging.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70220},
pmid = {41393810},
issn = {2352-8729},
abstract = {INTRODUCTION: This study aimed to identify phenotypes of subtle variation in multidomain cognitive performance and examine their longitudinal associations with Alzheimer's disease and related dementias (AD/ADRD) biomarkers and cognitive outcomes.

METHODS: Among 1192 cognitively unimpaired (CU) older adults from the Baltimore Longitudinal Study of Aging, latent profile analysis (LPA) identified phenotypes based on baseline patterns of neuropsychological test performance. Mixed-effects and Cox models examined longitudinal differences in cognitive status and AD/ADRD biomarkers (phosphorylated tau-181 [pTau181], amyloid-beta 42/40 ratio [Aβ42/Aβ40], neurofilament light [NfL], and glial fibrillary acidic protein [GFAP]) across phenotypes.

RESULTS: LPA identified the following cognitive phenotypes: Overall Low Average, Dysexecutive (n = 112); Overall Average, Low Memory (n = 284); Overall Average, High Memory (n = 449); High Executive, Relatively Low Memory (n = 214); and Overall High Performing (n = 133). Phenotypes differed in longitudinal rates of cognitive decline and increases in NfL.

DISCUSSION: Subtle variations in neuropsychological performance among CU older adults have implications for long-term cognitive health and may help inform Alzheimer's disease and related dementias diagnosis and disease monitoring.

HIGHLIGHTS: Significant cognitive heterogeneity exists in CU older adults.LPA identified phenotypes based on cognitive performance.Personality and psychosocial characteristics differed by cognitive phenotype.Cognition over time and risk of cognitive impairment differed by cognitive phenotypes.The phenotype with greatest executive dysfunction had the fastest increase in NfL.},
}

@article {pmid41393654,
year = {2025},
author = {Arai, H},
title = {MRI-Based Medial Temporal Atrophy May Reflect Amyloid PET Positivity in Cognitively Normal Individuals: A Preliminary Study.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96751},
pmid = {41393654},
issn = {2168-8184},
abstract = {This study investigated whether magnetic resonance imaging (MRI)-based medial temporal morphometry can predict amyloid positron emission tomography (PET) positivity in cognitively normal individuals. Sixteen consecutive participants (eight amyloid PET-positive and eight PET-negative) were retrospectively identified, all within the normal cognitive range (Mini-Mental State Examination 28-30). Amyloid PET was performed using florbetapir, with visual interpretation as the primary diagnostic criterion and Centiloid values as supportive measures. MRI-derived volumetric analysis was conducted using the voxel-based specific regional analysis system for Alzheimer's disease (AD) to quantify medial temporal atrophy. Although between-group differences in hippocampal indices did not reach statistical significance, the PET-positive group showed a trend toward greater atrophy, and centiloid values correlated positively with medial temporal indices. Receiver operating characteristic analysis indicated fair discrimination, highest for the volume-of-interest-to-gray-matter ratio (area under the curve = 0.83). These preliminary findings suggest that subtle hippocampal alterations on routine structural MRI may mirror early amyloid pathology even before cognitive impairment, supporting the potential of MRI-based morphometric assessment as an adjunctive biomarker for early AD detection.},
}

@article {pmid41393341,
year = {2025},
author = {Mekulu, K and Aqlan, F and Yang, H},
title = {Agentic artificial intelligence in cognitive screening: A translational roadmap for dementia care.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407989},
pmid = {41393341},
issn = {2542-4823},
abstract = {Conventional dementia screening tools, whether paper tests or static artificial intelligence (AI) models, capture only a snapshot of cognition and need to be adminstered periodically. Yet decline is dynamic, shaped by environment, comorbidities, and life history. Current approaches rarely adapt, integrate feedback, or provide transparent reasoning that clinicians can trust. We propose agentic AI systems: modular agents built on large language models (LLMs) that collaborate, adapt, and mirror interdisciplinary care. The Cognitive Agent Lab exemplifies this framework, emphasizing functional aspects (inputs, outputs, workflows) and non-functional aspects (transparency, adaptivity, robustness, clinical alignment). Embedding reasoning and collaboration, agentic AI offers a roadmap toward more personalized and explainable cognitive health tools.},
}

@article {pmid41393340,
year = {2025},
author = {Porsteinsson, AP and Sabbagh, M and Tariot, PN and Church, KJ and San Martin, J and Ooi, KC and Daggett, S and Hale, MD and Holub, R and Moebius, HJ},
title = {Fosgonimeton in mild-to-moderate Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251405817},
pmid = {41393340},
issn = {2542-4823},
abstract = {BACKGROUND: Fosgonimeton, a small-molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, was studied in participants with Alzheimer's disease (AD).

OBJECTIVE: To assess the efficacy and safety of fosgonimeton in AD.

METHODS: LIFT-AD was a randomized, placebo-controlled, Phase 2/3 trial (NCT04488419; 23Jun2020), the primary analysis (N = 287) included participants with mild-to-moderate AD not receiving concomitant acetylcholinesterase inhibitors (AChEIs) randomized 1:1 to daily subcutaneous fosgonimeton 40 mg or placebo. The primary endpoint, the Global Statistical Test (GST) score, combined ADAS-Cog11 and ADCS-ADL23. Secondary endpoints included ADAS-Cog11, ADCS-ADL23, and NfL. Exploratory endpoints included plasma biomarkers of AD. Safety included all dosed participants, including those receiving and not receiving AChEIs or randomized to fosgonimeton 70 mg (N = 549).

RESULTS: The trial did not achieve its primary or secondary endpoints; between-group difference in the least-square mean change (SE) from baseline to Week 26 in the GST score was -0.08 (0.10) (p = 0.70), -0.70 (0.77) (p = 0.35) in ADAS-Cog11, and +0.67 (0.92) (p = 0.61) in ADCS-ADL23. This showed small differences favoring fosgonimeton versus placebo. Nominally significant changes in plasma biomarkers were observed in p-τ217 only. Fosgonimeton had an acceptable safety profile. Serious AEs were balanced between groups (4.2% fosgonimeton, 6.9% placebo). More participants in the fosgonimeton group (14.2%) discontinued due to AEs versus placebo (4.6%), mostly from injection site reactions.

CONCLUSIONS: Fosgonimeton did not significantly improve ADAS-Cog11 or ADCS-ADL23 versus placebo. However, the consistently observed non-significant improvements favoring fosgonimeton suggests potentially relevant biological activity with fosgonimeton and that positive modulation of HGF signaling may impact components of the pathophysiologic processes of neurodegenerative diseases.},
}

@article {pmid41393339,
year = {2025},
author = {Parhizi, B and Kolady, R and Vogel, MT and Singh, RK and Bekena, S and Chokkalingam, R and Zhu, Y and Babulal, GM},
title = {Driving into diagnosis: Leveraging high-resolution telematics and sensorimotor profiling to identify preclinical Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407543},
pmid = {41393339},
issn = {2542-4823},
abstract = {BACKGROUND: Early detection of preclinical Alzheimer's disease (AD) could expand preventative care. Current biomarkers are costly, invasive, or lack generalizability. Driving and sensorimotor performance may reveal prodromal changes.

OBJECTIVE: We tested whether features from high-frequency driving trips detect preclinical AD and whether demographic, genetic, or sensorimotor data improve accuracy.

METHODS: Drivers aged ≥ 65 (n = 254) from Driving Real-World In-Vehicle Evaluation System (DRIVES) completed cerebrospinal fluid Aβ42/Aβ40 and amyloid Positron emission tomography (PET) to label amyloid positive (preclinical AD) or negative. A GPS datalogger recorded location (1 Hz) and accelerometer/gyroscope (20 Hz) data between June 2022 and January 2024. Eleven driving features (e.g., average speed, jerk, idle time, turns) were extracted per trip. Vision, hearing, olfaction, gait, and grip strength were assessed. TabNet models classified amyloid status using (1) driving only, (2) driving plus age and APOE ε4, and (3) driving plus age, APOE ε4, sex, and education. LightGBM models evaluated sensorimotor features. Performance was measured on a 20% held-out test set (AUC, accuracy, precision, recall, F1).

RESULTS: The top-performing model (driving, age, APOE ε4, sex, education) achieved an AUC of 0.84, accuracy of 0.85, and F1 score of 0.85. Key predictors were idle time, turns, and average jerk. Sensorimotor models performed modestly (AUCs of 0.66 [sensory alone] and 0.67 [sensory and sociodemographic]), with grip strength and word-in-noise scores as the top contributors.

CONCLUSIONS: A high-frequency trip's driving telemetry, combined with age and APOE ε4 status, discriminates preclinical AD, outperforming multisensory measures. Driving offers a scalable, digital biomarker to complement conventional testing. Monitoring may enable population-level screening for older adults at risk.},
}

@article {pmid41393338,
year = {2025},
author = {Georgescu, MF and Fischer, IC and Beydoun, MA and Vaccarino, V and Pietrzak, RH},
title = {Subjective cognitive decline among older U.S. military veterans: A 3-year, nationally representative, longitudinal study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407258},
pmid = {41393338},
issn = {2542-4823},
abstract = {Subjective cognitive decline (SCD) is an early risk marker for dementia. This study examined the 3-year incidence and predictors of SCD using the Medical Outcomes Study Cognitive Functioning Scale-Revised in a national sample of 1858 U.S. military veterans aged ≥60. Clinically significant SCD occurred in 5.4% of veterans, with an average decline of 1.73 standard deviations. Lower perceived resilience-specifically lower endorsement of "I bounce back after hardship" (35.1% relative variance explained) and "Coping with stress can make me stronger" (33.8%)-chronic pain (18.7%) and sleep difficulties (12.4%) emerged as the strongest predictors of SCD. Interventions targeting these risk factors may help mitigate SCD in veterans.},
}

@article {pmid41393111,
year = {2025},
author = {Costa, T and Liloia, D},
title = {Are current etiological theories of Alzheimer's disease falsifiable? An epistemological assessment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1708234},
pmid = {41393111},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) research is plagued by a proliferation of competing etiological theories, often coexisting without undergoing systematic critical comparison. This article examines the epistemological limitations of the traditional falsifiability criterion, formulated by Karl Popper, and demonstrates how this principle fails to function effectively in the context of AD research. Biological complexity, the absence of unequivocal biomarkers, institutional resistance to paradigm shifts, and academic incentives to preserve dominant hypotheses all contribute to the erosion of falsifiability as an operational standard. In response, we propose an alternative framework based on Bayesian inference, understood as eliminative induction-a process in which scientific theories are modeled as probabilistic hypotheses with gradable plausibility, continuously updated considering new evidence. Within this framework, models are not regarded as literally "true," but as pragmatic tools whose predictive performance determines their scientific value. We advocate for a more comparative, predictive, and transparent scientific practice, wherein progress does not hinge on identifying a unique cause or on proving (or disproving) a hypothesis, but rather on enhancing our ability to rationally distinguish among competing models using quantitative criteria.},
}

@article {pmid41393110,
year = {2025},
author = {Kim, EH and Lee, YJ and Moon, YS and Kwon, OD and Kwon, DR},
title = {Evaluation of microcurrent as an adjunct to donepezil therapy in an Alzheimer's disease mouse model: a pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1689593},
pmid = {41393110},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder due to Aβ plaque accumulation, followed by loss of synapses and decline in cognitive abilities. Donepezil is currently one of the standard pharmacological treatments for Alzheimer's disease. Recently, microcurrent (MC) therapy has emerged as a non-pharmacological adjunct for AD management. Recently, microcurrent therapy emerged as a non-pharmacological alternative to treat AD.

OBJECTIVE: The study investigates the therapeutic outcomes of the MC as an adjuvant to donepezil in mitigating cognitive dysfunction in the transgenic mouse model (5XFAD).

METHODS: Transgenic 5xFAD mice were assigned to the control, donepezil, MC, or MC + donepezil (combination) groups. Behavioral performance was assessed using the novel object recognition (NOR) and radial arm maze (RAM) tests. Amyloid burden, glial activation, cytokine expression, apoptotic signaling, and intracellular pathways (PI3K-AKT, AMPK, and JAK2/3) were analyzed by immunohistochemistry and Western blotting.

RESULTS: Combined treatment with donepezil and microcurrent showed a trend toward improved cognitive performance and reduced pathology compared to donepezil alone, although these differences were not statistically significant. Aβ plaque burden in the cortex and the hippocampus was reduced by approximately 68%, thereby exceeding reductions observed with either treatment alone. Microglial and astroglial activation (Iba1, GFAP, and CD68) and pro-inflammatory cytokines (TNF-α and IL-1β) were reduced in both the donepezil and combination groups compared with untreated 5xFAD mice, with no significant difference between 5xD and 5xD + MC. Apoptotic markers (cleaved caspase-3 and cleaved PARP) were significantly reduced in both treatment groups compared with untreated controls but not significantly different between donepezil and combination therapy. At the molecular level, both donepezil and combination therapy activated PI3K-AKT and AMPK signaling and increased inhibitory phosphorylation of GSK-3β compared with untreated 5xFAD mice; no significant difference was observed between the two treatment groups.

CONCLUSION: Donepezil combined with microcurrent therapy showed comparable efficacy to donepezil alone, with numerical trends toward further improvement in cognitive function and pathology, but without statistically significant differences. Both treatments reduced Aβ burden, attenuated glial activation, and modulated survival-related pathways to a similar extent. These findings support a multi-target therapeutic strategy and highlight the translational potential of integrating microcurrent therapy with standard pharmacological treatment for AD.},
}

@article {pmid41393109,
year = {2025},
author = {Sacchi, L and Arcaro, M and Bocca, G and Schmid, L and Carandini, T and Ghezzi, L and Pintus, M and Pietroboni, AM and Fenoglio, C and Serpente, M and Conte, G and Triulzi, F and Lanzarotti, R and Dolci, C and Galimberti, D and Arighi, A},
title = {Association between Klotho levels in cerebrospinal fluid and choroid plexus enlargement in neurodegeneration.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1688996},
pmid = {41393109},
issn = {1663-4365},
abstract = {BACKGROUND: Klotho is a longevity-associated protein found in membrane-bound and secreted forms, with the latter detectable in blood and cerebrospinal fluid (CSF). Circulating Klotho mainly originates from the kidney, while the choroid plexus (CP) secretes it into the CSF. CP dysfunction is associated with reduced Klotho expression and neurodegeneration and may result in CP enlargement on magnetic resonance imaging (MRI). In this preliminary study, we investigated Klotho levels in neurodegenerative patients and their association with CP enlargement.

MATERIALS AND METHODS: We retrospectively analyzed 40 patients from the IRCCS Ca' Granda Ospedale Policlinico, Milan, including 32 neurodegenerative patients (Deg) and 8 cognitively normal controls (NonDeg). CSF and serum Klotho levels were measured using an ELISA kit. KL-VS and apolipoprotein E (APOE) genotyping were performed. CP volumes were segmented using ITK-SNAP and normalized to total intracranial volume (TIV), resulting in a measure known as the CP volume fraction (CPVF). A multivariate linear regression analysis was conducted, adjusting for diagnostic group, age, sex, APOEε4, CPVF, and gray matter volume fraction (GMVF).

RESULTS: CSF Klotho levels were significantly lower in Deg patients (mean = 729 pg./mL, SD = 364) compared to NonDeg individuals (mean = 1,077 pg./mL, SD = 220) (t = 3.44, p = 0.003). Higher CPVF (β = -0.34, 95% CI [-0.64, -0.05], p = 0.023) was independently associated with lower CSF Klotho levels.

CONCLUSION: In this preliminary study, we observed a strong association between CSF Klotho levels and CP enlargement. Reduced CSF Klotho levels, due to CP dysfunction, may contribute to neurodegeneration. If confirmed in larger cohorts, this association suggests that CSF Klotho may serve as a biomarker for CP enlargement, possibly reflecting its underlying dysfunction.},
}

@article {pmid41392985,
year = {2025},
author = {Herz, J},
title = {From synaptic guardian to neurodegenerative culprit: rewiring the amyloid-β feedback loop in Alzheimer's disease.},
journal = {The Journal of clinical investigation},
volume = {135},
number = {24},
pages = {},
doi = {10.1172/JCI200393},
pmid = {41392985},
issn = {1558-8238},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Amyloid beta-Peptides/metabolism ; *Synapses/metabolism/pathology ; Animals ; Feedback, Physiological ; },
abstract = {Studies of amyloid-β (Aβ) in Alzheimer's disease pathology have revealed the peptide's complex roles in synaptic function. The study by Siddu et al. in this issue clarifies the contexts in which Aβ peptides may be synaptogenic or synaptotoxic. This commentary integrates the study's major findings with the salient findings of others that, over recent years, have redefined Aβ from a troublesome waste product into a physiological agent of the innate immune response and a modulator of synaptic homeostasis. Convergent evidence demonstrates how free, nonaggregated Aβ supports synaptic structure and activity, whereas oligomeric assemblies enact an adaptive brake on excitatory drive that can become maladaptive with age and inflammation. This redefined perspective on Aβ function emphasizes an evolutionarily conserved feedback loop linking neuronal activity, amyloid generation, and synaptic tuning that protects energy balance under stress but, when dysregulated, promotes proteostatic failure, persistent neuroinflammation, and network dysfunction characteristic of Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Amyloid beta-Peptides/metabolism
*Synapses/metabolism/pathology
Animals
Feedback, Physiological

@article {pmid41392969,
year = {2025},
author = {Zaheer, S and Baindoor, S and Connolly, NMC and Siebenbrodt, K and Bauer, S and Rosenow, F and Andersen, JS and Venø, MT and Kjems, J and Henshall, DC and Prehn, JHM},
title = {Temporal Dynamics of tsRNA Regulation Mark an Abrupt Transition After Epileptogenesis.},
journal = {Journal of neurochemistry},
volume = {169},
number = {12},
pages = {e70317},
doi = {10.1111/jnc.70317},
pmid = {41392969},
issn = {1471-4159},
support = {18/CRT/6214//Taighde Éireann - Research Ireland Centre for Research Training in Genomics Data Science/ ; H2020 FET - GA 964712//Horizon 2020 'PRIME - A Personalised Living Cell Synthetic Computing Circuit for Sensing and Treating Neurodegenerative Disorders'/ ; H2020 MSCA RISE GA 873127//Horizon 2020 'InterTau - Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease modifying drugs/ ; 21/RC/10294_P2//Taighde Éireann - Research Ireland/ ; 602130//European Union's "Seventh Framework" Programme (FP7)/ ; },
mesh = {Animals ; Rats ; Male ; Argonaute Proteins/metabolism/genetics ; *Epilepsy/genetics/metabolism ; Rats, Sprague-Dawley ; *RNA, Transfer/genetics/metabolism ; Gene Expression Regulation ; },
abstract = {Epileptogenesis involves widespread molecular remodeling, including transcriptional and post-transcriptional changes that reshape neuronal networks. While microRNAs have been extensively studied in this context, the contribution of transfer RNA-derived small RNAs (tsRNAs) remains largely unexplored. Understanding how tsRNAs engage in Argonaute 2 (Ago2)-mediated regulation during epileptogenesis could uncover new layers of post-transcriptional control relevant to seizure development and progression. Recent studies increasingly recognize transfer RNA-derived small RNAs or tsRNAs, especially those bound to Argonaute 2 (Ago2), as functional regulators of gene expression. Here, we analyzed Ago2-immunoprecipitated small RNA-Seq data along with matching transcriptomic and proteomic data across seven defined timepoints in a rat model of epilepsy that was induced using perforant pathway stimulation (PPS). The analysis showed dynamic shifts in Ago-2 bound tsRNA expression, with early and intermediate stages showing upregulation of shorter tsRNA fragments, whereas Day of First Seizure (DOFS) and chronic timepoints showed a shift toward 5' tiRNAs, including highly upregulated GlyGCC-derived fragments. Cluster analysis using Weighted Gene Co-Expression Network Analysis (WGCNA) identified modules specific to the DOFS timepoint where tsRNAs clustered together with genes enriched in pathways including neuronal metabolism, mitochondrial function, and synaptic stability. Target prediction analysis using RNAhybrid at DOFS predicted targets in 3' UTR, 5' UTR, and CDS regions showing an association with glycolysis, protein localization, and vesicle trafficking. Subsequent gene-disease association analysis further associated the predicted targets with neurodegenerative conditions including but not limited to Alzheimer's disease, intellectual disability, and epilepsy. This study highlights that tsRNAs potentially play a temporal dynamic regulatory role in epileptogenesis with an evident shift in tsRNA accumulation at DOFS suggesting a potential rewiring of post-transcriptional control at the completion of epileptogenesis. This work also highlights a first integrative approach of tsRNA downstream effects on the transcriptome and proteome in epilepsy and suggests innovative tsRNA-driven mechanisms relevant to disease progression.},
}

Animals
Rats
Male
Argonaute Proteins/metabolism/genetics
*Epilepsy/genetics/metabolism
Rats, Sprague-Dawley
*RNA, Transfer/genetics/metabolism
Gene Expression Regulation

@article {pmid41392765,
year = {2025},
author = {Clelland, JD and Cure, HW and Canizares, AM and Anderson, JH and Rawal, B and Wong, SA and Kerner, N and Huey, ED and Honig, LS and Devanand, DP and Clelland, CL},
title = {A proof-of-concept study: investigating the impact of COMT genotype and proline on negative symptoms in Alzheimer's disease.},
journal = {BJPsych open},
volume = {12},
number = {1},
pages = {e15},
doi = {10.1192/bjo.2025.10926},
pmid = {41392765},
issn = {2056-4724},
abstract = {BACKGROUND: Negative neuropsychiatric symptoms, such as apathy, are a core feature of Alzheimer's disease. Previous studies have shown that levels of fasting plasma proline and differential activity of the catechol-O-methyltransferase (COMT) enzyme, which metabolises dopamine, influence negative symptoms in patients with severe psychiatric illness and those at risk for psychosis. For patients with the COMT high activity enzyme (as assessed via the COMT Val[158]Met polymorphism), high plasma proline was associated with less severe negative symptoms. Conversely, high proline was associated with more severe negative symptoms in patients with the low activity COMT enzyme.

AIMS: In this proof-of-concept cross-sectional study, we tested the hypothesis that proline and COMT Val[158]Met interact to modify negative symptom severity across neuropsychiatric disease, specifically now investigating patients with Alzheimer's disease dementia.

METHOD: Least Absolute Shrinkage and Selection Operator regression was employed to model the interaction between proline and COMT on negative symptoms in n = 50 patients with probable Alzheimer's disease or mild cognitive impairment with underlying Alzheimer's disease biomarkers.

RESULTS: The proline × COMT interaction significantly predicted symptoms as assessed via the negative items of the Positive and Negative Symptom Scale, interaction coefficient 0.025, p = 0.031, with a trend toward significance when assessed via the Scale for Assessment of Negative Symptoms in Alzheimer's disease, interaction coefficient 0.075, p = 0.055. Higher proline was beneficial for both Val/Val and Val/Met dementia patients, but detrimental to patients with the low activity Met/Met COMT enzyme.

CONCLUSIONS: Higher proline also has opposing effects on negative symptoms by COMT genotype in patients with dementia and further supports the development of therapeutics aimed at modulating this interaction pathway across neuropsychiatric disorders.},
}

@article {pmid41392395,
year = {2025},
author = {Giangiulio, O and Maccarone, R},
title = {The Blood-Brain Barrier as an Integration Hub in Alzheimer's Disease: How Microbiota Metabolites Modulate Central Signal Processing.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {12},
pages = {e70703},
doi = {10.1002/cns.70703},
pmid = {41392395},
issn = {1755-5949},
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/physiopathology ; *Blood-Brain Barrier/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Signal Transduction/physiology ; },
abstract = {BACKGROUND: While both gut-brain axis dysfunction and blood-brain barrier (BBB) breakdown are documented in Alzheimer's disease (AD), current research treats these as separate phenomena. However, emerging evidence suggests that the BBB may function as an active integration interface that processes microbiota-derived metabolites and thereby potentially modulates how peripheral signals influence cognitive health.

OBJECTIVE: This review synthesizes current evidence on microbiota metabolites as modulators of BBB integration capacity, discussing how such mechanisms may contribute to variability in cognitive outcomes despite similar gut microbiome profiles by demonstrating how BBB signal-integration mechanisms determine gut-brain communication effectiveness in AD.

METHODS: We analyzed peer-reviewed literature from 2010 to 2025, focusing on BBB dynamic properties, microbiota metabolite effects on BBB function, and their integration patterns, emphasizing functional evidence supporting the BBB's active signal processing capabilities.

RESULTS: Current evidence suggests that the BBB exhibits integration properties, including dynamic permeability regulation, context-dependent metabolite processing, and coordinated responses to complex signal streams. Short-chain fatty acids enhance integration capacity through HDAC inhibition and coordinated receptor activation, while lipopolysaccharides and trimethylamine N-oxide may overwhelm integration processes through TLR4-mediated disruption. BBB dysfunction precedes classical AD pathology and correlates with altered metabolite processing capacity. Individual variations in BBB integration capacity may help account for why individuals with similar gut microbiome profiles show different cognitive outcomes.

CONCLUSION: Viewing the BBB as an active integration interface offers a useful perspective for organizing current evidence on gut-brain interactions in AD. This conceptual perspective suggests that therapeutic strategies might benefit from supporting BBB integration capacity and optimizing metabolite-processing mechanisms alongside improving gut health.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/physiopathology
*Blood-Brain Barrier/metabolism
*Gastrointestinal Microbiome/physiology
Animals
Signal Transduction/physiology

@article {pmid41392302,
year = {2025},
author = {Akhbari, MH and Movahedi, F and Zameni, M and Shahavi, MH},
title = {Developing a QSPR model for Alzheimer's drugs using topological indices and M-polynomial: A computational study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-31486-0},
pmid = {41392302},
issn = {2045-2322},
abstract = {Topological indices, which are numerical descriptors that encode molecular structure, are widely used in computational drug discovery due to their efficiency and interpretability. In this study, we developed a robust quantitative structure-property relationship (QSPR) framework to predict the core physicochemical properties of nine clinically relevant Alzheimer's disease drugs, including Donepezil, Galantamine, and Memantine. We employed a streamlined computational approach, using MATLAB and the M-polynomial method, to efficiently calculate a series of degree-based topological indices. Through comprehensive regression analyses, we identified strong correlations between degree-based topological indices and key physicochemical properties, including boiling point and molar refractivity. While linear models provided a reasonable baseline, nonlinear models, particularly cubic and power equations, delivered significantly improved predictive accuracy. The analysis highlighted the critical interplay between the choice of the index and the regression model. For instance, the cubic model was frequently the most effective for predicting properties such as boiling point and flash point, while the power model performed best for molar refractivity and polarizability. Notably, the redefined first Zagreb index and the modified first Zagreb index exhibited exceptional predictive capacity, reflecting their sensitivity to structural features that govern physicochemical behavior. The strong performance of these QSPR models underscores their potential to accelerate the rational design of Alzheimer's therapeutics. By enabling rapid, cost-effective, and reliable property prediction prior to synthesis, this framework offers a valuable tool for future drug development efforts.},
}

@article {pmid41392219,
year = {2025},
author = {Shen, Y and Wang, X and Liu, X and Wang, G and Hou, X and Zhou, X},
title = {Research Progress of Lipid Metabolism-Mediated Neuroinflammation in Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-025-01648-9},
pmid = {41392219},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease closely associated with age. The main clinical manifestations include cognitive impairment, including visuospatial ability, memory, language, and behavioral disorders. These manifestations considerably impair the patients' ability to perform daily activities. Although the pathogenesis of AD remains unclear, many studies have confirmed the essential role of abnormal lipid metabolism and inflammatory response in AD occurrence and progression. In this review, based on the relationship between lipid metabolism disorders and neuroinflammation, the regulatory mechanism of lipid mediators, and the role of microglia, we systematically discuss how lipid metabolism affects the pathological process of AD by regulating the inflammatory response.},
}

@article {pmid41392105,
year = {2025},
author = {Barani, M and Zargari, F and Mirinejad, S and Madani, F and Hajinezhad, MR and Sargazi, S},
title = {Ginsenoside Rg3-encapsulated pegylated niosomes exhibit multimodal therapeutic potential in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32528-3},
pmid = {41392105},
issn = {2045-2322},
support = {4021411//National Institute for Medical Research Development/ ; },
abstract = {Ginsenoside Rg3 (GRg3), a bioactive compound extracted from ginseng, has demonstrated the ability to inhibit Aβ production and deposition. In this study, PEGylated GRg3-loaded niosomes were developed and characterized for potential AD treatment. Their efficacy was assessed using in vitro and in vivo models, as well as molecular dynamics simulations of self-assembly. Our formulation achieved a relatively high encapsulation efficiency of 83.02% and a controlled release profile, with 75.73% of the drug released over 48 h. In vitro, co-administration of Aβ with free or PEGylated GRg3-loaded niosomes markedly reduced the levels of Total Antioxidant Capacity, Malondialdehyde (MDA), and caspase-3 gene expression compared to the Aβ-only group. In vivo evaluations revealed that treatment with the niosomal formulation did not significantly alter behavioral parameters, MDA levels, or Superoxide Dismutase activity. However, catalase activity was significantly higher than in the control group. Histopathological and immunohistochemical analyses showed reduced neurovascular damage and preservation of blood-brain barrier (BBB) and hippocampal integrity in the treated group. MD simulations confirmed the spontaneous self-assembly of surfactant molecules into a bilayer structure with successful incorporation of GRg3. Our findings underscore the potential of PEGylated niosomes as efficient nanocarriers for GRg3 delivery in the AD treatment.},
}

@article {pmid41392092,
year = {2025},
author = {Leffa, DT and Povala, G and Ferreira, PCL and Ferrari-Souza, JP and Bauer-Negrini, G and Rodrigues, MS and Amaral, L and Lussier, FZ and Medeiros, MS and Soares, C and Aguzzoli, CS and Macedo, AC and Therriault, J and Rosa-Neto, P and Tudorascu, DL and Zimmer, ER and Bellaver, B and Pascoal, TA},
title = {In vivo-measured Lewy body pathology is associated with neuropsychiatric symptoms across the Alzheimer's disease continuum.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41392092},
issn = {1476-5578},
support = {24AARFD-1243899//Alzheimer's Association/ ; AARFD-22-923814//Alzheimer's Association/ ; AARFD-23-1150249//Alzheimer's Association/ ; AARFD-24-1313939//Alzheimer's Association/ ; 24AACSF-1200375//Alzheimer's Association/ ; AARFD-22-974627//Alzheimer's Association/ ; 88887.951210/2024-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education)/ ; 5R01AG073267//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 5R01AG075336//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Intracellular alpha-synuclein aggregates, known as Lewy bodies (LB), are commonly observed in Alzheimer's disease (AD) dementia. Post-mortem studies have shown a higher frequency of neuropsychiatric symptoms among individuals with AD and LB co-pathology. However, the effects of in vivo-measured LB pathology on neuropsychiatric symptoms in AD remain underexplored. This study aimed to evaluate cross-sectional and longitudinal effects of in vivo-measured LB pathology on neuropsychiatric symptoms across the AD continuum. We analyzed data from 1169 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants had in vivo measures of LB pathology (assessed using an alpha-synuclein seed amplification assay), amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels in cerebrospinal fluid, and neuropsychiatric symptoms evaluated using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Logistic and Cox proportional hazards regression models were used to assess cross-sectional and longitudinal effects, respectively, adjusting for age, sex, and cognitive status. Participants had a mean baseline age of 73.05 (SD 7.22) years, 47.13% were women, 426 (36.44%) cognitively unimpaired, and 743 (63.56%) cognitively impaired. In cross-sectional analyses, LB pathology was associated with higher rates of anxiety, apathy, motor disturbances, and appetite disturbances. In longitudinal analyses, LB pathology increased the risk of developing psychosis and anxiety. These effects were independent of Aβ and p-tau. Our results suggest that in vivo-measured LB pathology is closely associated with neuropsychiatric symptoms across the AD continuum. These findings underscore the potential of in vivo LB detection as a marker for identifying individuals at increased risk of neuropsychiatric symptoms, both in clinical trials and in clinical practice.},
}

@article {pmid41392001,
year = {2025},
author = {Saha, S and Spalzang, S and Padhy, SK and Parmar, A},
title = {Reflections on a Study of Low-Dose Agomelatine as Add-on for Agitation in Alzheimer's Disease.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.11.011},
pmid = {41392001},
issn = {1545-7214},
}

@article {pmid41391736,
year = {2025},
author = {Chen, H and Zhang, Z and Yi, W and Wang, N and Dong, X and Xing, Y and Liu, Q and Wu, Y and Ma, X},
title = {Bone-brain crosstalk: emerging roles of osteocalcin in central nervous system disorders.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.028},
pmid = {41391736},
issn = {1873-7544},
abstract = {Despite significant advancements in understanding the pathogenesis of various central nervous system (CNS) disorders, challenges remain in the early intervention and targeted therapies for common neurodegenerative and psychiatric conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), anxiety, depression, and strokes. Recent studies have increasingly focused on the interaction between the peripheral and central nervous systems, emphasizing the regulatory influence of peripheral mechanisms on CNS disorders. This evolving perspective paves the way for innovative treatment strategies for CNS diseases, with the bone-brain axis emerging as a key regulatory pathway. This axis was first systematically proposed to highlight the role of bone-derived hormones in brain function. Importantly, bone tissue extends its functions beyond mere structural support and movement; it secretes molecules like osteocalcin (OCN) that influence neuronal and glial cell activities. This interaction is vital for regulating multiple CNS processes, including mood, cognition, inflammation, and the formation and differentiation of myelin. Upon release from bone tissue, OCN enters the bloodstream and affects peripheral organs via the Gprc6a receptor, while also crossing the blood-brain barrier to interact with receptors such as Gpr158 and Gpr37 in specific brain areas. This intra-brain interaction significantly impacts the progression and prognosis of various CNS disorders. This article undertakes a comprehensive analysis of OCN modulation in CNS disorders and its underlying mechanisms, laying the groundwork for further exploration of its clinical applications and suggesting new research avenues and therapeutic strategies for CNS diseases.},
}

@article {pmid41391685,
year = {2025},
author = {Wang, H and Qiao, Y and Lu, H and Bo, X and Chen, F and Pu, N and Zhou, Y and Cheng, Q},
title = {Central integration mechanisms of neurovascular unit dysfunction and novel synergistic therapeutic strategies.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107224},
doi = {10.1016/j.nbd.2025.107224},
pmid = {41391685},
issn = {1095-953X},
abstract = {The neurovascular unit (NVU) is a highly integrated multicellular complex composed of neurons, astrocytes, microglia, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix (ECM). It forms the structural and functional basis of the blood-brain barrier (BBB) and is pivotal for maintaining the homeostasis of the brain. Traditional neuroprotective strategies targeting individual cell types have shown limited efficacy in central nervous system (CNS) diseases, mainly due to the neglect of intricate intercellular crosstalk within the NVU. In this review, we first systematically summarize the core mechanisms by which the NVU functional unit causes NVU dysfunction in representative acute CNS injuries (ischemic/hemorrhagic stroke, traumatic brain injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), and systemic diseases (diabetic encephalopathy, depression). Based on this, we innovatively summarize and clarify six major cross-disease pathological mechanisms of NVU dysfunction, including intercellular communication disorders, abnormal epigenetic modifications, microbiome-NVU interaction dysregulation, metabolic reprogramming dysfunction, neuroimmune-vascular coupling imbalance, and mechanical microenvironment imbalance. Additionally, we integrate emerging NVU models (co-culture systems, organoids, microfluidic chips, 3D bioprinting) with multi-omics technologies to establish a cross-scale dynamic research paradigm, and propose multicomponent coordinated regulatory strategies for NVU-targeted therapies. This framework aims to expand the understanding of NVU-centered pathological processes across diverse CNS diseases and provides a novel theoretical basis for precise therapeutic interventions, thereby bridging the gap between basic research and clinical translation.},
}

@article {pmid41391557,
year = {2025},
author = {Liu, C and Zhao, Y and Dao, JJ and Ma, YK and Liu, J and Qiao, CM and Cui, C and Shen, YQ and Chen, SX and Yu, L and Zhao, WJ},
title = {Food-borne polystyrene microplastic exposure exacerbates cognitive deficiency via enhanced neuronal synaptic damage and neuroinflammation in Alzheimer's disease.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154371},
doi = {10.1016/j.tox.2025.154371},
pmid = {41391557},
issn = {1879-3185},
abstract = {The impact of polystyrene microplastics (PS-MPs) on the nervous system has been documented, yet the potential role of PS-MPs exposure in exacerbating neuronal damage and neuroinflammation in Alzheimer's disease (AD) remains unclear. Our research demonstrated that exposure to PS-MPs (50mg/kg) caused hippocampal mitochondrial damage in APP/PS1 mice, reduced expression of hippocampal mitochondrial and synapse-associated proteins, inhibited ErbB4 signaling pathway, and damaged hippocampal neurons. Additionally, PS-MPs exposure induced overactivation of astrocytes and microglia with NLRP3 pathway activation, increased β-amyloid (Aβ) deposition, and ultimately worsened cognitive dysfunction in APP/PS1 mice. Subsequent in vitro findings showed that PS-MPs (100μg/mL) exacerbated hippocampal neuronal damage under Aβ pathology, suppressed ErbB4 pathway, and disrupted mitochondrial and synaptic function. The compromised hippocampal neurons enhanced microglial NLRP3 pathway activation. These findings suggest that exposure to PS-MPs induces hippocampal neuronal damage, impairs mitochondrial and synaptic function, and exacerbates neuroinflammation and cognitive deficits, ultimately contributing to AD progression. These findings enhance our understanding of the mechanisms by which MPs expedite the progression and influence management of AD.},
}

@article {pmid41391511,
year = {2025},
author = {Gawai, M and Nistane, N and Tatode, AA and Qutub, M and Umekar, MJ and Premchandani, T and Taksande, JB},
title = {Transforming Anti-Alzheimer's therapy by targeting endogenous receptorrial system through ligand-conjugated Nanoformulations.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102994},
doi = {10.1016/j.arr.2025.102994},
pmid = {41391511},
issn = {1872-9649},
abstract = {Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder, contributing to the majority of dementia cases in the elderly globally. Characterized by progressive cognitive decline, AD is associated with complex neuropathological changes, including the accumulation of amyloid-beta (Aβ) plaques and tau tangles, synaptic loss, and neuroinflammation. One of the significant challenges in treating AD is the blood-brain barrier (BBB), which prevents many therapeutic agents from reaching the brain. Despite advancements in understanding AD's pathology, limited treatment options are available, largely due to the inability of conventional drugs to effectively target the brain. Ligand-conjugated nanoparticles (NPs) are promising for targeted drug delivery to the brain. These NPs, engineered with ligands that can bind to specific receptors or transporters on the BBB, facilitate the crossing of the barrier via receptor-mediated endocytosis or adsorptive-mediated transcytosis. This strategy enhances therapeutic agents' bioavailability and cellular uptake, offering a potential solution to overcome current limitations in AD treatment. Using nanotechnology to design ligand-conjugated NPs for targeted and sustained drug delivery could significantly improve therapeutic outcomes for AD patients by addressing key pathological processes in the brain.},
}

@article {pmid41391505,
year = {2025},
author = {Liu, Y and Zhang, J and Li, W and Qu, Q and Shan, Z and Liu, C and Jiao, K and Hou, X},
title = {Osthole Ameliorates Cognitive Impairment in Ovariectomized Rats via Estrogen-Mediated Enhancement of Cholinergic Function and Regulation of Neurotransmitter Homeostasis.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110806},
doi = {10.1016/j.neuropharm.2025.110806},
pmid = {41391505},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E2, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.},
}

@article {pmid41391342,
year = {2025},
author = {Guévremont, D and Roy, J and Garvey, A and McLean, C and Cutfield, N and Williams, J},
title = {Plasma microRNA predict cognitive decline in Parkinson's disease.},
journal = {Parkinsonism & related disorders},
volume = {143},
number = {},
pages = {108149},
doi = {10.1016/j.parkreldis.2025.108149},
pmid = {41391342},
issn = {1873-5126},
abstract = {BACKGROUND: Parkinson's disease (PD), the second most common neurodegenerative disease, is currently diagnosed clinically by impairments in motor control. PD, however, includes a diversity of non-motor symptoms, such as cognitive decline. Thus, it is imperative to establish a diagnostic framework for PD which reflects this heterogeneous phenotype. While misfolded α-synuclein is a cellular hallmark of PD and candidate biofluid marker, microRNA are an important class of biomarkers that are stable and easily detectable in blood, and are dysregulated at post-mortem in PD patients. This study aimed to establish PD plasma microRNA biomarkers that reflect cognitive abilities, as determined by the Montreal Cognitive Assessment (MoCA).

METHODS: Using custom-designed low-density TaqMan arrays we assessed plasma levels of 187 neurodegeneration-related microRNA, in cross-sectional (n = 102), and longitudinal cohorts (n = 26) as well as in post-mortem brain tissue (n = 16).

RESULTS: We found numerous microRNA were altered with increasing cognitive decline in PD and that the overall direction of change moved towards downregulation. A notable exception was miR-192-5p which was consistently upregulated in plasma and was found to be downregulated at postmortem in the superior frontal gyrus. Overall, microRNA identified were largely distinct from those known to be regulated in Alzheimer's disease. Focusing on a longitudinal cohort, controlled for disease progression and age we showed that miR-151-3p and miR-192-5p provided the best predictive model for separating cognitively normal PD patients from those who decline cognitively.

CONCLUSION: Plasma microRNA are altered in PD patients, can predict cognitive decline and therefore may be clinically useful biomarkers.},
}

@article {pmid41391236,
year = {2025},
author = {Padrela, BE and Tecelão, S and Kirsebom, BE and Geier, O and Tranfa, M and Masserini, F and Sneve, MH and Slivka, M and Falch, ES and Pålhaugen, L and Mahroo, A and Eickel, K and Thomas, DL and Günther, M and Selnes, P and Bjørnerud, A and Walhovd, KB and Fjell, AM and Barkhof, F and Petr, J and Fladby, T and Mutsaerts, HJMM},
title = {Blood-brain barrier water exchange in relation to amyloid, cognition and cerebrovascular burden.},
journal = {NeuroImage. Clinical},
volume = {49},
number = {},
pages = {103926},
doi = {10.1016/j.nicl.2025.103926},
pmid = {41391236},
issn = {2213-1582},
abstract = {Blood-brain barrier (BBB) water exchange may serve as a sensitive early biomarker for Alzheimer's disease and age-related cognitive decline. This study applied a non-invasive multi-echo arterial spin labeling (ASL) technique to measure BBB water exchange time (Tex), cerebral blood flow (CBF), and arterial transit time (ATT) in 160 adults aged 50 years and older. Participants were classified as cognitively normal (CN), having subjective cognitive decline (SCD), or mild cognitive impairment (MCI). They were assessed for amyloid status and cerebrovascular burden. Compared to CN participants, Tex was significantly lower in both SCD (-9.5 %) and MCI (-14.5 %) groups, suggesting that reductions in BBB water exchange emerge early in the course of cognitive decline. In contrast, CBF was reduced only in MCI participants (-20.8 % compared to CN), and ATT was significantly increased only in individuals with severe cerebrovascular burden (Fazekas score 3). Notably, Tex showed a stepwise decrease with increasing Fazekas scores (1-2), supporting its sensitivity to moderate small vessel disease. No associations were found between Tex and amyloid positivity after adjusting for age and sex. These findings indicate that Tex alterations may precede changes in traditional perfusion markers and are more closely related to vascular and early cognitive changes than to amyloid pathology. BBB water exchange mapping may therefore provide a promising, non-invasive tool to detect early neurovascular dysfunction that contributes to cognitive decline in aging populations, potentially offering a useful biomarker for early intervention trials targeting vascular contributions to dementia.},
}

@article {pmid41390894,
year = {2025},
author = {Sasanian, N and Halipi, V and Sjögren, M and Bengtsson, J and Bernson, D and Esbjörner, EK},
title = {Ganglioside GM1 slows down Aβ(1-42) aggregation by a primary nucleation inhibitory mechanism that is modulated by sphingomyelin and cholesterol.},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-025-01846-y},
pmid = {41390894},
issn = {2399-3669},
support = {2019.0238//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; },
abstract = {The conversion of soluble amyloid-β peptides into fibrils is central in Alzheimer's disease. Lipids modulate amyloid-β aggregation, but whilst the mechanistic effect of individual lipid species is increasingly addressed, principles explaining their combinatorial contributions in biologically heterogenous membranes remain to be established. We used kinetic analyses to establish an inhibitory mechanism of GM1 gangliosides on the aggregation of amyloid-β variant Aβ(1-42) by which membrane-associated GM1 sequesters soluble Aβ(1-42) and retards primary nucleation. The kinetic inhibition increased in presence of the raft-enabling lipids cholesterol and sphingomyelin, although these lipids, intrinsically, catalysed primary and secondary nucleation respectively. These results decipher important trade-offs between the specific chemical properties of lipids and their general contributions to the physical state of membranes, show principles of competition, and identify low fluidity domains as key regulators of membrane-mediated Aβ(1-42) aggregation. The study thereby highlights a versatile, regulatory role of membranes in the molecular pathology of Alzheimer's disease.},
}

@article {pmid41390810,
year = {2025},
author = {Gallo, C and Verrillo, L and Manzo, E and Cauzzi, E and La Barbera, L and Sabatino, G and De Paolis, ML and Sciacca, MFM and Barra, G and Peroni, E and Monasson, O and Dell'Isola, M and Carbone, D and Nobili, A and Ziaco, M and Fioretto, L and Pirozzi, M and D'Ippolito, G and Castiglia, D and Soluri, A and Nuzzo, G and Milardi, D and Miano, MG and D'Amelio, M and Fontana, A},
title = {Microglial clearance, neuroprotection and cognitive recovery via a novel synthetic sulfolipid in Alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03634-w},
pmid = {41390810},
issn = {1742-2094},
support = {PG/2018/0494374//Regione Campania/ ; PG/2018/0494374//Regione Campania/ ; AIRALTZH-AGYR2021//Italian Association for Alzheimer's Disease/ ; PRIN 2022PAAYZE//Ministero dell'Università e della Ricerca/ ; AARG-18-566270//American Alzheimer's Association/ ; RF-2018-12365527//Ministero della Salute/ ; PNRR-MAD-2022-12376849//Ministero della Salute/ ; PO FESR LAZIO 2014/2020//Regione Lazio/ ; 2022BNZLMN//Italian Ministry of University and Research/ ; },
}

@article {pmid41390778,
year = {2025},
author = {Fu, M and Tran, T and Pasaniuc, B and Vossel, K and Chang, TS},
title = {Multi-task learning identifies shared genetic risk for late-onset epilepsy and alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32329-8},
pmid = {41390778},
issn = {2045-2322},
abstract = {Aging populations face increasing incidence of neurological disorders, including Alzheimer's disease (AD) and late-onset epilepsy (LOE), which demonstrate a bidirectional relationship where AD is a risk factor for LOE and LOE is a risk factor for AD. While the APOE gene is a known shared risk factor, comprehensive genetic studies for LOE remain limited. This study employed a multi-task learning framework using Elastic Net modeling to systematically identify shared genetic risk factors between AD and LOE. We analyzed electronic health records from UCLA Health System (N = 416,212; genetic subset N = 16,500) and validated findings in the All of Us dataset (N = 52,493). Longitudinal analyses confirmed strong bidirectional associations between AD and LOE. The multi-task learning approach identified eight shared-risk single nucleotide polymorphisms mapping to key genes including the APOE-TOMM40-APOC1 cluster, BIN1, CLU, PVRL2, and TRAPPC6A. These shared-risk genes were enriched in pathways related to lipid metabolism, amyloid catabolic processes, and tau protein binding. A shared genetic risk score effectively stratified patients into distinct AD-LOE risk groups. This study represents an initial systematic identification of potential shared genetic factors between AD and LOE using multi-task learning. While our findings suggest possible shared genetic contributions, particularly in the APOE region, and highlight tau-mediated mechanisms as potential therapeutic targets, further validation is needed to establish the extent of genetic overlap between these conditions.},
}

@article {pmid41390776,
year = {2025},
author = {AlOkda, A and Yadav, S and Pacis, A and Jacob-Tomas, S and Parkhitko, AA and Van Raamsdonk, JM},
title = {Cyrene: a novel geroprotective compound that extends lifespan and healthspan in C. elegans and Drosophila.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-025-00309-x},
pmid = {41390776},
issn = {2731-6068},
support = {AG082801/AG/NIA NIH HHS/United States ; GM146869/GM/NIGMS NIH HHS/United States ; },
abstract = {As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and healthspan in C. elegans, improving locomotor function and resistance to oxidative, thermal, osmotic, genotoxic, and proteotoxic stress. It also confers protection in neurodegenerative models of Alzheimer's, Parkinson's, and Huntington's disease. Cyrene is effective when delivered during development or early adulthood and requires administration before day 8 to extend longevity. Its benefits are independent of bacterial metabolism and at least partially independent of the FOXO transcription factor DAF-16. Importantly, Cyrene also extends lifespan and enhances oxidative stress resistance in Drosophila melanogaster, demonstrating cross-species efficacy. These findings identify Cyrene as a novel geroprotective compound that promotes longevity, resilience, and neuroprotection. Conservation across species supports future work to dissect molecular mechanisms and test its potential in mammals.},
}

@article {pmid41390681,
year = {2025},
author = {Saeed, R and Tariq, HZ and Althobaiti, A and Sadeghian, N and Taslimi, P and Al-Rashida, M and Islam, T and Thabet, HK and Aftab, H and Şenol, H and Ameen, M and Li, J and Shafiq, Z},
title = {Design, synthesis, and multi-target evaluation of 4-phenyl quinoline-8-sulfonate thiosemicarbazones as potential anti-Alzheimer agents.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32012-y},
pmid = {41390681},
issn = {2045-2322},
}

@article {pmid41390476,
year = {2025},
author = {Jia, L and Chen, Y and Li, H and Zhao, K and Ge, S and Wang, C and Zhao, J and Li, F and Zhang, L and Yao, A},
title = {The glymphatic system in neurodegenerative diseases and brain tumors: mechanistic insights, biomarker advances, and therapeutic opportunities.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-025-02203-9},
pmid = {41390476},
issn = {2051-5960},
support = {26A310011//The Plan for Key Scientific Research Projects of Higher Education Institutions in Henan Province for 2026/ ; YNZX2024005//The research project of 988th Hospital of Joint Logistic Support Force of PLA/ ; LHGJ20230703//The joint construction project of Henan Province/ ; KFJJ23-09M//The opening project of State Key Laboratory of Explosion Science and Technology (Beijing Institute of Technology)/ ; },
abstract = {Dysfunction of the glymphatic system (GS), a brain-wide waste clearance pathway dependent on polarized aquaporin-4 (AQP4) water channels on astrocytic endfeet, is increasingly recognized as a critical mechanism in both neurodegenerative diseases and brain tumors. In Alzheimer's (AD) and Parkinson's (PD) diseases, impaired glymphatic function leads to the accumulation of neurotoxic proteins, including amyloid-β (Aβ), tau, and α-synuclein (α-syn). Contributing factors include loss of AQP4 polarization, reduced arterial pulsatility, genetic risks (e.g., APOE4, FAM171A2 mutations), and sleep disturbances. These functional impairments can be quantified using neuroimaging biomarkers such as the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and choroid plexus volume (CPV), which correlate with pathological burden and clinical decline, though the direct physiological interpretation of these metrics requires further validation. Conversely, in glioblastoma and other brain tumors, mechanical compression and lactate-driven acidosis obstruct perivascular fluid transport, promoting an immunosuppressive tumor microenvironment that limits T-cell infiltration and confers therapeutic resistance. Here, too, glymphatic dysfunction is reflected by a reduced ALPS index, which correlates with tumor grade, peritumoral edema, and survival. Emerging therapeutic strategies aimed at restoring GS function include pharmacological interventions (e.g., circadian regulators, AQP4 modulators), non-invasive techniques (e.g., cervical lymphatic stimulation, gamma stimulation, exercise), and surgical approaches (e.g., lymphatic-venous anastomosis). Advances in multimodal MRI and artificial intelligence (AI)-enhanced analytics further support novel diagnostic capabilities. This review highlights the dual role of the GS across neurological disorders and underscores its potential as a therapeutic target for enhancing waste clearance and immune modulation. However, significant challenges remain, including the validation of human biomarkers, elucidating bidirectional tumor-glymphatic crosstalk, and translating preclinical discoveries into clinical practice.},
}

@article {pmid41390473,
year = {2025},
author = {Yang, C and Chu, F and Chen, X and Meng, F and Li, Y and Chen, J and Sun, C and Shang, Y and Guo, R and Wang, J and Wu, C and Duan, H and Shao, M and Yuan, W},
title = {Glutamine: fructose-6-phosphate amidotransferase (GFAT) in the pathology of diseases: a review.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-025-02898-8},
pmid = {41390473},
issn = {2058-7716},
support = {202403021221004, 2024030212211348, 202203021221300//Natural Science Foundation of Shanxi Province (Shanxi Province Natural Science Foundation)/ ; },
abstract = {Glutamine: fructose-6-phosphate amidotransferase (GFAT), a conserved enzyme across prokaryotic and eukaryotic species, is the first and rate-limiting step in the hexosamine biosynthetic pathway (HBP), diverting 2-5% of fructose-6-phosphate derived from glucose toward the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a key substrate for the glycosylation of proteins and lipids. While substantial progress has been made in elucidating the basic biochemical properties and regulatory mechanisms of GFAT, its functional impact on pathological processes remains incompletely understood. Emerging evidence implicates GFAT in a spectrum of human diseases, including cancer, diabetes, cardiovascular disorders, and neurodegenerative conditions such as Alzheimer's disease. This review aims to provide a comprehensive synthesis of current insights into GFAT's role in disease etiology, with the goal of informing future research and therapeutic strategies targeting this essential metabolic regulator.},
}

@article {pmid41390238,
year = {2025},
author = {Mummery, CJ and Rasmussen, J and Blackburn, D and Coulthard, E and Davies, RR and Dorsey, R and Fox, NC and Hosseini, AA and Ivenso, C and Jones, M and Kennelly, SP and Kipps, C and Lashley, D and Mackay, G and Negi, R and Nilforooshan, R and Passmore, PA and Perry, R and Raymont, V and Rowe, JB and Russ, TC and Taylor, JP and Burns, A},
title = {Lecanemab appropriate use recommendations for clinical practice in the UK.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336597},
pmid = {41390238},
issn = {1468-330X},
abstract = {Lecanemab is an anti-amyloid monoclonal antibody, recently approved in the UK as a treatment for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD) in adults who are apolipoprotein E ε4 gene (APOE4) heterozygotes or non-carriers.A group of UK neurologists, old age psychiatrists and geriatricians with expertise in AD convened to agree appropriate use recommendations for lecanemab in UK clinical practice. The primary focus of these recommendations is safety.Eligibility criteria for lecanemab in the UK include (a) a clinical diagnosis of MCI or mild dementia due to AD, (b) the presence of amyloid-β pathology, confirmed using approved methods (ie, an amyloid positron emission tomography scan or cerebrospinal fluid assay) and (c) APOE4 heterozygous or non-carrier status. Eligibility screening should be conducted in secondary care and those identified as being potentially eligible for lecanemab should be referred to a specialist centre for confirmation of the likely pathological diagnosis, APOE4 counselling and testing and a multidisciplinary consensus decision regarding treatment eligibility. Lecanemab is administered as an intravenous infusion every 2 weeks, and those eligible for treatment should have brain magnetic resonance imaging (MRI) scans prior to the 1st, 5th, 7th and 14th infusions. Specific guidance is provided for safety monitoring and management of potential adverse reactions, including amyloid-related imaging abnormalities and infusion-related reactions.The introduction of lecanemab into UK clinical practice provides an important opportunity to improve services for all people living with dementia, not just those eligible for lecanemab treatment.},
}

@article {pmid41390237,
year = {2025},
author = {Ancidoni, A},
title = {Appropriate use recommendations in search of reimbursement: lecanemab and the UK dilemma.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-337659},
pmid = {41390237},
issn = {1468-330X},
}

@article {pmid41390197,
year = {2026},
author = {Yabuki, Y and Shioda, N},
title = {RNA-mediated aggregation mechanism of prion-like proteins and its application to drug discovery.},
journal = {Journal of pharmacological sciences},
volume = {160},
number = {1},
pages = {64-68},
doi = {10.1016/j.jphs.2025.11.006},
pmid = {41390197},
issn = {1347-8648},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/etiology ; *RNA/metabolism/chemistry ; *Drug Discovery/methods ; G-Quadruplexes ; *Prion Proteins/metabolism/chemistry ; *Prions/metabolism/chemistry ; RNA-Binding Proteins/metabolism ; tau Proteins/metabolism ; *Protein Aggregates ; Animals ; alpha-Synuclein/metabolism ; Phase Transition ; *Protein Aggregation, Pathological ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as α-synuclein and Tau that contribute to the pathogenesis of neurodegeneration remain poorly understood. Although prion-like proteins are known to undergo liquid-liquid phase separation (LLPS) followed by a sol-gel transition in vitro, the key factors governing their phase transition remain to be elucidated in vivo. Most prion-like proteins are classified as RNA-binding proteins, and recent studies suggest that RNA plays a critical role in mediating both LLPS and the subsequent sol-gel transition of these proteins. In the review, we summarized our findings on RNA G-quadruplexes (rG4s) as a pathological key molecule in neurodegenerative disorders and introduce recent advances in RNA-induced phase transition of prion-like proteins.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy/etiology
*RNA/metabolism/chemistry
*Drug Discovery/methods
G-Quadruplexes
*Prion Proteins/metabolism/chemistry
*Prions/metabolism/chemistry
RNA-Binding Proteins/metabolism
tau Proteins/metabolism
*Protein Aggregates
Animals
alpha-Synuclein/metabolism
Phase Transition
*Protein Aggregation, Pathological

@article {pmid41390193,
year = {2026},
author = {Ohi, Y and Hada, K and Murata, Y and Kodama, D and Wakiya, Y},
title = {Bidirectional effects of orexin receptor antagonists on long-term potentiation in the hippocampus of wild type and Alzheimer's disease model mice.},
journal = {Journal of pharmacological sciences},
volume = {160},
number = {1},
pages = {37-40},
doi = {10.1016/j.jphs.2025.11.003},
pmid = {41390193},
issn = {1347-8648},
mesh = {Animals ; *Alzheimer Disease/physiopathology/drug therapy ; *Orexin Receptor Antagonists/pharmacology/administration & dosage ; *Long-Term Potentiation/drug effects ; Disease Models, Animal ; *Azepines/pharmacology/administration & dosage ; *Triazoles/pharmacology/administration & dosage ; *Hippocampus/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; *Pyridines/pharmacology ; *CA1 Region, Hippocampal/drug effects ; },
abstract = {The orexinergic system is dysregulated in patients with Alzheimer's disease (AD). In the present study, we evaluated the effects of chronic administration of dual orexin receptor antagonists, suvorexant (Suv) and lemborexant (Lem), on long-term potentiation (LTP) in the hippocampal CA1 region of wild-type (WT) and APP[NL-G-F] knock-in (APP-KI) mice. LTP was enhanced in APP-KI mice compared with WT mice. Chronic administration of Suv and Lem further potentiated LTP in WT mice. In contrast, in APP-KI mice, Suv moderately and Lem markedly reduced LTP. These findings suggest that orexin receptor antagonists bidirectionally modulate LTP in WT and AD model mice.},
}

Animals
*Alzheimer Disease/physiopathology/drug therapy
*Orexin Receptor Antagonists/pharmacology/administration & dosage
*Long-Term Potentiation/drug effects
Disease Models, Animal
*Azepines/pharmacology/administration & dosage
*Triazoles/pharmacology/administration & dosage
*Hippocampus/drug effects
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
*Pyridines/pharmacology
*CA1 Region, Hippocampal/drug effects

@article {pmid41390157,
year = {2025},
author = {Light, SW and Tomasino, F and Del Salto, M and Vela, A and Wolf, MS and Sideman, AB},
title = {'It keeps your body strong, your muscles strong, your brain strong:' perceptions about the role of physical activity and nutrition in brain health among middle-aged Latinos.},
journal = {Ethnicity & health},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/13557858.2025.2600276},
pmid = {41390157},
issn = {1465-3419},
abstract = {OBJECTIVES: Latinos are disproportionately impacted by Alzheimer's disease and related dementias (ADRD). It is estimated that interventions targeting lifestyle and health behaviors could prevent or delay up to 50% of ADRD cases worldwide. This study aimed to explore middle-aged Latinos' perceptions of the link between physical activity and nutrition with the maintenance of brain health.

DESIGN: Individual, semi-structured interviews were conducted with 30 English- or Spanish-speaking Latinos 35 to 64 years old. Participants were recruited via social media, flyers, direct contact of participants from prior studies, and snowball sampling. Questions addressed knowledge about the brain, perceptions of aging, and ideas of how to care for the brain. Responses that emerged pertaining to physical activity and nutrition were analyzed using conceptual content analysis to quantify the frequency of themes and identify trends.

RESULTS: Most participants were female (n = 18) and college educated (n = 17), with an average age of 47 years; two thirds reported being foreign born, and half reported lower acculturation levels. Physical activity and nutrition were spontaneously described as strategies to promote brain health by 22 and 24 participants, respectively. With regards to physical activity, walking was most often mentioned (n = 8), followed by yoga (n = 4). Few participants clarified frequency (n = 3), duration (n = 1), or intensity (n = 2). With regards to nutrition, common strategies mentioned were increasing fruit and vegetable consumption (n = 19), limiting processed foods (n = 9), and taking vitamins or supplements (n = 9).

CONCLUSION: Most participants demonstrated foundational knowledge of the link between nutrition, physical activity, and brain health. Some misconceptions were identified, such as participants overestimating the benefits of vitamins/supplements, which have weak correlations with preventing cognitive decline. Messaging may benefit from emphasizing recommendations regarding the role of frequency, duration, and intensity in physical activity, and specific nutrient, portioning, and preparation recommendations for dietary practices. Incorporating these messages into intergenerational programming may be particularly beneficial.},
}

@article {pmid41390089,
year = {2025},
author = {Sheng, J and Wang, L and Zhang, Q and Chien Chou, JT and Zhang, R and Li, T and Lu, Y},
title = {Integrating multimodal data to identify single nucleotide polymorphism-related biomarkers and regulatory mechanisms in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.022},
pmid = {41390089},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease with unclear regulatory mechanisms at the cell-type level. A multi-omics model called single nucleotide polymorphisms (SNPs)-transcriptomic-single-nucleus ribonucleic acid sequencing (snRNA-seq) integration (STSNI) is proposed to identify SNPs-related biomarkers and regulatory mechanisms in AD. Differential expression analysis identified differentially expressed genes (DEGs) between AD patients and healthy controls (HCs) in the GSE118553 dataset. Cell-type annotation in the GSE138852 dataset revealed several cell subclusters, and DEGs were identified within these subclusters. Intersection analysis among DEGs from the GSE118553 dataset, cell-subcluster-specific DEGs from the GSE138852 dataset, and SNP-associated genes from the ADNI2 dataset yielded 14 overlapping genes. Using the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms, six biomarkers were identified. Functional enrichment and gene set enrichment analysis (GSEA) linked these biomarkers to pathways such as carboxylic acid catabolic process, exocytic vesicle membrane, and carbon metabolism. Meanwhile, six cell types were identified, including astrocytes, endothelial cells, oligodendrocytes, oligodendrocyte progenitor cells (OPCs), microglia, and neurons. The biomarker-transcription factor (TF) network indicated that Cispb M4676 regulates IQGAP2, NRXN1, GRIA3 and FGF14. Overall, our study identified six SNP-related biomarkers (IQGAP2, HHAT, FGF14, CTNNA3, GRIA3, and NRXN1) associated with AD. The STSNI framework provided novel insights into the cellular and molecular mechanisms underlying AD. Significance Statement: As the global population continues to age, Alzheimer's disease (AD) has emerged as a major public health concern. The pathological changes associated with AD include the formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss with gliosis proliferation. Bioinformatics methods are used to explore the immune infiltration characteristics, biological pathways and regulatory mechanisms of single nucleotide polymorphisms (SNPs) related key genes in AD. The pathogenesis of AD from the overall level and single-cell level is explored based on SNPs-related genes, combined with snRNA-seq data and transcriptome data. This study provides an opportunity for the discovery of novel diagnostic molecular markers and potential treatment targets to serve as the foundation for the development of more effective management techniques for AD.},
}

@article {pmid41390037,
year = {2025},
author = {Georgiadou, D and Chroni, A},
title = {Structural and functional insights into naturally occurring apolipoprotein E variants with protective effects against Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149644},
doi = {10.1016/j.ijbiomac.2025.149644},
pmid = {41390037},
issn = {1879-0003},
abstract = {Apolipoprotein E (apoE), a major protein for lipid transport in circulation and the brain, has three common isoforms, apoE2, apoE3 and apoE4. APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Recently identified rare apoE variants, the apoE3(R136S)-Christchurch, apoE3(V236E)-Jacksonville and apoE4(R251G), appear to exert protective functions against AD and reduce the disease risk, but the molecular basis behind these effects is unknown. ApoE is a structurally dynamic protein, undergoing significant rearrangements that are important for its biological function. To examine the structural basis behind the properties of the protective apoE variants, we analyzed their structural and thermodynamic integrity both in APOE3 and APOE4 allelic backgrounds compared to their wild-type counterparts. Circular dichroism spectroscopy showed that only the V236E variation significantly alters the secondary structure of apoE3 and apoE4 in lipid-free form. This variant was also less prone to oligomerization. Chemical denaturation analysis indicated changes in the unfolding profile of V236E and R251G apoE variants in lipid-free form. Thermal unfolding analysis revealed small thermodynamic alterations in each variant compared to their wild-type apoE counterparts in lipid-free form, but a thermodynamic stabilization in lipoprotein-associated form. Additionally, following lipidation, all protective apoE variants were found to enhance the viability of SK-N-SH neuroblastoma cells and reduce the production of TNFα from BV2 microglia cells. Overall, these findings suggest that the specific amino acid changes found in AD-protective apoE variants can induce changes in the molecule's stability and conformation that may underlie common functional consequences, which are independent of the apoE background.},
}

@article {pmid41389972,
year = {2025},
author = {Siraganahalli Eshwaraiah, PK and Bairy, KL and Kiran, A and Reddy K, S and Konuri, A and Nayak, V},
title = {"Neuropharmacological Insights into Artesunate alone and Rivastigmine Co-Therapy: Synergistic Modulation of Cognitive Impairment in Alzheimer's Disease".},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178470},
doi = {10.1016/j.ejphar.2025.178470},
pmid = {41389972},
issn = {1879-0712},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition, neuroinflammation, oxidative stress, and hippocampal neurodegeneration, leading to cognitive decline. Artesunate has shown neuroprotective potential in previous models. This study evaluated artesunate alone and in combination with rivastigmine in an Aβ1-42 induced AD rat model.

METHODS: Six-month-old Wistar rats received intracerebroventricular injections of Aβ1-42 to induce AD. The animals were treated orally with artesunate (28 mg/kg) or rivastigmine (1 mg/kg), alone or in combination, for 30 days. Cognitive function was assessed via novel object recognition, passive avoidance, and Morris water maze tests. Hippocampal tissue was analyzed for Aβ1-42, NF-κB, TNF-α, IL-1β, malondialdehyde, glutathione, and acetylcholinesterase activity. Histological examination of the CA1 and CA3 regions was used to assess neuronal viability and dendritic morphology.

RESULTS: AD-vehicle rats exhibited marked deficits in recognition, aversive, and spatial memory, alongside elevated levels of Aβ1-42, proinflammatory mediators, and oxidative stress, with reduced glutathione and acetylcholinesterase activity. Artesunate significantly improved cognitive performance and biochemical markers, with combination therapy showing greater efficacy. Histology revealed pronounced neuronal loss and dendritic degeneration in AD-vehicle rats, which were attenuated by artesunate, particularly when artesunate was combined with rivastigmine, preserving pyramidal neuron and dendritic spine density.

CONCLUSION: Artesunate exerts neuroprotective effects in experimental AD by attenuating amyloid deposition, neuroinflammation, and oxidative stress and preserving hippocampal neuronal architecture. Coadministration of rivastigmine provides synergistic cognitive and neuroprotective benefits, supporting further investigation of this combination as a potential therapeutic approach for AD.},
}

@article {pmid41389931,
year = {2025},
author = {Boras, MM and Krulj, V and Karahmet, A and Omerbasic, K and Nawaz, A and Pavković, D and Sher, EK},
title = {Oxidative Stress-Induced mechanisms in neurodegeneration and Eryptosis: Implications for neurological and systemic disorders.},
journal = {Brain research},
volume = {},
number = {},
pages = {150111},
doi = {10.1016/j.brainres.2025.150111},
pmid = {41389931},
issn = {1872-6240},
abstract = {The significant association between the development of neurological diseases, like Alzheimer's, Parkinson's or depression and oxidative stress occurs from the disturbance in the balance between oxidative and antioxidative processes due to chronic stress. Unlike previous reviews that focused only on neurological or systemic diseases, this review discusses the mechanisms that connect oxidative stress and neuroinflammation or eryptosis in both neurological, neurodegenerative, and various systemic diseases, clarifying two completely distinct mechanisms of response to oxidative stress that are common to multiple clinical conditions. This review explores the complex involvement of oxidative damage in neurodegeneration and explains its contribution to inflammation, protein aggregation, and disruption of cellular functions. Crucial components in this process are reactive oxygen and reactive nitrogen species, which can be generated both endogenously or exogenously. Primary sources of ROS in cells are NADPH oxidases, mitochondria, xanthine oxidase and growth factor receptors. Elevated ROS levels disrupt cellular homeostasis and cause oxidative damage and inflammatory responses in neurological disorders characterised by the activation of microglia, astrocytes, and infiltrating CD4 + T cells. Similarly, in systemic disease, this disruption happens through eryptosis. In addition, chronic stress damages antioxidant defence, which further worsens pathological processes. A deeper understanding of the underlying mechanisms provides novel insights into therapeutic strategies for reducing the effects of oxidative stress in both neurological and systemic diseases.},
}

@article {pmid41389915,
year = {2025},
author = {Chen, X and Zhu, Y and Li, M and Zhou, C and Luo, F and Li, Z and Zhang, J and Xing, L and Liu, W},
title = {Effects of Acetamiprid on DNA Methylation, Transcriptomics, and Neurogenesis in Human Mesenchymal Stem Cells.},
journal = {Environmental toxicology and pharmacology},
volume = {},
number = {},
pages = {104904},
doi = {10.1016/j.etap.2025.104904},
pmid = {41389915},
issn = {1872-7077},
abstract = {Acetamiprid (ACE), a Neonicotinoid insecticides (NEOs), is highly selective for insect nicotinic acetylcholine receptors (nAChRs). However, increasing evidence of hazards was reported in mammals. We investigated the effects of ACE on both global DNA methylation and epigenetic change, transcriptomic dysregulation, and neural differentiation. ACE decreased AluYb8 methylation levels in human mesenchymal stem cells. TET2 expression was enhanced suggesting that it was involved in the active DNA demethylation caused by ACE. Global DNA methylation pattern identified 87 significant differentially methylated positions (DMPs) and transcriptomic analysis identified 385 differentially expressed genes (DEGs). Pathways related to the psychiatric system, including Alzheimer's disease and TGF-β, were significantly enriched. ACE inhibited the expression of neurogenesis marker MAP2 and SNCA, which was repressed by TETs inhibitor Bobcat339. Our results suggested that exposure to ACE disturbed DNA methylation, and resulted in the impaired neural differentiation revealed by abnormal expression of neuronal and PD-related marker protein.},
}

@article {pmid41389844,
year = {2025},
author = {Shi, H and Zhao, Y},
title = {Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106103},
doi = {10.1016/j.neuint.2025.106103},
pmid = {41389844},
issn = {1872-9754},
abstract = {Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau4RDΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau4RDΔK280 cells while reducing the amount of tau4RDΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau4RDΔK280 in vitro. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau4RDΔK280 in vitro. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau4RDΔK280 cells by preventing the formation of tau4RDΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau4RDΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.},
}

@article {pmid41389629,
year = {2025},
author = {Ruiz de Martín Esteban, S and Grande, MT and Martínez-Relimpio, AM and Herráez-Aguilar, D and Mostany, R and Hillard, CJ and Hind, WH and Romero, J},
title = {Treatment with a botanical mixture of cannabidiol:Δ[9]-tetrahydrocannabinol enhances microglial phagocytosis and shapes amyloid plaques in a mouse model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {194},
number = {},
pages = {118902},
doi = {10.1016/j.biopha.2025.118902},
pmid = {41389629},
issn = {1950-6007},
abstract = {The potential use of phytocannabinoids in neurodegenerative disorders is currently under intense investigation based on their potential anti-inflammatory, antioxidant, and neuroprotective effects. Here, we tested the effects of chronic (28 days) treatment with a complex botanical mixture of purified cannabidiol:Δ[9]-tetrahydrocannabinol (CBD:THC, 99:1) in male 5xFAD mice, a murine model of Alzheimer's disease that recapitulates amyloid pathology. Effects of exposure to this cannabinoid mixture were evaluated using behavioral tests (elevated plus maze for anxiety, tail suspension for depression-like behavior, rotarod for motor coordination, open field for locomotor activity, and novel object recognition for memory), quantification of protein expression (IL-1β, CD40, TREM2, COX2), assessment of functional parameters (microglial phagocytic activity by flow cytometry), and in vivo multiphoton microscopy (time-course of changes of neuritic plaque structural features). Twice daily dosing with 50 mg/kg subcutaneously (s.c.) significantly reduced locomotion, increased anxiety- and depression-like behaviors and had no effect on memory and motor coordination. In vivo imaging experiments suggest that the CBD:THC treatment enhanced microglial phagocytic activity on amyloid plaques; this effect was observed both in plaque features (multiphoton microscopy measurements) as well as in microglia (flow cytometry data). Exposure to CBD:THC induced significant changes in in vivo microglia-amyloid interactions, increasing phagocytic activity and reducing the amyloid peptide accumulation in the neuritic plaques. Thus, CBD:THC (99:1) may be a promising treatment to reduce amyloid pathology, though caution should be noted due to the behavioral alterations observed, i.e., increased anxiety- and depression-like behaviors as well as decreased locomotion.},
}

@article {pmid41389606,
year = {2025},
author = {Lu, JH and Zhao, CH and Qiu, YQ and Shen, LQ and Zhang, M and Zhu, H},
title = {Design, synthesis, and multi-target evaluation of Chromone-based derivatives as promising anti-Alzheimer's disease agents.},
journal = {Bioorganic chemistry},
volume = {168},
number = {},
pages = {109350},
doi = {10.1016/j.bioorg.2025.109350},
pmid = {41389606},
issn = {1090-2120},
abstract = {A series of novel chromone derivatives were designed and synthesized, primarily composed of enamine/hydrazine/hydrazide-based chromone derivatives. Their potential for multi-target (acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), amyloid-beta-40/42 (Aβ40/42), Tau) therapy against Alzheimer's disease was systematically evaluated. In vitro studies demonstrated that compound C20 exhibited potent and selective AChE inhibitory activity with no significant effect on butyrylcholinesterase (BChE), and showed strong MAO-B inhibition with an IC50 value of 0.06 ± 0.04 μM. Both compounds C20 and D21 showed good inhibitory effects on the aggregation of Aβ40/42 and Tau proteins, with overall IC50 values around 1 μM. Additionally, D21 promoted the degradation of Aβ40/42 (Aβ40, IC50 = 2.151 μM; Aβ42, IC50 = 3.622 μM). Cellular experiments revealed that C20 and D21 could reduce intracellular and extracellular Aβ protein deposition to varying degrees, demonstrating significant protective effects in reversing Aβ40/42 oligomer-induced neurotoxicity while also decreasing intracellular reactive oxygen species (ROS) production. These findings highlight the promising potential of compounds C20 and D21 as multi-target therapeutic agents for Alzheimer's disease (AD).},
}

@article {pmid41389410,
year = {2025},
author = {Li, X and Yan, S and Li, M and Liu, R and Lu, Q and Lu, M and Bai, F and Shen, QD},
title = {Piezoelectric nanoparticle-driven rhythmic ultrasound neuromodulation for treatment of early-stage Alzheimer's disease.},
journal = {Biomaterials},
volume = {328},
number = {},
pages = {123905},
doi = {10.1016/j.biomaterials.2025.123905},
pmid = {41389410},
issn = {1878-5905},
abstract = {Synaptic dysfunction and loss are central drivers of cognitive decline in Alzheimer's disease (AD), yet current therapeutic approaches targeting amyloid-β or tau pathology have largely failed to rescue synaptic function. Neural oscillations and synaptic plasticity are tightly coupled and underpin functional brain networks, suggesting that modulating oscillatory dynamics may offer new therapeutic avenues. Here, we developed a strategy for precise, non-genetic neuromodulation using focused ultrasound and piezoelectric Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) nanoparticles to generate targeted, gamma-frequency electromagnetic fields in the hippocampal CA3 subregion of early-stage AD mouse models. This rhythmic stimulation effectively restored impaired gamma oscillations, enhanced synaptic plasticity, and remodeled memory-related network connectivity, as validated by local field potential recordings, patch-clamp electrophysiology, and functional MRI. Mechanistically, we demonstrate that NF-κB transcription factor activation during rhythmic stimulation regulates AMPAR trafficking by balancing synaptic internalization and delivery, with concurrent upregulation of P300-mediated histone acetylation. Our findings establish a novel paradigm for spatially precise, periodic neuromodulation that restores hippocampal information processing and network function in early AD, highlighting the therapeutic potential of piezoelectric nanomaterials for neural circuit repair in AD and other neurodegenerative diseases characterized by impaired neural rhythms.},
}

@article {pmid41389327,
year = {2025},
author = {Zanetti, L and Regoni, M and Monzani, E and Mini, C and Di Giorgio, G and Morari, M and Valtorta, F and Sassone, J},
title = {Protocol to count the number of noradrenergic neurons in mouse locus coeruleus by unbiased stereology.},
journal = {STAR protocols},
volume = {7},
number = {1},
pages = {104273},
doi = {10.1016/j.xpro.2025.104273},
pmid = {41389327},
issn = {2666-1667},
abstract = {Loss of noradrenergic (NE) neurons in the locus coeruleus (LC) occurs in both Alzheimer's disease (AD) and Parkinson's disease (PD): pharmacological therapies aimed at neuroprotection in brain area are needed. Here, we present a protocol for assessing the absolute number of NE neurons in the mouse LC by unbiased stereological counting. We describe steps for preparing the brain slices, delineating the region of interest, counting the neurons, and using the Stereo Investigator software. For complete details on the use and execution of this protocol, please refer to Regoni et al.[1].},
}

@article {pmid41389278,
year = {2025},
author = {Pini, L and Allegra, M and Imbimbo, BP},
title = {Do anti-amyloid antibodies modulate brain function in Alzheimer's disease?.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-8},
doi = {10.1159/000549946},
pmid = {41389278},
issn = {1660-2862},
abstract = {Alzheimer's disease therapeutics increasingly target amyloid-β (Aβ) plaques using monoclonal antibodies, exemplified by lecanemab and donanemab, which show modest cognitive benefits linked to amyloid reduction. However, their impact on brain function remains poorly understood. Cerebral pseudoatrophy, observed with several anti-Aβ antibodies, complicates interpretation of volumetric changes, as these may reflect downstream effects of amyloid clearance rather than true neurodegeneration. Functional brain markers, including FDG-PET, could clarify both pseudoatrophy mechanisms and drug effects on neural activity, assessing preservation of cognitive substrates. Recent analyses of the DIAN-TU-001 trial on gantenerumab revealed substantial amyloid reduction without detectable metabolic changes, highlighting the need for disease-modifying trials to incorporate functional and structural co-primary endpoints. Integrating multimodal assessments in clinical and preclinical studies can provide a comprehensive framework to evaluate therapeutic efficacy and guide development of next-generation AD treatments.},
}

@article {pmid41389269,
year = {2025},
author = {Isaković, J and Athanassiadis, A and Khubeis, M},
title = {Stem cells strike back: advancements in Alzheimer's and Parkinson's disease treatment and modeling efforts from 2019 to 2024.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {2},
pmid = {41389269},
issn = {1432-1440},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Parkinson Disease/therapy ; *Stem Cell Transplantation/methods ; Animals ; Clinical Trials as Topic ; *Stem Cells/cytology/metabolism ; Cell Differentiation ; },
abstract = {This review critically evaluates the current state of stem cell therapy (SCT) for treating and modeling of Alzheimer's (AD) and Parkinson's disease (PD). It includes an in-depth analysis of both preclinical and clinical studies, with a particular focus on clinical trials conducted between 2019 and 2024, reflecting recent advancements in the field. Preclinical studies were examined to elucidate the molecular mechanisms underlying SCT and identify developments that could be translated into clinical practice. Within these studies, stem cells, including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs), have shown high differentiation and proliferation abilities. These properties, along with their capacity to inhibit inflammation, prevent apoptosis, and stimulate angiogenesis, make them promising candidates for treating AD and PD. Over the past 15 years, 76 SCT-based trials have been conducted-27 for AD and 48 for PD-with more than half occurring in the past 5 years. Despite the promise of SCT, the field faces challenges such as ethical concerns regarding the use of ESCs, heterogeneity of isolated cultures, and inconsistent results across preclinical trials. Novel materials and electromagnetic fields (EMFs) offer potential solutions to these issues. While bioengineering approaches can enhance the successful engraftment of transplanted stem cells, EMFs can direct the cells' migration and differentiation. In conclusion, although significant progress has been made in SCT, ongoing efforts are needed to address existing challenges. Nevertheless, SCT holds considerable promise for the future, offering potential breakthroughs in the treatment of neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/therapy
*Parkinson Disease/therapy
*Stem Cell Transplantation/methods
Animals
Clinical Trials as Topic
*Stem Cells/cytology/metabolism
Cell Differentiation

@article {pmid41389093,
year = {2025},
author = {Goel, F and Garg, VK},
title = {Noni (Morinda citrifolia) and Neurodegeneration: Exploring its Role in Oxidative Stress, Neuroinflammation, and Cell Survival Pathways.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {289},
pmid = {41389093},
issn = {1559-1182},
mesh = {*Oxidative Stress/drug effects ; Humans ; *Morinda/chemistry ; Animals ; Cell Survival/drug effects/physiology ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; *Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; *Plant Extracts/pharmacology/therapeutic use ; },
abstract = {Neurodegenerative illnesses like Alzheimer's, Parkinson's, and Huntington's diseases are characterized by neuronal progressive loss, oxidative injury, neuroinflammation, and cell survival pathway disturbance. Noni (Morinda citrifolia), a multifarious plant with phytochemical content that includes iridoids, flavonoids, polyphenols, and alkaloids, is of particular interest as a candidate following the demonstration of neuroprotective activity. This review addresses the molecular mechanism of neuroprotection of noni on the basis of its ability to modulate oxidative stress, suppress neuroinflammation, and control cell survival pathways. Noni activates the Nrf2/ARE pathway, which results in enhanced endogenous antioxidant defense mechanisms such as SOD, CAT, and GPx, scavenging ROS. Additionally, it suppresses neuroinflammation by inhibiting the NF-κB pathway, which reduces the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, noni controls cell survival through the PI3K/Akt/mTOR and MAPK pathways, promoting neuronal resistance and anti-apoptosis. Preclinical evidence is strong in showing the efficacy of noni against neurodegeneration, but clinical evidence is needed to ascertain its translational potential. However, despite promising preclinical evidence highlighting noni's neuroprotective potential, a significant gap remains in its clinical validation underscoring the need for a comprehensive evaluation of current findings to guide future translational research. This article stresses the multifaceted neuroprotective effects of noni and reasserts its therapeutic potential against neurodegenerative diseases.},
}

*Oxidative Stress/drug effects
Humans
*Morinda/chemistry
Animals
Cell Survival/drug effects/physiology
*Neuroinflammatory Diseases/drug therapy/pathology/metabolism
*Signal Transduction/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/pathology/metabolism
*Plant Extracts/pharmacology/therapeutic use

@article {pmid41388863,
year = {2025},
author = {Pardo-Seco, J and Camino-Mera, A and Bello, X and Gómez-Carballa, A and Castelo-Martínez, L and Martínez-Cadenas, C and Martinón-Torres, F and Salas, A},
title = {Whole-Genome Sequencing in Galicia Reveals Male-Biased Pre-Islamic North African Ancestry, Subtle Population Structure, and Microgeographic Patterns of Disease Risk.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {24},
pages = {e71253},
pmid = {41388863},
issn = {1530-6860},
support = {//European Regional Development Fund/ ; },
mesh = {Humans ; Male ; Spain ; *Whole Genome Sequencing/methods ; Africa, Northern/ethnology ; Phylogeny ; Female ; *Genome, Human ; Genetics, Population ; *Black People/genetics ; *Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; North African People ; },
abstract = {Galicia, at the westernmost edge of Europe, exhibits distinctive genetic traits compared to other Iberian populations. We present the first whole-genome sequencing (WGS) study of a Galician population (GALOMICS; n = 91; 17.2 M variants; https://galomics.genpob.eu), analyzed alongside WGS data from other Spanish and continental populations (n = 1078). Contrary to recent claims of extreme genetic stratification, Galicia's structure reflects broader Iberian patterns, characterized by one major genetic cluster and four minor, localized ones. Analyses of the Spanish National DNA Bank (NDNAB; n = 453) confirm this pattern, with three Galician clusters, one clearly predominant. Phylogenetic analysis places Galician clusters on terminal, recently diverged branches, challenging earlier models suggesting ancient separation. Slightly elevated homozygosity, driven by the Porto do Son cluster, suggests mild regional inbreeding. A notable North African/Middle Eastern ancestry component (13.5%-16.5%) appears, likely introduced via trans-Mediterranean contact ca. 620-670 ce, predating the Islamic conquest of 711 ce, with a subtle south-to-north gradient and a male-biased signal (Y-DNA: 21.2%; mtDNA: 1.1%). This calls for reexamining assumptions about Islamic-era ancestry. Finally, Polygenic Risk Scores for common diseases (e.g., cancer, Alzheimer's disease, diabetes, autism) show geographic variability aligned with genetic substructure, highlighting the relevance of regional genomics to public health policy.},
}

Humans
Male
Spain
*Whole Genome Sequencing/methods
Africa, Northern/ethnology
Phylogeny
Female
*Genome, Human
Genetics, Population
*Black People/genetics
*Genetic Predisposition to Disease
Polymorphism, Single Nucleotide
North African People

@article {pmid41388839,
year = {2025},
author = {},
title = {Correction to "ACLY regulates autolysosome acidification through tubulin acetylation-mediated assembly of V-ATPase subunits in Alzheimer's disease model mice".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71018},
doi = {10.1002/alz.71018},
pmid = {41388839},
issn = {1552-5279},
}

@article {pmid41388838,
year = {2025},
author = {Mundada, NS and Lyu, X and Brown, CA and Sadeghpour, N and McGrew, E and Xie, L and Cook, PA and Gee, J and Yushkevich, PA and Das, SR and Wolk, DA and , },
title = {Enrichment of patients with concomitant limbic-predominant age-related TDP-43 encephalopathy (LATE) on the Alzheimer's disease continuum using hippocampal volume.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70970},
pmid = {41388838},
issn = {1552-5279},
support = {P30-AG072979/NH/NIH HHS/United States ; RF1-AG069474/NH/NIH HHS/United States ; R01-AG056014/NH/NIH HHS/United States ; R01-AG072796/NH/NIH HHS/United States ; AACSF-23-1152241//Alzheimer's Association and Fred Barbara Erb Foundation/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; U19 AG024904/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Hippocampus/pathology/diagnostic imaging ; *Alzheimer Disease/pathology/diagnostic imaging ; Male ; Female ; Magnetic Resonance Imaging ; *TDP-43 Proteinopathies/pathology/diagnostic imaging ; Aged ; Atrophy/pathology ; Positron-Emission Tomography ; Aged, 80 and over ; Cognitive Dysfunction/pathology/diagnostic imaging ; Cross-Sectional Studies ; tau Proteins/metabolism ; Dementia ; },
abstract = {INTRODUCTION: Clinical overlap between Alzheimer's disease (AD) and limbic-predominant age-related transactive response DNA binding protein 43 (TDP-43) encephalopathy (LATE), combined with the absence of validated in vivo biomarkers, complicates identification of mixed AD/LATE pathology. We labeled individuals along the AD continuum with suspected concomitant LATE using the lower quartile hippocampal volume (HV) cut-off and examined associated atrophy and cognitive profiles.

METHODS: We studied cognitively impaired (CI) Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with T1-magnetic resonance imaging (MRI) and amyloid- and tau-positron emission tomography (PET). Participants were classified into suspected (s) AD+sLATE-, AD-sLATE+, or AD+sLATE+ based on amyloid status and HV quartiles. Medial temporal lobe (MTL) and whole-brain atrophy patterns and cognitive profiles were compared cross-sectionally and longitudinally. Classification was validated in an autopsy cohort.

RESULTS: AD+sLATE+ showed greater anterior hippocampal (AH) and amygdala atrophy than AD+sLATE-. AD-sLATE+ and AD+sLATE+ showed greater anterior MTL atrophy and worse memory and language performance. AD+sLATE+ also exhibited faster cognitive decline.

DISCUSSION: A simple HV quartile cut-off may help identify mixed AD/LATE pathology and support clinical trial enrichment.

HIGHLIGHTS: Quartiles of HVs stratify CI individuals. Approach distinguishes suspected AD+sLATE-, AD-sLATE+, and AD+sLATE+ subgroups. The method is simple, scalable, and requires no complex modeling or biomarker panels. It enables practical identification of mixed pathology in clinical settings. It supports trial enrichment by excluding or targeting mixed pathology cases.},
}

Humans
*Hippocampus/pathology/diagnostic imaging
*Alzheimer Disease/pathology/diagnostic imaging
Male
Female
Magnetic Resonance Imaging
*TDP-43 Proteinopathies/pathology/diagnostic imaging
Aged
Atrophy/pathology
Positron-Emission Tomography
Aged, 80 and over
Cognitive Dysfunction/pathology/diagnostic imaging
Cross-Sectional Studies
tau Proteins/metabolism
Dementia

@article {pmid41388822,
year = {2025},
author = {Rozenblum, G and Ait-Aissa, K and Zahran, G and Alipour, M and Sahyoun, AM and Munkhsaikhan, U and Kassan, A and Ishrat, T and Wang, Q and Abidi, AH and Kassan, M},
title = {Unraveling the oral microbiome's role in Alzheimer's disease: From pathophysiology to therapeutic potential.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71011},
doi = {10.1002/alz.71011},
pmid = {41388822},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/microbiology/physiopathology ; *Microbiota/physiology ; *Mouth/microbiology ; *Dysbiosis/microbiology/complications ; Fusobacterium nucleatum ; Amyloid beta-Peptides/metabolism ; },
abstract = {Oral dysbiosis contributes to Alzheimer's disease (AD) by promoting neuroinflammation. Pathobionts such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum release virulence factors that induce amyloid beta aggregation and tau hyperphosphorylation, while the loss of commensals like Streptococcus salivarius and Neisseria spp. impairs anti-inflammatory protection, worsening neuronal damage. P. gingivalis is strongly linked to an increased risk of AD, especially in individuals with systemic conditions like diabetes, hypertension, and chronic kidney disease. Its presence in brain tissue correlates with a higher likelihood of AD, while salivary Veillonella and periodontal pathogens in gingival crevicular fluid show potential as non-invasive biomarkers for early AD detection. Therapeutic strategies targeting the oral microbiota, such as gingipain inhibitors, antimicrobials, probiotics, and prebiotics, show promise for mitigating AD risk. However, causal mechanisms and clinical efficacy remain to be fully established. Maintaining microbial balance through preventive and targeted modulation represents an innovative approach to reducing AD susceptibility. HIGHLIGHTS: We identified Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum as key oral pathogens driving Alzheimer's disease (AD) via gingipain-induced amyloid beta aggregation, systemic inflammation, and blood-brain barrier disruption. Our study revealed diabetes, hypertension, and chronic kidney disease (CKD) amplify AD risk through shared oral dysbiosis, with uremic toxins (CKD) and hyperglycemia (diabetes) exacerbating neuroinflammation. We propose Veillonella in saliva and Porphyromonas gingivalis in gingival crevicular fluid as non-invasive AD biomarkers, correlating with 6 to 10× higher AD risk when detected in brain tissue. Gingipain inhibitors (e.g., COR388), nitrate-reducing probiotics, and integrated dental-neurology care are promising interventions to disrupt the oral-brain axis. We advocate for oral microbiome screening in high-risk populations (apolipoprotein E ε4 carriers, diabetics) and interdisciplinary approaches to AD prevention.},
}

Humans
*Alzheimer Disease/microbiology/physiopathology
*Microbiota/physiology
*Mouth/microbiology
*Dysbiosis/microbiology/complications
Fusobacterium nucleatum
Amyloid beta-Peptides/metabolism

@article {pmid41388821,
year = {2025},
author = {Castellano, T and Wang, TC and Nolan, E and Wu, Y and Zhang, M and Clifton, M and Janve, VA and Durant, A and Regelson, A and Cody, K and Harrison, T and Engelman, CD and Jagust, W and Albert, M and Johnson, S and Resnick, SM and Sperling, R and Bilgel, M and Saykin, A and Vardarajan, B and Mayeux, R and , and Betthauser, T and Bennett, DA and Schneider, J and De Jager, P and Menon, V and Tosun, D and Mormino, E and Archer, DB and Dumitrescu, L and Hohman, TJ and Koran, ME},
title = {APOE, ABCA7, and RASGEF1C are associated with earlier onset of amyloid deposition from more than 4000 harmonized positron emission tomography images.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71006},
doi = {10.1002/alz.71006},
pmid = {41388821},
issn = {1552-5279},
support = {K76AG088554//Intramural Research Program of the NIA/NIH/ ; P50-AG008702.ROS/MAP//The Columbia University Alzheimer's Disease Research Center/ ; P30AG10161//The Columbia University Alzheimer's Disease Research Center/ ; P30AG72975//The Columbia University Alzheimer's Disease Research Center/ ; R01AG15819//The Columbia University Alzheimer's Disease Research Center/ ; R01AG17917//The Columbia University Alzheimer's Disease Research Center/ ; U01AG46152//The Columbia University Alzheimer's Disease Research Center/ ; U01AG61356//The Columbia University Alzheimer's Disease Research Center/ ; AACSF-22-973008/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; *Alzheimer Disease/genetics/diagnostic imaging ; Aged ; *ATP-Binding Cassette Transporters/genetics ; *Apolipoproteins E/genetics ; *Brain/diagnostic imaging/metabolism ; *ras Guanine Nucleotide Exchange Factors/genetics ; Age of Onset ; Aged, 80 and over ; },
abstract = {INTRODUCTION: New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes.

METHODS: Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA.

RESULTS: Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA.

DISCUSSION: APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD.

HIGHLIGHTS: Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses.},
}

Humans
Positron-Emission Tomography
Male
Female
*Alzheimer Disease/genetics/diagnostic imaging
Aged
*ATP-Binding Cassette Transporters/genetics
*Apolipoproteins E/genetics
*Brain/diagnostic imaging/metabolism
*ras Guanine Nucleotide Exchange Factors/genetics
Age of Onset
Aged, 80 and over

@article {pmid41388809,
year = {2025},
author = {Moreno, N and Shchankin, N and Fung, L and Puangmalai, N and Bhatt, N and Haque, MA and Zhao, Y and Keene, CD and Limon, A and Kayed, R},
title = {APOE isoform-associated tau oligomer polymorphs differ in synaptotoxicity and seeding activity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70965},
doi = {10.1002/alz.70965},
pmid = {41388809},
issn = {1552-5279},
support = {AG06071801/NH/NIH HHS/United States ; AG07245801/NH/NIH HHS/United States ; AG07725301/NH/NIH HHS/United States ; AG05402506/NH/NIH HHS/United States ; AG077484/NH/NIH HHS/United States ; AG070255/NH/NIH HHS/United States ; AG073133/NH/NIH HHS/United States ; AG067952/NH/NIH HHS/United States ; },
mesh = {*tau Proteins/metabolism/genetics ; Humans ; *Apolipoproteins E/genetics/metabolism ; Protein Isoforms/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; Female ; Male ; *Synapses/pathology/metabolism ; Aged ; Animals ; },
abstract = {INTRODUCTION: Pathological tau aggregates form distinct polymorphic species across diseases and even across Alzheimer's disease (AD) patients. However, tau aggregate polymorphism across the apolipoprotein E isoforms (APOE ε2, ε3, ε4), the strongest predictors of late-onset AD development, is unknown.

METHODS: This study assessed the conformational and bioactivity properties of tau oligomers from 14 patients with varying APOE genotypes.

RESULTS: Tau oligomers differ in proteolytic stability and cleavage site profiles across the APOE isoforms, indicating conformationally distinct polymorphs. APOE isoform-associated tau oligomers affect synaptic plasticity differently, with ε4-associated oligomers having the highest potency and strongest impact on synaptic functioning. Bioactivity assays reveal that ε4-associated oligomers demonstrate particularly high seeding activity. Interestingly, tau oligomer synaptotoxicity and seeding activity are independent characteristics.

DISCUSSION: The APOE isoforms are associated with distinct tau oligomer polymorphs with varying bioactivity, underscoring the importance of considering APOE status when generating AD therapies. Polymorph-specific targeting of pathological tau species could provide a novel method of combating AD.

HIGHLIGHTS: Conformational and bioactivity distinctions of tau oligomers have not yet been investigated across the APOE isoforms (ε2, ε3, ε4). Tau oligomers differ in conformational properties across the APOE isoforms. APOE ε4-relevant tau oligomers strongly impair synaptic plasticity and demonstrate high tau seeding activity. APOE ε4-relevant tau oligomers exist as a particularly toxic species, making them an ideal target for tau-based AD therapies.},
}

*tau Proteins/metabolism/genetics
Humans
*Apolipoproteins E/genetics/metabolism
Protein Isoforms/genetics/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
Female
Male
*Synapses/pathology/metabolism
Aged
Animals

@article {pmid41388808,
year = {2025},
author = {Cary, GA and Li, Q and Wiley, JC and Paisie, CA and Du, Y and Zoeller, EL and Duong, D and Fu, H and Seyfried, NT and Levey, AI and Betarbet, R and Carter, GW and , },
title = {Integrated phenotypic and proteomic screening identifies top-tier Alzheimer's disease therapeutic targets.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71008},
doi = {10.1002/alz.71008},
pmid = {41388808},
issn = {1552-5279},
support = {//Sun Health Research Institute Brain and Body Donation Program of Sun City/ ; //Arizona Alzheimer's Disease Core Cente/ ; //Arizona Department of Health Services/ ; U54 AG065187/AG/NIA NIH HHS/United States ; },
mesh = {*Proteomics/methods ; *Alzheimer Disease/metabolism/genetics/drug therapy ; Animals ; Phenotype ; Mice ; *Microglia/metabolism ; Presenilin-2/genetics/metabolism ; Humans ; RNA, Small Interfering ; Cell Line ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder. Hundreds of therapeutic targets have been nominated through genetic and multi-omic studies, but effective prioritization remains a major bottleneck.

METHODS: We applied an integrative screening framework to assess 29 candidate targets from risk-enriched biological domains. Using disease-relevant murine BV2 microglial cell lines with stable Psen2 knockdown, we performed small interfering RNA-mediated perturbations followed by cellular phenotypic assays and quantitative proteomics.

RESULTS: Twenty-five candidate targets significantly altered at least one phenotype, with stronger effects in Psen2 knockdown cells. Integrated proteomic analyses identified several perturbations that reversed AD-associated molecular patterns. Five targets-Ap2a2, Pdhb, Pdha1, Dlat, and Psmc3-impacted both phenotypes and related proteomic responses.

DISCUSSION: We established a scalable platform for target functional validation that bridges unbiased systems-level assessments of AD risk with experimental evidence. The Emory-Sage-Structural Genomics Consortium-Jax Center Target Enablement to Accelerate Therapy Development for Alzheimer's Disease center will prioritize further resource development for these validated targets.

HIGHLIGHTS: A screening platform was created to identify the most potent targets from nominated hypotheses. Integrated analysis of cellular proteomics and assay phenotypes was performed. Targets capable of reversing disease-associated proteomic signal were identified. The most impactful targets were strongly implicated in Alzheimer's disease pathogenesis.},
}

*Proteomics/methods
*Alzheimer Disease/metabolism/genetics/drug therapy
Animals
Phenotype
Mice
*Microglia/metabolism
Presenilin-2/genetics/metabolism
Humans
RNA, Small Interfering
Cell Line

@article {pmid41388803,
year = {2025},
author = {Sundaresh, SN and Vogel, EW and Hue, CD and Zhang, H and Staniszewski, A and Berman, HL and Gill, Z and Asam, K and Liang, S and Shen, L and Gnanaprakash, M and Acquarone, E and Masone, A and Fà, M and Kanaan, NM and Morrison, B and Arancio, O and Nicholls, RE},
title = {PP2A methylesterase, PME-1, and PP2A methyltransferase, LCMT-1, control sensitivity to impairments caused by injury-related oligomeric tau.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70947},
doi = {10.1002/alz.70947},
pmid = {41388803},
issn = {1552-5279},
support = {12347//Paul G. Allen Frontiers Group/ ; W81XWH-12-1-0579//U.S. Department of Defense/ ; W81XWH-15-1-0550//U.S. Department of Defense/ ; HT9425-23-1-0384//U.S. Department of Defense/ ; },
mesh = {Animals ; *tau Proteins/metabolism/toxicity ; *Carboxylic Ester Hydrolases/metabolism/genetics ; Humans ; *Protein O-Methyltransferase/metabolism/genetics ; Mice ; *Brain Injuries, Traumatic/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; *Tauopathies ; *Protein Phosphatase 2/metabolism ; },
abstract = {INTRODUCTION: Oligomeric species of tau are a hallmark of Alzheimer's disease (AD). Given the evidence implicating protein phosphatase 2A (PP2A) in the molecular pathogenesis of tauopathies, we sought to determine whether manipulating the expression of enzymes that regulate PP2A activity, such as leucine carboxyl methyltransferase 1 (LCMT-1) and protein methylesterase 1 (PME-1), would alter pathological responses to oligomeric tau.

METHODS: We tested the effect of LCMT-1 and PME-1 overexpression on cognitive and electrophysiological impairments caused by exposure to either recombinant oligomeric human tau or oligomeric tau prepared from mice subjected to blast-induced traumatic brain injury.

RESULTS: We found that LCMT-1 overexpression reduced sensitivity while PME-1 overexpression increased sensitivity to tau-induced impairments. Moreover, shockwave exposure increased the propensity of endogenous tau to form toxic oligomers.

DISCUSSION: These results suggest that manipulating LCMT-1 or PME-1 activity may represent novel therapeutic approaches for disorders involving exposure to pathogenic forms of oligomeric tau.

HIGHLIGHTS: LCMT-1 and PME-1 overexpression alters sensitivity to oligomeric tau-induced impairments. Blast-induced traumatic brain injury increases the propensity of tau to oligomerize. Pathogenic tau-induced cognitive impairments were dependent on its oligomeric form.},
}

Animals
*tau Proteins/metabolism/toxicity
*Carboxylic Ester Hydrolases/metabolism/genetics
Humans
*Protein O-Methyltransferase/metabolism/genetics
Mice
*Brain Injuries, Traumatic/metabolism
Male
Disease Models, Animal
Mice, Inbred C57BL
*Tauopathies
*Protein Phosphatase 2/metabolism

@article {pmid41388643,
year = {2025},
author = {Mason, AC and Fatih, N and Sofat, R and Rentsch, CT and Smeeth, L and Bhaskaran, K and Chaturvedi, N and Garfield, V},
title = {Disentangling the relationship between glucose, insulin and brain health: A UK Biobank study.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70353},
pmid = {41388643},
issn = {1463-1326},
support = {220283/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; SCA/01/NCF/22//Diabetes Research and Wellness Foundation/ ; NIHR303160//NIHR/ ; },
abstract = {BACKGROUND: Glycaemic traits are associated with poorer brain health and dementia risk. Recent advances in genetic instruments for specific glycaemic markers enable an in-depth investigation of the likely nature of associations and underlying mechanisms between diabetes-related mechanisms and brain health and dementia.

METHODS: We used two-sample Mendelian randomisation (MR) in the UK Biobank (UKB) (maximum N = 357 883 White British, mean age 56.9 years, 54% female) applying inverse-variance weighted MR as our main estimator alongside MR-Egger, weighted median estimator (WME) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) as sensitivity tests. Instruments were 53 insulin resistance, 109 fasting glucose, 48 fasting insulin and 15 2-h post-load glucose genetic variants with variant-outcome effects estimated adjusting for 10 PCs. We checked core MR assumptions and sought to replicate results in an independent Alzheimer's dementia genome-wide association study (GWAS).

RESULTS: In UKB, higher 2-h post-load glucose was associated with a 69% increased Alzheimer's dementia risk (odds ratio 1.69 [95% confidence interval 1.38-2.07]), though this did not replicate in an independent GWAS. Fasting insulin, fasting glucose and postprandial glucose did not influence total brain, hippocampal or white-matter hyperintensity volumes.

DISCUSSION: The association between elevated 2-h post-load glucose and increased Alzheimer's risk supports a potential role for postprandial hyperglycaemia in dementia. The lack of associations between fasting or postprandial glucose and hippocampal, total-brain or white matter hyperintensity volumes suggests this risk may operate independently of gross structural atrophy.

CONCLUSION: Genetically proxied postprandial hyperglycaemia contributes to increased Alzheimer's risk in mid-life, warranting replication in other populations and ancestries to confirm and clarify underlying mechanisms.},
}

@article {pmid41388626,
year = {2025},
author = {Stringhi, R and Pelucchi, S and D'Andrea, L and La Greca, F and Zianni, E and Targa, L and Mosconi, C and Vandermeulen, L and Ascagni, M and Speciani, MC and Gardoni, F and Scheggia, D and Edefonti, V and Di Luca, M and Marcello, E},
title = {Cyclase-Associated Protein 2 gene delivery as a potential multi-target approach for preventing synaptic failure in Alzheimer's disease.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2025.12.023},
pmid = {41388626},
issn = {1525-0024},
abstract = {Alzheimer's Disease (AD) is marked by synaptic failure, with actin cytoskeleton alterations playing a key role in its pathogenesis. Cofilin, a regulator of actin dynamics in dendritic spines, forms cofilin-actin rods upon exposure to Amyloid-β (Aβ) oligomers, contributing to synaptic loss. Cyclase-associated protein 2 (CAP2) is crucial for regulating cofilin activity. During long-term potentiation, CAP2 dimerization is relevant for cofilin translocation to spines required for spine remodeling. In AD, CAP2 is downregulated, thus disrupting synaptic CAP2/cofilin complexes. To investigate the neuroprotective potential of CAP2 overexpression in preventing Aβ-induced synaptic dysfunction, we used adeno-associated virus serotype 9 (AAV) gene delivery to elevate CAP2 levels in APP/PS1 mice-a model of amyloid pathology-starting from the asymptomatic stage. APP/PS1 animals received bilateral stereotaxic injection of either AAV expressing CAP2 or a control AAV. This approach preserved synaptic CAP2/cofilin interaction, maintained synaptic plasticity pathways, and sustained cognitive function. CAP2 overexpression reduced cofilin-actin rod formation and mitigated tau abnormalities. Notably, CAP2 is present in cofilin-actin rods, and its dimerization is required to prevent Aβ-driven synaptic loss but not to protect neurons from rod formation. These findings highlight CAP2 upregulation as a promising strategy to enhance neuronal resilience and counteract Aβ synaptic toxicity in AD.},
}

@article {pmid41388533,
year = {2025},
author = {Khan, AR and Makhoul, GW and Raji, MA},
title = {Mirtazapine for gastrointestinal side effects of glucagon-like peptide-1 receptor agonist therapy in older adults.},
journal = {Endocrine regulations},
volume = {59},
number = {1},
pages = {260-264},
doi = {10.2478/enr-2025-0030},
pmid = {41388533},
issn = {1336-0329},
mesh = {Humans ; Aged ; Female ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Mirtazapine/therapeutic use ; *Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptides/adverse effects ; *Gastrointestinal Diseases/chemically induced/drug therapy ; Nausea/chemically induced/drug therapy ; Vomiting/chemically induced/drug therapy ; Glucagon-Like Peptide 1 ; },
abstract = {Objective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) play a role in management of type 2 diabetes (T2D) and obesity by promoting glycemic control and weight reduction. Beyond these benefits, GLP-1 RAs have demonstrated positive effects on cardiovascular, renal, and neurological health, with emerging evidence supporting their therapeutic potential in conditions such as chronic kidney disease, asthma, obstructive sleep apnea, Parkinson's disease, and Alzheimer's disease. However, their widespread clinical use is often hindered by gastrointestinal side effects including nausea, anorexia, vomiting, and diarrhea that limit adherence and dose titration. Effective management of these adverse effects is essential to optimize treatment outcomes and maintain long-term therapy. Case report. A 72-year-old woman with a history of cognitive impairment, T2D, atrial fibrillation, obesity, and mood disorders presented with persistent gastrointestinal symptoms while receiving semaglutide. Dose escalation was restricted due to severe nausea, vomiting, and diarrhea, which markedly affected her quality of life. To manage these symptoms, mirtazapine was initiated. Following its introduction, the patient reported significant improvement in gastrointestinal tolerance enabling continued semaglutide therapy and successful dose advancement. Additional benefits included enhanced mood, better sleep, and overall well-being. No adverse effects related to mirtazapine were observed throughout the treatment. Conclusion. This case suggests that mirtazapine may be beneficial in mitigating GLP-1 RA-induced gastrointestinal side effects, thereby improving adherence and therapeutic efficacy. Further research is needed to evaluate the safety, mechanism, and generalizability of this approach in broader clinical practice.},
}

Humans
Aged
Female
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetes Mellitus, Type 2/drug therapy
*Mirtazapine/therapeutic use
*Hypoglycemic Agents/adverse effects
Glucagon-Like Peptides/adverse effects
*Gastrointestinal Diseases/chemically induced/drug therapy
Nausea/chemically induced/drug therapy
Vomiting/chemically induced/drug therapy
Glucagon-Like Peptide 1

@article {pmid41388396,
year = {2025},
author = {Tsagkari, D and Panagiotidou, E and Tavernarakis, N},
title = {The role of lipid metabolism in neuronal senescence.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70181},
pmid = {41388396},
issn = {2211-5463},
support = {GA-101087071//the General Secretariat for Research and Innovation of the Greek Ministry of Development/ ; 15546//Hellenic Foundation for Research and Innovation/ ; HFRI-FM17C3- 0869//Hellenic Foundation for Research and Innovation/ ; },
abstract = {Senescence is a complex cellular state characterised by irreversible growth arrest and metabolic reprogramming. In neurons, senescence has been mainly observed in the context of ageing and age-related neurodegeneration. Lipid metabolism plays a critical role in cellular homeostasis, with emerging evidence suggesting that alterations in lipid species, including fatty acids, cholesterol, sphingolipids and phospholipids, fundamentally drive or contribute to the senescent phenotype in both neuronal and non-neuronal cells in the brain. Namely, changes in lipid species levels result in the accumulation of lipid droplets (LDs), leading to dysregulation of membrane dynamics, and in turn to the production of bioactive lipid mediators, which collectively shape the senescence-associated secretory phenotype (SASP) in the brain. In this review, we describe the cell type-specific patterns of lipid dysregulation in neurons, astrocytes, microglia and other glial cells during senescence, highlighting the role of key lipid species and their association with senescence markers and phenotypes. Furthermore, we discuss the bidirectional relationship between lipid metabolism and mitochondrial dysfunction in cellular senescence. We also examine the molecular mechanisms through which lipid metabolic pathways can orchestrate neural senescence and their contribution to ageing and age-related neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Finally, we review emerging therapeutic strategies targeting lipid metabolic pathways to modulate neural senescence and potentially ameliorate age-associated brain pathology.},
}

@article {pmid41388352,
year = {2025},
author = {Akinluyi, ET and Takahashi-Yamashiro, K and Connolly, MG and Poon, WW and Macauley, MS},
title = {Interplay between CD33 and TREM2 in Alzheimer's Disease: Potential Mechanistic Insights into Microglial Function in Amyloid Pathology.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00805},
pmid = {41388352},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, tau neurofibrillary tangles, and progressive neuronal loss leading to cognitive decline. With millions affected worldwide, there remains an urgent need for innovative treatment strategies to combat this disease. Genome-wide association studies (GWAS) have identified genes expressed in microglia, the resident immune cells of the brain, as key mediators of AD susceptibility. Among microglial risk genes, CD33 and TREM2 stand out for their contrasting roles in AD risk. Accumulating evidence indicates that these receptors converge on overlapping signaling pathways to regulate microglial activation and Aβ clearance. Here, we review the current understanding of CD33 and TREM2 biology in AD, with a focus on their potential crosstalk and functional antagonism. We propose potential mechanistic models by which human CD33 isoforms regulate TREM2 activity in either the absence or presence of Aβ pathology and discuss therapeutic strategies targeting this axis. Together, these insights suggest new avenues for microglia-targeted interventions in AD.},
}

@article {pmid41388319,
year = {2025},
author = {Hwang, J and Moon, SY and Lee, H and Lee, J and Park, YK and Jeong, JH and Hong, CH and Jung, J and Na, HR and Cho, SH and Sung, J and Lee, SJ and Choi, SH},
title = {Polygenicity and APOE ε4 shape response to intervention in mild cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {262},
pmid = {41388319},
issn = {1758-9193},
support = {No. RS-2021-KH112636 and No. RS-2024-00337993//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC) funded by the Korea government (Ministry of Health & Welfare and MSIT)/ ; No. CRC22013-600//National Research Council of Science and Technology (NST) Aging Convergence Research Center funded by the Korea government (MSIT)/ ; No. NRF-2020M3E5D2A01084721//Basic Science Research Program through the National Research Foundation of Korea funded by the Korea government (MSIT)/ ; No. 2023R1A2C2002925//National Research Foundation of Korea grant funded by the Korea government (MSIT)/ ; No. 2022-0-00448/RS-2022-II220448//Institute of Information and Communications Technology Planning and Evaluation (IITP) funded by the Korea government (MSIT)/ ; },
mesh = {Humans ; *Cognitive Dysfunction/genetics/therapy/psychology ; *Apolipoprotein E4/genetics ; Male ; Female ; Aged ; Neuropsychological Tests ; *Multifactorial Inheritance/genetics ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Multidomain lifestyle interventions have shown effectiveness in preventing dementia, but identifying high-risk groups most likely to benefit remains unclear.

METHODS: We re-evaluated the SUPERBRAIN-MEET multidomain intervention study in mild cognitive impairment (MCI) patients, incorporating polygenic risk scores (PRS) for Alzheimer's disease and APOE ε4 status using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total index as the primary outcome.

RESULTS: Both intervention and control groups showed cognitive improvement over 24 weeks, with greater gains in the intervention arm. Relative intervention efficacy (RIE) increased with higher genetic risk, being most pronounced among APOE ε4 carriers and individuals with high PRS. When both factors were considered jointly, APOE ε4 carriers with high PRS exhibited the largest RIE (β = 7.54, SE = 2.59, p = 0.005), driven by markedly greater improvement in the intervention group. The secondary outcomes did not show as consistent results as RBANS total index.

DISCUSSION: These findings suggest that MCI individuals who are APOE ε4 carriers with high PRS may benefit most from multidomain interventions. These results support the complementary use of PRS and APOE status for identifying high-risk subgroups most likely to benefit from multidomain interventions.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05023057. Registered on 26 August 2021.},
}

Humans
*Cognitive Dysfunction/genetics/therapy/psychology
*Apolipoprotein E4/genetics
Male
Female
Aged
Neuropsychological Tests
*Multifactorial Inheritance/genetics
Treatment Outcome
Aged, 80 and over
Middle Aged

@article {pmid41388301,
year = {2025},
author = {Caceres-Palomo, L and Sanchez-Mejias, E and Trujillo-Estrada, L and Perez-Moreno, JJ and Lopez-Oliva, E and Lim, TE and DeFlitch, L and Chang, SH and Kampman, L and Corces, MR and Blurton-Jones, M and Moreno-Gonzalez, I and Pascual, A and Vitorica, J and Garcia-Leon, JA and Gutierrez, A},
title = {Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03607-z},
pmid = {41388301},
issn = {1742-2094},
support = {UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG), SNGJ4-11 (to LCP)//Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía/ ; UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG), SNGJ4-11 (to LCP)//Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía/ ; UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG), SNGJ4-11 (to LCP)//Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía/ ; P30 AG066519/NH/NIH HHS/United States ; P01AG073082, U01AG072573, and UM1HG012076 to MRC./NH/NIH HHS/United States ; P30 AG066519/NH/NIH HHS/United States ; PI21/00915 and PI24/00274 (to AG) and PI21/00914 and PI24/00308 (to JV)//Instituto de Salud Carlos III/ ; PI21/00915 and PI24/00274 (to AG) and PI21/00914 and PI24/00308 (to JV)//Instituto de Salud Carlos III/ ; PI-0276-2018 (to JAGL)//Consejería de Salud y Familias, Junta de Andalucía/ ; B1-2020_04 (to JAGL)//Universidad de Málaga/ ; },
}

@article {pmid41388214,
year = {2025},
author = {Li, W and Wang, X and Liu, J and Chen, Y},
title = {The Role of c-Abl in Alzheimer's Disease: Guilty or not Guilty?.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-025-01650-1},
pmid = {41388214},
issn = {1573-6830},
support = {81602796//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. Extracellular senile plaques composed of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles (NFTs) containing the hyperphosphorylated tau protein, excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. The nonreceptor tyrosine kinase c-Abl plays a complex dual role in AD through the regulation of signaling pathways such as oxidative stress, DNA repair, and apoptosis. c-Abl mitigates early neuronal damage by activating antioxidant enzymes and potentially promoting homologous recombination (HR) repair. However, its aberrant activation is associated with Aβ plaque formation, tau phosphorylation, neuronal cell death, and synaptic dysfunction. Its synergistic interaction with Aβ and tau exacerbates the neurodegenerative pathology. This article provides a systematic review of the molecular mechanisms of c-Abl in AD, including its dual role in oxidative stress, synergistic regulation of neuronal function with Aβ and the tau protein, involvement in the maintenance of genomic stability, and potential as a therapeutic target.},
}

@article {pmid41388182,
year = {2025},
author = {McCoy, ND and Gawrys, SP and Mackintosh, SG and Byrum, S and Kosari, N and Zhou, A and Mansoor, MAM and Ikeno, Y and Isola, JVV and Stout, MB and Schneider, A and Masternak, MM and Mason, JB},
title = {Ovarian somatic tissue rejuvenates circulating apolipoproteins and promotes cognitive health in postreproductive female mice.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41388182},
issn = {2509-2723},
support = {R15AG061795/NH/NIH HHS/United States ; R56AG074499/NH/NIH HHS/United States ; R01AG069742/NH/NIH HHS/United States ; 24A12//Ed and Ethel Moore Alzheimer's Disease Research Program, Florida Department of Health/ ; P30 AG050911/AG/NIA NIH HHS/United States ; GCRLE-4501//The Global Consortium for Reproductive Longevity and Equality/ ; UTA01159//Utah Agricultural Experiment Station/ ; },
abstract = {Women experience more pronounced lipidomic changes with aging than men, which may contribute to the higher rates of Alzheimer's disease seen in postmenopausal women. Our earlier findings showed that transplantation of young ovarian somatic tissues or cells produced positive health-enhancing results in postreproductive females. In the current experiments, we looked to find key health-enhancing ovarian cells and pathways involved in this phenomenon. We conducted physiological and molecular analysis on animals/samples from old, postreproductive mice that received young ovarian tissue/cell transplants. Our analysis revealed a loss with age and a restoration with ovarian tissue/cell exposure, of serum biomarkers of lipid signaling and histological and behavioral markers of cognitive function. We further found, with single-cell transcriptomics and Raman spectroscopy, two candidate ovarian somatic cell types implicated in the restoration of health through a lipid signaling-based process. These results have identified key factors toward the determination of how germ cell-independent ovarian somatic tissues restore health through regulation of lipid signaling and dementia in postreproductive female mice.},
}

@article {pmid41388145,
year = {2025},
author = {Ehret, F and Doludda, B and Liu, H and Nexhipi, S and Huang, H and Rost, F and Overall, RW and Barde, W and Rünker, AE and Sieweke, M and Dahl, A and Schmidt, MHH and Kempermann, G},
title = {Lifestyle shapes preclinical social and microglial deficits in an Alzheimer's disease mouse model.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41388145},
issn = {1476-5578},
support = {98 597//Volkswagen Foundation (VolkswagenStiftung)/ ; 98 597//Volkswagen Foundation (VolkswagenStiftung)/ ; 19038//Alzheimer Forschung Initiative (Alzheimer Forschung Initiative e.V.)/ ; },
abstract = {Alzheimer's disease has a long preclinical phase, during which no overt signs of the manifest disease are present, but subtle, usually non-specific changes are already detectable. Emerging early biomarkers underscore the importance of this phase for preventive measures including lifestyle interventions. As a reductionistic model for lifestyle factors, we used a novel enrichment paradigm in which App[NL-G-F] knock-in mice were continuously tracked until 7 months of age. Despite minimal plaque burden and no memory impairment at that age, there were early and progressive deficits in social parameters - such as following behavior, social interaction, and exploration - suggesting preclinical behavioral vulnerability. Altered correlations between adult neurogenesis and social parameters linked neural plasticity to preclinical behavior. Plasma profiling at 3 months identified early systemic shifts in markers of inflammation and apoptosis that predicted later cortical pathology. We found increased microglia coverage in more socially active animals. More actively exploring controls, but not App[NL-G-F] mice, exhibited more ramified and less amoeboid microglia, suggesting that AD pathology impairs immune surveillance at a very early stage. Single-cell RNA sequencing of hippocampal microglia revealed that enrichment dampened interferon-responsive microglia, which typically increase as amyloidosis advances. A shifted immune response was also measured by reduced transcripts related to antigen processing and presentation and by increased chemokine signaling. Our study demonstrates that the preclinical phase of AD is not silent, but even in a reductionistic knock-in model characterized by early interwoven preclinical changes in multiple domains, including brain plasticity, behavioral trajectories, sociality and immunity.},
}

@article {pmid41388139,
year = {2025},
author = {Lima, MR and Capstick, A and Geranmayeh, F and Nilforooshan, R and Matarić, M and Vaidyanathan, R and Barnaghi, P},
title = {Evaluating spoken language as a biomarker for automated screening of cognitive impairment.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-025-01263-1},
pmid = {41388139},
issn = {2730-664X},
support = {EP/W031892/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; MR/T001402/1//RCUK | Medical Research Council (MRC)/ ; },
abstract = {BACKGROUND: Timely and accurate assessment of cognitive impairment remains a major unmet need. Speech biomarkers offer a scalable, non-invasive, cost-effective solution for automated screening. However, the clinical utility of machine learning (ML) remains limited by interpretability and generalisability to real-world speech datasets.

METHODS: We evaluate explainable ML for screening of Alzheimer's disease and related dementias (ADRD) and severity prediction using benchmark DementiaBank speech (N = 291, 64% female, 69.8 ± 8.6 years). We validate generalisability on pilot data collected in-residence (N = 22, 59% female, 76.2 ± 8.0 years). To enhance clinical utility, we stratify risk for actionable triage and assess linguistic feature importance.

RESULTS: We show that a Random Forest trained on linguistic features for ADRD detection achieves a mean sensitivity of 69.4% (95% confidence interval (CI) = 66.4-72.5) and specificity of 83.3% (78.0-88.7). On pilot data, this model yields a mean sensitivity of 70.0% (58.0-82.0) and specificity of 52.5% (39.3-65.7). For prediction of Mini-Mental State Examination (MMSE) scores, a Random Forest Regressor achieves a mean absolute MMSE error of 3.7 (3.7-3.8), with comparable performance of 3.3 (3.1-3.5) on pilot data. Risk stratification improves specificity by 13% on the test set, offering a pathway for clinical triage. Linguistic features associated with ADRD include increased use of pronouns and adverbs, greater disfluency, reduced analytical thinking, lower lexical diversity, and fewer words that reflect a psychological state of completion.

CONCLUSIONS: Our predictive modelling shows promise for integration with conversational technology at home to monitor cognitive health and triage higher-risk individuals, enabling early screening and intervention.},
}

@article {pmid41387998,
year = {2025},
author = {Yumlembam, S and Singh, K and Gupta, A and Adhikarimayum, P and Kumari, A and Sarangthem, K and Singh, LR},
title = {S-allyl cysteine and alliin enhance catalase activity and prevent aggregation to counter oxidative stress in alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30035-z},
pmid = {41387998},
issn = {2045-2322},
support = {09/476(0100)2020-EMR-I//CSIR/ ; },
abstract = {Oxidative stress is a key driver of Alzheimer's disease (AD), often linked to reduced activity of catalase, a major antioxidant enzyme. In AD, catalase is not only less active but also found as part of harmful protein aggregates with amyloid-β in brain plaques. Finding safe molecules that can boost catalase activity and stop it from aggregating could, therefore, offer a new strategy to lower disease progression. In this study, we examined two natural organosulfur compounds from garlic-S-allyl cysteine (SAC) and Alliin-for their effects on catalase. We found that both compounds significantly increased catalase activity in a concentration-dependent manner by stabilizing its structure and enhancing its thermodynamic stability. Furthermore, Molecular docking and Simulation studies revealed that SAC and Alliin bind at an allosteric site, promoting structural compaction and enhancing stability. Importantly, these compounds also reduced the tendency of catalase to form amyloid-like aggregates, a feature directly relevant to AD pathology. Our findings provide new mechanistic insights into how SAC and Alliin act on catalase-both stabilizing the enzyme and resulting in an increase in its activity along with lowering its aggregation propensity. This suggests that SAC and Alliin may serve as promising, natural candidates for therapeutic intervention in Alzheimer's disease.},
}

@article {pmid41387918,
year = {2025},
author = {Dougnon, G and Matsui, H},
title = {Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {67},
pmid = {41387918},
issn = {2047-9158},
support = {22K20681//Japan Society for the Promotion of Science/ ; 23K14672//Japan Society for the Promotion of Science/ ; JP 22484842//Japan Society for the Promotion of Science/ ; JP 23790744//Japan Society for the Promotion of Science/ ; JP23gm1710010//Japan Agency for Medical Research and Development/ ; P24wm0625506//Japan Agency for Medical Research and Development/ ; JPMJMS2024//Moonshot Research and Development Program/ ; },
mesh = {Humans ; *Lipofuscin/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Aging/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Oxidative Stress/physiology ; Amyloid beta-Peptides/metabolism ; Microglia/metabolism ; Lysosomes/metabolism ; Biomarkers/metabolism ; },
abstract = {Lipofuscin, a marker of aging, is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons. Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradation. However, recent findings suggest that lipofuscin may play a role in modulating age-related neurodegenerative processes, and several questions remain unanswered. For instance, why do lipofuscin granules accumulate preferentially in aged neurons and microglia? What happens to these pigments upon neuronal demise? Particularly in neurodegenerative diseases like Alzheimer's disease (AD), why does amyloid β (Aβ) deposition usually begin in late adulthood or during aging? Why do lipofuscin and amyloid plaques appear preferentially in grey matter and rarely in white matter? In this review, we argue that lipofuscin should be revisited not as a simple biomarker of aging, but as a potential modulator of neurodegenerative diseases. We synthesize emerging evidence linking lipofuscin to lysosomal dysfunction, oxidative stress, lipid peroxidation and disease onset-mechanisms critically implicated in neurodegeneration. We also explore the potential interactions of lipofuscin with Aβ and their spatial location, and summarize evidence showing that lipofuscin may influence disease progression via feedback loops affecting cellular clearance and inflammation. Finally, we propose future research directions toward better understanding of the mechanisms of lipofuscin accumulation and improved lysosomal waste clearance in aging.},
}

Humans
*Lipofuscin/metabolism
*Alzheimer Disease/metabolism/pathology
*Aging/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Oxidative Stress/physiology
Amyloid beta-Peptides/metabolism
Microglia/metabolism
Lysosomes/metabolism
Biomarkers/metabolism

@article {pmid41387800,
year = {2025},
author = {Guo, H and Guo, T and Wang, X and Bao, Y and Zhang, Z and Xue, F and Cheng, D},
title = {LAX1 as a core biomarker in Alzheimer's disease and periodontitis via the STAT signaling pathway.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-025-06865-x},
pmid = {41387800},
issn = {1471-2318},
support = {20241084 to Han Guo//the Medical Science Research Project in Hebei Province, PR China/ ; H2025206332//Natural Science Foundation of Hebei Province/ ; },
abstract = {BACKGROUND: The relationship between Alzheimer's disease (AD) and chronic periodontitis (PD) rarely share the medical spotlight, yet epidemiological mirroring hints at a common inflammatory root.

METHODS: Mining four GEO (Gene Expression Omnibus) cohorts (211 AD + 27 controls; 24 PD + 23 controls), batch-corrected and validated by principal component analysis (PCA)/t-distributed stochastic neighbour embedding (t-SNE)/uniform manifold approximation and projection (UMAP), we identified 61 shared differentially expressed genes (DEGs) with lymphocyte transmembrane adaptor 1 (LAX1) ranked first in weighted gene co-expression network analysis (WGCNA), maximum clique centrality (MCC), Degree, edge percolated component (EPC) and Stress algorithms, tightly co-expressed with colony-stimulating factor 3 receptor (CSF3R) and signal transducer and activator of transcription 1/3 (STAT1/3). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) uniquely highlighted the "LAX1/CSF3R/STAT" triad in apoptosis and JAK-STAT cascades. CIBERSORT de-convolution showed LAX1 covaried with plasma-cell, mast-cell and M0-macrophage infiltration.

RESULTS: Plasma from 42 AD and 38 stage-III/IV PD patients showed elevated soluble LAX1 (sLAX1) correlating with Mini-Mental State Examination (MMSE) decline (r =-0.67) and clinical attachment loss (r = 0.71), outperforming Aβ42 and receptor activator of nuclear factor-κB ligand (RANKL) in receiver operating characteristic (ROC) analyses (area under the curve [AUC] = 0.91). We hypothesised that LAX1 orchestrates the dialogue via the STAT axis. In human periodontal-ligament fibroblasts and 5 × FAD glia exposed to Porphyromonas gingivalis LPS or amyloid-β42 (Aβ42), LAX1 overexpression (pCMV6-LAX1) amplified STAT1/3 phosphorylation, elevated interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by 2.3-3.1-fold and escalated p53, cleaved caspase-3 and FAS, whereas LAX1 small interfering RNA (siRNA) abolished these effects. In other words, targeting of the LAX1 validated that the inflammatory/apoptotic signature scales with LAX1 abundance.

CONCLUSION: LAX1 gates STAT-dependent neuroinflammation and periodontal destruction, offering a druggable checkpoint and blood-based biomarker for these convergent chronic diseases.},
}

@article {pmid41387730,
year = {2025},
author = {Daniel Estrella, L and Sveeggen, TM and de la Guardia, G and Cacho, J and Stauch, KL and Bagher, P},
title = {A systematic review of the cerebrovascular adaptations following exposure to spaceflight or ground-based analogs: lessons from human and animal studies.},
journal = {NPJ microgravity},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41526-025-00540-6},
pmid = {41387730},
issn = {2373-8065},
support = {HL155618/HL/NHLBI NIH HHS/United States ; 80NSSC19K0392/NASA/NASA/United States ; },
abstract = {Human space exploration is rapidly advancing, with long-term expeditions becoming more common. Long-term space missions introduce prolonged exposure to microgravity and ionizing radiation, which elicit stress responses throughout many organ systems. As the cerebrovascular system is responsible for regulating blood flow to the brain, it is imperative to understand the effects of the space environment on the cerebrovascular system. Cerebrovascular alterations are also linked to neurological diseases such as Alzheimer's Disease, Parkinson's Disease, glaucoma, and stroke. This systematic review evaluates the current literature to demonstrate that spaceflight conditions (actual or ground-based analogs) can lead to changes in the cerebrovascular system at the network, cellular, and molecular levels. These findings demonstrate differences and similarities between cerebrovascular alterations due to the space environment and neurological conditions, highlighting that the mechanisms behind the reversibility and readaptation to Earth following spaceflight could inform treatments of neurological disease.},
}

@article {pmid41387393,
year = {2026},
author = {Roberts, SJ and Luckett, T and Ivynian, S and DiGiacomo, M},
title = {Elder Clowning Interventions for Persons With Dementia in Long-Term Care: A Systematic Review and Metasynthesis of Qualitative Research.},
journal = {Dementia (London, England)},
volume = {25},
number = {1},
pages = {192-214},
doi = {10.1177/14713012251366738},
pmid = {41387393},
issn = {1741-2684},
mesh = {Humans ; *Dementia/psychology/therapy ; Qualitative Research ; *Long-Term Care ; Quality of Life/psychology ; Aged ; Interpersonal Relations ; *Laughter Therapy/methods ; },
abstract = {Elder clowning is a psychosocial intervention delivered to persons living with dementia in long-term care. It aims to improve quality of life through interpersonal interaction and connection. This review aimed to synthesise international cross-disciplinary qualitative research regarding elder clowning specialist capabilities, engagement techniques, and potential benefits, for persons living with dementia, their families, and staff. The method was informed by systematic review methodologies. A comprehensive search of major health databases was undertaken. The search identified 198 studies, 15 articles from 10 studies were appraised and included in the review. Three major themes resulted from the synthesis: 1) understanding the elder clown, 2) journeying together to cultivate connection, and 3) promoting wellbeing through connection. Elder clowns were suggested to be perceptive, attuned, empathetic, present, adaptive, and performative. These capabilities supported a wide range of engagement techniques used to prepare for, approach, initiate, sustain, redirect, appeal for, and exit engagement with persons with dementia, which resulted in potential benefits across cognitive, behavioural, emotional, social, and experiential domains. The synthesis offers a common rubric for describing the components of elder clowning interventions for use across disciplines and identifies potential benefits to aid in the design of future trials of effectiveness.},
}

Humans
*Dementia/psychology/therapy
Qualitative Research
*Long-Term Care
Quality of Life/psychology
Aged
Interpersonal Relations
*Laughter Therapy/methods

@article {pmid41387343,
year = {2025},
author = {Park, J and Kim, B and Ha, M and Park, M and Ryu, H and Yu, H and Park, S and Roh, YS and Lim, KH and Hong, JT and Han, SB and Park, CW and Yong, SB and Park, H},
title = {CRISPRa Lipid Nanocomplex-Mediated Mt3 Targeting Enhances Astrocytic Endocytosis of Amyloid-β in an Alzheimer's Disease Mouse Model.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e03725},
doi = {10.1002/advs.202503725},
pmid = {41387343},
issn = {2198-3844},
support = {RS-2025-16068284//Korea government (MSIT)/ ; RS-2025-02273102//Korea government (MSIT)/ ; RS-2024-00440787//Bio & Medical Technology Development Program of the National Research Foundation (NRF)/ ; GTL24021-000//National Research Council of Science & Technology (NST)/ ; },
abstract = {Metallothionein 3 (Mt3) is crucial for cellular homeostasis and neuroprotection, with accumulating evidence linking it to amyloid-beta (Aβ) clearance by astrocytes. This study developed a CRISPR activator (CRISPRa) system using lipid nanoparticles to selectively upregulate Mt3 in astrocytes, aiming to enhance Aβ endocytosis in an Alzheimer's disease (AD) mouse model. To directly assess the therapeutic potential of Mt3 activation in a specific brain region, stereotaxic injection is utilized to deliver the CRISPRa lipid nanocomplexes. This approach enabled precise in vivo brain delivery and Mt3 activation. The findings reveal that CRISPRa lipid nanocomplex-mediated Mt3 upregulation significantly boosts Aβ uptake by astrocytes, leading to a marked reduction in Aβ plaque accumulation in AD mouse brains. These results highlight CRISPRa lipid nanocomplex-mediated Mt3 targeting as a promising strategy to enhance endogenous Aβ clearance, presenting a novel therapeutic avenue for AD.},
}

@article {pmid41387197,
year = {2025},
author = {Fredriksen-Goldsen, KI and Teri, L and Kim, HJ and Jones-Cobb, B and LaFazia, D and McKenzie, G and Petros, R and Jung, H and Oswald, AG and Hoy-Ellis, C and Emlet, C},
title = {Innovations in Dementia Empowerment and Action: RCT for Underserved Communities.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70189},
pmid = {41387197},
issn = {1532-5415},
support = {R01AG055488//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {BACKGROUND: Research has revealed dementia disparities among underserved older adults. Built upon standard-Reducing Disability in Alzheimer's Disease (s-RDAD), Innovations in Dementia Empowerment and Action (IDEA) is designed and culturally tailored for underserved communities through an empowerment stigma-reduction cognitive-behavioral intervention and tested with sexual and gender minority (SGM) adults and care partners.

METHODS: The study is a 2-arm (IDEA and s-RDAD), single-blind, randomized controlled trial (RCT) with a staggered multiple baseline design. With 161 dyads (person living with dementia/care partner), the aim of the study is to compare the two arms via between and within group differences on primary (physical activity) and secondary outcomes (e.g., quality of life, physical functioning, and resource literacy) at post-treatment, and 30 and 56 week follow-up.

RESULTS: When comparing the two arm between-group differences, the IDEA care partners' community resource literacy was significantly higher at 30-week follow-up than for s-RDAD (contrast = 0.10, p = 0.005). While both intervention arms demonstrated efficacy with significant improvement in physical activity (contrastIDEA = 0.10, p = 0.010; contrasts-RDAD = 0.14, p < 0.001) and quality of life (contrastIDEA = 0.06, p < 0.001; contrasts-RDAD = 0.03, p = 0.035) for the person with dementia at post-treatment, positive treatment effects on physical activity (contrastIDEA = 0.09, p = 0.032) and quality of life (contrastIDEA = 0.03, p = 0.040) persisted at 30 weeks for IDEA but not for s-RDAD.

CONCLUSION: While both intervention arms were efficacious, IDEA demonstrated sustained efficacy. The cultural tailoring of interventions is promising to address disparities in dementia care and interventions in underserved communities. Future research is needed for the translation of this efficacious intervention to the larger community.

CLINICALTRIALS: gov identifier: NCT03550131.},
}

@article {pmid41386992,
year = {2025},
author = {Myers, AK and Sakheim, M and Rivell, C and Fengler, C and Festa, LK and Guerra, KM and Jarrahy, L and Shin, R and Case, M and Chapman, C and Basel, L and Springer, S and Kern, N and Gidicsin, J and Cho, G and Kim, S and Tighiouart, M and Golden, JA},
title = {Anxiety-associated behaviors following ablation of Miro1 from cortical excitatory neurons.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0436-25.2025},
pmid = {41386992},
issn = {2373-2822},
abstract = {Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety (American Psychological Association, 2013). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction (Norkett et al., 2017; Khaliulin et al., 2025). Mitochondria dynamically translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction (Picard et al., 2016). Mitochondrial Rho-GTPase 1 (Miro1) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility and homeostasis (Fransson et al., 2003). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development and function (Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-Cre mice and used mice of either sex for experiments. We found that mitochondrial mis-localization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle cortical disorganization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting behavior and abnormal home cage activity. The mice exhibited anxiety-like behavior and avoided confined spaces, features that have been linked to several human behavioral disorders. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate intracellular mitochondrial dynamics to some anxiety-like behaviors.Significance Statement Neuropsychological disorders such as autism spectrum disorder, schizophrenia, and bipolar disorder have overlapping endophenotypes. While the mechanisms underlying these disorders are poorly understood, recent evidence implicates mitochondrial dysfunction and cellular mis-localization playing a role. Mitochondria support energy requirements and other physiological functions in cells. Previous research from our lab has shown distinct dynamic localization patterns within migrating excitatory and inhibitory neurons during development. To further examine the importance of mitochondrial localization, we ablated MIRO1, a protein important for coupling mitochondria to motor proteins, in excitatory neurons. The mis-localization of mitochondria in migrating excitatory neurons is associated with diminished motor skills and anxiety-like behavior in post-natal mice.},
}

@article {pmid41386518,
year = {2025},
author = {Contreras, PR and Henriquez, F and Gonzalez-Campo, C and Altschuler, F and Fraile-Vazquez, M and Ferreira, PC and Bellaver, B and Karikari, T and Pascoal, TA and Okuma, C and Gonzalez-Billault, C and Court, F and Cerda, M and Lillo, P and Khondoker, M and Hornberger, M and Slachevsky, A},
title = {Impact of cardiometabolic factors and AD plasma biomarkers on white matter hyperintensities volume in individuals with cognitive complaints from the global south.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.013},
pmid = {41386518},
issn = {1873-7544},
abstract = {White matter hyperintensities (WMH) are a magnetic resonance imaging (MRI) sign associated with cognitive complaints in the Alzheimer's Disease (AD) continuum, including the pre-dementia steps. Cardiovascular and neurodegenerative pathophysiology have been postulated as relevant factors in the origin of WMH in AD. However, this evidence comes mainly from northern global populations, where the epidemiological profile differs from other geographical regions. This study explores the relationship between WMH, cardiometabolic and plasma neurodegeneration biomarkers in individuals with cognitive complaints from a developing country in the global south, where cardiometabolic risk factors are highly prevalent. We analyzed 112 individuals with cognitive complaints, assessing plasma pTau217, Aβ42/Aβ40 ratio, blood pressure, and glycemia levels while quantifying and segmenting WMH volumes. Multiple regression analyses revealed that diastolic blood pressure was significantly associated with WMH in specific white matter tracts, including the anterior thalamic radiation, cingulum, forceps minor, and subcortical regions. In contrast, no associations were found with glycemia, pTau217, Aβ42/40, or systolic blood pressure. These findings suggest that cardiovascular factors could be more critical in WMH development than neurodegeneration markers in this population. Our study, in addition to reflecting, in part, the associations between cardiovascular risk factors and WMH, highlights the need for further research on neurovascular contributions to dementia pathophysiology in these populations, emphasizing the role of neurovascular integrity, blood-brain barrier function, and cerebrospinal fluid circulation in underrepresented geographical contexts.},
}

@article {pmid41386339,
year = {2025},
author = {Baviskar, PS and Mahajan, HS},
title = {"Unveiling Alzheimer's Disease (1901-2025): Historical Insights, Global Burden, Biological Mechanisms, Diagnostics, And Therapeutic Strategies".},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102990},
doi = {10.1016/j.arr.2025.102990},
pmid = {41386339},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), first identified by Dr. Alois Alzheimer in 1906, has evolved from a rare presenile dementia to a global health crisis affecting over 58 million people as of 2020, with projections reaching 152 million by 2050. Manuscript offers a comprehensive overview of AD, tracing its historical origins, epidemiological trends, pathophysiological mechanisms, diagnostic advancements, and therapeutic strategies. The pathogenesis of AD is multifactorial, involving amyloid-β plaque accumulation, tau protein hyperphosphorylation, cholinergic deficits, oxidative stress, and metal ion dyshomeostasis. These mechanisms converge to cause progressive neurodegeneration, cognitive decline, and behavioral disturbances. Clinically, AD manifests through a spectrum of neuropsychiatric symptoms, progressing from mild cognitive impairment to severe dementia, with distinct phenotypes and overlapping features with other dementias like DLB and VaD. Diagnostic approaches have advanced from clinical observation to biomarker-based precision, incorporating CSF and plasma tau assays, neuroimaging modalities (MRI, PET, SPECT), and AI-driven models for early detection. Despite these innovations, definitive diagnosis remains challenging due to symptom heterogeneity and overlap with other conditions. Therapeutically, the landscape has shifted from symptomatic treatments (e.g., cholinesterase inhibitors, memantine) to disease-modifying agents. Recent FDA approvals of monoclonal antibodies like Aducanumab, Lecanemab, and Donanemab mark a new era in targeted immunotherapy. However, many candidates targeting amyloid and tau pathways have failed in trials, underscoring the complexity of AD. Emerging drug delivery systems, including nanocarriers and intranasal formulations, aim to overcome the BBB and enhance therapeutic efficacy. The manuscript emphasizes the urgent need for integrative, personalized, and scalable solutions to manage AD's growing burden.},
}

@article {pmid41386298,
year = {2025},
author = {Ealy, A and Serapiglia, AM and Panicker, N},
title = {Sterile Innate Immune Mechanisms in Neurodegenerative diseases.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {111039},
doi = {10.1016/j.jbc.2025.111039},
pmid = {41386298},
issn = {1083-351X},
abstract = {Neurodegenerative diseases are characterized by the dysfunction and death of susceptible neuronal populations. Increasing evidence has demonstrated that sustained neuroinflammation and activation of innate immune complexes underlie neurodegeneration, worsening disease progression and outcomes. Sterile inflammation (which occurs in the absence of infection) can be triggered by neurodegenerative disease-associated misfolded proteins. These studies highlight the need to decipher the complexities of innate immune signaling mechanisms and their contribution to neuropathology. In this review, we focus on major neurodegenerative diseases that have a well-documented neuroinflammatory component: Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) and Frontotemporal Dementia (FTD). In the context of these diseases, we discuss recent advances in innate-immune mechanisms that have been demonstrated to partake in disease progression and neurodegeneration. These include evolutionarily conserved innate-immune signaling complexes whose uncontrolled activation amplifies neurodegeneration, damaging lipid droplets that accumulate within myeloid cells and prevent their ability to clear toxic protein aggregates, as well as genome-wide studies implicated genes/proteins. The individual and/or concerted actions of these pathways could be leveraged to rationally target the pathogenesis or progression of neurodegenerative diseases.},
}

@article {pmid41386198,
year = {2025},
author = {Iqbal, S and Liu, L and Marshall, GA and Sarkis, RA},
title = {Plasma p-Tau217 and p-Tau181 levels in Well-Controlled versus Drug-Resistant focal epilepsy.},
journal = {Epilepsy & behavior : E&B},
volume = {175},
number = {},
pages = {110855},
doi = {10.1016/j.yebeh.2025.110855},
pmid = {41386198},
issn = {1525-5069},
abstract = {BACKGROUND: Compared to patients with well-controlled epilepsy, those with drug-resistant epilepsy often experience greater morbidity, mortality, and accelerated aging. Plasma biomarkers pTau217 and pTau181 align with cerebrospinal fluid tau values and amyloid PET imaging, correlating with Alzheimer's disease (AD) pathology. These minimally invasive markers may help explore links between neurodegeneration and epilepsy. This study assessed plasma pTau217 and pTau181 levels in patients with drug-resistant (DR) and well-controlled (C) epilepsy to determine whether poor seizure control correlates with elevated biomarkers.

METHODS: Adults aged 18-65 with focal epilepsy were prospectively recruited from the Brigham and Women's Hospital Epilepsy Clinic. Clinical data, including time since last seizure, were obtained from electronic health records. Plasma pTau181 and pTau217 levels were measured and analyzed in relation to seizure control, MRI lesion presence, antiseizure medication use, and time since last seizure.

RESULTS: Plasma was collected from 103 patients: 48 well-controlled (C, 31.3 % female) and 55 drug-resistant (DR, 50.9 % female). Mean ages were 38.7 ± 12.3 years (C) and 37.0 ± 11.6 years (DR). Log-transformed mean plasma levels were not significantly different: pTau181 (DR: 2.17 ± 0.99 vs. C: 2.33 ± 0.87, p = 0.35) and pTau217 (DR: 3.87 ± 0.97 vs. C: 4.10 ± 0.95, p = 0.23). No correlation was observed between plasma tau and time since last seizure: pTau181 (ρ = +0.001, p = 0.99), pTau217 (ρ = +0.13, p = 0.18). Tau levels did not differ based on use of synaptic vesicle protein 2A inhibitors or sodium channel blockers.

DISCUSSION: Interictal plasma biomarkers of neurodegeneration are not elevated in adults with poorly controlled epilepsy and do not correlate with time since last seizure or specific antiseizure medications. Future studies should explore whether subpopulations exist with increased risk or early markers of accelerated aging.},
}

@article {pmid41385865,
year = {2025},
author = {Kim, S and Kumar, V and Shin, SJ and Nam, Y and Park, YH and Jang, S and Park, JY and Kim, DH and Moon, M},
title = {In silico virtual screening of natural small molecules for dual inhibition of Aβ and tau aggregation in Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118876},
doi = {10.1016/j.biopha.2025.118876},
pmid = {41385865},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is defined by the accumulation of amyloid beta (Aβ) plaques and twisted fibers of hyperphosphorylated tau, with their aggregation driving neurodegeneration and cognitive decline. Presently, the majority of therapies in development are largely single-targeted, focusing either on Aβ or tau aggregation. This highlights a significant gap in strategies that can simultaneously modulate aggregation of both proteins in AD. This study employed an integrated in silico approach to identify phenolic small molecules capable of modulating both Aβ and tau aggregation. From a library of 160 natural compounds, fifteen phenolic-structured compounds inhibited Aβ aggregation by more than 50 %, and subsequent in silico screening identified baicalein, genkwanin, 2-hydroxycinnamaldehyde, and gallic acid as potential dual inhibitors. To further evaluate their dual-modulating potential, we conducted molecular docking, molecular dynamics simulations, and pharmacokinetic predictions. First, molecular docking with multiple conformers of Aβ and tau showed that all four compounds bound strongly to key aggregation-prone residues. Second, molecular dynamics simulations further demonstrated stable interactions with dimeric Aβ and tau. Third, pharmacokinetic predictions supported drug-likeness, including favorable blood-brain barrier permeability and systemic clearance. Finally, Thioflavin T assays were subsequently conducted to examine whether the computationally predicted anti-aggregation potential was reflected in biological outcomes, and the results confirmed that the predicted interactions were partially recapitulated under in vitro conditions. Together, our findings provide mechanistic and pharmacokinetic support for the further development of these phenolic compounds as Aβ and tau-targeting agents in early-stage AD therapy.},
}