RevDate: 2025-12-15
CmpDate: 2025-12-15

Satyadev N, Piura YD, Tipton PW, et al (2026)

Standardizing "Rapid": Applying the Clinical Dementia Rating to Define Rapidly Progressive Dementia.

Neurology, 106(1):e214439.

BACKGROUND AND OBJECTIVES: Rapidly progressive dementia (RPD) accounts for 3%-4% of dementia cases yet presents a disproportionate clinical challenge given the wide differential diagnosis and the need to quickly identify potentially treatment-responsive causes. The lack of a standardized definition of RPD challenges generalization of published findings and precludes multisite studies. We sought to determine whether a standardized definition, based on the Clinical Dementia Rating (CDR), could reliably distinguish individuals with a broad spectrum of causes of RPD early in the symptomatic course.

METHODS: RPD was defined as dementia (global CDR ≥1) developing within 1 year or incapacitation (global CDR ≥2) within 2 years of symptom onset. Patients with suspected RPD were referred from inpatient and outpatient settings at Mayo Clinic in Florida (Jacksonville, FL) and Washington University in St. Louis (Saint Louis, MO) and prospectively evaluated (RaPID cohort). Retrospective data from participants assessed across 46 research centers were also analyzed (National Alzheimer's Coordinating Center [NACC] data set). Characteristics and rates of progression (main outcome) were compared between typically progressive and RPD. Univariable and multivariable analyses were performed using Mann-Whitney U/Kruskal-Wallis (continuous) and Fisher exact/χ[2] tests (binary), respectively. Our definition of RPD was compared against definitions identified through a scoping review conducted using a validated 6-stage approach.

RESULTS: In the RaPID cohort, 185 of 248 (74.6%) patients met our CDR-based RPD definition (median [range] age-at-symptom onset: 68.8 years [22.0-90.7]; 45.4% female). Autoimmune (55/185, 29.7%), neurodegenerative (51/185, 27.6%), and prion diseases (35/185, 18.9%) predominated. Among 20,418 NACC participants with cognitive impairment, 836 (4.1%) met our RPD definition (median [range] age-at-symptom onset: 74 years [24-103]; 57.1% female). Neurodegenerative diseases predominated, especially Alzheimer disease (485/836, 58.0%). Individuals with RPD declined substantially faster (ΔCDR sum-of-boxes/year: RaPID, 14.4 ± 5.3 vs 4.3 ± 4.3, p < 0.001; NACC, 6.7 ± 3.1 vs 1.7 ± 1.4, p < 0.001). Our scoping review identified 22 studies that applied 10 distinct definitions of RPD. Uniquely, our CDR-based definition clearly distinguished individuals with a broad spectrum of causes of RPD, assessed across multiple sites/settings, supporting early diagnosis with minimal resource requirements.

DISCUSSION: The CDR-based definition of RPD effectively identified individuals with a broad spectrum of causes of RPD early in the symptomatic course. The need for training and time to reliably administer the CDR may limit application of the proposed definition of RPD. Validation in additional cohorts is required to support generalizability.

RevDate: 2025-12-15

Zu J, Li C, Cui M, et al (2025)

Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.

Brain : a journal of neurology pii:8380271 [Epub ahead of print].

Synaptic loss is an early hallmark of Alzheimer's disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy, and 3D reconstruction techniques in an AD mouse model, we analysed synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.

RevDate: 2025-12-15

Brown CA, Mundada NS, Cousins KAQ, et al (2025)

Evaluation of Copathology and Clinical Trajectories in Individuals With Tau-Clinical Mismatch.

JAMA neurology pii:2842838 [Epub ahead of print].

IMPORTANCE: Even within individuals who are amyloid positive, clinical symptoms can be impacted by Alzheimer pathology, other pathologic proteins, and cognitive reserve or resilience. Understanding how each of these factors contributes to a patient's clinical presentation is crucial for prognosis and treatment decisions in the era of disease-modifying therapies.

OBJECTIVE: To evaluate tau-clinical mismatch as a means to identify those more likely to harbor copathology and/or exhibit resilience to Alzheimer pathology.

This was a longitudinal, observational cohort study conducted from 2004 to 2024. The setting included multiple academic medical centers in the US participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) or Penn Alzheimer's Disease Research Center (Penn-ADRC). Included in the analysis were individuals with clinical assessment and measures of either tau positron emission tomography (tau-PET) or phosphorylated tau 217 (p-tau217) who were selected from individuals positive for amyloid β (Aβ+) in the ADNI cohort (aged 55-95 years) and the Penn-ADRC cohort (aged 54-92 years).

EXPOSURES: Clinical assessment (Clinical Dementia Rating Sum of Boxes [CDR-SB]) and tau burden (tau-PET or p-tau217) for mismatch group classification.

MAIN OUTCOMES AND MEASURES: Cross-sectional measures of neurodegeneration (medial temporal lobe volume and thickness, cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature), α-synuclein cerebrospinal fluid seed-amplification assay, and longitudinal CDR-SB.

RESULTS: A total of 365 participants (mean [SD] age, 75.4 [7.9] years; 192 female [52.6%]) in the ADNI tau-PET group and 524 participants (mean [SD] age, 77.1 [7.9] years; 268 male [51.1%]) in the ADNI p-tau217 group were selected from the 998 individuals who were Aβ+ in the ADNI cohort and used to generate tau-clinical mismatch models with 55.6% to 57.1% classified as canonical (CDR-SB commensurate to tau), 23.7% to 24.7% as resilient (CDR-SB < tau), and 19.3% to 19.7% as vulnerable (CDR-SB > tau). Vulnerable groups had evidence of greater likelihood of copathology, with TDP-43 neurodegeneration patterns and α-synuclein positivity. Mismatch groups showed diverging clinical trajectories with earlier cognitive impairment in vulnerable groups and later impairment in resilient individuals. Similar findings were seen when applied to an independent dataset of 244 individuals (mean [SD] age, 73.7 [6.8] years; 139 female [57.0%]) of the 248 who were Aβ+ in Penn-ADRC cohort. Finally, these models were applied to a cohort receiving antiamyloid therapy to show the utility of this method for predicting individual cognitive trajectories during therapy.

CONCLUSION AND RELEVANCE: Results of this cohort study suggest that tau-clinical mismatch identified individuals more likely to have an accelerated disease course due to the presence of copathology and those exhibiting greater cognitive resilience to disease pathology. These models provide an important tool that can be implemented in clinical practice to provide improved individualized prognosis and, potentially, monitoring of response to disease-modifying therapy.

RevDate: 2025-12-15

Zuliani G, Brombo G, Romagnoli T, et al (2025)

Effectiveness of acetylcholinesterase inhibitors and memantine in patients affected by severe dementia.

GeroScience [Epub ahead of print].

The efficacy of acetylcholinesterase inhibitors (AChEI) and memantine (ME) in severe dementia remains uncertain, and real world data are limited. We evaluated the progression of cognitive decline and mortality rates in a cohort of outpatients with severe dementia treated with AChEI and/or ME or not treated, from the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). Overall, 703 patients (mean age:78.3 ± 7.2 years; females:56.1%) with severe dementia (Mini-Mental State Examination-MMSE ≤ 10/30) were included [407 late-onset Alzheimer's disease (LOAD), 126 Lewy body dementia (LBD), 170 vascular dementia (VD)]. Patients were grouped by treatment status: untreated (AChEI - /ME - ; n.70), AChEI only (AChEI + ; n.294), ME only (ME + ; n.215), combined therapy (AChEI + /ME + ; n.124). During follow-up (mean:1.7 ± 0.3 years; range:0.2-2.9 years) the mean MMSE scores declined by - 1.7 points (Standard Deviation: -1.55 to -1.9) in AChEI - /ME - (p for trend:0.001), - 1.5 points (-1.55 to -1.9) in AChEI + (p:0.001), - 0.7 points (-0.5 to -0.9) in ME + (p:0.09), while it increased by + 0.7 points (+ 0.4 to + 1.0) in AChEI + /ME + (p:0.001). Survival rates were 8% in AChEI - /ME - , 10% in AChEI + , 28% in ME + , and 49% in AChEI + /ME + . In Cox proportional hazards analysis (age and sex adjusted), AChEI + /ME + exhibited a 39% reduction in total mortality compared with no treatment (HR:0.61; 95%CI:0.49-0.77; p < 0.001), ME + displayed a 22% reduction (HR:0.78; 95%CI:0.65-0.94; p:0.007), while AChEI + showed no association (HR:0.97; 95%CI:0.80-1.18; p:0.75). When the Cox proportional hazards models were stratified by dementia subtype, consistent significant patterns were observed in LOAD and LBD. In this real-world cohort of older adults with severe dementia, the combination therapy (ME + AchEI) seems to be associated with the best outcomes, including a stabilization of cognitive function and reduced total mortality.

RevDate: 2025-12-15

Robinson L, Bray J, Melis V, et al (2025)

Effects of hydromethylthionine mesylate and rivastigmine in a pharmacological mouse model of Alzheimer's disease.

Behavioural pharmacology pii:00008877-990000000-00165 [Epub ahead of print].

The results from clinical trials have indicated that the tau aggregation inhibitor hydromethylthionine mesylate (HMTM) produces disease-modifying effects in Alzheimer's disease (AD) patients when administered alone, but less of an effect when administered in conjunction with cholinesterase inhibitors (ChEIs). The use of ChEIs for AD has been supported by their ability to reverse scopolamine-induced cognitive impairments in rodents reminiscent of those seen in AD patients. We have previously shown that another tau aggregation inhibitor, methylthionine chloride (MTC), is able to reverse scopolamine-induced deficits in spatial learning and memory. The objective here was to determine the symptomatic efficacy of HMTM and rivastigmine, alone or in combination, in a scopolamine model of AD. Female NMRI mice were treated systemically with scopolamine (0.5 mg/kg) or vehicle in combination with ChEI rivastigmine (0.5 mg/kg) or HMTM (5 or 15 mg/kg) daily before assessment of spatial learning and memory performance in a reference memory task in the water maze. Systemic administration of scopolamine induced significant impairments in the spatial learning of the mice compared to vehicle treatment. These deficits were reversed by treatment with HMTM at both doses and with rivastigmine when given alone. Furthermore, coadministration of rivastigmine with HMTM ameliorated the impairments induced by scopolamine. These findings extend our previous observations with MTC and confirm that HMTM also has a dual mode of action, disease modification through tau aggregation inhibition, but also having symptomatic effects through its normalisation of cholinergic activity.

RevDate: 2025-12-15

Leng L, Liao Z, Lu P, et al (2025)

Real-world experience with baseline characteristics and safety of lecanemab for Alzheimer's disease in Eastern China.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundLecanemab reduces amyloid levels and modestly slows cognitive decline in a large cohort of early Alzheimer's disease (AD) but lacks real-world safety data in Chinese population.ObjectiveThe real-world study aims to analyze baseline characteristics and preliminary safety of lecanemab for AD in Zhejiang Province, and to evaluate the efficacy of plasma biomarkers for patient screening.MethodsThis multi-center study included 190 patients with AD in Zhejiang Province, who completed baseline assessments and received lecanemab treatment with follow-up.ResultsThe study included 176 participants with early AD and 14 moderate. In the early AD (mean age 68.04 years, Mini-Mental State Examination 20.03 and Montreal Cognitive Assessment 14.93), 124 (70.5%) participants were female, and 127 (72.1%) were junior high school education level or less. APOE4 heterozygote was predominant (48.9%). Logistic regression for distinguishing early AD from the Aβ negative cognitively unimpaired populations showed that p-Tau 217 independently provided better classification efficacy (area under the curve = 0.9983, p < 0.0001). In the early AD, 29 (16.5%) participants experienced infusion-related reactions (IRR) after the first-dose lecanemab, and amyloid-related imaging abnormalities (ARIA) were identified in 17 patients (9.7%), while 3 (21.4%) with IRR and none ARIA observed in the moderate AD.ConclusionsThe real-world lecanemab cohort had more females, lower educational level, and higher disease burden compared with the clinical trial cohort. Overall lecanemab exhibited a manageable short-term safety profile with no measurable cognitive efficacy. Extensive monitoring and management are required for ARIA of clinically importance. The plasma p-Tau 217 showed high accuracy for early AD screening.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Seto M, Klinger HM, Clifton M, et al (2025)

Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease.

bioRxiv : the preprint server for biology pii:2025.11.21.689770.

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.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Li Y, Zhang Y, Liu M, et al (2025)

Polyphenol-rich Morus nigra L. extract mitigates neuroinflammation and cognitive impairment through gut-brain axis modulation in an Alzheimer's disease rat model.

Frontiers in pharmacology, 16:1695768.

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.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Rubiño-Díaz JÁ, M Zapata-Moreno (2025)

Highly sensitive early-onset Alzheimer's disease: a case report.

Frontiers in psychology, 16:1688924.

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.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Kim EH, Lee YJ, Moon YS, et al (2025)

Evaluation of microcurrent as an adjunct to donepezil therapy in an Alzheimer's disease mouse model: a pilot study.

Frontiers in aging neuroscience, 17:1689593.

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.

RevDate: 2025-12-14

Barani M, Zargari F, Mirinejad S, et al (2025)

Ginsenoside Rg3-encapsulated pegylated niosomes exhibit multimodal therapeutic potential in Alzheimer's disease.

Scientific reports pii:10.1038/s41598-025-32528-3 [Epub ahead of print].

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.

RevDate: 2025-12-14
CmpDate: 2025-12-14

Ehret F, Rogers CL, Fontanesi J, et al (2026)

Radiation Therapy for Non-Malignant Central Nervous System Tumors, Disorders, and Illnesses - Current Applications and Future Directions.

Seminars in radiation oncology, 36:77-94.

Radiation therapy has a central role in the treatment of various malignant central nervous system tumors, including gliomas, high-grade meningiomas, and brain metastases. This also applies to a plethora of non-malignant central nervous system lesions, such as vestibular schwannomas and arteriovenous malformations, and, in specific situations, for selected functional and psychiatric disorders. In patients with these conditions, the goal of radiation therapy is generally to preserve and stabilize function. In addition, as these illnesses, with some exceptions such as arteriovenous malformations, are rarely life-threatening, the risks of radiation therapy must be interpreted in a different context than for patients with malignancy. Given the continuous and growing interest in the use of radiation therapy for non-malignant tumors and functional conditions, this review summarizes the current and future directions in central nervous system applications, addressing its use for the management of vestibular schwannomas, arteriovenous malformations, trigeminal neuralgia, tremor, Alzheimer's disease, and other psychiatric conditions, such as obsessive-compulsive disorder, addiction, and eating disorders.

RevDate: 2025-12-14

Chen H, Zhang Z, Yi W, et al (2025)

Bone-brain crosstalk: emerging roles of osteocalcin in central nervous system disorders.

Neuroscience pii:S0306-4522(25)01176-5 [Epub ahead of print].

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.

RevDate: 2025-12-14

Gawai M, Nistane N, Tatode AA, et al (2025)

Transforming Anti-Alzheimer's therapy by targeting endogenous receptorrial system through ligand-conjugated Nanoformulations.

Ageing research reviews pii:S1568-1637(25)00340-X [Epub ahead of print].

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.

RevDate: 2025-12-14

Liu Y, Zhang J, Li W, et al (2025)

Osthole Ameliorates Cognitive Impairment in Ovariectomized Rats via Estrogen-Mediated Enhancement of Cholinergic Function and Regulation of Neurotransmitter Homeostasis.

Neuropharmacology pii:S0028-3908(25)00514-3 [Epub ahead of print].

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.

RevDate: 2025-12-13

Mummery CJ, Rasmussen J, Blackburn D, et al (2025)

Lecanemab appropriate use recommendations for clinical practice in the UK.

Journal of neurology, neurosurgery, and psychiatry pii:jnnp-2025-336597 [Epub ahead of print].

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.

RevDate: 2025-12-13

Sheng J, Wang L, Zhang Q, et al (2025)

Integrating multimodal data to identify single nucleotide polymorphism-related biomarkers and regulatory mechanisms in Alzheimer's disease.

Neuroscience pii:S0306-4522(25)01169-8 [Epub ahead of print].

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.

RevDate: 2025-12-13

Shi H, Y Zhao (2025)

Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments.

Neurochemistry international pii:S0197-0186(25)00176-7 [Epub ahead of print].

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.

RevDate: 2025-12-13

Ruiz de Martín Esteban S, Grande MT, Martínez-Relimpio AM, et al (2025)

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.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 194:118902 pii:S0753-3322(25)01096-0 [Epub ahead of print].

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.

RevDate: 2025-12-13

Li X, Yan S, Li M, et al (2025)

Piezoelectric nanoparticle-driven rhythmic ultrasound neuromodulation for treatment of early-stage Alzheimer's disease.

Biomaterials, 328:123905 pii:S0142-9612(25)00825-7 [Epub ahead of print].

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.

RevDate: 2025-12-13
CmpDate: 2025-12-13

Isaković J, Athanassiadis A, M Khubeis (2025)

Stem cells strike back: advancements in Alzheimer's and Parkinson's disease treatment and modeling efforts from 2019 to 2024.

Journal of molecular medicine (Berlin, Germany), 104(1):2.

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.

RevDate: 2025-12-13
CmpDate: 2025-12-13

Khan AR, Makhoul GW, MA Raji (2025)

Mirtazapine for gastrointestinal side effects of glucagon-like peptide-1 receptor agonist therapy in older adults.

Endocrine regulations, 59(1):260-264 pii:enr-2025-0030.

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.

RevDate: 2025-12-13

Akinluyi ET, Takahashi-Yamashiro K, Connolly MG, et al (2025)

Interplay between CD33 and TREM2 in Alzheimer's Disease: Potential Mechanistic Insights into Microglial Function in Amyloid Pathology.

ACS chemical neuroscience [Epub ahead of print].

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.

RevDate: 2025-12-12

Fredriksen-Goldsen KI, Teri L, Kim HJ, et al (2025)

Innovations in Dementia Empowerment and Action: RCT for Underserved Communities.

Journal of the American Geriatrics Society [Epub ahead of print].

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.

RevDate: 2025-12-12

Jiang H, Escamilla S, Beestrum M, et al (2025)

Cost-effectiveness of testing biofluid biomarkers to diagnose Alzheimer's disease: a systematic review.

The European journal of health economics : HEPAC : health economics in prevention and care [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) affects tens of millions of individuals and their families in the world. As AD progresses, the effectiveness of treatment declines, making a timely diagnosis crucial. One promising approach for timely diagnosis is testing biofluid biomarkers in patients' blood and cerebrospinal fluid (CSF). However, a comprehensive evaluation of whether these tests are cost-effective is missing. Here, we conducted a systematic review to assess the cost-effectiveness of testing biofluid biomarkers to diagnose AD.

METHOD: We searched PubMed, Embase, Cochrane Library, and Web of Science for studies published until October 2024. Studies were included if published in English, conducted an economic evaluation of CSF or blood biomarker testing to diagnose AD, and provided economic outcomes. We assessed the quality of studies using the CHEERS 2022 criteria.

RESULTS: Nine studies were included: six evaluated CSF biomarker tests and three on blood biomarker tests. All studies used model-based simulations (decision trees or Markov models) rather than trial-based evaluations. CSF biomarker tests were mostly cost-effective compared to neurocognitive assessments or neuroimaging, while blood biomarker tests showed mixed results. Key cost-effectiveness contributors included AD prevalence, diagnostic accuracy, and treatment effectiveness. Studies met ~ 80% of the CHEERS criteria, with missing information on patient engagement.

CONCLUSION: Our review supports that biofluid biomarker testing could be cost-effective to diagnose AD. Given the lack of trial-based economic evaluations, model-based studies are a valuable starting point. Future evaluations should incorporate patient-centered outcomes and consider the emotional value and other socio-economic factors that affect patients and families suffering from AD.

RevDate: 2025-12-12

Villarejo Galende A, González-Sánchez M, Hilario A, et al (2025)

Severe symptomatic amyloid-related imaging abnormalities in Alzheimer's disease: Two case reports and systematic review of reported cases.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundAmyloid-related imaging abnormalities (ARIA) are a recognized complication of anti-amyloid monoclonal antibodies for Alzheimer's disease (AD). While typically asymptomatic, a subset of patients develops severe clinical symptoms and radiological findings requiring intensive management. Data on their presentation, treatment, and outcomes remain limited.ObjectiveWe report two cases and analyze the clinical features of all published cases of severe symptomatic ARIA, with a focus on associated risk factors, therapeutic approaches, and patient outcomes.MethodsWe report two cases of severe symptomatic ARIA in patients treated with gantenerumab. A systematic review was conducted following PRISMA guidelines using MEDLINE, Web of Science, and manual reference screening. We included case reports and series providing individual-level data on symptomatic ARIA episodes classified as severe by clinical criteria. Demographic, genetic, clinical, radiological, therapeutic, and outcome data were extracted.ResultsThirty-six cases were included (2 new and 34 from 21 publications). Fifteen cases were associated with lecanemab, 10 with gantenerumab, 6 with donanemab, and 5 with other antibodies. APOE ε4 was present in 62.5%, including 10 ε4/ε4 homozygotes. Baseline MRI showed hemorrhagic markers in 10 cases, including superficial siderosis in 2 of the 5 patients with isolated macrohemorrhages. Most episodes occurred within 6 months of treatment. Symptoms included altered consciousness (75%), focal deficits (66.7%), seizures (38.9%), and headache (36.1%). ARIA-E resolved in all non-fatal cases. Corticosteroids were used in 72%. Among the patients whose outcome data were available, 15 patients recovered completely, 10 had persistent deficits, and 10 died.ConclusionsSevere symptomatic ARIA is a rare but serious adverse effect of anti-amyloid therapy. Standardized diagnostic and therapeutic guidelines are needed to minimize ARIA-related morbidity and mortality.PROSPERO registration no. CRD420251055067.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Mu L, Y Wang (2025)

The role of gut microbiota-derived metabolites in neuroinflammation.

Neuroprotection (Chichester, England), 3(2):131-144.

Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation-bile acids, trimethylamine-N-oxide, and indole derivatives-as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Schwartz SS, Rhea EM, Banks WA, et al (2025)

Beta cells to brain cells: The pivotal role of insulin and glucose metabolism in Alzheimer's disease.

Neuroprotection (Chichester, England), 3(2):145-164.

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

RevDate: 2025-12-12
CmpDate: 2025-12-12

Zhang R, Liu YY, Xia X, et al (2025)

Unvalidated efficacy and significant risks hinder clinical use of deep cervical lymphatic-venous anastomosis for Alzheimer's disease.

Frontiers in aging neuroscience, 17:1671741.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the pathological accumulation of amyloid-beta (Aβ) plaques and tau tangles. Recent studies suggest that dysfunction of the cerebral lymphatic clearance system may contribute to the progression of AD. This review critically examines the potential of deep cervical lymphatic-venous anastomosis (LVA) as a treatment for enhancing brain protein clearance and reducing cognitive decline in AD patients. Although animal models indicate that improving lymphatic drainage could facilitate Aβ clearance, clinical evidence is still insufficient. Current studies often have small sample sizes, short follow-up periods, and methodological weaknesses. Despite preliminary reports of cognitive improvements in small-scale clinical trials, the efficacy of LVA remains unproven, making widespread clinical adoption premature. Ethical concerns and technical challenges also pose significant barriers to clinical implementation. Rigorous randomized controlled trials (RCTs) are necessary to assess the long-term safety and efficacy of LVA for treating AD. Furthermore, the establishment of clear ethical and regulatory frameworks is essential before clinical use.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Zhang X, Zhong M, Li Y, et al (2025)

Oral microbiota and central nervous system diseases: A review.

Neuroprotection (Chichester, England), 3(1):79-94.

Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health. Impaired homeostasis of the oral microbiota can lead to pathological changes, resulting in central nervous system (CNS) diseases. However, the mechanisms and clinical value of how the oral microbiome influences the brain remain unclear. This review summarizes recent clinical findings on the role of the oral microbiota in CNS diseases and proposes potential approaches to understand the way the oral microbiota and brain communicate. We propose three underlying patterns involving neuroinflammation, neuroendocrine regulation, and CNS signaling between oral microbiota and CNS diseases. We also summarize the clinical characteristics and potential utilization of the oral microbiota in ischemic stroke, Alzheimer's and Parkinson's disease, intracranial aneurysms, and mental disorders. Although the current findings are preliminary and clinical evidence is incomplete, oral microbiota is a potential biomarker for the clinical diagnosis and treatment of CNS diseases.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Saxena SK, Sharma D, Kumar S, et al (2025)

Decoding the role of large heat shock proteins in the progression of neuroinflammation-mediated neurodegenerative disorders.

Neuroprotection (Chichester, England), 3(1):48-62.

Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases (NDs). Potential neurotoxic changes in the intra- and extracellular environment are typical hallmarks of many NDs. Treatment of ND is challenging, as the symptoms in these patients arises when a significant numbers of neurons have already been destroyed. Heat shock proteins (HSPs) can bind to recipient cells that are susceptible to stress, such as neurons, in the extracellular environment, therefore enhancing stress resistance. Among all, HSP60, HSP70, and HSP90 are highly conserved molecular chaperones involved in protein folding and assembly, maintaining cellular homeostasis in the central nervous system. Notably, α-synuclein accumulation is a major pathophysiology in Parkinson's disease, where HSP90 modulates the assembly of α-synuclein in vesicles to prevent its accumulation. Moreover, HSP90 regulates the activity of the glycogen synthase kinase-3β protein, which is crucial in diabetes mellitus-associated neurocognitive disorder. Therefore, understanding the molecular mechanism by which HSPs facilitate protein aggregation and respond to inflammatory stimuli, including metabolic disease such as diabetes, is essential for understanding the significance of HSPs in NDs. This review emphasizes the role of various HSPs in the progression of NDs such as Alzheimer's, Parkinson's, multiple sclerosis, and Huntington's disease, including diabetes, which is one of the major risk factors for neurodegeneration.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Hanumanthappa R, Parthasarathy A, Heggannavar GB, et al (2024)

Recent advances in therapeutic strategies for Alzheimer's and Parkinson's disease using protein/peptide co-modified polymer nanoparticles.

Neuroprotection (Chichester, England), 2(4):255-275.

The blood-brain barrier (BBB), which protects the brain from foreign molecules, makes delivery of drugs to the central nervous system is challenging. Nanoparticles (NPs) have been used over the past decade as drug delivery systems for the treatment of many disorders with great results. However, the effectiveness of NPs in delivering drugs to the brain for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD) is limited by the BBB. A recent breakthrough in nanotechnology delivery systems involves the use of surface-modified polymer NPs that enhance drug absorption and transport across the BBB; however, the technology still has some limitations. Studies conducted over the past few years have demonstrated that NPs modified with peptides or proteins can effectively cross the BBB via specific receptors, thus enhancing their delivery efficiency. In this review, we explore the use of polymer NPs combined with peptides and proteins for the treatment of AD and PD. This discussion focuses on the pathophysiology of these diseases, the BBB, and the potential of therapeutics based on co-modifying NPs with peptides and proteins. Additionally, we outline future directions for the use of polymer NPs conjugated with these biomolecules.

RevDate: 2025-12-11
CmpDate: 2025-12-12

Su X, Takayanagi R, Maeda H, et al (2025)

Sex-related upregulation of bone morphogenetic protein signaling inhibits adult neurogenesis in APP[NL-G-F] alzheimer's disease model mice.

Biology of sex differences, 16(1):103.

BACKGROUND: Bone morphogenetic proteins (BMPs) have been reported in many studies to be related to adult neurogenesis. Neurogenic impairment is a hallmark of Alzheimer's disease (AD), while the involvement of BMPs remains unclear.

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

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

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

RevDate: 2025-12-11
CmpDate: 2025-12-12

Jannati A, Thompson K, Toro-Serey C, et al (2025)

Concurrent detection of cognitive impairment and amyloid positivity with a multimodal machine learning-enabled digital cognitive assessment.

Alzheimer's research & therapy, 17(1):261.

BACKGROUND: Early identification of cognitive impairment and brain pathology associated with Alzheimer's disease (AD) is essential to maximize benefits from lifestyle interventions and emerging pharmacologic disease-modifying treatments (DMT). Digital cognitive assessments (DCAs) can quickly capture an array of metrics that can be used to train machine-learning (ML) models to concurrently evaluate different outcomes. DCAs have the potential to optimize clinical workflows and enable efficient assessment of cognitive function and the likelihood of a given underlying pathology.

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

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

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

RevDate: 2025-12-11

Riley S, Nguyen V, Bhattacharjee R, et al (2025)

TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.

Scientific reports pii:10.1038/s41598-025-30121-2 [Epub ahead of print].

β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.

RevDate: 2025-12-12

Ang S, Zhang X, Hong J, et al (2025)

The safety and efficacy of gamma frequency auditory and visual stimulation in the treatment of alzheimer's disease: a systematic review and meta-analysis.

Translational psychiatry, 15(1):523.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and significant global health burden. Current treatments offer limited benefits, highlighting the need for novel therapies. Gamma-frequency auditory and visual stimulation (GFAVS), utilizing 40 Hz neuromodulation, has gained attention as a non-invasive treatment for cognitive deficits and underlying pathophysiology in AD.

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

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

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

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

RevDate: 2025-12-12
CmpDate: 2025-12-12

Huang S, M Zhang (2024)

The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs.

Neuroprotection (Chichester, England), 2(2):100-119.

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

RevDate: 2025-12-12
CmpDate: 2025-12-12

Zhu Y, Liao L, Gao S, et al (2024)

Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms.

Neuroprotection (Chichester, England), 2(1):16-32.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well-established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy-related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high-frequency rTMS (HF-rTMS) regimen has value in AD therapy, and that promising single-site protocols, such as HF-rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.

RevDate: 2025-12-11

Zhang L, Li L, Cao P, et al (2025)

An Efficient Transfer Learning With Prompt Learning for Brain Disorders Diagnosis.

IEEE journal of biomedical and health informatics, PP: [Epub ahead of print].

The limited availability of training data significantly restricts the performance of deep supervised models for brain disease diagnosis. It is crucial to develop a learning framework through cross-disease transfer learning that can extract more information from the limited data. To address this challenge, we concentrate on prompt learning and endeavor to extend its application to the brain networks. Specifically, we propose a novel prompt learning framework called BPformer, which integrates knowledge transferred across diseases via specific prompts while keeping the original architecture of BPformer unchanged. The specific prompts incorporate 1) a mask prompt to determine whether the edges are noisy or discriminating, 2) disorder prompts for modeling consistent and disorder-specific knowledge, and 3) adaptive instance-level prompts to account for inter-individual variations. We evaluate BPformer on the private center Nanjing Medical University dataset, the public Autism Brain Imaging Data Exchange dataset, and the public Alzheimer's Disease Neuroimaging Initiative dataset. We demonstrate the effectiveness of the proposed model across various disease classification tasks, including major depressive disorder, bipolar disorder, alzheimer's disease, and autism spectrum disorder diagnoses. In addition, the proposed method enables disease interpretability and subtype analysis, empowering physicians to provide patients with more accurate and fine-grained treatment plans.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Mohanty R, Wheatley S, Chiotis K, et al (2025)

Distinct cerebrovascular pathways underlying Alzheimer's disease-related neurodegeneration.

Acta neuropathologica, 150(1):64.

The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer's disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = - 20, 95% CI - 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < - 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = - 0.2, 95% CI - 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.

RevDate: 2025-12-11

Taylor LW, Simzer EM, Young LFP, et al (2025)

Confirmation of p-tau Ser356's association with Alzheimer's disease pathology and lowering in response to WZ4003 treatment in brain slice cultures. Reply to: "Phospho-tau Ser356 is mostly confined to pre-NFT neurons in Alzheimer's pathology".

Acta neuropathologica, 150(1):63.

RevDate: 2025-12-11

Begines P, Fernández-Bolaños JG, Ó López (2025)

An updated patent review of acetylcholinesterase inhibitors for the treatment of alzheimer's disease (2021 - present).

Expert opinion on therapeutic patents [Epub ahead of print].

INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex and not fully elucidated etiology. An exponential rise in its incidence underscores the urgent need for effective therapeutic strategies. AD imposes a significant economic burden on public healthcare systems and on patient's families.

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

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

RevDate: 2025-12-11
CmpDate: 2025-12-11

Li W, Huang W, Zhou P, et al (2025)

Sporoderm-removed ganoderma lucidum spore powder (S-GLSP) alleviates neuroinflammation injury by regulating microglial polarization through inhibition of NLRP3 inflammasome activation.

Frontiers in pharmacology, 16:1690192.

INTRODUCTION: Sporoderm-Removed Ganoderma lucidum Spore Powder (S-GLSP), derived from the spores of the medically valued fungus Ganoderma lucidum, exhibits diverse pharmacological activities and shows considerable potential in the treatment of Alzheimer's disease (AD). However, its underlying mechanisms of action remain incompletely elucidated. This study aims to investigate the protective effects of S-GLSP against AD and to explore the molecular mechanisms involved.

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

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

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

RevDate: 2025-12-11
CmpDate: 2025-12-11

Monteiro R, Dunn JT, Rodriguez G, et al (2025)

Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.

Research square pii:rs.3.rs-8031077.

Alzheimer's disease (AD) is frequently accompanied by neuropsychiatric symptoms (NPS), among which apathy, one of the most prevalent and burdensome, accelerates cognitive decline and disease progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing of AD subjects revealed abnormal immune gene expression uniquely associated with apathy. In this study, we investigated whether these changes are also linked to apathy-like behavior in 5xFAD mice, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies these behaviors. We first validated the expression of apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-month-old 5xFAD mice using RT-qPCR. Separate cohorts of similarly aged 5xFAD and WT mice then received SB290157 and/or methylphenidate for two weeks. Results indicate that increased immune-related genes, including Tyrobp, C3 , C3ar , C1qa , C1qb , and C1qc expression, were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment significantly improved nest-building behavior, reduced C3 and C3ar protein expression, as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Pandey P, Rajput S, Gaur T, et al (2025)

Animal models in human surgery and implant innovation: ethical considerations and scientific advancements.

Annals of medicine and surgery (2012), 87(12):8291-8303.

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

RevDate: 2025-12-11
CmpDate: 2025-12-11

Li X, Gao W, Ye Q, et al (2025)

The Role and Therapeutic Potential of the cGAS-STING Signaling Pathway in Alzheimer's Disease.

Brain and behavior, 15(12):e71130.

PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, posing a significant challenge to global public health. As a core signaling pathway in the mammalian innate immune system, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in maintaining intracellular homeostasis. This review aims to systematically elucidate the role and therapeutic potential of the cGAS-STING signaling pathway in AD, focusing on its involvement in key pathological processes and its relevance to AD risk factors.

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

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

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

RevDate: 2025-12-11
CmpDate: 2025-12-11

O'Donnell AJ, Zhao X, Parr A, et al (2025)

Early Outcomes of Lecanemab for Alzheimer's Disease in the Veterans Health Administration.

Journal of clinical medicine, 14(23): pii:jcm14238277.

Background/Objectives: While lecanemab (Leqembi) and several amyloid targeting therapies were approved for Alzheimer's disease, questions remain on real-world implementation, safety, and effectiveness. The objective of this study was to describe the uptake and early outcomes of Veterans initiating lecanemab. Methods: This retrospective cohort study included Veterans who initiated lecanemab in the Veteran's Health Administration (VHA) between October 2023 and July 2024. Treatment persistence and monitoring, change in Montreal Cognitive Assessment (MoCA) score, incidence of adverse events, including amyloid-related imaging abnormalities (ARIA), and healthcare utilization were analyzed at 7 months. Results: Overall, 32 Veterans (mean [SD] age 75.3 [6.0] years, 100% male, 97% white, 84% urban dwelling) initiated lecanemab. Seventeen patients (53%) had mild cognitive impairment, 15 (47%) had mild dementia; mean baseline MoCA score was 21.3 (SD 3.4). At 7 months following treatment initiation, we assessed process, safety, and effectiveness outcomes. Process outcomes: In all, 25 patients (78%) were persistent with treatment. Safety outcomes: Three patients (9%) experienced a stroke, and 7 (22%) experienced ARIA. Effectiveness outcomes: Only 12 (38%) patients had a MoCA completed by 7 months, and the mean change in MoCA was 0.0 (SD 3.7, p = 1.0). A follow-up amyloid positron emission tomography (PET) scan was completed by 9 (28%) patients, and 5 had reductions in amyloid. Conclusions: Initial observations in a small VHA cohort suggest that uptake of lecanemab was limited, and the finding that nearly 30% of patients experienced ARIA or stroke within 7 months of initiation underscores the importance of monitoring the lecanemab safety and effectiveness long-term. These early findings should be interpreted cautiously given the limited sample size and very limited follow-up MoCA data.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Vieira RC, Nascimento LA, Nascimento AA, et al (2025)

NCIVISION: A Siamese Neural Network for Molecular Similarity Prediction MEP and RDG Images.

Molecules (Basel, Switzerland), 30(23): pii:molecules30234589.

Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer's disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Tsopka IC, Pontiki E, Sigala I, et al (2025)

Design, Synthesis, Biological Evaluation, and In Silico Studies of Novel Multitarget Cinnamic Acid Hybrids.

Molecules (Basel, Switzerland), 30(23): pii:molecules30234582.

Chronic inflammation is implicated in the development of various multifactorial diseases, including cancer, diabetes, arthritis, cardiovascular disorders, Alzheimer's disease, and autoimmune diseases. The enzymes that play a key role in the onset of the inflammation are cyclooxygenases (COXs) and lipoxygenases (LOXs). In recent years, cinnamic acid hybrid molecules, particularly those incorporating a nitric oxide (NO) donor moiety, have attracted considerable attention as potential pharmacological agents for the treatment of multifactorial diseases. In the present study, novel cinnamic acid-nitric oxide (NO) donor hybrids were synthesized as multitarget agents and evaluated for their antioxidant, anti-inflammatory, and cytotoxic properties. In particular, hybrids 5a-i, 6a-i, 9a-i, and 11 were synthesized and evaluated as lipid peroxidation and LOX inhibitors, while selected molecules were further tested as COX-1 and COX-2 inhibitors. Hybrids 6a-i, 9a-i, and 11 that contain a NO donor moiety, were additionally tested as albumin denaturation inhibitors and for their ability to release NO. The results indicated that compound 9a is a promising multitarget agent, exhibiting the lowest IC50 for LOX inhibition, significant antioxidant activity, and the highest NO donor potency. Furthermore, compound 9e demonstrated significant inhibitory activity against both COX-2 and LOX, suggesting its potential as a dual COX-LOX inhibitor. Additionally, compound 6i exhibited the strongest cytotoxic activity among the tested compounds, with EC50 values ranging from 36 to 45 μM across multiple cancer cell lines. All synthesized compounds were also evaluated through in silico studies.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Kimble R, OM Shannon (2025)

Can Beetroot (Beta vulgaris) Support Brain Health? A Perspective Review on Alzheimer's Disease.

Nutrients, 17(23): pii:nu17233790.

Alzheimer's disease (AD), the leading cause of dementia, has limited treatment options despite extensive pharmacological research. This has increased interest in dietary strategies that act across multiple pathological mechanisms. Beetroot (Beta vulgaris), known for its cardiovascular and metabolic benefits, contains a distinctive combination of bioactive compounds including inorganic nitrate, betalains, and polyphenols. Together these constituents influence vascular function, oxidative stress, mitochondrial efficiency, inflammation, and the microbiota. Previous reviews have typically focused on dietary nitrate in dementia prevention or have examined nitrate and betalains separately. In contrast, this review synthesises evidence on beetroot as a combined neuroprotective food. Preclinical data indicate that beetroot and its key constituents enhance antioxidant defences, support neuronal bioenergetics, and modulate cholinergic and inflammatory pathways. Human studies further suggest that nitrate-rich beetroot can improve cerebral blood flow and vascular responsiveness, and that higher intakes of plant-derived nitrate are associated with reduced cognitive decline. However, findings are inconsistent, most trials are small and short in duration, and research directly involving people with AD is scarce. By integrating vascular, antioxidant, and microbiome perspectives, this review identifies beetroot as a promising yet underexplored dietary candidate for AD management. Further mechanistic studies and multidomain approaches combining metagenomics, biomarkers, neuroimaging, and cognitive outcomes are needed.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Calzoni E, Cusumano G, Bertoldi A, et al (2025)

Rhubarb-Derived Extracellular Vesicles Mitigate Oxidative Stress and Metabolic Dysfunction in an Alzheimer's Cellular Model.

Nutrients, 17(23): pii:nu17233771.

Background/Objectives: Extracellular vesicles derived from edible plants have emerged as bioactive nanostructures with potential therapeutic and nutraceutical properties and are currently being investigated as natural carriers for the treatment of oxidative stress-induced damage and oxidative stress-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). Recent studies suggest that PDEVs exhibit high stability within the gastrointestinal tract and selective tissue-targeting abilities, facilitating the efficient delivery of bioactive molecules. Methods: This study investigates the antioxidant effects of Rheum rhabarbarum-derived EVs by assessing the antioxidant activity through different in vitro assays and their effects on oxidative stress and energy metabolism in the cellular model of Alzheimer's disease. Results: Rhubarb-derived EVs showed measurable antioxidant capacity in chemical assays and were non-toxic under the tested conditions. Treatment reduced intracellular ROS levels and modulated oxidative stress-related proteins, suggesting a potential protective effect against oxidative damage. Moreover, metabolic analysis revealed a decrease in glycolytic activity, indicating a potential restoration of cellular bioenergetic homeostasis. Conclusions: These results provide preliminary evidence supporting the nutraceutical interest of rhubarb-derived EVs in counteracting oxidative stress, while further studies will be needed to confirm their biological relevance and therapeutic potential.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Brehar FM, Costea D, Tataru CP, et al (2025)

The Fluidic Connectome in Brain Disease: Integrating Aquaporin-4 Polarity with Multisystem Pathways in Neurodegeneration.

International journal of molecular sciences, 26(23): pii:ijms262311536.

The way in which Aquaporin-4 (AQP4) is localized on the astrocytes' surface-i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels-represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity also facilitates glymphatic transport, the maintenance of the blood-brain barrier (BBB) functions, ion buffering, and neurotransmitter removal, and helps regulate neurovascular communications. The growing body of literature suggests that the loss of AQP4 polarity-a loss in the organization of AQP4 channels to the perivascular membrane-is associated with increased vascular, inflammatory, and metabolic disturbances in the context of many neurological diseases. As a result, this review attempts to synthesize both experimental and clinical studies to highlight that AQP4 depolarization often occurs in conjunction with early signs of neurodegeneration and neuroinflammation; however, we are aware that the loss of AQP4 polarity is only one factor in a complex pathophysiological environment. This review examines the molecular structure responsible for maintaining the polarity of AQP4-such as dystrophin-syntrophin complexes, orthogonal particle arrays, lipid microdomains, trafficking pathways, and transcriptional regulators-and describes how the vulnerability of these systems to various types of vascular stress, inflammatory signals, energy deficits, and mechanical injury can lead to a loss of AQP4 polarity. Furthermore, we will explore how a loss of AQP4 polarity can lead to the disruption of perivascular fluid movement, changes in blood-brain barrier morphology, enhanced neuroimmune activity, changes in ionic and metabolic balance, and disruptions in the global neural network synchronization. Importantly, we recognize that each of these disruptions will likely occur in concert with other disease-specific mechanisms. Alterations in AQP4 polarity have been observed in a variety of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, and glioma; however, we also observe that the same alterations in fluid regulation occur across all of these different diseases, but that no single upstream event accounts for the alteration in polarity. Ultimately, we will outline emerging therapeutic avenues to restore perivascular fluid transport, and will include molecular-based therapeutic agents designed to modify the anchoring of AQP4, methods designed to modulate the state of astrocytes, biomaterials-based drug delivery systems, and therapeutic methods that leverage dynamic modulation of the neurovascular interface. Future advances in multi-omic profiling, spatial proteomics, glymphatic imaging, and artificial intelligence will allow for earlier identification of AQP4 polarity disturbances and potentially allow for the development of more personalized treatment plans. Ultimately, by linking these concepts together, this review aims to frame AQP4 polarity as a modifiable aspect of the "fluidic connectome", and highlight its importance in maintaining overall brain health across disease states.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Ishikawa K, Fujikawa R, Okita K, et al (2025)

Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?.

International journal of molecular sciences, 26(23): pii:ijms262311494.

With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammation and impaired clearance of cellular debris, processes that are primarily regulated by microglia, the resident immune cells of the brain. As aging progresses, microglia exhibit reduced surveillance and motility, diminished phagocytic efficiency, and transition into a proinflammatory, hyperresponsive state. Such maladaptive microglia contribute to synaptic loss, white matter deterioration, and the spread of neurodegenerative pathology. Conversely, single-cell transcriptomic studies have identified distinct microglial subsets, including CD11c[+] microglia, which show upregulation of lysosomal and lipid metabolism pathways, enhanced debris clearance, and elevated neurotrophic factor expression. These features suggest that certain microglial populations adopt protective or adaptive phenotypes that preserve neural integrity. However, under chronic inflammation or pathological conditions, even protective microglia may become inflammation-promoting. This review summarizes current evidence on microglial changes in aging, frailty, and neurodegeneration, emphasizing their dual roles and discussing strategies that modulate microglial function to maintain brain health and prevent or treat frailty and age-related diseases.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Muzaffar S, Tyagi A, S Pugazhenthi (2025)

Therapeutic Potential of Irisin in Neurodegenerative Diseases.

International journal of molecular sciences, 26(23): pii:ijms262311348.

Irisin is a myokine secreted by muscle in response to exercise. It is derived from a transmembrane protein called fibronectin type III domain-containing protein 5 (FNDC5). The Fndc5 gene is expressed in several tissues, including skeletal muscle, brain, adipose tissue, heart, kidney, and lung. Irisin is cleaved from FNDC5 protein by the enzyme furin and released into circulation. In addition to exercise, several drugs have been shown to increase the production of irisin. Administration of exogenous irisin mimics the beneficial actions of exercise. Irisin can cross the blood-brain barrier and exert neuroprotective actions in the brain. It has been shown to reverse Alzheimer's pathologies in clinical and animal studies. Irisin also exerts protective effects against obesity, diabetes, and cardiovascular disease, diseases that often coexist with aging AD patients. Multiple approaches have been taken to suggest that exercise may act through irisin. Studies have provided direct evidence linking the two using Fndc5 gene deletion and irisin antibodies. Irisin binds to αVβ1/β5 integrins to mediate the activation of integrin-FAK pathways. While exercise as a lifestyle modification for healthy aging is well recognized, it may present limitations in some aging populations, especially those with disease conditions, including Parkinson's disease. Administration of exogenous irisin or small molecules that increase the expression of endogenous irisin or facilitate its actions are some alternate approaches that can mimic the beneficial actions of exercise. This review discusses the therapeutic potential of irisin in the treatment of neurodegenerative and other aging-associated diseases.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Adamski P, Szeleszczuk Ł, Gackowski M, et al (2025)

Creatine and Taurine as Novel Competitive Inhibitors of Acetylcholinesterase: A Biochemical Basis for Nutritional Modulation of Brain Function.

International journal of molecular sciences, 26(23): pii:ijms262311309.

Acetylcholinesterase (AChE) is a key enzyme responsible for terminating cholinergic neurotransmission by hydrolyzing acetylcholine. While clinically approved AChE inhibitors such as donepezil, rivastigmine, and galantamine are used in the symptomatic treatment of Alzheimer's disease and related dementias, little is known about the modulatory effects of common dietary compounds on AChE activity. In this study, we investigated the influence of creatine (CR) and taurine (TA)-two widely consumed nutritional supplements with reported neuroprotective and cognitive-enhancing properties-on AChE. Enzyme kinetics were evaluated using a modified Ellman's method, and Lineweaver-Burk analyses revealed that both CR and TA act as competitive inhibitors. Calculated parameters (Km, Vmax), inhibition constants (Ki), and half maximal inhibitory concentrations (IC50) consistently indicated stronger potency for CR (IC50 = 0.0056 ± 0.00018 mM) compared to TA (IC50 = 0.0097 ± 0.00035 mM). To complement the experimental data, molecular docking was performed using two crystal structures of human AChE. Docking confirmed that both ligands preferentially occupy the active-site region in a manner consistent with competitive inhibition, with CR showing more favorable binding scores than TA. Although markedly weaker than clinical drugs, these findings provide the first biochemical and in silico evidence that CR and TA directly interact with AChE, suggesting subtle cholinergic modulation relevant to cognitive function and neuroprotection.

RevDate: 2025-12-10

Mi F, Li H, Pan D, et al (2025)

Effect of organismal rhythmic activity on Aβ clearance by the glymphatic system.

European journal of medical research pii:10.1186/s40001-025-03646-5 [Epub ahead of print].

Abnormal deposition of β-amyloid (Aβ) is a significant pathological feature of neurodegenerative diseases, particularly Alzheimer's disease (AD). The glymphatic system (GS) plays a crucial role in Aβ clearance. Various rhythmic activities of the organism dynamically influence Aβ clearance by modulating GS function. In this paper, we systematically review the mechanisms linking cardiovascular rhythms, respiratory rhythms, neural rhythms, circadian rhythms, and exercise patterns to Aβ clearance via the GS. Cardiovascular rhythms affect cerebral perfusion pressure and vascular pulsation to regulate GS transport efficiency; respiratory rhythms modulate intracranial pressure and cerebrospinal fluid (CSF) circulation through thoracic pressure variations; neural rhythms (including delta waves during non-rapid eye movement (NREM) sleep and neurovascular coupling) synchronize neuro-glial-vascular interactions to enhance GS clearance. Circadian rhythms coordinate these primary rhythms by regulating melatonin levels and cerebral blood flow, while exercise patterns adjust GS function via aquaporin-4 (AQP4) polarization. Additionally, we elaborate on the cascade effect of AD resulting from rhythmic dysregulation. A thorough understanding of how rhythmic activities impact Aβ clearance by the GS may offer new perspectives and potential intervention strategies for the prevention and treatment of AD through the concept of "synchronized multiple rhythms"-a novel framework that integrates multi-rhythm synergy. Clinically, this work provides a theoretical basis for developing targeted interventions, such as personalized exercise timing regimens, respiratory rhythm training, and closed-loop neurovascular feedback devices, to restore GS function in AD patients.

RevDate: 2025-12-10

Du M, Li N, Li T, et al (2025)

Chimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates.

Nature communications pii:10.1038/s41467-025-67207-4 [Epub ahead of print].

While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the other arm to harness the unique endocytic properties of FcγRIIb to direct the recognized pathogenic antigens to lysosomes for irreversible degradation. The FcRTAC platform demonstrates broad therapeutic potential across multiple disease-relevant targets, including IgE, proprotein convertase subtilisin/kexin type 9 (PCSK9) and amyloid-β (Aβ). Notably, a single intravenous administration of blood brain barrier (BBB)-penetrating adeno-associated viral vector (AAV) encoding an Aβ-targeting FcRTAC construct achieves sustained therapeutic effects, establishing proof-of-concept for AAV-mediated delivery of an Aβ degrader as a strategy for Alzheimer's disease treatment. Our comprehensive investigation of binding properties of FcRTACs reveals critical molecular determinants of function and enables development of optimized engineering approaches. In summary, our approach represents a versatile therapeutic platform for treating diverse diseases ranging from autoimmune disorders to neurodegenerative conditions, while simultaneously serving as a user-friendly, plug-and-play research tool for extracellular protein knockout in basic biological research.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Kubohira Y, Okano N, Taharabaru T, et al (2026)

A water-soluble β-cyclodextrin polymer reduces cholesterol accumulation and autophagy dysfunction in vitro and in Niemann-Pick type C disease model mice.

Carbohydrate polymers, 374:124676.

Niemann-Pick disease type C (NPC) and Alzheimer's disease (AD) are characterised by cognitive dysfunction and neurological impairment. In both diseases, the abnormal accumulation and disruption of cholesterol homeostasis in the brain may contribute to the pathogenesis and exacerbation of symptoms. Cyclodextrins (CDs) are attracting attention as therapeutic agents that can reduce free cholesterol in the brain. A water-soluble β-CD polymer (β-CDP) consisting of multiple β-CDs cross-linked by epichlorohydrin was recently developed and reportedly has improved safety and higher circulation time in the bloodstream. In this study, we evaluated the potential of β-CDP as a promising therapeutic agent for NPC and AD. β-CDP lowered free cholesterol levels and reversed autophagy dysfunction in cholesterol-accumulated human neuroblastoma cells. Longer circulation time in the bloodstream and reduced cholesterol accumulation in NPC mice were also observed after its subcutaneous administration. These results suggest that β-CDP may be a safe therapeutic agent in the treatment of NPC and AD.

RevDate: 2025-12-10

Supasai S, Suntaratti P, Odton M, et al (2025)

HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl3/D-galactose rat model of Alzheimer's disease.

Experimental neurology pii:S0014-4886(25)00448-0 [Epub ahead of print].

Alzheimer's disease (AD), the leading cause of dementia, is pathologically defined by the accumulation of amyloid-β and tau pathology, resulting in progressive cognitive decline. Our previous work demonstrated that high mobility group box 1 (HMGB1): a pivotal regulator of … HMGB1 Box A plasmids alleviated cellular senescence and restored cognitive performance in aged rat models, supporting their therapeutic potential for neurodegenerative disorders such as AD. In this study, we investigated the efficacy of HMGB1 Box A gene therapy in an AD-like rat model chronically induced by AlCl3 and D-galactose. Following the onset of AD pathology, Box A plasmids were administered weekly at varying doses over eight weeks. Box A treatment significantly improved behavioral outcomes, including responsiveness, locomotor activity, and learning and memory performance. At the neuropathological level, Box A reduced hippocampal Aβ accumulation and tau pathology, restored neuronal density, and attenuated synaptic degeneration. Moreover, it suppressed hippocampal microgliosis, astrogliosis, and the expression of proinflammatory mediators. Box A also diminished markers of cellular senescence in the hippocampus. These findings demonstrate that HMGB1 Box A gene therapy confers multi-level neuroprotective effects in AD, from molecular and cellular restoration to behavioral recovery. This strategy holds strong promise as a disease-modifying treatment for AD, contributing to improved well-being by advancing therapeutic innovation to promote healthy aging and combat age-related neurodegenerative diseases.

RevDate: 2025-12-10

Xu J, He Z, Pan Y, et al (2025)

Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer's disease: Modulating oxidative stress and neuroinflammation.

Biomaterials advances, 181:214619 pii:S2772-9508(25)00446-7 [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Hooshmandi E, Rafiei E, Owjfard M, et al (2025)

Neuroprotective and Immunomodulatory effects of human hair follicle stem cells on streptozotocin-induced memory impairment in rats: insights into inflammation and neurotrophic mechanisms.

Molecular biology reports, 53(1):178.

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD), a primary cause of dementia, involves cognitive decline and neuroinflammation. Human hair follicle stem cells (hHFSCs) have shown neuroprotective potential, but their effects on immune modulation, especially in xenogeneic transplantation, remain unclear. This study aimed to investigate the therapeutic potential of hHFSCs against memory impairment and neuroinflammation induced by streptozotocin (STZ) in male rats.

METHODS: Adult male Sprague-Dawley rats were intracerebroventricularly injected with STZ (3 mg/kg) to induce AD-like cognitive deficits. hHFSC transplantation (1 × 10[6]) was done on days 4, 14, and 21 post-surgery. Y-maze and Passive avoidance were used to assess memory. Hippocampal tissue was analyzed for mRNA expression of pro/anti-inflammatory factors and neurotrophic markers using quantitative RT-PCR. Histological evaluation quantified hippocampal pyramidal neurons and volume.

RESULTS: STZ significantly impaired memory in passive avoidance test, but not Y-maze. hHFSC significantly improved memory performance. mRNA analysis revealed elevated BDNF, TGFβ, and GFAP levels in the STZ group. The increased TGFβ and GFAP levels continued following hHFSC treatment, indicating a compensatory response. Moreover, pro-inflammatory factors (IL-1β, IL-6, and TNFα) were upregulated following hHFSC therapy, suggesting persistent neuroinflammation. hHFSC led to anti-inflammatory effects through the elevation of IL-10. In addition, hHFSCs significantly reduced hippocampal atrophy and neuronal loss induced by STZ.

CONCLUSION: hHFSCs exhibit partial neuroprotective effects against STZ-induced memory impairment. The simultaneous upregulation of pro- and anti-inflammatory markers underscores the complexity of the inflammatory response in this xenogeneic model. Future investigations should consider immunocompromised models or immunosuppressive protocols better to isolate the therapeutic effects of hHFSCs from immune responses.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Yu SP, Gu X, Jiang MQ, et al (2025)

Combined Preventive and Preconditioning Treatments for the Comorbidity of Alzheimer's Disease and Ischemic Stroke in a GluN3A Knockout Mouse and a 5xFAD Mouse.

Cells, 14(23): pii:cells14231871.

Alzheimer's disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5-2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke.

RevDate: 2025-12-10

He Q, Xia Y, Shen Q, et al (2025)

Relationships between sarcopenia and Alzheimer's disease: screening for mitochondria-related biomarkers.

Computer methods in biomechanics and biomedical engineering [Epub ahead of print].

This study aims to identify mitochondrial-related biomarkers for sarcopenia and Alzheimer's disease (AD). Through the GEO database and machine learning algorithms, three diagnostic biomarkers (FKBP5, PRKAG1, and FBP2) were identified, and the constructed models showed good diagnostic accuracy in both internal and external datasets. Furthermore, multiple analyses such as GSEA, immune infiltration, and drug prediction were conducted. These findings provide new insights into shared pathological mechanisms and clinical diagnosis and treatment of sarcopenia and AD. Further clinical and experimental studies are needed to validate these results.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Pang R, Jia Q, Ma C, et al (2025)

Alzheimer's Disease: The Current and Emerging Treatment Approaches.

Behavioural neurology, 2025:9627699.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) as its main pathological features. It mainly manifests as cognitive dysfunction, and its pathological process may occur before symptom onset. However, the current drugs and methods for treating AD have unsatisfactory therapeutic outcomes. Therefore, finding a treatment that can inhibit the progression of AD by targeting its pathological features is an urgent need. This review summarizes the current traditional drugs that can delay the progression of AD and new drugs that act on the pathological characteristics of AD and highlights the potential value of related plant extracts. In addition, this review explores the application of different vectors, such as viral vectors and nanoparticles, in gene therapy and drug delivery. These data will provide novel ideas for new drug development and the search for new therapeutic mechanisms.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Wang X, Yang F, Chen P, et al (2025)

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Alzheimer's Disease: A Novel Cell-Free Therapeutic Strategy and Diagnostic Biomarker.

International journal of nanomedicine, 20:14375-14391.

With the ongoing trend of population aging worldwide, the incidence of Alzheimer's disease (AD) is steadily increasing. In the absence of effective therapeutic options for atypical forms of AD, reducing its prevalence and improving treatment outcomes have become pressing priorities. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have attracted growing attention as a new cell-free therapeutic approach for AD due to their high stability, low immunogenicity, and minimal tumorigenic risk. This review provides a comprehensive overview of the pathological mechanisms underlying AD, highlights the diagnostic potential of MSC-EVs, and elaborates on their therapeutic advantages and mechanisms of action. Furthermore, it addresses the key challenges and considerations associated with the clinical translation of MSC-EVs.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Toyli A, Shaik A, Zhao C, et al (2025)

The heart-brain axis: unraveling the interconnections between cardiovascular and Alzheimer's diseases.

Frontiers in cardiovascular medicine, 12:1685461.

Cardiovascular disease (CVD) and Alzheimer's disease (AD) are leading causes of death and disability worldwide, and recent research has increasingly illuminated a complex, bidirectional relationship between the two. This review synthesizes epidemiological, mechanistic, imaging, and genetic evidence linking CVD and AD through the heart-brain axis-a network of interrelated physiological and demographic pathways. We detail how cerebral hypoperfusion, inflammation, blood-brain barrier dysfunction, imbalance of the autonomic nervous system, and systemic amyloidosis contribute to shared neurodegenerative and cardiovascular outcomes. Multi-organ imaging studies, including MRI and PET, reveal that dysfunction of the cardiovascular system correlates with brain atrophy, white matter lesions, glymphatic impairment, and accumulation of AD-related proteinopathies. Genetic analyses further support overlapping risk architectures, particularly involving APOE and loci associated with lipid metabolism, vascular integrity, and inflammation. Age and sex are critical modifiers, with midlife CVD exerting the strongest influence on later cognitive decline, and sex-specific physiological responses shaping disease susceptibility. Finally, we explore how modifiable lifestyle factors, pharmacologic interventions, and precision medicine approaches targeting inflammatory and vascular pathways can jointly reduce the burden of both CVD and AD. Multidisciplinary collaboration to understand the interconnected biology of the heart and brain is essential for advancing integrated prevention and treatment strategies in aging populations.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Yang C, Li B, Yang S, et al (2025)

Electroacupuncture Prevents Against AD-Like Phenotypes in APP/PS1 Mice: Investigation of the Mechanisms From Cerebral Microangiopathy.

CNS neuroscience & therapeutics, 31(12):e70696.

BACKGROUND: Electroacupuncture (EA) has been widely used in Alzheimer's disease (AD) treatment. However, its underlying mechanisms remain poorly elucidated.

PURPOSE: This study aimed to investigate the effects of EA on AD-like phenotypes and explore the mechanisms.

METHODS: We first evaluated AD-like behaviors and cerebral blood flow (CBF) changes in APPswe/PS1dE9 (APP/PS1) mice at different ages. Subsequently, the therapeutic effects of EA at acupoints Baihui (GV20), Guanyuan (CV4), and Zusanli (ST36), as well as sunitinib, a PDGFRβ-specific inhibitor, on AD-like phenotypes in APP/PS1 mice were investigated. CBF was monitored by laser speckle imaging, and hippocampal synaptic ultrastructure and microvascular morphology were examined by transmission electron microscopy (TEM). Western blot was performed to measure related protein expression. Finally, functional ultrasound (fUS) imaging was used to assess changes in brain-wide functional connectivity.

RESULTS: Compared with age-matched wild-type (WT) mice, 6- and 9-month-old APP/PS1 mice exhibited significant cognitive decline, while all age groups (3-, 6-, and 9-month-old) of APP/PS1 mice showed significantly reduced CBF. APP/PS1 mice showed elevated expression of microvascular markers in both the hippocampus and cortex. EA significantly ameliorated AD-like behaviors and prevented CBF reduction as well as microvascular deformation in 6-month-old APP/PS1 mice compared with non-treatment group. TEM and western blot analysis revealed damaged synaptic structure and reduced synaptic proteins in APP/PS1 mice, all of which were markedly alleviated by EA treatment. In addition, EA treatment downregulated the aberrantly elevated expression of PDGFRβ and CD31, enhanced the levels of tight junction proteins (Occludin, Claudin-5, and ZO-1) and glucose transporter 1 (GLUT1), and suppressed the expression of inflammatory proteins. Of note, intervention with sunitinib also improved AD-like behaviors in APP/PS1 mice. Remarkably, fUS imaging results showed that EA enhanced the functional connection between hippocampal regions of APP/PS1 mice.

CONCLUSION: Our data demonstrates that EA ameliorates AD-like phenotypes, potentially through preventing microangiopathy.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Lin Z, Hong Y, Hu Y, et al (2025)

White matter hyperintensity modulates the amyloid-tau-cognition association and anti-amyloid treatment efficacy in asymptomatic older adults.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70990.

INTRODUCTION: White matter hyperintensities (WMH), a key imaging biomarker of small vessel injury, may play a complex role in Alzheimer's disease (AD). We hypothesize that WMH not only directly contributes to cognitive decline but also moderates the relationship among AD pathology, treatment, and cognitive decline.

METHODS: A total of 1169 participants with 240-week follow-up in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were analyzed. Linear regression models examined WMH's contribution to cognitive decline, its interaction with Aβ on p-Tau217 level, and its interaction with anti-amyloid treatment on cognitive decline.

RESULTS: Increase in WMH volume independently contributed to cognitive decline (p = 0.0028). Baseline WMH significantly moderated the relationship between Aβ change and p-Tau217 change (p = 0.0035). Specifically, Aβ accumulation correlated with p-Tau217 increase only in participants with low baseline WMH. WMH growth was associated with cognitive decline only in the treatment group (p < 0.0001).

DISCUSSION: WMH modulates the interplay of pathologies, emphasizing the need for comprehensive treatment approaches targeting multiple pathways.

HIGHLIGHTS: White matter hyperintensity (WMH) independently contributed to cognitive decline. WMH modulated the longitudinal relationship between Aβ and p-Tau217. WMH interacted with anti-amyloid treatment on longitudinal cognitive decline.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Moretti DV, Kuhn E, Dubbelman M, et al (2025)

Clinical definition, biological characterization, and detection guidelines of subjective cognitive decline due to Alzheimer's disease and related dementia: A position paper from ISTAART SCD PIA.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70847.

Subjective cognitive decline (SCD)-self-perceived cognitive worsening without objective deficits-has emerged as a clinically meaningful, potential early manifestation of Alzheimer's disease (AD). Positioned at the intersection of normal aging, neuropsychiatric symptoms, and preclinical neurodegeneration, SCD offers a unique window for early detection and intervention. However, detection heterogeneity, variable prognostic trajectories, and limited equity in assessment hinder its full clinical utility. This position paper synthesizes current evidence on SCD's diagnostic complexity, neurobiological underpinnings, and modifiable influences. We highlight the need for harmonized assessment frameworks, scalable digital tools, inclusive research, and ethically grounded biomarker disclosure practices. Importantly, we advocate for personalized, (non-)pharmacological interventions targeting this early phase. By refining the conceptualization and operationalization of SCD, we can better identify individuals at heightened AD risk and deliver timely, equitable, and meaningful prevention strategies. SCD represents a pivotal inflection point in the dementia continuum-and a call to shift toward proactive brain health. HIGHLIGHTS: Subjective cognitive decline (SCD) may signal early-stage Alzheimer's despite normal test performance. Diagnostic heterogeneity limits current clinical and research utility. Biomarkers and digital tools could enhance risk stratification in SCD. Mental health and social context shape symptom reporting and outcomes. SCD offers a window for tailored (non-drug) preventive interventions.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Feng Y, Wang S, Xia H, et al (2025)

Meningeal lymphatics as a therapeutic target for neurodegenerative disorders.

Translational neurodegeneration, 14(1):65.

Advancements in visualization methods have brought the meningeal lymphatic system (MLS) into the spotlight. The meningeal lymphatic vessels (mLVs) play a vital role in draining cerebrospinal fluid and immune cells, acting as a central hub for immune surveillance in the brain. Age-related morphological and functional declines of mLVs suggest their involvement in the pathogenesis of neurodegenerative disorders (NDDs). In this article, we summarize key discoveries about the MLS over the past decade, highlight the neuro-immune crosstalk in the meninges, and discuss the role of mLVs in both brain homeostasis and neurodegeneration. As a critical regulator of brain function and a potential therapeutic target, the MLS offers a promising avenue for the diagnosis and treatment of NDDs, particularly Alzheimer's Disease.

RevDate: 2025-12-09
CmpDate: 2025-12-10

Lee WJ, Cho K, Lee D, et al (2025)

Therapeutic Efficacy of Autologous Blood-Derived Stem Cells with Growth Factors in Moderate to Severe Alzheimer's Disease: A Clinical Trial.

Molecular neurobiology, 63(1):277.

Alzheimer's disease (AD) is characterized by cognitive decline, memory loss, and a gradual loss of daily functioning. Unfortunately, despite extensive research, effective treatments for AD remain limited. Of these, stem cell-based therapies show promise for their regenerative potential and ability to modulate pathological processes. Autologous blood-derived stem cells (ABSCs), which are isolated from a patient's own blood, have demonstrated therapeutic efficacy in AD. This clinical study evaluated the safety and efficacy of ABSCs on patients with AD and investigated the changing levels of growth factors derived from ABSCs treatment. The efficacy of the treatment on cognitive function was assessed using the Mini-Mental State Examination, Clinical Dementia Rating, and AD Assessment Scale-Cognitive Subscale, all widely used tools to assess cognitive function in patients with AD. The neuroimaging and molecular mechanisms were the secondary outcomes. The neuroimaging examinations performed included PET-CT with amyloid imaging, for assessing amyloid plaque deposition in the brain at baseline and at 3 and 6 months after treatment; FDG-PET, for measuring brain glucose metabolism and acquiring insights into neuronal activity and overall brain function; and MRI, performed at baseline and follow-up, for assessing structural brain changes. ABSCs treatment resulted in notable improvements in cognitive function, reductions in amyloid plaque burden, and improved neuroimaging outcomes. Autologous stem cell therapy also reduced the risk of immune rejection, offering a safety advantage over allogeneic stem cell therapies. Furthermore, the use of growth factors to enhance stem cell efficacy aligns with existing research demonstrating improvements in stem cell limitations. This study provides compelling evidence that ABSCs combined with growth factors exhibit significant therapeutic potential for patients with moderate to severe AD. Our findings indicate that our current combination treatment may offer a multi-target approach to addressing the complex pathogenesis of neurodegenerative diseases and is thereby a potentially sustainable therapeutic strategy for AD. Furthermore, the combination of ABSCs with growth factors can potentially provide a much-needed therapeutic alternative for AD.

RevDate: 2025-12-09

Majumder M, Dutta D, Paidi RK, et al (2025)

Activation of PPARα by gemfibrozil lowers tau-associated neuropathology in the MAPT mouse model of Alzheimer's disease.

Brain research pii:S0006-8993(25)00652-3 [Epub ahead of print].

The current dogma states that inhibiting tau accumulation and its associated neuropathologies might be a relevant strategy to prevent neuronal loss and cognitive dysfunction in Alzheimer's disease (AD). The present study demonstrates the therapeutic potential of an FDA-approved lipid lowering drug and an agonist of peroxisome proliferator and activated receptor α (PPARα), called gemfibrozil, in reducing tau accumulation and associated neuropathologies in the MAPT (PS19) mouse model of AD, expressing P301S mutated form of human tau protein in neurons. Daily oral treatment of gemfibrozil in MAPT mice reduced total tau and phosphorylated form of tau in the hippocampal subregions including CA1 and DG. Concurrently, gemfibrozil treatment upregulated PPARα level in the hippocampus and that was accompanied with inhibition of microgliosis and astrogliosis. Gemfibrozil also attenuated the loss of synaptic plasticity as determined by the expression of post-synaptic protein, PSD95, and calcium influx in the hippocampal tissue. The instrumental role of PPARα in gemfibrozil-mediated reduction of tauopathy was confirmed as PPARα deficiency in MAPT mice significantly augmented tau and phospho-tau accumulation in the hippocampus and gemfibrozil treatment failed to reverse tau pathology and gliosis in the brain of PPARα deficient MAPT mice. Lastly, gemfibrozil improved the cognitive function of MAPT mice during the symptomatic phase of disease progression, but it failed to reverse cognitive impairment in the PPARα deficient MAPT mice. These data suggest that neuroprotective effects of gemfibrozil in MAPT mice is mediated by PPARα. Moreover, targeting PPARα by small molecules like gemfibrozil may hold translational potential against tauopathy.

RevDate: 2025-12-09

Zhang X, Yang J, Xiao M, et al (2025)

Yangxue Qingnao Wan ameliorates cognitive impairment in scopolamine-induced AD mice via modulating neuropeptide signaling pathways and suppressing neuroinflammation.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 150:157602 pii:S0944-7113(25)01237-1 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD), a fatal neurodegenerative disorder with increasing incidence worldwide, remains a significant therapeutic challenge. Yangxue Qingnao Wan (YXQNW), a traditional Chinese medicine, has shown promise in AD treatment. However, its intricate mechanism of action necessitates further investigation. Clarifying YXQNW's active components and molecular targets could advance novel therapeutic strategies for AD.

PURPOSE: This research aimed to identify anti-AD bioactive compounds in YXQNW and investigate their mechanisms using transcriptomic profiling and network proximity analysis.

METHODS: The neuroprotective effects of YXQNW were evaluated in scopolamine (SCOP)-induced AD mice through behavioral tests, histopathological assessments, and biochemical analyses (acetylcholinesterase activity, oxidative stress markers and pro-inflammatory cytokines). Transcriptomic analysis was employed to explore YXQNW's regulatory targets and pathways. Key targets were validated by RT-qPCR, immunofluorescence (IF) and Western blot. Network proximity was used to predict anti-AD components, followed by in vitro mechanism validation in SCOP-induced HT22 cells using Gpr139 agonist and antagonist.

RESULTS: YXQNW ameliorated spatial memory deficits, cholinergic dysfunction, oxidative stress, and neuroinflammation in vivo. Transcriptomics analysis uncovered significantly modulation of neuropeptide signaling pathways, including upregulation of Gpr139 and downregulation of Gal/Galr1, mitigating cognitive impairment. Network proximity identified 8 anti-AD components, with Palmatine, Ligustilide, and Obtusifolin demonstrating efficacy in reducing oxidative stress, inflammation, and neuronal damage in vitro, and could also regulate the expression of neuropeptides. Moreover, Palmatine inhibits neuroinflammation via regulating Gpr139 protein expression.

CONCLUSIONS: YXQNW alleviates AD-like pathology by restoring cholinergic homeostasis, suppressing oxidative stress and neuroinflammation, and regulating neuropeptide signaling. And its active ingredient (Palmatine) can inhibit inflammatory response by regulating the expression of Gpr139 protein. This study supports YXQNW's clinical application and provides novel insights for AD drug discovery.

RevDate: 2025-12-09

Taj T, Kaushik M, Islam A, et al (2025)

Microbiota-brain interaction: The role of gut-derived proteins in addressing various neurological disorders including Parkinson's (PD) and Alzheimer's diseases (AD).

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 193:118861 pii:S0753-3322(25)01055-8 [Epub ahead of print].

The microbiota-brain interaction is a complex network connecting gut microbiota to the enteric nervous system (ENS) and the central nervous system (CNS) that are crucial for neurotransmission and neurological health. Metabolites such as short-chain fatty acids (SCFA), neurotransmitters, and neuromodulators from the gut microbiota influence behavior and brain function. This review focuses on the study related with gut bacteria, including Bifidobacterium infantis and Lactobacillus species, producing various metabolites in gut including bile acids, SCFA, histamine, and others to communicate with the brain or CNS. Dysbiosis can lead to neurological conditions such as anxiety, depression, PD, and AD. SCFAs from gut bacteria bind to the free fatty acid receptors of intestinal epithelial cells (IECs), affecting neurones and influencing neuroactivity. Gut bacteria also produce neurotransmitters that regulate growth hormone release through interactions with the CNS and endocrine systems. Brain signals interact directly with the pituitary and adrenal glands through the hypothalamic-pituitary-adrenal (HPA) axis, which in turn communicates with enteroendocrine cells (EECs). Investigating probiotics, prebiotics, and dietary changes could open new avenues for treatment for mental and neurological problems.

RevDate: 2025-12-09

Shi Y, Zhang H, Cong S, et al (2025)

Benzylpiperidine-pyridazin-3(2H)-one derivatives as potential multifunctional agents against Alzheimer's disease.

European journal of medicinal chemistry, 303:118437 pii:S0223-5234(25)01202-4 [Epub ahead of print].

Based on multitarget-directed-ligands (MTDLs) strategy, a series of benzylpiperidine-pyridazin-3(2H)-ones were designed, synthesized and evaluated as innovative multifunctional agents for Alzheimer's disease (AD). Biological evaluation revealed that most compounds exhibited excellent acetylcholinesterase (AChE) inhibition, potent antioxidant activity and moderate β-amyloid (Aβ1-42) aggregation inhibition. Among them, compound 7a emerged as a synergistic multifunctional agent with significant inhibition of AChE (EeAChE: IC50 = 0.21 μM; HsAChE: IC50 = 13 nM) and anti-Aβ activity (IC50 = 2.92 μM for self-induced Aβ1-42 aggregation; IC50 = 1.28 μM for disaggregation of Aβ1-42 fibrils; IC50 = 3.72 μM for Cu[2+]-induced Aβ1-42 aggregation; IC50 = 2.16 μM for disaggregation of Cu[2+]-induced Aβ1-42 fibrils). In addition, 7a was endowed with the potential to serve as antioxidant (2.88 Trolox equivalents), metals chelator and anti-neuroinflammatory agent for synergistic treatment. Moreover, 7a exhibited pronounced neuroprotective effects across multiple cellular models. Pharmacokinetically, 7a displayed favorable brain penetration (AUCbrain/plasma = 0.77) and sustained exposure. In vivo evaluation demonstrated that 7a effectively ameliorated scopolamine-induced cognitive impairment in the Morris water maze, which was associated with restored cholinergic function and mitigated oxidative stress in mice. The synergistic multi-target efficacy combined with favorable pharmacokinetic properties underscores its potential as a disease-modifying therapeutic agent for AD.

RevDate: 2025-12-09

Kim SR, Kim SK, Kobayashi H, et al (2025)

Efficacy of MR Imaging Findings in Clinical Management of Hepatic Encephalopathy and Alzheimer's Disease.

Hepatology research : the official journal of the Japan Society of Hepatology [Epub ahead of print].

In the aging society, distinguishing hepatic encephalopathy (HE) from Alzheimer's disease (AD) poses significant clinical challenges attributed to overlapping neuropsychiatric symptoms including memory loss, disorientation, and impaired daily functioning. Traditional diagnostic approaches relying on clinical assessment and biochemical markers often prove insufficient, necessitating advanced neuroimaging techniques for differential diagnosis. This review examines magnetic resonance imaging (MRI) techniques for differential diagnosis of HE and AD, focusing on T1-weighted imaging findings characteristic of HE, and voxel-based specific regional analysis system (VSRAD) applications in AD diagnosis. Analysis of the literature encompassed peer-reviewed articles examining neuroimaging patterns, diagnostic accuracy, and clinical correlations in both HE and AD. T1-weighted MRI displays bilateral symmetric hyperintensity at the globus pallidus in 70%-90% of HE patients attributed to manganese deposition secondary to impaired hepatic clearance, and provides evidence of HE-related brain changes independent of ammonia levels. VSRAD analysis reveals characteristic medial temporal lobe atrophy patterns in AD, with diagnostic accuracy rates of 91.6% for very mild, 95.8% for mild, and 98.2% for moderate-to-severe AD. Clinical studies demonstrate that brain atrophy detected by VSRAD correlates significantly with functional impairment in activities of daily living, independent of conventional liver function parameters. The integration of T1-weighted MRI and VSRAD analysis provides enhanced diagnostic accuracy for differentiating HE-associated cognitive impairment from primary neurodegenerative conditions, offering valuable prognostic information regarding functional capacity and cognitive trajectory. This systematic neuroimaging approach enables more precise therapeutic decision-making, signals treatment expectations, and directs rehabilitation planning and long-term care strategies in an aging population with increasing prevalence of both hepatic and neurodegenerative disorders.

RevDate: 2025-12-09

Nakamura Y, Kurokawa T, Terashima S, et al (2025)

Efficacy and safety of a novel, extended-release rivastigmine transdermal patch (TW-4752N) in patients with Alzheimer's disease: A 24-week randomized, double-blind trial with a 28-week open-label extension.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundRivastigmine may offer greater efficacy and convenience of use with a novel formulation than previously reported.ObjectiveTo evaluate the efficacy and safety of a novel, twice-weekly rivastigmine patch (TW-4752N) (TW) in Alzheimer's disease (AD) patients with mild to moderate dementia.MethodsThis was a multicenter, phase III, double-blind study comparing TW and an existing rivastigmine transdermal patch (RT) with an open-label extension. The primary endpoint was the change in ADAS-Jcog total score at week 24 from baseline. Secondary endpoints included the ADAS-Jcog total score at weeks 8, 16, and 24.ResultsA total of 354 and 362 patients were available for efficacy and safety analysis, respectively. Changes in ADAS-Jcog total score at week 24 from baseline were similar between the two groups in the full analysis set with an intergroup difference of -0.84 ± 0.44 (95% CI, -1.695 to 0.016) and with the upper limit of the 95% CI being below the non-inferiority margin of 1.1, demonstrating the non-inferiority of TW. However, analysis of the per-protocol set demonstrated a significant intergroup difference in favor of TW likely suggesting a greater treatment effect with TW than with RT (p = 0.032). Adverse events (AEs) reported in ≥3% of patients were similar between the groups, with the only AE with an intergroup difference of ≥10% in incidence being application site pruritus (TW/RT, 27.6%/17.1%).ConclusionsTW represents a viable alternative option of interest to patients with AD, providing comparable or potentially greater efficacy than RT and comparable safety, as well as greater convenience of use.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Burd SG, Bogolepova AN, Lebedeva AV, et al (2025)

[Epileptic seizures in patients with Alzheimer's disease].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 125(11):36-43.

Neurodegenerative diseases are one of the leading causes of epileptic seizures with onset in later life. Particular attention is paid to Alzheimer's disease (AD), as a disease that accounts for up to 70% of cases of all types of dementia, and, according to the literature, shares genetic and pathophysiological mechanisms with epilepsy. This paper reviews the literature on the prevalence of epilepsy in AD patients. The reasons for the widely varying data (ranging from 0.5 to 64%) depending on the selected population, the reliability of the established diagnosis, the form and genetic characteristics of the disease, as well as the examination methods used, are considered. The main risk factors for the development of AD and epilepsy, semiotics and features of seizures in patients with AD, as well as approaches to the treatment of such patients, are also covered.

RevDate: 2025-12-09

Jafari EA, Alshahawey M, Zaman MA, et al (2025)

Characterizing Alzheimer's Disease and Related Dementia in a Hypertension Population Within the State of Florida Using Electronic Health Record-Based Data.

Clinical pharmacology and therapeutics [Epub ahead of print].

Hypertension is a known modifiable risk factor for Alzheimer's disease and related dementia (ADRD). However, it is unknown how variance in hypertension control, antihypertensive medications, and social determinants of health, such as social deprivation index (SDI), influence the risk of developing ADRD. Validated hypertension computable phenotype algorithms were applied to electronic health record data from the OneFlorida Data Trust (1/1/2013-12/31/2016), to identify apparent treatment-resistant hypertension (aTRH), and hypertension-control levels (well-controlled hypertension, intermediate-controlled hypertension, uncontrolled hypertension). The primary outcome was a new ADRD diagnosis using validated ICD-9/10 codes. Multiple adjusted stepwise logistic regression models were used to identify factors associated with ADRD development. ADRD cumulative hazard incidence per hypertension control levels was assessed using the Nelson-Aalen estimator and log-rank test. A total of 57,273 hypertension patients with 6401 (11%) incident ADRD cases were included in the analysis. The average age was 67 years, with 57% females and 32% identifying as Black or African American. aTRH was a significant ADRD predictor (OR: 1.327, 95% CI: 1.234-1.427), compared to other hypertension phenotypes. aTRH was also significantly associated with a higher incidence of ADRD over time (P < 0.0001). Patients prescribed thiazide diuretics (OR: 0.894, 95% CI: 0.837-0.956) and fixed-dose combination medications (OR: 0.804, 95% CI: 0.732-0.882) had a lower risk of ADRD. A linear relationship between SDI quartiles and ADRD risk was found. aTRH was significantly associated with the development of ADRD. Our study also highlights the importance of comprehensive hypertension control and socioeconomic interventions in preventing or reducing ADRD risk in hypertension patients.

RevDate: 2025-12-08

Li G, Li P, Huang L, et al (2025)

[Protective effects of quercetin, the key component of Zuo Gui Wan, against Alzheimer's disease via the PI3K/AKT pathway: insights from network pharmacology, molecular docking, and cell experiments].

Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences [Epub ahead of print].

OBJECTIVES: To investigate the protective mechanism of quercetin, the core component of Zuo Gui Wan, against Alzheimer's disease through the PI3K/AKT signaling pathway, based on network pharmacology, molecular docking, and cell experi-ments.

METHODS: The active components of Zuo Gui Wan were identified by searching TCMSP, PubChem, Swiss Target Prediction, and BATMAN-TCM databases, and their potential targets were predicted. The target information was standardized using Uniprot, and Alzheimer's disease-related target genes were obtained from Drugbank, GeneCards, and OMIM. The intersection of these datasets was used to identify the potential targets of Zuo Gui Wan for treating Alzheimer's disease. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of potential targets was visualized using Cytoscape 3.10.1 software and the STRING database. The key active compounds and core potential targets for treating Alzheimer's disease with Zuo Gui Wan were identified through calculation. Based on the enrichment analysis results and literature, quercetin and the PI3K/AKT pathway were selected for verification. Molecular docking and binding ability prediction between quercetin and the core target AKT were performed using CB-Dock2, and visualization was conducted with AutoDock and PyMOL software. Finally, Aβ1-42-induced HT-22 mouse hippocampal neuronal cells were used to construct an Alzheimer's disease cell model. Quercetin, the PI3K inhibitor LY294002, and the activator EGF were used as interventions. The groups were divided as follows: Control, Aβ1-42, Aβ1-42+Quercetin 2.5 μM, Aβ1-42+Quercetin 5 μM, Aβ1-42+Quercetin 10 μM, Aβ1-42+EGF, and the PI3K/AKT modulation group: Control, LY294002, LY294002+Quercetin 10 μM, LY294002+EGF. CCK-8 assays were performed to detect cell viability, while JC-1, Calcein AM-PI, and Hoechst staining were used to assess cell apoptosis. Western blotting was employed to detect the expression of relevant target proteins.

RESULTS: Network pharmacology and cell experiments collectively demonstrate that the key active ingredient of Zuo Gui Wan, quercetin, targets core proteins such as AKT1 and GSK3β through a network-based approach, significantly enriching the PI3K/AKT pathway. Molecular docking results indicate that quercetin has a strong binding affinity with AKT. Experimental validation in the Aβ1-42 oligomer-induced HT-22 model reveals that quercetin significantly activates the PI3K/AKT signaling pathway, which is inhibited by Aβ1-42 oligomers, as well as Bcl-2 protein expression. It also suppresses the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. JC-1, Hoechst 33342, and Calcein AM-PI staining results further show that quercetin can significantly alleviate apoptosis induced by Aβ1-42 oligomers in HT-22 cells. Treatment with the PI3K inhibitor LY294002 in HT-22 cells leads to reduced cell viability and decreased expression of p-AKT/AKT and Bcl-2 proteins, while increasing the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. Additionally, apoptosis levels increase as observed in JC-1, Hoechst 33342, and Calcein AM-PI staining, all of which can be reversed by quercetin and the PI3K agonist EGF.

CONCLUSIONS: Quercetin, the key active ingredient of Zuo Gui Wan, exerts its protective effects against Alzheimer's disease by regulating the PI3K/AKT signaling pathway, inhibiting neuronal cell damage and apoptosis.

RevDate: 2025-12-08
CmpDate: 2025-12-08

Menczel Schrire Z, Mitchell HF, Low LF, et al (2025)

NeuroMusic: protocol for a randomised-controlled trial of keyboard and singing music training programmes for older adults with mild cognitive impairment.

BMJ open, 15(12):e104158 pii:bmjopen-2025-104158.

INTRODUCTION: Music-based training programmes, such as learning how to play an instrument or sing in a choir, have been suggested as potential interventions for promoting healthy brain ageing in older adults at risk of cognitive decline because of their ability to enhance cognitive functions and potentially promote neuroplasticity. However, there is limited empirical evidence in older adults at risk of dementia, especially that evaluates both piano and singing interventions and their effects on cognition and neuroplasticity. In this protocol, we outline a study to assess the efficacy of keyboard and singing music training programmes on reducing cognitive decline and other outcomes in older adults with Mild Cognitive Impairment (MCI).

METHODS AND ANALYSIS: This randomised, single-blind, controlled, parallel-group trial aims to enrol 432 individuals with MCI from the community in Sydney, Australia. Participants are randomly allocated to participate in either keyboard lessons, singing lessons or a film discussion control group once a week for 3 months. The primary objective is to assess the effectiveness of two music training programmes (keyboard and choral singing) for enhancing verbal memory after 3 months compared with control. Additionally, we will examine how these music-based interventions affect other aspects of cognition, mood, sleep, overall well-being, markers of brain plasticity and blood biomarkers of Alzheimer's disease and neurodegeneration. Tertiary objectives are to identify factors that impact the success of the interventions, such as participation rates, engagement levels and key demographic and clinical features. Outcomes are collected at baseline and at 3 and 9 months. The primary endpoint analysis will include all randomised participants to estimate the treatment effect using intention-to-treat principles. Primary and secondary outcomes will be analysed using linear mixed models and effect size measures will be calculated.This study will be the first robust, randomised controlled trial to assess the potential and relative value of music engagement for cognitive decline in high-risk MCI individuals, as well as broader effects on other markers of mental health, well-being and neurodegeneration. Co-designed with implementation in mind, the music interventions can potentially be delivered within memory clinic or community settings.

ETHICS AND DISSEMINATION: The Sydney University Human Research Ethics Committee (2023-026) has approved this protocol. The trial findings will be shared through conferences, publications and media.

TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12623000407695), Registered 21/04/2023 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385552 PROTOCOL VERSION: 2.02 29/11/2024.

RevDate: 2025-12-08

Pan L, Song X, Su G, et al (2025)

N-Sulfated Heparan Sulfate Promotes Reelin Signaling as a Co-receptor.

Journal of the American Chemical Society [Epub ahead of print].

Heparan sulfate (HS) plays a central role in signal transduction, while Reelin is an essential signaling protein in both the developing and adult brain. A Reelin COLBOS variant was recently discovered with enhanced HS binding and resilience against autosomal dominant Alzheimer's disease (ADAD), underscoring the importance of Reelin-HS interactions. However, the glycan determinants of Reelin-HS interactions have not been well-characterized, which we systematically investigated here. Surface plasmon resonance (SPR) showed that full length Reelin binds HS with high affinity (KD = 17 ± 5 nM), which is enhanced by the COLBOS variant (KD = 10 ± 2 nM). Competition SPR and glycan array studies further revealed that HS N-sulfation is critical for Reelin-HS binding, consistent with Haddock modeling. In cell surface binding assays, heparinase treatment, which degrades HS, or the knockout of a key HS N-sulfation enzyme (NDST1) significantly reduced Reelin attachment. Functionally, a cellular split-luciferase assay showed that heparinase treatment or adding heparin in culture medium reduces Reelin-induced ApoER2 dimerization, demonstrating that HS is a coreceptor for Reelin receptor activation. In contrast, N-desulfated heparin does not inhibit Reelin receptor dimerization. Our work establishes HS as a coreceptor for Reelin signaling and N-sulfation as a key glycan determinant of Reelin-HS recognition. Our work provides mechanistic insights into diverse neurodevelopmental and neurodegenerative diseases associated with Reelin signaling and suggests novel therapeutic strategies targeting HS sulfation.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Aggarwal G, Salas J, Vellas B, et al (2025)

High circulating adropin levels predict long-term blood pressure variability in old adults: evidence from the Multidomain Alzheimer Prevention Trial.

American journal of physiology. Heart and circulatory physiology, 329(6):H1684-H1692.

Hypertension and elevated visit-to-visit variability in blood pressure (BP) increase the lifetime risk of cardiovascular, kidney, and neurodegenerative diseases. Adropin, a hepatokine with autocrine/paracrine actions, contributes to cardiometabolic cross talk and mediates cellular stress responses across metabolic and cardiovascular tissues. Human cross-sectional and exercise studies suggest links between adropin, endothelial function, and vascular elasticity. Whether circulating adropin levels reflect risk of poor BP control remains unclear. We examined relationships between plasma adropin concentrations, BP, and visit-to-visit BP variability in older, community-dwelling participants from the Multidomain Alzheimer Prevention Trial (MAPT: n = 443; means ± SD age, 75.9 ± 4.5 yr; 60% female). BP and heart rate while in the supine position were assessed every 6 mo for 5 yr (8.1 ± 1.3 measurements/participant). Multivariate regression modeling revealed a positive association between adropin and variation independent of the mean (VIM) in systolic BP (R = 0.329, F7,429 = 7.454, P < 0.001). Predictors included adropin (β = 0.165, P < 0.001), age (β = 0.146, P < 0.005), sex (male = 1, female = 0; β = -0.130, P = 0.005), and antihypertensive medication use (yes = 1, no = 0; β = 0.188, P < 0.001). Stratification by medication use suggested that the association between adropin and systolic BP VIM is confined to participants on antihypertensive therapy (R = 0.347, F6,188 = 4.302, P < 0.001; adropin, β = 0.233, P = 0.001). However, analysis by grouping participants in tertiles ranked by adropin or systolic BP VIM suggests that, although the relationship is notably weaker, it is not absent for participants not on antihypertensive medications. In conclusion, elevated plasma adropin concentrations associate with systolic BP variability in older adults with hypertension. These findings identify adropin as a potential biomarker of poor BP control.NEW & NOTEWORTHY This study identifies circulating levels of the hepatokine adropin as a novel biomarker of blood pressure (BP) variability in older adults. Using longitudinal data from the Multidomain Alzheimer Prevention Trial, we show that higher adropin levels predict greater systolic BP variability, particularly in participants receiving antihypertensive therapy. These findings link a hepatokine with cardiovascular risk and suggest that adropin measurement may improve stratification of individuals at risk for poor BP control and treatment resistance.

RevDate: 2025-12-09

Anonymous (2025)

Erratum.

Neuro-degenerative diseases, 25(4):228.