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

Shamsi A, Alrouji M, AlOmeir O, et al (2025)

Correction: CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.

Frontiers in cellular neuroscience, 19:1739705.

[This corrects the article DOI: 10.3389/fncel.2025.1681891.].

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

Hanchate AD, Nothelle SK, Kinosian B, et al (2025)

Telemedicine: a substitute or complement for home-based medical care? the experience of Medicare enrollees with dementia.

Health affairs scholar, 3(12):qxaf229.

INTRODUCTION: As Alzheimer's disease and related dementias (ADRD) progress, many individuals become homebound and increasingly depend on home-based medical care (HBMC), such as clinician house calls. The COVID-19 pandemic spurred a rapid expansion of telemedicine under Medicare, but its impact on outpatient care by modality-HBMC, telemedicine, and office-based-among enrollees with ADRD remains unclear.

METHODS: Using national Medicare claims, we examined changes in primary care visits-categorized as office-based, HBMC, and telemedicine-between the pre-expansion period (March 2019-February 2020) and the late post-expansion period (March-November 2021), when telemedicine use had stabilized. Analyses were stratified by regions with low vs high HBMC provider availability.

RESULTS: Regions with high HBMC availability saw a 13.6% greater increase in HBMC visits and a 5.0% greater increase in all visits compared to low-availability regions. Both groups had similar increases in telemedicine and declines in office-based visits. HBMC growth reflected broader access, with more beneficiaries receiving HBMC post-expansion. However, gains were concentrated among non-Hispanic White enrollees, with no significant changes for non-Hispanic Black or Hispanic enrollees.

CONCLUSION: These findings suggest that Medicare's telemedicine waivers expanded, rather than replaced, HBMC. Sustaining these policies may support aging in place for individuals with dementia, though disparities in access remain a critical concern.

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

Torres U, Bernal D, Gurrutxaga I, et al (2025)

Preclinical Alzheimer's and vascular biomarkers alter brain aging in cognitively normal adults: a MRI-based study.

Frontiers in aging neuroscience, 17:1653074.

INTRODUCTION: The aging global population underscores the need to understand brain aging and its links to neurodegenerative diseases. While most brain aging studies use cognitive impairment as exclusion criteria, preclinical biomarkers may influence results, potentially masking early pathological effects. This study evaluates how preclinical AD and vascular biomarkers impact brain aging models in cognitively normal subjects.

METHODS: Using baseline data from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS), we analyzed 1,380 cognitively unimpaired participants (50+ years) stratified into five groups based on cerebrospinal fluid biomarkers (Aβ42, t-tau, p-tau) and vascular pathology (Fazekas scale, microbleeds). Structural MRI volumes of cortical/subcortical regions were normalized and compared using Nadaraya-Watson kernel regression. Bootstrapping and Bonferroni-corrected statistical tests assessed differences in the relationship between age and brain volume between groups.

RESULTS: Significant differences emerged in the relationship between age and brain volume in biomarker-negative and biomarker-positive groups, particularly in the entorhinal cortex, amygdalas, and basal forebrain (p < 0.01). The AD and mixed AD/vascular groups showed the largest deviations. Gender-specific analyses revealed stronger effects in males. Vascular pathology alone affected distinct regions (e.g., left entorhinal cortex) without amygdala involvement, suggesting disease-specific atrophy patterns.

DISCUSSION: Preclinical AD and vascular biomarkers significantly alter brain aging in cognitively normal individuals. These findings highlight the importance of biomarker stratification in brain age studies to avoid biased estimates. Entorhinal cortex and amygdala volumes may serve as sensitive early indicators of neurodegeneration, supporting their use in targeted interventions and personalized monitoring.

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

Lima R, Barradas G, S Bermúdez I Badia (2025)

Music-induced physiological markers for detecting Alzheimer's disease using machine learning.

Frontiers in aging neuroscience, 17:1701970.

INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive cognitive and emotional decline, highlighting the need for novel, non-invasive biomarkers to aid in early detection, monitoring, and stage-specific interventions. This study investigates music-evoked physiological responses as potential biomarkers of AD and evaluates their translational value using machine learning (ML).

MATERIALS AND METHODS: A total of 36 AD patients, spanning different severity levels, listened to emotionally evocative musical excerpts while electrodermal activity and facial electromyography (corrugator and zygomaticus muscles) were recorded. Machine learning models were then trained on these signals to classify the presence and severity of AD and to detect residual emotion-specific physiological responses elicited by music.

RESULTS: Physiological reactivity to music declined with disease progression, with positive emotions eliciting more distinct responses than negative ones. The Random Forest classifier distinguished AD patients from healthy controls with 70.5% accuracy, while the Naïve Bayes model predicted severity with 65.6% accuracy, demonstrating that ML models can detect subtle music-evoked physiological differences even in individuals with AD.

DISCUSSION: Music-evoked physiological signals reflect the hierarchical disruption of emotion-related neural circuits in AD and hold promise as complementary biomarkers for disease presence and stage. When combined with machine learning (ML), these measures provide a non-invasive, ecologically valid approach to support early detection, monitoring, and the development of stage-specific interventions.

RevDate: 2025-12-10

Emad M, Waheed R, Mostafa Z, et al (2025)

Exploring pyrazolidinone and pyrazolidinedione scaffolds for Alzheimer's therapy: multitarget COX-2 inhibitors with anti-amyloid β, anti-tau, antioxidant, and neuroprotective activities.

RSC medicinal chemistry [Epub ahead of print].

COX-2 enzyme is implicated in Alzheimer's disease (AD) through amyloid beta (Aβ) accumulation, tau aggregation, and neuroinflammation. However, clinical outcomes of COX-2 inhibitors in AD have been inconsistent. This study explores a novel series of pyrazolidinones and pyrazolidinediones as selective COX-2 inhibitors. Among these, 4-hydrazonopyrazolidinediones exhibited potent COX-2 inhibition, reducing PGE2 release in a THP-1 cell model. Compounds 15 and 16 demonstrated multitargeting potential by inhibiting Aβ and tau aggregation (PHF6 and R3) and showed significant neuroprotective effects against Aβ and H2O2-induced toxicity in SH-SY5Y cells without cytotoxicity. Additionally, both compounds displayed high permeability in PAMPA and MDCK-MDR1 assays, indicating their potential to cross the blood-brain barrier and reach therapeutic targets. These findings highlight the potential of reviving COX-2 inhibitors as multitargeted therapeutic agents for AD, offering a promising strategy to address multiple pathological aspects of the disease, including neuroinflammation, amyloid aggregation, and tau pathology.

RevDate: 2025-12-10

Paveliev M, Melnikova A, Samigullin DV, et al (2025)

Second harmonic generation for brain imaging: pathology-related studies.

Biophysical reviews [Epub ahead of print].

Microscopy of the brain has been facing problems of contrast and thick tissue imaging. Second harmonic generation (SHG) is a non-linear effect of the light interaction with the imaged material, resulting in photon emission at half the wavelength of the absorbed light. SHG microscopy provides an unprecedented opportunity for imaging collagen and other noncentrosymmetric protein fibrils in unstained thick tissue samples and in the live brain via a regular multiphoton setup. This opens a remarkable methodological window for imaging pathological processes of high importance, including brain trauma, fibrosis, tumorigenesis, and neuroimplant-induced foreign body response. Moreover, SHG is a valuable tool for imaging astrocytes and nerve fiber microtubules. Third harmonic generation enhanced by three-photon resonance with the Soret band of hemoglobin is combined with SHG to resolve the microstructure of blood vessel walls and astrocyte-process endfeet on gliovascular interfaces. Here, we review current state-of-the-art methods in the field of brain imaging applications of SHG, including research on brain and spinal cord injury, glioma, ischemia, Alzheimer's disease, neuroimplantation, and brain meninges. We then address the method development perspective in the broader context of other tissue pathologies. Finally, we account for recent progress in artificial intelligence applications for SHG microscopy data analysis.

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

Teipel S, Akmatov M, Michalowsky B, et al (2025)

Association of cancer with neuropathological markers of Alzheimer's disease and related dementias.

Alzheimer's & dementia (Amsterdam, Netherlands), 17(4):e70222.

INTRODUCTION: We assessed associations of cancer diagnoses with neuropathology of Alzheimer's disease (AD) and related dementias.

METHODS: We retrieved 2288 cases from the National Alzheimer Coordinating Center (NACC) cohort with available information on cancer diagnoses and neuropathological scoring of Braak stages, Thal amyloid phases, neuritic plaques, TDP-43 pathology, and Lewy body pathology. We used Bayesian ordinal regression to assess associations of prevalent or incident cancer diagnoses with global cognition and postmortem neuropathological scores.

RESULTS: We found extreme evidence (Bayes factor [BF] > 2000) that both prevalent and incident cancer diagnoses were associated with better global cognition, strong evidence (BF = 26) for an association of a prevalent cancer diagnosis with lower TDP-43 pathology, and weak evidence (BF = 3.2) for an association with lower Lewy body pathology.

DISCUSSION: Our data suggest that selective survival and biological effects may contribute to the lower risk of dementia in people with a cancer diagnosis.

HIGHLIGHTS: A prevalent diagnosis of cancer was associated with a lower risk of cognitive decline in older individuals.A prevalent diagnosis of cancer was associated with a lower risk of TDP-43 pathology and Lewy body pathology in older individuals.Effects of cancer on TDP-43 pathology were maintained when controlling for degree of cognitive decline.

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

Pinyopornpanish K, Yarach U, Angkurawaranon C, et al (2025)

Creation of structural MRI brain templates for middle to late adulthood in the Thai population using single and multi-scanner data.

Quantitative imaging in medicine and surgery, 15(12):11729-11742.

BACKGROUND: The global increase in elderly populations, particularly in low- and middle-income countries, underscores the rising prevalence of age-related conditions, such as Alzheimer's disease. Structural magnetic resonance imaging (MRI) plays a crucial role in Alzheimer's disease research and early diagnosis; however, manual brain segmentation is labor-intensive, time-consuming, and prone to inter-rater variability. Automated segmentation using existing brain templates from Mongoloid, Caucasoid, and Negroid populations may not be suitable for Thai individuals due to anatomical differences, emphasizing the need for population-specific templates. This study aimed to develop structural MRI brain templates tailored for cognitively normal Thai adults aged 50-70 years, using both single- and multi-scanner data.

METHODS: This study developed structural brain templates tailored for cognitively normal Thai adults aged 50-70 years. Participants underwent 3D T1-weighted MRI scans across three scanners. The image processing pipeline included bias field correction, rigid registration to standard space, and iterative non-rigid registration to ensure anatomical consistency. Two templates were created: TH150, based on data from a single scanner site, and TH240, constructed from multi-site data collected across three scanners.

RESULTS: Two templates were created: TH150 and TH240, which exhibited nearly identical brain spatial dimensions (width, length, and height). These features closely align with those obtained from individual brains through manual measurement, confirming the reliability of the template construction pipeline. Compared to CN200 and US200, the Thai templates showed 16-22% less gray matter, 2-9% less white matter, and 27-68% more cerebrospinal fluid. These differences likely reflect age-related changes, as the Thai templates were constructed from individuals aged 50-70 years, whereas the CN200 and US200 templates represent younger populations.

CONCLUSIONS: These Thai adults aged 50-70 years population-specific templates reveal morphological differences from Chinese and Western templates. The high consistency between TH150 and TH240 supports methodological robustness, providing a foundation for future neuroimaging research and applications.

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

Hsu CC, Chang CC, Lee JF, et al (2025)

The Relationship Between Brain Structure and Neuropsychiatric Symptoms in Patients With Mild Cognitive Impairment and Alzheimer's Dementia.

International journal of geriatric psychiatry, 40(12):e70182.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are highly prevalent from mild cognitive impairment (MCI) to Alzheimer's dementia (AD). Understanding the link between NPS and regional brain changes can provide insight into neural correlates of disease progression.

METHODS: This cross-sectional study analyzed 1536 older adults from the National Alzheimer's Coordinating Center comprising 860 healthy controls, 389 patients with MCI, and 287 patients with AD. The NPSs were evaluated with the Neuropsychiatric Inventory (NPI), which measures severity in four domains: mood, psychosis, frontal, and total symptoms. Magnetic resonance imaging quantified regional gray matter volumes (GM), cerebrospinal fluid volume (CSF), and white matter hyperintensity (WMH) volumes to see their correlations with NPS.

RESULTS: All volumes showed the smallest in dementia, the intermediate in MCI, and the largest in healthy controls. Higher total NPI scores were significantly associated with smaller volumes of hippocampal and gray matter volumes and larger cerebrospinal fluid volume, with the strongest correlations in the dementia group. By domain, NPI-mood symptoms were correlated with reduced hippocampal, temporal, and frontal volumes. NPI-psychosis symptoms also correlated with frontotemporal regions, but less extensively. Mood symptoms were most strongly linked to temporolimbic atrophy.

CONCLUSION: The study supports associations between emerging neuropsychiatric manifestations and accumulating structural brain damage along the pathological cascade.

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

Barahona-López C, Plans-Beriso E, Diez-Echave P, et al (2025)

Personalized prevention of neurodegenerative diseases: scoping review and evidence gap map.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70980.

Neurodegenerative diseases represent a major public health challenge due to their high prevalence and poor prognosis. Identifying biomarkers to stratify individuals by their risk of developing these diseases may help to define new personalized prevention interventions. The objective of this study was to conduct a scoping review of biomarkers for primary and secondary personalized prevention of neurodegenerative diseases. The search targeted biomarkers in adults or high-risk subpopulations in clinical or public health settings for Alzheimer's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Ultimately, 286 papers were included in the review and the interactive gap map. There is a strong focus on Alzheimer's disease, and most papers included -omics-based biomarkers and/or used artificial intelligence. Genetics/genomics are at the forefront of current scientific research, although there is a notable gap in studying gene-environment interactions, and studies in clinical settings are still scarce. HIGHLIGHTS: Research indicates a strong focus on Alzheimer´s disease and limited research in other diseases. Genetics and genomics are at the forefront of current scientific research. We found biomarkers for predicting progression in mild cognitive decline. There is a notable gap in studying gene-environment interactions. Studies investigating biomarkers in a clinical context are still scarce.

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

Monserratt LH, Morales JA, Mohammed A, et al (2025)

Validity of gold-standard clinical outcome assessments in U.S. Latinx-Hispanic participants enrolled in Alzheimer's disease clinical trials: A literature review.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70918.

There is an urgency to achieve equitable representation of Latinx-Hispanic participants in Alzheimer's disease (AD) clinical trials. Valid instruments for these communities contribute to the generalizability of clinical trial outcomes. The aim of this study was to review articles reporting studies that conducted a thorough assessment of the validity and reliability of three gold-standard cognitive measures with U.S. Latinx-Hispanic communities. We reviewed validity/reliability studies of the Clinical Dementia Rating (CDR), Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog), and Repeatable Battery of the Assessment of Neuropsychological Scales (RBANS) among U.S. Latinx-Hispanic communities. Database searches included PubMed and PsycINFO. For the CDR, one study assessed validity and the other reliability. For the RBANS, one study evaluated the diagnostic accuracy, and another conducted an equating analysis. No studies addressed the validation/reliability of ADAS-Cog. Our literature review revealed limited studies examining the validity and reliability of the CDR, ADAS-Cog, and RBANS in U.S. Latinx-Hispanic communities. HIGHLIGHTS: Various government entities are mandating increased enrollment of the Latinx-Hispanic communities in AD clinical trials without considering the potential negative impact of study results when invalid COAs are used in underrepresented communities. Our investigation demonstrates three gold-standard COAs routinely used in AD clinical trials have mostly not been validated on the Latinx-Hispanic communities residing in the United States. We recommend specific actions to support the development of valid clinical outcome measures for the Latinx-Hispanic communities.

RevDate: 2025-12-10

Anonymous (2025)

Correction to "Putaminal hypermetabolism identifies Lewy body co-pathology in Alzheimer's disease".

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e71013.

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

Ye BS, Park SH, Jeon S, et al (2025)

Degenerative pathologies on cortical biopsy, dopaminergic depletion, and shunt efficacy in iNPH.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70974.

INTRODUCTION: Coexisting degenerative pathologies may influence the efficacy of ventriculoperitoneal (VP) shunting in idiopathic normal pressure hydrocephalus (iNPH).

METHODS: We evaluated 58 iNPH patients who underwent VP shunting with cortical biopsy assessing pathologies including amyloid beta (Aβ). Concordance between biopsy-identified Alzheimer's pathology and amyloid positron emission tomography (PET) and the influence of magnetic resonance imaging-based iNPH indices, dopamine transporter (DAT) imaging, and biopsy pathologies on postoperative outcomes were examined.

RESULTS: Aβ pathology was found in 23 patients (39.7%) and showed high concordance with amyloid PET (95.2%). Although Aβ positivity was associated with poorer 1-year cognitive outcome, and cognitive improvement reached significance only in Aβ-negative patients, both Aβ-positive and Aβ-negative groups exhibited functional improvement after surgery. Lower anterior striatal DAT uptake was paradoxically associated with better postoperative outcomes, particularly in Aβ-positive individuals.

DISCUSSION: Cortical biopsy provides information concordant with amyloid PET, and biopsy-confirmed Alzheimer's pathology and dopaminergic status influence shunt efficacy. VP shunting remains beneficial in iNPH even with degenerative comorbidities.

HIGHLIGHTS: Cortical biopsy findings showed high concordance with amyloid PET in iNPH patients. AD pathology was linked to poorer cognitive and functional outcomes after surgery. VP shunting remained beneficial even in patients with comorbid AD pathology. Lower anterior striatal DAT uptake was paradoxically associated with better outcomes. Combined use of biopsy and DAT imaging may aid prognostication in iNPH management.

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

van Wetering J, Geut H, Bol JJ, et al (2025)

Correction: Neuroinflammation is associated with Alzheimer's disease co-pathology in dementia with Lewy bodies.

Acta neuropathologica communications, 13(1):250.

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

He D, Langhough RE, Van Hulle C, et al (2025)

Development of language composites for enhanced sensitivity to multiple plasma biomarkers.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70975.

BACKGROUND: While language deficits are among the earliest detectable signs of Alzheimer`s disease (AD), no existing composites integrate connected speech - essential for capturing real-world communication - limiting precise detection and personalized interventions.

METHODS: We analyzed cohort data from 824 non-demented adults and constructed three language composites: a theoretical composite based on expert knowledge, a connected speech-specific composite derived from the theoretical composite, and an empirical language composite optimized for predicting cognitive progression. We compared their longitudinal sensitivity to plasma tau phosphorylated at threonine 217 (p-tau217), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP).

RESULTS: The empirical language composite showed superior and consistent sensitivity (faster decline rate) with all three biomarkers. Proper name recall declined uniquely with increased p-tau217, while animal fluency declined selectively with higher NfL and GFAP.

DISCUSSION: An empirical language composite captures holistic cognitive-communicative decline, while individual measures may imply a biomarker-specific language profile. Our findings support the clinical utility of plasma biomarkers and language-specific composites as sensitive early indicators of disease progression.

HIGHLIGHTS: Empirical language composite had optimal sensitivity to plasma p-tau217, NfL, GFAP. It comprises words/minute, filled pauses, proper name recall, and animal fluency. It offers potential for language-dominant ADRD precise detection and monitoring.

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
CmpDate: 2025-12-10

Karimi-Zandi L, Aminyavari S, M Zahmatkesh (2025)

Hippocampal synaptic plasticity impairment and melatonin synthesis reduction in cognitive decline of a rodent model of Alzheimer's disease-like pathology.

Pflugers Archiv : European journal of physiology, 478(1):4.

Melatonin, the pineal gland hormone, is produced in several extra-pineal tissues. The arylalkylamine N-acetyltransferase (AANAT) enzyme activity determines the overall rate of tissue melatonin synthesis. A decline in AANAT enzyme activity during acute amyloid-β (Aβ) neurotoxicity and reduced melatonin levels in Alzheimer's patients have been reported. These findings raise the question of whether brain melatonin synthesis is altered during cognitive decline. We investigated whether cognitive impairment induced by Aβ administration could affect the activation status of AANAT, a key hippocampal enzyme of melatonin synthesis. Male Wistar rats received intra-cerebroventricular Aβ injection. Two weeks after Aβ administration, the neuroinflammation was assessed by interleukin-1 (IL-1β) immunohistochemical staining. Hippocampal long-term potentiation (LTP) was evaluated using the technique of local field recording. The cognitive function was assessed using the Morris water maze behavioral test.The hippocampal AANAT activation status was assessed by Western blotting, and HPLC was used for melatonin level analysis. Aβ-induced spatial memory and LTP impairments were confirmed by increased escape latencies and alterations in the fEPSP slope. The Aβ provided a neuroinflammatory context, demonstrated by increased in the IL-1𝛽 staining. These alterations were accompanied by a reduction in the activation status of AANAT, as indicated by the p-AANAT/total AANAT ratio, in both the electrophysiology and behavioral experimental groups.These data suggest that the local activation status of AANAT may be contributed in the cognitive function of the hippocampus in a rodent model of cognitive decline induced by Aβ administration.

RevDate: 2025-12-09

Salman Y, Goloubeva J, Huyghe L, et al (2025)

Specific atrophy patterns distinguish tau and TDP-43 pathology: a longitudinal MRI ante-mortem study.

Acta neuropathologica communications pii:10.1186/s40478-025-02200-y [Epub ahead of print].

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

Xiong Z, Dodson BP, Rogers MB, et al (2025)

Microbial production of short-chain fatty acids attenuates long-term neurologic impairment after traumatic brain injury.

Journal of neuroinflammation, 22(1):285.

BACKGROUND: Traumatic brain injury (TBI) triggers persistent gut microbiome dysbiosis characterized by depletion of short-chain fatty acid (SCFA)-producing bacteria. However, the link between SCFA depletion and long-term neurologic impairment (LTNI) after TBI remains unclear. Previously, we and others noted the involvement of metabolite-sensing receptors and SCFA ligands in mouse models of neurodegenerative diseases, including Alzheimer's. Here, we further investigated SCFA-mediated neuroprotection in LTNI at both microbiome and single-cell resolution using the controlled cortical impact (CCI) model of TBI with a high-yielding SCFA diet to examine their mechanistic role in pathogenesis.

METHODS: C57BL6/J mice were randomized to CCI (6 m/s, 2 mm) or sham surgery. Following surgery, mice were randomized to a study diet based on a balanced modification of the AIN93-G diet containing either 15% high amylose maize starch (HAMS) control diet or acetylated and butyrylated HAMS (HAMSAB) for 6 months to model increased SCFA production by bacterial fermentation in the gut. Morris water maze test and nesting assessment were performed at 1, 3, and 6 months after injury. The longitudinal gut microbiome changes were investigated by 16 S rRNA amplicon and metagenomic sequencing of fecal pellets at baseline, 1 month, and 6 months post-injury. At 6 months, pericontusional tissue was collected for single-cell RNA-sequencing following the 10X Genomics protocol or histologic analysis.

RESULTS: Compared to the HAMS control diet, HAMSAB diet remodeled the CCI murine gut microbiome at an early phase, increased various SCFA-producing taxa, and attenuated neurologic deficits up to 6 months after CCI. In mice fed HAMSAB diet, single-cell transcriptomics and pathway analysis identified the promotion of neurogenesis, including increased doublecortin-positive immature neurons. In myeloid cells, HAMSAB induced an anti-inflammatory phenotype, inhibiting pro-inflammatory signaling interaction such as midkine signaling, and promoted differentiation to disease-associated microglia (DAM). Simultaneously, SCFAs reduced neurodegenerative pathway activity in neurons and glial cells and reduced phosphorylated tau deposition in pericontusional cortex.

CONCLUSIONS: Diet-facilitated microbial production of acetate and butyrate attenuates behavioral deficits of LTNI after TBI and produces enduring benefits at the single-cell level on the neuro-inflammatory and neuro-progenitor responses. This therapeutic approach could have a broader potential to prevent neurodegenerative disease.

RevDate: 2025-12-09

Dixon P, E Anderson (2025)

Associations of Alzheimer's disease with inpatient hospital costs and with quality-adjusted life years: evidence from conventional and Mendelian randomization analyses in the UK Biobank.

Cost effectiveness and resource allocation : C/E pii:10.1186/s12962-025-00684-y [Epub ahead of print].

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

Böck D, Tidecks L, Wilhelm M, et al (2025)

Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer's disease.

Nature communications, 16(1):10973.

Prime editing offers versatile genome modifications with therapeutic potential; yet its use to modulate neural circuitry remains underexplored. Here, we used adeno-associated viral vectors to deliver prime editors into the mouse brain and introduced the naturally occurring Adrb1[A187V] variant of the β1-adrenergic receptor, linked to short sleep in humans and mice. Editing reached up to 28.1% in the cortex six months after intracerebroventricular injection and increased excitability of β1-noradrenergic neurons. This enhanced wake-associated behaviors, including home cage activity, locomotion, exploration, and recognition memory, while reducing slow wave activity (SWA) during non-rapid eye movement (NREM) sleep indicating reduced build-up of sleep pressure during active phases. In a mouse model of Alzheimer's disease, Adrb1[A187V] installation restored physiological REM sleep and again reduced NREM sleep SWA following spontaneous activity. Together, these findings demonstrate the feasibility of prime editing for reprogramming genetic circuits in the brain and reveal beneficial effects of the Adrb1[A187V] variant on activity and sleep regulation.

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

Trinklein TJ, Rubakhin SS, Okyem S, et al (2025)

Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer's disease mouse models.

Nature communications, 16(1):10969.

The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer's disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APP[NL-G-F] mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging, trapped ion mobility spectrometry, and fluorescence microscopy. Our approach improves detectability and spatial-chemical resolution. We couple these measurements with a computational pipeline for multimodal image coregistration and discovery of plaque-altered lipids. Here, we show the lipids in and around Aβ plaques are highly heterogeneous. Integration of our data with existing spatial transcriptomics data suggests that region-specific accumulation of simple gangliosides is likely driven by lysosomal degradation of complex species. Together, this work provides a generalizable framework to understand lipid alterations within the Aβ plaque microenvironment.

RevDate: 2025-12-09

Ngo TC, Nguyen HL, Truong DH, et al (2025)

Multifunctional Roles of Natural Aaptodine in Alzheimer's Disease: Insights from DFT and MD Studies.

The journal of physical chemistry. B [Epub ahead of print].

The multifunctional properties of aaptodine A in preventing oxidative stress and inhibiting amyloid-beta (Aβ) aggregation, both of which are considered the main causes of Alzheimer's disease (AD), are the focus of this study. Using the M06-2X and M06 density functional theory (DFT) methods, the study examines the scavenging of HO[·] and HOO[·] radicals, as well as the reactions involving Fe[3+]/Cu[2+] chelation. Docking and molecular dynamics (MD) simulations further assess the inhibitory effect of aaptodine A on Aβ aggregation. The findings indicate that aaptodine A exhibits a strong ability to scavenge the HO[·] radical (rate constant k = 1.69 × 10[10] M[-1] s[-1]); however, it is ineffective against the HOO[·] radical. Furthermore, aaptodine A demonstrates significant chelating activity with Cu[2+], particularly showing effective scavenging ability for both Cu[2+] and Fe[3+] ions when the complex formation occurs with two ligands. These bioactivities help suppress the formation of reactive free radicals, often associated with metal ions, and mitigate Cu[2+]-induced neurotoxicity linked to Aβ in AD. Additionally, analyses using MM/PBSA and the accelerated weight histogram (AWH) methods reveal that aaptodine A exhibits a strong binding affinity to Aβ42 fibril structures. Its binding affinities are comparable to those of curcumin, a well-known compound recognized for its ability to inhibit the formation of Aβ fibrils and oligomers. The AWH results with tetramer indicate that aaptodine A binds to both toxic oligomeric species and the mature fibril. As a result, aaptodine A exhibits potential antioxidant activity through a secondary mechanism and may serve as a promising candidate for inhibiting toxic Aβ aggregates associated with AD.

RevDate: 2025-12-09

Boopathi S, Garduño-Juárez R, MM Gromiha (2025)

Herpes Simplex Virus Glycoprotein D Associated with Aβ1-42 Tetramers Mediates Neurotoxicity by Perturbing Neuronal Membrane Integrity: A Molecular Dynamics Simulation.

ACS chemical neuroscience [Epub ahead of print].

Alzheimer's disease (AD) is characterized by deleterious amyloid plaques deposited in the brain, formed through the interaction of Amyloid β-peptides (Aβ1-42) with the cell membrane. Despite promising preclinical results, Aβ1-42 aggregation inhibitors have not delivered the anticipated benefits in clinical trials for AD. This discrepancy may stem from the fact that the cause of sporadic AD is unknown. Mounting evidence suggests that herpes simplex virus type-1 (HSV-1) may significantly contribute to the onset of AD by facilitating the aggregation of Aβ1-42 into oligomers, leading to neurotoxicity and neuronal cell loss in the brain. However, the mechanism of neurotoxicity remains elusive. Understanding the relationship between the HSV-1 envelope glycoprotein D (gD) and Aβ1-42 oligomers and their impact on neuronal membranes, is the most demanding task for unveiling the underlying mechanism. Thus, we performed extensive all-atom molecular dynamics (MD) simulations to thoroughly investigate the molecular mechanism underlying the interaction between the gD protein and Aβ1-42 oligomers in both aqueous environments and in the presence of lipid bilayers, which mimic the composition of neuronal membranes in vivo. Our simulation study provides valuable insights into the initial stages of this process, in which the Aβ1-42 tetramer (Aβ1-42t) associates with gD via hydrogen bonds formed at their interface. Consequently, we observed that Aβ1-42t-gD, rather than Aβ1-42t alone, demonstrates significant adsorption to the membrane, driven by robust electrostatic interactions between the charged residues of Aβ1-42t-gD and the phosphate groups of lipids such as POPC, POPS, POPE, and PSM. This interaction significantly reduces the electrostatic and van der Waals interactions among the lipids, in contrast to Aβ1-42t binding alone. As a result, disruptions of the lipid membrane integrity are more pronounced upon the Aβ1-42t-gD binding than the Aβ1-42t alone. This study provides atomic-level evidence that gD amplifies Aβ1-42t-membrane interactions, potentially altering membrane phase behavior and contributing to the initial molecular events underlying neuronal dysfunction, thereby suggesting a link between HSV-1 infection and the pathogenesis of 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

Song J, Lu Q, Zhang S, et al (2025)

Precuneus-to-hippocampus connectivity links LTP-like plasticity to cognitive function in subjective cognitive decline and mild cognitive impairment.

NeuroImage pii:S1053-8119(25)00639-1 [Epub ahead of print].

BACKGROUND: Disruptions in synaptic plasticity and alterations in effective connectivity (EC) involving the hippocampus and amygdala are hallmarks of early Alzheimer's disease (AD). However, the interplay between these neurophysiological changes and their relationships with cognitive functions in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) remains poorly understood.

METHODS: Transcranial magnetic stimulation (TMS) and resting-state functional magnetic resonance imaging (rs-fMRI) were used to assess long-term potentiation (LTP)-like plasticity and EC involving the amygdala and hippocampus in 34 individuals with SCD, 27 with MCI, and 35 healthy controls (HC). Between-group differences in cognitive performance, EC alterations, and LTP-like plasticity were examined and their relationships were assessed via correlation and mediation analyses.

RESULTS: Both SCD and MCI groups exhibited disrupted EC between the amygdala/hippocampus and the inferior occipital gyrus, inferior parietal lobule (IPL), medial frontal lobe (MFL), and precuneus. Also, both LTP-5min and LTP-10min were significantly reduced in MCI group compared to SCD and HC groups. Importantly, EC from the left hippocampus to the IPL and from the IPL, MFL, and precuneus to the hippocampus was correlated with memory and executive functions. Moreover, precuneus-to-hippocampus EC was positively correlated with LTP-10min and mediated the relationship between LTP-like plasticity and cognitive performance.

CONCLUSIONS: This study provides novel evidence that precuneus-to-hippocampus EC mediates the link between synaptic plasticity and cognitive function in SCD and MCI, suggesting the precuneus-hippocampus pathway as a promising target for early diagnosis and intervention.

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

Rabbani G, Mohammad A, Khan ME, et al (2025)

A flexible carbon nanotube field-effect transistor-based immunosensor for the selective and sensitive detection of salivary lysozyme: A biomarker of Alzheimer's disease.

Bioelectrochemistry (Amsterdam, Netherlands), 169:109193 pii:S1567-5394(25)00296-8 [Epub ahead of print].

In the modern era, Alzheimer's disease (AD) is one of the most common causes of dementia, with its prevalence increasing over time. Collecting brain tissues for research related to neurodegenerative diseases is challenging due to the need for highly trained neurosurgeons to perform surgery and extract brain tissue. Access to human brain tissue is limited, as sampling faces technical, ethical and cost obstacles. Therefore, developing a noninvasive method to detect biomarkers for an accurate diagnosis of AD is crucial. In this study, we selected lysozyme (LYZ) as a model analyte to quantify in saliva because LYZ levels are upregulated in AD patients. Nafion-anchored carbon nanotubes (Nafion/CNTs) nanocomposite was successfully synthesized and deposited on the polyethylene terephthalate (PET) substrate and utilized in the fabrication of FET-based immunosensor, with anti-LYZ covalently immobilized. Under the optimized conditions, the immunosensor displayed a linear correlation in the range of 0.05 to 100 μg/mL with a LOD of 0.05 μg/mL. The immunosensor exhibited high specificity against interfering molecules and was effectively employed in detecting LYZ in human saliva sample, yielding satisfactory recoveries. This noninvasive method for quantifying LYZ as AD biomarker offers a straightforward and sensitive approach to detection, suggesting significant potential applications in clinical diagnostics.

RevDate: 2025-12-09

Bahrani AA, Nelson PT, Abner EL, et al (2025)

White matter hyperintensity regression: Fact or artifact?.

Neurobiology of aging, 159:33-46 pii:S0197-4580(25)00211-8 [Epub ahead of print].

White matter hyperintensities (WMH) are an MRI-based biomarker associated with aging, Alzheimer's disease, and vascular dementia. Although the volume of WMH typically increases over time (growth) for individuals, WMH volume in some cases can also decrease (regress). This suggests the presence of active brain injury recovery mechanisms. Whether WMH regression reflects a true biological phenomenon or results from imaging artifacts or measurement errors, however, remains controversial. Here, we review published reports, following PRISMA search guidelines, describing or referring to WMH regression, the methods used to detect and quantitate regression, and proposed underlying mechanisms. Of 174 reviewed articles, 31 (26 original research studies and five case reports) were identified as directly related to WMH regression. Technical factors such as differences in longitudinal scan parameters, motion artifacts, and the interval between baseline and follow-up scans can affect WMH volume measurements. These factors may lead to inaccurate conclusions if appropriate controls are not employed. Although the use of standardized and systematic measurement protocols is essential, there is strong evidence indicating that WMH regression is a robust and biologically important phenomenon that may be influenced by clinical interventions. Further studies are needed to investigate WMH regression in relation to cerebrovascular risk mitigation and other therapeutic strategies.

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

Salas A, Navarro L, Martinón-Torres F, et al (2025)

Beyond behavioral studies: Exploring the multi-omics impact of music on human health.: Comment on Can arts-based interventions improve health? A conceptual and methodological critique by Martin Skov and Marcos Nadal.

Physics of life reviews, 56:91-93 pii:S1571-0645(25)00145-9 [Epub ahead of print].

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
CmpDate: 2025-12-09

Ferreira PCL, Bellaver B, Povala G, et al (2026)

Evaluating Plasma p-tau217 as an Endpoint for Alzheimer Disease Clinical Trials.

Neurology, 106(1):e214441.

BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau 217 (p-tau217) levels have been shown to parallel neurofibrillary tangle and cognitive decline over time. Although recent clinical trials have demonstrated exploratory drug effects on plasma p-tau217, little is known about plasma p-tau217 effect size and performance as an endpoint in Alzheimer disease (AD) clinical trials. Therefore, the objective of this study was to assess the longitudinal performance and potential utility of plasma p-tau217 as a primary endpoint in early-stage AD clinical trials.

METHOD: This retrospective study included participants from 4 cohorts: ADNI (a multisite observational study), BICWALZS (a South Korean memory clinic-based cohort), MYHAT-NI (a Southwestern Pennsylvania population-based cohort), and WRAP (older adults at risk for AD). Eligible participants had plasma p-tau217 measurements at least at 2 timepoints, along with baseline Aβ PET imaging and clinical assessments. Linear mixed-effects models were used to assess associations between plasma p-tau217 trajectories and clinical or biomarker outcomes. Effect size was defined as the mean annual rate of change in p-tau217 divided by its standard deviation. We calculated the sample size required for a hypothetical clinical trial designed to detect a 25% drug effect with 80% power at a 0.05 test level.

RESULTS: A total of 716 individuals were included in the analysis: 413 cognitively unimpaired (CU) participants (58.6% female; mean age = 70.6 years, SD = 7.9) and 303 cognitively impaired (CI) participants (54.7% female; mean age = 73.2 years, SD = 7.4). In Aβ-positive individuals, the annual rate of change in plasma p-tau217 was similar between CU (0.07 pg/mL/y, SD = 0.11) and CI (0.08 pg/mL/y, SD = 0.13) groups. Effect size was 0.64 and 0.62 in CU and CI Aβ-positive individuals, respectively. The minimum sample size required per study group to detect a 25% drug effect was 610 for the CU Aβ-positive and 664 for the CI Aβ-positive group. Notably, selecting individuals with intermediate Aβ levels (Centiloid 20-40) yielded higher effect sizes (CU: 0.85; CI: 0.72), which reduced the required sample sizes per study group to 342 for CU and 492 for CI.

DISCUSSION: Our findings support that changes in plasma p-tau217 represent a robust endpoint for clinical trials targeting CU or CI individuals with Aβ pathology.

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

Bender AC, Berezuk C, Pellerin KR, et al (2026)

Association of Sleep Spindle Activity With Cognitive Decline in Early Clinical Stages of Alzheimer Disease.

Neurology, 106(1):e214459.

BACKGROUND AND OBJECTIVES: Sleep architecture, including spindles and slow oscillations, is disrupted in Alzheimer disease (AD). How changes in these sleep elements relate to cognitive decline is less clear. Our objectives were to examine changes in sleep macroarchitecture and microarchitecture in early clinical stages of AD compared with older adult controls (CTLs) and to investigate their associations with longitudinal cognitive change.

METHODS: This was both a cross-sectional and longitudinal study performed at Mass General Brigham Hospitals, where participants with early AD or CTLs underwent overnight ambulatory scalp EEG and longitudinal cognitive testing. We compared sleep microarchitectural features extracted from the EEG, including spindle activity, across the brain topography and between groups. We then performed longitudinal analyses using mixed-effects models to test the association of these sleep features with changes in cognition on the Montreal Cognitive Assessment (MoCA), collected annually for up to 7 years.

RESULTS: AD (n = 47, mean age 74.1 years, 66% female) and CTL (n = 43, mean age 72.6 years, 56% female) groups spent a similar proportion of sleep time in each stage of sleep. Sleep efficiency, however, was lower in the AD group (mean: CTL 75.1% vs AD 70.9%; p = 0.034). We found a significant reduction in spindle range power (11-16 Hz) in patients with AD compared with CTLs, particularly in the temporal regions (mean normalized power at EEG channels T3/T4: CTL 3.13 ± 1.13 vs AD 2.48 ± 1.01; p = 0.005). In participants with longitudinal MoCA scores (AD = 26, CTL = 25), reduced temporal lobe spindle density (β = 0.61, 95% CI 0.35-0.87; false discovery rate [FDR]-adjusted p < 0.001) and temporal lobe spindle power (β = 0.56, 95% CI 0.22-0.88; FDR-adjusted p = 0.005) were each associated with a faster rate of cognitive decline.

DISCUSSION: Temporal lobe sleep spindle activity is reduced in early clinical stages of AD and is associated with a faster rate of cognitive decline. Our results underscore the importance of including temporal lobe measurements when assessing sleep neurophysiology in AD, which is not standard in polysomnography. Future work examining the relationship between AD biomarkers and reduced spindle activity is needed to elucidate the potential mechanisms underlying these findings.

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

Wagh AR, MH Glickman (2025)

Molecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBB[+1].

Proceedings of the National Academy of Sciences of the United States of America, 122(50):e2504528122.

UBB[+1], a ubiquitin variant protein resulting from a frameshift in the ubiquitin-B gene, is a pathological hallmark of Alzheimer disease (AD). At the cellular level, UBB[+1] disrupts the ubiquitin-proteasome system while inducing autophagy. Notably, UBB[+1] itself is secreted via autophagosome-like vesicles. Here, we demonstrate that UBB[+1] can be removed from the cell by degradative and secretory autophagy. Sequestosome 1 (SQSTM1)/p62 functions as a pivotal ubiquitin receptor for UBB[+1], recognizing its ubiquitin domain and facilitating loading into autophagosomes. Oligomerization of SQSTM1/p62 was critical to isolate UBB[+1] in bodies preventing its aggregation. Intriguingly, both gain- and loss-of-function SQSTM1/p62 suppressed UBB[+1] secretion, causing intracellular retention: SQSTM1/p62 knockout led to UBB[+1] accumulation in insoluble aggregates, while its overexpression promoted the formation of p62-UBB[+1] bodies. We further identified distinct roles for SNARE-mediated membrane fusion in secretory autophagy of UBB[+1]. Specifically, the R-SNARE SEC22B and the Q-SNAREs Syntaxin-4 and SNAP23 participated in UBB[+1] exocytosis. Disruption of SEC22B impaired the fusion of UBB[+1]-containing autophagosomes with the plasma membrane, reducing UBB[+1] secretion without affecting its intracellular turnover. Inhibition of lysosomes partially stabilized UBB[+1] indicating that degradation and secretion are complementary processes that determine the fate of UBB[+1]. This study elucidates the dual roles of autophagy in managing neurotoxic proteins, highlighting SQSTM1/p62 as a key mediator of UBB[+1] trafficking and secretion. Although ubiquitin typically acts as a degradation signal, our findings reveal a rare instance of a ubiquitin-related protein driving secretory autophagy. These findings advance our understanding of cellular mechanisms underlying the clearance of misfolded proteins in neurodegenerative diseases.

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

Serra L, Bonarota S, Di Domenico C, et al (2025)

Surface-based but not voxel-based morphometry reveals structural abnormalities in individuals with subjective cognitive decline.

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

BackgroundSubjective cognitive decline (SCD) refers to individuals who perceive a decrease in their cognitive functioning despite no detectable deficits on neuropsychological tests, and may represent the earliest clinical stage of Alzheimer's disease (AD).ObjectiveThe aim of this study was to assess grey matter (GM) volumes and cortical folding patterns in individuals with SCD compared with the broader AD spectrum.MethodsA total of 107 participants were enrolled: 31 with AD, 23 with amnestic mild cognitive impairment (aMCI), 25 with SCD and 28 healthy participants (HS). All participants underwent neuropsychological assessment and 3T MRI to acquire T1-weighted images, which were processed using CAT-12 for voxel-based morphometry (VBM) and surface-based morphometry (SBM).ResultsVBM revealed expected atrophic patterns in AD and aMCI patients compared to SCD and HS, with no volumetric differences found between SCD individuals and HS. Notably, AD patients showed cortical surface abnormalities in all SBM measures. aMCI patients showed reduced cortical thickness and gyrification compared to SCD and HS. In contrast, SCD individuals showed reduced gyrification and sulcal depth compared to HS.ConclusionsThese findings suggest that cortical surface abnormalities may manifest early in the AD continuum, whereas volumetric changes occur later. The use of multiparametric MRI techniques may be beneficial in detecting subtle changes within the AD spectrum, highlighting the potential for early identification of structural changes associated with cognitive decline in SCD individuals. Further research is warranted to explore these relationships and their implications for early intervention strategies in AD.

RevDate: 2025-12-09

Du E, J Tian (2025)

Hippocampal transcriptome-wide association analysis of shared genetic risks between posttraumatic stress disorder and Alzheimer's disease.

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

BackgroundThe etiopathogenesis of Alzheimer's disease (AD) is puzzled by the heterogeneous nature of this neurodegenerative disorder. In recent years, clinical and basic research has accentuated a relationship between post-traumatic stress disorder (PTSD) and AD risk. Despite several pathways related to neuroinflammation, metabolic disturbances, and stress, emerging evidence implicates genetic risks at the nexus of PTSD and AD. However, the shared susceptibility genes and potential polygenic overlap between the two conditions is relatively understudied.ObjectiveThis study aims to assess the shared genetic risk between AD and PTSD by leveraging large-scale genomic sequencing data through hippocampus-specific transcriptome-wide association studies (TWAS).MethodsWe focused on a shared vulnerable brain region between AD and PTSD, the hippocampus, to investigate shared genetic risks between the two brain disorders. Functional annotation for TWAS-identified cross-disease susceptibility genes was performed to identify AD/PTSD-related biological pathways.ResultsFUSION TWAS analysis identified 120 susceptibility genes common to both disorders at the nominal significance of 0.05. Further functional annotation uncovered multiple pivotal biological pathways, especially those related to cell metabolism. Metabolic pathway analysis topped lipid metabolism-related pathways such as "acyl-CoA hydrolysis" that overlaps AD and PTSD risk. Deregulation of these common susceptibility genes in the hippocampus may potentiate PTSD and AD in sequence through hippocampal dysmetabolism.ConclusionsThese preliminary findings from computational analysis shed light on the genetic association between AD and PTSD, which will endorse further investigation through experimental approaches for a better understanding of the link between the two conditions from a perspective of precision medicine.

RevDate: 2025-12-09

Asih PR, Morris CW, Wang H, et al (2025)

Plasma soluble TREM2 is associated with plasma pTau-181 and pTau-231 in cognitively normal older adults at risk of Alzheimer's disease.

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

BackgroundCSF and blood soluble TREM2 (sTREM2) levels have been found to increase at early stage of Alzheimer's disease (AD). The relationships between sTREM2, AD-related biomarkers, and other neuroinflammation biomarkers remain unclear. Moreover, the impact of rare variants in TREM2 gene (R47H/R62H), which are associated with increased risk of AD, on plasma sTREM2 has not been elucidated.ObjectiveInvestigate the association of plasma sTREM2 levels with brain amyloid-β (Aβ) load and AD-related blood biomarkers, i.e., phosphorylated tau (pTau)-181, pTau-231, GFAP, NFL, and other neuroinflammation and peripheral inflammation markers in cognitively normal (CN) older adults at risk of AD (CN Aβ+) compared to CN Aβ-, including the effect of AD-linked TREM2 rare variants.MethodsPlasma sTREM2 concentrations were measured by MesoScale Discovery (MSD) assay from the KARVIAH cohort. Participants underwent cognitive tests and PET amyloid imaging. Genetic data and blood biomarkers were included for correlation analysis. Associations with plasma sTREM2 were investigated upon stratification by PET-Aβ load SUVR ((CN Aβ- (n = 65) and CN Aβ+ (n = 35)) as the main analysis. A subgroup analysis based on the TREM2 R47H and R62H genotype was conducted as exploratory analysis.ResultsPlasma sTREM2 positively correlated with plasma pTau181, and pTau231 in CN Aβ+ group. Plasma sTREM2 positively correlated with serum microglial kynurenine pathway metabolites. Plasma sTREM2 and brain Aβ load were higher in R47H TREM2 carriers compared to non-carriers.ConclusionsOur findings suggest plasma sTREM2 relates to downstream tau processes in amyloid-positive individuals, providing novel insights into the roles of peripheral TREM2 signaling that reflects microglial activity in early AD neuropathological development.

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

Miao X, Luo K, Li Y, et al (2025)

A Novel Palmitoylation-Related Molecular Signature for Predicting and Therapeutically Targeting Alzheimer's Disease.

Molecular neurobiology, 63(1):276.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and hyperphosphorylated tau pathology. Although palmitoylation has been implicated in AD, its specific mechanisms remain poorly defined. To investigate this, seven transcriptomic datasets were obtained from the GEO database. Differential expression and Gene Set Enrichment Analysis (GSEA) were performed across five training sets (GSE5281, GSE29378, GSE36980, GSE122063, and GSE132903). By intersecting differentially expressed genes (DEGs) with palmitoylation-related genes from GeneCards, 65 AD-associated palmitoylation-related genes (AD-PRGs) were identified. Functional enrichment analyses (KEGG and GO) were performed on these genes. Furthermore, seven key AD-PRGs (CALM1, VAMP2, SYT1, MET, BAG3, TJP1, NOTCH1) were prioritized using protein-protein interaction (PPI) networks and three machine learning algorithms (LASSO, SVM-RFE, and Random Forest). A diagnostic model constructed from these seven genes exhibited strong predictive performance, with AUC values of 0.834 in the training set and 0.907/0.865 in two external validation sets (GSE33000, GSE44770). Single-gene GSEA indicated associations with synaptic function and oxidative phosphorylation pathways. Protein docking analyses using GRAMM (Global RAnge Molecular Matching) and PISA (Proteins, Interfaces, Surfaces, and Assemblies) further suggested interactions between these key genes and Aβ/tau, supporting their involvement in AD pathogenesis. Additionally, regulatory network analysis identified 23 miRNAs, 33 transcription factors, and 14 potential therapeutic agents targeting these key genes. Our findings underscore the importance of palmitoylation in synaptic dysfunction-notably VAMP2 and SYT1 roles in vesicle recycling and neurotransmitter release-and offer promising targets for novel therapeutic strategies in AD.

RevDate: 2025-12-09

Gao Y, Lin S, Jiang M, et al (2025)

The association between individualized functional connectivity disruption and metabolic abnormality in alzheimer's disease and mild cognitive impairment: insights from multimodal neuroimaging.

Neuroradiology [Epub ahead of print].

PURPOSE: The aim of this study was to leverage fluorodeoxyglucose-positron emission tomography (FDG-PET) and blood oxygen level dependent-functional magnetic resonance imaging (BOLD-fMRI) to perform a comprehensive multi-modal analysis of metabolic alteration and individualized functional connectivity in Alzheimer's Disease (AD) and mild cognitive impairment (MCI) and characterize the relationship of these alterations with neurocognitive scores.

METHODS: We analyzed data from 71 subjects, including those with AD, MCI and Health Control (HC), using FDG-PET and BOLD-fMRI acquired from Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined network functional connectivities (FC) base on Independent Component Analysis (ICA), analyzed regional standardized uptake value ratios (SUVR) and their relationships with neurocognitive scores.

RESULTS: Both AD and MCI showed metabolic and functional connectivity abnormalities in Default Mode Network (DMN) region. We also found abnormalities in the somatomotor system in AD, which may be an early predictive indicator of AD. In MCI, both metabolic and functional connectivity abnormalities appear in precuneus, and these two modes were closely related, indicating that the precuneus may be a core region in the transition of healthy individuals to MCI.

CONCLUSION: This study demonstrated that the individual brain network technology based on ICA, combined with the metabolic characteristics of FDG-PET, facilitates the development of personalized early diagnosis for AD/MCI, enhances our understanding of the underlying neuropathological mechanisms, and also promotes the development of interdisciplinary technologies.

RevDate: 2025-12-09

Asnacios S, Staneva G, Thon G, et al (2025)

Alzheimer's disease amyloid-β affects membrane structure and mechanical properties of human neural progenitors.

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

BackgroundIn Alzheimer's disease (AD), neurogenesis and neuroplasticity are severely affected but there is not yet a consensus about the underlying mechanisms. The amyloid cascade hypothesis is associated with overproduction of the amyloid-β (Aβ) peptide in the brain and points out the soluble Aβ oligomers to be the primary toxic species.ObjectiveAs the ability of neuronal cells to deform is involved in neurogenesis and neuroplasticity processes, we investigated how an exposure to Aβ oligomers could affect the mechanical properties of the neural progenitor cells.MethodsHuman neural progenitor cells (h-NPCs) were derived from human embryonic pluripotent stem cells (h-ESCs). The effect of Aβ42 oligomers on the mechanical viscoelastic moduli of h-NPCs was determined using a custom-made microplate rheometer and the frequency analysis method. Fluorescence confocal microscopy of Di-4-ANEPPDHQ-stained cells was performed to assess the lipid order of h-NPC membranes. Aβ42 aggregation in the cell culture medium was thoroughly characterized by combining Thioflavin T fluorescence, dynamic light scattering, and transmission electron microscopy as complementary techniques.ResultsWe present here the first measurement of the visco-elastic moduli of a relevant model of h-NPC having the potential to differentiate in neuronal and glial subtypes. h-NPC exhibit a predominant elastic behavior, with low elastic modulus values of ∼200 Pa, in the range of those reported for the Young's modulus of glial cells and neurons in previous studies. Aβ42 oligomers induced 3-fold increase of both elastic and viscous h-NPC moduli, revealing a significant stiffening effect. This Aβ42-induced cell stiffening correlates with an increase in plasma membrane lipid order.ConclusionsOur findings raise questions about whether and how such Aβ42-induced effects on h-NPC deformability and membrane structure might have an impact on the differentiation of h-NPC which is at the root of neurogenesis, and could thus be involved in AD.

RevDate: 2025-12-09

Fang H, Tang A, Tang C, et al (2025)

Multimodal PET/MR Imaging in Early-onset Alzheimer's Disease With Parkinsonism due to a Novel Presenilin-1 (M233I) Mutation.

Clinical nuclear medicine pii:00003072-990000000-02009 [Epub ahead of print].

We report the multimodal PET/MR imaging findings in a 31-year-old woman with a novel presenilin 1 (PSEN1) missense mutation (c.699G>A, p.M233I) who developed progressive cognitive decline and parkinsonian features. Multimodal imaging, including glucose metabolism, dopamine transporter function, amyloid-β pathology, and tau protein PET imaging, combined with structural MRI, revealed widespread abnormalities concordant with her clinical manifestations. Findings included glucose hypometabolism, dopaminergic dysfunction, amyloid and tau deposition, and cerebellar atrophy. This case highlights the diagnostic value of multiprobe PET/MR imaging in characterizing complex neurodegenerative phenotypes and expands the genotypic and phenotypic spectrum of PSEN1-associated early-onset Alzheimer's disease (EOAD) with parkinsonism.

RevDate: 2025-12-09

Lu Z, Zhou H, Tang H, et al (2025)

Neural stem cell transplantation attenuates cognitive decline and neuroinflammation in a mouse model of Alzheimer's disease with chronic cerebral hypoperfusion.

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [Epub ahead of print].

Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) frequently coexist in aging populations, synergistically aggravating neurodegeneration. To assess the therapeutic potential of stem cell interventions, an AD + CCH mouse model was generated by combining APP/PS1 mice with bilateral common carotid artery stenosis. Neural stem cells (NSCs) or induced pluripotent stem cells (iPSCs) were transplanted into the lateral ventricles at 5 months of age. Behavioral testing, Nissl staining, Western blotting, and immunofluorescence were conducted at 9 and 12 months to evaluate cognition, neuronal survival, cell death pathways (LC3-II, cleaved caspase-3, NLRP3), glial polarization, and neurotrophic/synaptic markers (BDNF, VEGF, VAChT, PSD95). CCH exacerbated AD-related cognitive deficits, neuronal loss, and activation of autophagic, apoptotic, and pyroptotic pathways, accompanied by enhanced M1 microglial polarization, astrogliosis, and downregulation of BDNF and VAChT. NSCs transplantation significantly improved cognitive performance, preserved neuronal integrity, attenuated glial activation, and restored neurotrophic and synaptic protein expression, characterized by increased BDNF, VEGF, and PSD95 levels and partial recovery of VAChT. In contrast, iPSCs transplantation failed to exert comparable effects. These findings demonstrate that NSCs, but not iPSCs, mitigate AD + CCH-induced neuropathology by re-establishing the balance between inflammatory, neurotrophic, and synaptic signaling, supporting NSCs as a promising therapeutic approach for AD with vascular comorbidity.

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

Wang W, Wang L, Zhong X, et al (2025)

cGAS-STING Signaling in Central Nervous System Diseases: Neuroinflammatory Mechanisms and Immune Regulation.

Cell biochemistry and function, 43(12):e70146.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as a critical cytosolic DNA-sensing mechanism that orchestrates innate immune activation in response to cellular stress. In the central nervous system (CNS), this pathway demonstrates highly context-specific and cell-type-dependent functions, ranging from promoting neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), to modulating immune surveillance and therapeutic responsiveness in glioma. This review systematically delineates the molecular mechanisms, activation patterns, and regulatory networks of cGAS-STING signaling in the CNS. We highlight its dualistic roles in both inflammatory exacerbation and antitumor immunity, and further discuss recent advances in therapeutic strategies, including pharmacological modulators, blood-brain barrier (BBB)-penetrating delivery platforms, and nanotechnology-based precision interventions. Finally, we propose future directions focused on decoding tissue-specific immunodynamics and developing spatiotemporally controlled, multiorgan immunoregulatory frameworks. Together, this review underscores cGAS-STING as a promising therapeutic axis in the evolving landscape of neuroimmunology.

RevDate: 2025-12-09

Schmitz M, Thüne K, Fischer AL, et al (2025)

Evidence for different seeding activities of misfolded tau in classical and rapidly progressive Alzheimer's disease.

Brain pathology (Zurich, Switzerland) [Epub ahead of print].

Alzheimer's disease (AD) may display various clinical phenotypes with different disease progressions, such as rapidly progressive Alzheimer's disease (rpAD) type. The reason for clinical heterogeneity is still unknown and not predictable. Here, we subjected frontal cortex-derived tau seeds from classical AD, rpAD patients and controls to tau real-time quaking-induced conversion (RT-QuIC) assay analysis and examined biochemical properties, toxicity, and the morphology of tau fibrils generated during the RT-QuIC applying a cell-based assay and transmission electron microscopy (TEM). We observed seeding activity of misfolded tau protein in AD patients, which was significantly higher than in control cases. Additionally, the RT-QuIC signal response revealed differences between AD cases with a classical clinical phenotype and those with a rapidly progressive course of the disease (rpAD). The RT-QuIC reaction seeded with brain from rpAD exhibited a shorter lag phase, higher area under the curve and a higher seeding end point dilution compared to classical AD, independent from the Braak stage. The cellular toxicity of thioflavin T-positive RT-QuIC products from rpAD-seeded reactions was higher compared to those seeded by classical AD and controls. Morphological characterization of brain tissue-seeded RT-QuIC end-products via TEM showed that tau fibrils derived from rpAD seeded reactions revealed subtly different morphologies compared to classical AD. The study provides evidence for the existence of different tau assemblies in AD with different progression rates. As an alternative explanation, differences in the amounts of misfolded seed or the presence of other co-factors might influence the seeding activity of tau in AD and rpAD patients.

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

Ahmadi S, Khaledi S, Ahmadi K, et al (2025)

Amyloid Beta in Alzheimer's Disease: Mechanisms, Biomarker Potential, and Therapeutic Targets.

CNS neuroscience & therapeutics, 31(12):e70688.

MAIN PROBLEMS: The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau protein is two characteristic brain pathologies in Alzheimer's disease (AD). However, the Aβ hypothesis has recently faced challenges due to the limited clinical efficacy of anti-Aβ antibodies, such as aducanumab and lecanemab.

METHODS: This comprehensive review highlights recent advances and debates regarding the pathophysiology of Aβ peptides and plaques in AD, as well as their use as biomarkers and drug targets.

RESULTS: Aβ aggregation is primarily driven by an imbalance between its generation from amyloid precursor protein (APP) and its clearance from the brain, processes influenced by various risk factors. The toxicity of amyloid plaques is affected by the accumulation of different Aβ species with varying lengths and post-translational modifications of Aβ. Additionally, pathways including neuroinflammation, blood-brain barrier deterioration, autophagy and mitochondrial dysfunction, lipid raft changes, and oxidative stress have pivotal roles in AD. Therefore, a clear map of Aβ's upstream regulators and downstream effectors is crucial for developing effective diagnostics and treatments for AD.

CONCLUSIONS: Incorporating new research findings and ongoing debates surrounding the Aβ cascade hypothesis is crucial for improving early diagnosis and for guiding the development of effective treatments for AD.

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
CmpDate: 2025-12-09

Xu Q, Soto C, Shahnawaz M, et al (2025)

Multi agent large language models for biomedical hypothesis generation in drug combination discovery.

iScience, 28(12):113984.

Recent advancements in large language models (LLMs) have demonstrated their potential in scientific reasoning, but their ability to open-ended hypotheses in data-scarce domains remains underexplored. Here, we introduce Combinatorial Alzheimer's Disease Therapeutic Efficacy Decision (Coated-LLM), an AI-driven framework that is inspired by scientific collaboration to predict efficacious combinatorial therapy when data-driven prediction is infeasible. Coated-LLM employs multiple specialized LLM agents-Researcher, Reviewer s, and Moderator-to systematically generate and evaluate hypotheses through several in-context learning techniques. Using Alzheimer's disease (AD) as a test case, Coated-LLM outperformed traditional knowledge-based methods (accuracy: 0.74 vs. 0.52), with external validation achieving an accuracy of 0.82. In addition, a drug combination predicted from Coated-LLM was experimentally validated to significantly reduce amyloid aggregation in vitro. These findings highlight the potential of our framework to augment human reasoning in complex scientific reasoning tasks, offering a scalable approach for hypothesis generation in biomedical research.

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

Yu E, Zhang Y, Chen J, et al (2025)

Metabolic factors, gut microbiota, and cognitive performance: Mendelian randomization analysis.

Journal of Alzheimer's disease reports, 9:25424823251405877.

BACKGROUND: The associations between several metabolic factors, gut microbiota (GM), and cognitive performance have not been clearly identified. This study investigates their associations and GM's mediating effects.

OBJECTIVE: This study aimed to investigate the causal effects of key metabolic factors on cognitive performance and to determine whether gut microbiota mediate these associations.

METHODS: Genetic variants linked to four metabolic factors [body mass index (BMI), basal metabolic rate (BMR), systolic blood pressure (SBP), two-hour glucose], GM, and cognitive performance were selected from genome-wide association studies (GWAS). Univariable Mendelian randomization (MR) and mediation MR analyses were applied.

RESULTS: We found a protective effect of body metabolic rate (β = 0.061; 95% CI: 0.029, 0.093; p = 0.0002) and risk effect of body mass index (BMI, β = -0.047; 95% CI: -0.074, -0.019; p = 0.0009), systolic blood pressure (β = -0.049; 95% CI: -0.084, -0.014; p = 0.0063), and two-hour glucose (β = -0.043; 95% CI: -0.070, -0.016; p = 0.0017) on cognitive performance. In addition, the 2-step MR analysis further showed that the BMI-effect on cognitive performance was partially mediated by Rikenellaceae family, with a mediated proportion of 14.03% (95% CI: 0.99%, 27.06%; p < 0.05).

CONCLUSIONS: Our findings suggest that several metabolic factors influence cognitive performance, with gut microbiota potentially mediating these effects. These results provide insights into potential targets and useful biomarkers for understanding the pathogenesis and developing interventions for cognitive health.

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

Campos-Peña V (2025)

Editorial: Unraveling the mysteries of aging and the brain: advancements in understanding neurodegenerative diseases and dementia.

Frontiers in genetics, 16:1745907 pii:1745907.

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

Ikeda M, Ishibashi K, Amari M, et al (2025)

[18]F-MK-6240 uptake in cortical tau and hemorrhagic lesions in a case of Alzheimer's disease with possible crossed aphasia.

eNeurologicalSci, 41:100596.

We report neuroimaging findings from a 74-year-old right-handed male with Alzheimer's disease (AD) and lesions of cerebral amyloid angiopathy (CAA), utilizing [11]C-PiB-PET, [18]F-THK5351-PET, and [18]F-MK-6240-PET. [11]C-PiB-PET showed positive findings consistent with AD. [18]F-THK5351 accumulated in regions of astrogliosis due to tau pathology, subcortical hemorrhage, cortical superficial siderosis (cSS), and monoamine oxidase-B rich areas. [18]F-MK-6240 accumulated in regions with tau pathology, subcortical hemorrhage, and cSS, but not notably in CAA-related microbleeds (CMBs). [99m]Tc-ECD SPECT, conducted 9 years post-diagnosis, revealed reduced cerebral blood flow in the bilateral lower temporal lobes and the right posterior temporo-parietal lobes, overlapping the subcortical hemorrhage and cSS. The patient exhibited progression of global cognitive decline and persistent word fluency deficits (name listing) on neuropsychological examination from the early stage of the disease, irrespective of the right hemorrhagic lesions in the non-dominant hemisphere, suggesting possible crossed aphasia. This is the first report of [18]F-MK-6240 binding to a subcortical hemorrhage and cSS lesions, highlighting its binding differences compared to smaller vascular leakages, such as CMBs due to CAA. These results may help refine PET imaging interpretation and diagnostic accuracy for AD with concurrent CAA.

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: 2025-12-09

Wang Y, Lv M, Zhu W, et al (2025)

Study of the Aggregation Behavior of Proteins Related to Neurodegenerative Diseases Based on the Photoluminescence of Perovskite Nanocrystals.

Analytical chemistry [Epub ahead of print].

Neurodegenerative diseases (NDs) are closely associated with abnormal protein aggregation. In this study, SiO2-coated CsPbBr3 nanocrystals (CPB NCs) were exploited as label-free photoluminescence (PL) probes to investigate the aggregation behavior of amyloid β (Aβ), a key protein in Alzheimer's disease. The PL intensity of the CPB NCs in both aqueous dispersion and thin-film states decreased with increasing degree of Aβ aggregation. The relative PL intensity could quantitatively distinguish the aggregation states of Aβ, and the sensitivity of the thin-film system was twice that of the aqueous dispersion. This approach innovatively enabled the preliminary monitoring of protein aggregates without interfering with the aggregation process while avoiding the effects of reactive oxygen species generated during the aggregation and metal ions themselves on PL signals. Through threshold segmentation, the relative fluorescence intensity was further used to distinguish small-molecule drugs with disaggregation effects (ratio > 0.5) from those without (ratio ≈ 0). Based on a series of experiments, the photoinduced electron transfer mechanism was proposed to explain the change in the PL signal. Due to the electrostatic interaction between CPB NCs and proteins, this probe had potential for studying the aggregation states of other proteins (such as α-synuclein) related to NDs. Overall, this work offered new insights into the application of metal halide perovskites in biosensing as well as for the diagnosis and drug screening of NDs.

RevDate: 2025-12-09

Arnold M, Cui L, Stemmler M, et al (2025)

The Chinese version of the Short Cognitive Performance Test (SKT) - psychometric criteria and cross-validation.

Journal of clinical and experimental neuropsychology [Epub ahead of print].

The new Chinese version of the SKT (Syndrom-Kurz-Test) Short Cognitive Performance Test aims to detect early cognitive impairment and is a promising addition to neuropsychological test batteries in China and suitable for Chinese speaking patients. This study has three aims: 1. to assess whether the SKT's diagnostic accuracy is comparable to established cognitive impairment tests (e.g. Addenbrooke´s cognitive examination-III (ACE-III) and Montreal Cognitive Assessment-Basic (MoCA-B)); 2. to examine whether the three tests show intra-individual differences according to different types of mild cognitive impairment (single-domain amnestic MCI, semantic MCI and multiple-domain amnestic MCI); 3. to determine whether these tests distinguish between individuals with no cognitive impairment and those with subjective cognitive decline (SCD). The validation sample included 1038 older adults (mean age = 70.04, SD = 6.05) from the Chinese Preclinical Alzheimer's Disease Study (C-PAS). Participants underwent cognitive testing and received consensus diagnoses of normal cognition, MCI, or dementia. Sensitivity and specificity were calculated for each test. ANOVAs examined differences between MCI subtypes, and t-tests assessed group differences between normal cognition and SCD. Results: The SKT showed the highest discrimination between normal cognition and cognitive impairment (MCI or dementia), with a sensitivity of 85.4% and specificity of 69.8%. All three tests demonstrated significant score differences across MCI subtypes. Additionally, all tests significantly distinguished individuals with SCD from those without cognitive impairment (p < 0.01). Conclusions: The new Chinese produced weaker results than the established tests. However, given its strengths, it could be a useful tool for identifying cognitive impairment in certain situations.

RevDate: 2025-12-09

Takahashi M, Kitaura H, Nakahara A, et al (2025)

Dual Regulatory Roles of USP10 in Tau Pathology and Neuronal Fate During Alzheimer's Disease Progression.

Molecular and cellular biology [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal cell death, brain atrophy, and cognitive decline. Aggregation of Tau protein in neurons is a critical factor in the pathogenesis of AD. Tau aggregates increase as the disease progresses and contribute to neuronal cell death. This study investigated the role of ubiquitin-specific protease 10 (USP10) in Tau pathology and neuronal viability in AD. We found that the expression of USP10 was reduced in the brains of late-stage AD patients with severe Tau aggregate accumulation, which correlated with increased neuronal apoptosis. Mechanistically, our results suggest that USP10 downregulation in late-stage AD may be due to its degradation by the accumulation of p62, an inducer of selective autophagy. Brain-specific Usp10 knockout mice show increased neuronal apoptosis during embryonic development and postnatal brain atrophy. In the P301S-Tau transgenic mice, heterozygous Usp10 knockout lowered Tau levels and slightly improved early survival, suggesting USP10 has stage-dependent effects: its reduction lessens Tau burden early but worsens neuronal loss in late stage. This study identifies USP10 as a key regulator of Tau pathology and neuronal survival in AD.

RevDate: 2025-12-08

Yan G, Wu S, Qian Q, et al (2025)

Early diagnosis of Alzheimer's disease using machine learning and blood biomarkers.

BMC medical informatics and decision making pii:10.1186/s12911-025-03296-x [Epub ahead of print].

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

Zebardast F, Riethmüller MPS, K Nowick (2025)

Integrative gene co-expression network analysis reveals protein-coding and LncRNA genes associated with Alzheimer's disease pathology.

Scientific reports, 15(1):43395.

Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by widespread molecular changes, many of which remain poorly understood. While AD pathology progresses through specific brain regions, it is unclear whether these regions are affected similarly. Long non-coding RNAs (lncRNAs), emerging as key cellular regulators, remain largely uncharacterized in AD. Understanding how lncRNAs interact with protein-coding genes across brain regions could shed light on AD mechanisms and progression. To investigate this, we performed consensus weighted gene co-expression network analysis on 396 postmortem brain RNA-seq samples using a meta-analytic approach. Our analysis revealed substantial network rewiring in AD, particularly in the temporal cortex compared to the frontal cortex. The temporal cortex exhibited adaptive changes in gene interactions, while the frontal cortex showed a breakdown of healthy correlations-possibly reflecting regional differences in disease progression. We identified 46 protein-coding genes and 27 lncRNAs as key components in the AD network of the temporal cortex. Using known functions of protein-coding genes as reference points, we inferred potential functions for over 100 lncRNAs across both regions. These findings highlight novel lncRNA candidates potentially involved in AD and provide insights into their roles in both healthy and diseased brain states.

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: 2025-12-09

Singh R, Mishra A, Kumar V, et al (2025)

FTIR spectroscopy of plasma exosomes reveals distinct lipidomic and proteomic signatures for early Alzheimer's disease detection.

Clinica chimica acta; international journal of clinical chemistry, 581:120761 pii:S0009-8981(25)00640-0 [Epub ahead of print].

Alzheimer's disease (AD), the most common neurodegenerative disorder, is pathologically defined by amyloid-β plaques and tau tangles. Current diagnostic tools like CSF analysis and PET imaging are invasive or costly, limiting routine use. This study proposes a novel, label-free approach using Fourier-transform infrared (FTIR) spectroscopy to identify disease-specific biochemical signatures in plasma-derived small extracellular vesicles (sEVs) from 30 AD patients and 20 age-matched controls. sEVs were validated by ultracentrifugation, TEM, nanoparticle tracking (mean size: 98.7 ± 12.4 nm in AD vs. 102.3 ± 14.1 nm in controls), and Western blot for CD9, CD81, and TSG101. FTIR analysis revealed significant alterations in AD sEVs: consistent increase in lipid peroxidation (based on 3015 cm[-1], 1745 cm[-1] bands), 19.8 % change in β-sheet content, and 22.4 % enhancement in phosphate vibrations (1072 cm[-1]). Key spectral ratios showed excellent diagnostic accuracy, with the lipid peroxidation index (AUC = 0.998) and protein disorder index (AUC = 0.978). This rapid, cost-effective, and non-invasive method enables simultaneous assessment of lipid, protein, and glycan changes in AD. With broader validation, FTIR-based profiling of plasma sEVs could offer a transformative tool for early AD diagnosis and monitoring.

RevDate: 2025-12-08

Zhao D, Wang J, Zhang F, et al (2025)

Cerebral glymphatic system: structure, regulation, ageing, and mechanisms of encephalopathy.

Ageing research reviews pii:S1568-1637(25)00332-0 [Epub ahead of print].

The glymphatic system was initially considered as a perivascular channel, responsible for the clearance of substances within the brain. With the deepening comprehension of the functions of the extracellular space (ECS) and the discovery of meningeal lymphatic vessels and subarachnoid lymphatic-like membrane, it is proposed that the glymphatic system should be a complex system encompassing the perivascular space, ECS, and lymphatic-like structures, and it plays crucial roles in the delivery of substances, waste clearance, and neuroimmune functions within the brain. Recent studies have revealed that brain ECS essentially regulates these fundamental functions, including sleep, memory, and sensory processing. Here, in this review, we delineate advances in the roles of glymphatic system in structure, functions, ageing and brain diseases. The imaging technologies have facilitated a more nuanced understanding of the glymphatic system's architecture, particularly the pericellular space. The compartmentalized system, characterized by myelin sheath separation, serves as the conduit for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a predominant role in modulating the ISF within the deep brain region. Furthermore, we discuss the pathophysiological implications of excessive formaldehyde (FA) accumulation in the aging brain. Especially, ageing-associated FA can cross-link Aβ, tau, α-synuclein, hemoglobin and extracellular matrix in the ECS and/or endochylema, which leads to the disorder of ISF-CSF exchanges and encephalopathy onset, such as: Alzheimer's disease, Parkinson's disease, multiple sclerosis, gliomas and sleep disorders. Hence, glymphatic system including ECS may be a promising therapeutic target for brain diseases.

RevDate: 2025-12-08

Fujita Y, Yabe T, Yamada Y, et al (2025)

MEGF10 knockout promotes cortical and hippocampal amyloid deposition in AD mouse model.

Neuroscience letters pii:S0304-3940(25)00376-3 [Epub ahead of print].

Multiple epidermal growth factor (EGF)-like domains 10 (MEGF10) is a single-pass transmembrane protein expressed in neurons and astrocytes, functioning as a phagocytic receptor for apoptotic cells and mediating homotypic adhesion in the mammalian brain. We previously demonstrated that MEGF10 facilitates the uptake of toxic amyloid-β (Aβ) species Aβ42 and Aβ43 by neurons and astrocytes in vitro. However, whether MEGF10 also serves as a phagocytic receptor for Aβ in the brain in vivo, particularly under neurodegenerative conditions such as Alzheimer's disease (AD), remains unclear. To address this question, we generated MEGF10 knockout mice on an AD model background and analyzed brain Aβ deposition and Aβ42 levels. We observed a significant increase in Aβ deposition and Aβ42 levels in the hippocampus and cortex of MEGF10-deficient AD mice compared with AD model controls. To assess cognitive function, we performed the Y-maze test. MEGF10 knockout AD mice exhibited impaired spatial memory relative to wild-type controls; however, no significant difference was found between MEGF10 knockout AD mice and AD model controls. These findings suggest that MEGF10 contributes to Aβ clearance in the brain and support its role as a phagocytic receptor for Aβ in vivo, potentially helping to maintain brain homeostasis in the context of Alzheimer's pathology.

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: 2025-12-08

Banerjee S, Chandu PM, Sarkar M, et al (2025)

Engineering brain organoids and organ-on-chip systems for modeling neurodevelopmental and neurodegenerative pathophysiology.

Neurological research [Epub ahead of print].

OBJECTIVES: Neurodevelopmental and neurodegenerative disorders arise from complex disruptions in brain structure and function, many originating during early development. However, conventional in vitro and animal models often fail to capture the cellular diversity, temporal dynamics, and architectural complexity of the human brain. This review aims to synthesize recent advances in stem-cell-derived in vitro platforms, specifically brain organoids, assembloids, and organ-on-chip technologies, and evaluate how these systems are reshaping research on Alzheimer's and Parkinson's diseases by enabling more human-relevant modeling.

METHODS: We surveyed recent literature focusing on region-specific and vascularized organoids, integrated neuronal subtype models, and microfluidic organ-on-chip systems. Particular attention was given to studies demonstrating increased physiological relevance, enhanced modeling of disease-specific phenotypes, and expanding utility in translational research, therapeutic screening, and drug discovery pipelines.

RESULTS: Innovations in organoid engineering have enabled more faithful recapitulation of human brain development and degeneration. These platforms have advanced understanding of amyloid aggregation, neuroinflammatory processes, dopaminergic neuron vulnerability, and gut-brain axis contributions. The incorporation of vascular structures, improved microfluidic control, and assembly of multi-region neuronal circuits have strengthened functional readouts and boosted mechanistic insight. Collectively, these developments are accelerating preclinical therapeutic testing and enabling more predictive disease modeling.

DISCUSSION: Compared to prior reviews, this article uniquely integrates developmental and degenerative perspectives while evaluating emerging strategies that increase reproducibility and translational accuracy. Persistent limitations, including incomplete vascularization, cellular stress responses, and batch-to-batch variability, underscore the need for improved standardization and incorporation of immune components. Future directions that merge vascular, immune, and circuit-level complexity promise to advance organoid-based neuroscience toward personalized modeling and therapeutic application.

RevDate: 2025-12-08

Garcia MA, C García (2025)

Cognitive Difficulties among Middle-Aged and Older Latino Adults: Within-Group Variation Across U.S. States.

The journals of gerontology. Series B, Psychological sciences and social sciences pii:8374214 [Epub ahead of print].

OBJECTIVE: This study examined how cognitive difficulties, an early marker of memory impairment and a potential precursor to Alzheimer's disease and related dementias, vary across U.S. states among Latinos aged 45 and older.

METHODS: Using data from the 2008-2019 American Community Survey, we estimated logistic regression models to examine state-level differences in cognitive difficulties among Latinos aged 45 and older. We analyzed patterns within the pan-ethnic Latino population, stratified by nativity, Latino heritage, and country or region of origin.

RESULTS: We observed substantial heterogeneity in the prevalence of cognitive difficulties among Latino populations across states and subgroups. Pan-ethnic Latino populations in Pennsylvania, Massachusetts, Michigan, Ohio, and New Mexico exhibited notably higher rates of cognitive difficulties. When disaggregated by nativity, U.S.-born Latino populations consistently reported higher levels of cognitive difficulties compared to their foreign-born counterparts. Among these, Puerto Ricans, Dominicans, and Cubans showed the highest prevalence in several states. Our findings also highlight that the intersection of nativity, heritage, and state-level context shapes distinct cognitive risk profiles within the Latino population.

DISCUSSION: This study contributes to gerontological research by illuminating how structural, cultural, and geographic factors intersect to shape cognitive aging among diverse Latino populations. These findings underscore the importance of moving beyond pan-ethnic categorizations to understand cognitive health disparities within the Latino population. They also highlight the role of state-level sociopolitical environments in shaping cognitive health outcomes. Public health strategies should prioritize culturally and geographically tailored interventions, particularly in high-risk states, to improve access to cognitive screening and early diagnosis.

RevDate: 2025-12-08

Lv Y, Zhao X, Li D, et al (2025)

Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.

Protein & cell pii:8374226 [Epub ahead of print].

Mitochondrial calcium fluxes serve as pivotal regulators of optimal organellar function and cellular viability, yet the spatiotemporal regulation of nanodomain Ca2+ transients at mitochondria-ER contact sites (MERCS) and their integration into adaptive mitochondrial stress signaling remain unresolved. In this study, we employed custom-built high temporal-spatial resolution GI/3D-SIM imaging techniques to achieve nanoscale resolution of calcium transients. We identify that MERCS-localized calcium oscillations gate retrograde stress signaling. Mechanistically, we demonstrate that augmented mitochondria-associated ER membrane (MAMs) connectivity unexpectedly attenuated global mitochondrial Ca2+ efflux, which triggering ATF5 shuttling-mediated transcriptional licensing and calcium-sensitive epigenetic reprogramming that synergistically activating stress-resilience programs. Quantitative protein expression and transcriptome analyses confirm that CsA-mediated calcium retention mimics MAMs induction preserves mitochondrial integrity and protecting cells from apoptosis in Aβ1-42-challenged neurons through synchronized UPRmt activation. Our findings reveal a novel mechanism by which MERCS decode proteotoxic stress into transcriptional and epigenetic adaptations, offering therapeutic potential for neurodegenerative diseases.

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

Cantoni V, Casula EP, Tarantino B, et al (2025)

Home-Based Gamma Transcranial Alternating Current Stimulation in Patients With Alzheimer Disease: A Randomized Clinical Trial.

JAMA network open, 8(12):e2546556 pii:2842460.

IMPORTANCE: Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies.

OBJECTIVE: To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD.

This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate.

INTERVENTION: Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up.

MAIN OUTCOMES AND MEASURES: The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging.

RESULTS: Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale-cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study-Activities of Daily Living (-0.55; 95% CI, -0.89 to -0.21; P = .02), and Face-Name Association Test (-1.14; 95% CI, -1.66 to -0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale-cognitive subscale (-0.59; 95% CI, -1.02 to -0.16; P = .007), Alzheimer Disease Cooperative Study-Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05643326.

RevDate: 2025-12-08

Gotlieb E, Joseph B, Blank L, et al (2025)

Barriers and Consequences of Prior Authorization for Neurologic Medications: A Scoping Review.

JAMA neurology pii:2842313 [Epub ahead of print].

IMPORTANCE: Prior authorization (PA) is widely used by insurers to control health care costs and promote high-value care, but it can create significant barriers to accessing medications. This is particularly concerning in neurology, where timely treatment is critical to avoid disease progression and optimize patient outcomes.

OBJECTIVE: To assess the consequences, barriers, and facilitators of PA policies affecting access to pharmacologic treatment in 6 common neurologic conditions-Alzheimer disease, Parkinson disease, multiple sclerosis, migraine, cerebrovascular disease, and epilepsy-with focus on impacts on patients, clinicians, and administrators.

EVIDENCE REVIEW: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines for scoping reviews were followed, and the study protocol was registered on Open Science Framework. MEDLINE and Embase were searched up to November 1, 2024, using Ovid for studies that assessed the role of PA as a primary or secondary outcome for the 6 included neurologic conditions, or for neurology broadly if strongly applicable to the study aim, after the signage of the Affordable Care Act in March 2010. Abstract screening and full-text review were done in duplicate. Key information was charted in extraction, including study characteristics, demographics, methods, results, and implications for relevant stakeholders. The results were aggregated and thematically analyzed.

FINDINGS: A total of 364 studies were identified using our search strategy on Ovid, 278 records were screened, and 20 studies were included in this review. The most frequently identified consequences for patients were delays in care (60%) and increase in disease activity (25%). The most frequently identified consequence for clinicians (35%) and administrators (15%) was time burden. The most common facilitators were the use of clinical pharmacists or technicians (20%) and health system specialty pharmacies (15%).

CONCLUSIONS AND RELEVANCE: According to the results of this scoping review, PA can contribute to significant access barriers for people with neurological conditions and is associated with burden for all stakeholders involved. Reforms to PA can work towards more equitable access to medications for patients.

RevDate: 2025-12-08

Ke S, Chen Z, Qi Y, et al (2025)

Heyndrickxia coagulans as a next-generation probiotic: current evidence and future perspectives.

Food & function [Epub ahead of print].

Heyndrickxia coagulans, a spore-forming probiotic, has garnered significant attention due to its exceptional tolerance to gastric acid and heat, alongside its multifaceted therapeutic potential. This review systematically delineates the unique biological characteristics of this bacterium, which include high survivability mediated by its spore form (retaining 73% viability after microwave treatment at 260 °C), dual lactate fermentation pathways, and plasticity in ATP synthesis that depends on pH and growth rate. Clinical evidence supports its efficacy in managing metabolic disorders (e.g., type 2 diabetes and non-alcoholic fatty liver disease), gastrointestinal conditions (e.g., constipation and irritable bowel syndrome), and neuropsychiatric disorders (e.g., depression and Alzheimer's disease). The underlying mechanisms involve the production of short-chain fatty acids (SCFAs), modulation of the TLR4/MyD88/NF-κB signaling pathway, and suppression of oxidative stress. Notably, therapeutic effects are strain-specific: H. coagulans MTCC 5856 (2 × 10[10] CFU day[-1]) significantly reduces abdominal distension (P < 0.01), while the strain Unique IS-2 alleviates anxiety-like behaviors by upregulating hippocampal BDNF. Although toxicological assessments establish a no observed adverse effect level (NOAEL) of >1000 mg kg[-1] in rodent models, its limited capacity for intestinal colonization presents a clinical challenge. Future research should prioritize large-scale clinical trials, multi-omics mechanistic investigations, and the development of synbiotic formulations to fully realize its potential as a next-generation therapeutic agent.

RevDate: 2025-12-08

Zhang S, Wang T, Xue G, et al (2025)

Dysregulated mTOR signaling in Alzheimer's disease: Linking pathogenic mechanisms to emerging therapeutic strategies.

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

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and multifaceted pathogenic mechanisms (including amyloid-β [Aβ] plaques, tau neurofibrillary tangles, synaptic dysfunction, and neuroinflammation). Importantly, no effective disease-modifying treatment is currently available for AD. Emerging evidence implicates dysregulated mammalian target of rapamycin (mTOR) signaling as a key contributor to AD pathogenesis. This review analyzes how aberrant mTOR signaling influences major aspects of AD pathology, including Aβ production and clearance, tau protein hyperphosphorylation, autophagy dysfunction, synaptic plasticity impairments, neuroinflammation, and oxidative stress. Notably, hyperactivated mTOR accelerates AD progression through multiple mechanisms. It promotes Aβ accumulation and tau pathology, suppresses autophagic clearance of toxic aggregates, and disrupts neuronal homeostasis, thereby exacerbating cognitive decline. Consequently, mTOR has gained attention as a therapeutic target. This review evaluates the therapeutic potential of various mTOR-targeted interventions, such as the mTORC1 inhibitor rapamycin and its analogues (rapalogs), second-generation ATP-competitive mTOR inhibitors, and certain natural compounds and traditional Chinese medicine approaches. These strategies have demonstrated promise in mitigating AD-related pathology by enhancing autophagy, reducing Aβ/tau burden, and preserving synaptic and cognitive function in preclinical studies. However, the clinical translation of mTOR-targeted therapies faces key challenges, including poor blood-brain barrier penetration of many mTOR inhibitors, potential systemic side effects, and limited clinical validation to date. Further research is needed to optimize brain delivery, dosing regimens, and target specificity to fully realize the therapeutic potential of mTOR modulation in AD.

RevDate: 2025-12-08

Kiani I, Mohseni G, Hassani T, et al (2025)

Posterior cingulate cortex atrophy across the Alzheimer's disease spectrum: A cross-sectional MRI study linking volumetrics to cognitive decline.

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

BackgroundThe posterior cingulate cortex (PCC) is a metabolic hub within the default-mode network and an early target of Alzheimer's disease (AD) pathology, yet its quantitative relationship with cognition across the normal aging-mild cognitive impairment (MCI)-AD continuum remains incompletely defined.ObjectiveIn this study we aimed to compare PCC volumes across AD, MCI, and controls, and assess their relationship with cognitive performance.MethodsIn this single-center cross-sectional study, 161 participants (NL = 30, MCI = 60, AD = 71) underwent structural MRI. PCC volumes were automatically segmented and summed. Linear regressions adjusted for age and sex were performed to examine associations between PCC volumes and cognitive measures. False discovery rate correction was applied to multiple comparisons. Additional subgroup analyses were conducted by gender and education level using Mann-Whitney U tests, and ordinary least squares regression models tested for group × education interactions.ResultsMean Post-cin-T volume declined step-wise from NL (6.05 ± 0.21cm[3]) to MCI (5.64 ± 0.63cm[3]) to AD (4.98 ± 1.01cm[3]; p < 0.001). Post-cin-R and Post-cin-L showed parallel gradients. Higher MoCA scores correlated with larger PCC volumes (e.g., total: β = 0.069, p < 0.001), whereas higher CDR scores were linked to smaller volumes (total: β = -0.705, p < 0.001). Subgroup analyses revealed that higher-education participants showed broader PCC-cognition associations. Interaction analyses indicated no significant moderating effect of education on group-volume relationships.ConclusionsQuantitative PCC atrophy differentiates NL, MCI and AD and correlates robustly with cognitive performance, particularly in educated individuals. PCC volumetry may serve as a non-invasive MRI biomarker for early diagnosis and disease staging in the AD spectrum.

RevDate: 2025-12-08

Kandeel M, M Mahmoud (2025)

Comparative efficacy and safety of different brexpiprazole doses for agitation in Alzheimer's disease: A systematic review and network meta-analysis.

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

BackgroundAgitation in Alzheimer's disease significantly impacts patient outcomes and caregiver burden. Brexpiprazole has emerged as a promising treatment option, but optimal dosing remains unclear.ObjectiveTo evaluate the comparative efficacy and safety of different brexpiprazole doses in treating agitation associated with Alzheimer's disease through a systematic review and network meta-analysis (NMA).MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through January 2025. Four randomized controlled trials (N = 1451) comparing various brexpiprazole doses (0.5-3 mg/day) with placebo were included. Primary outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression-Severity Scale (CGI-S), and the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) scores, alongside safety measures.ResultsBrexpiprazole 2 mg demonstrated significant improvement in CMAI scores versus placebo (mean difference [MD]: -5.88; 95% CI: -8.13 to -3.63) and CGI-S scores (MD: -0.48; 95% CI: -0.95 to -0.01). Multiple doses showed significant NPI-NH improvements, with 2-3 mg showing the strongest effect (MD: -4.60; 95% CI: -7.54 to -1.66). Higher doses (2-3 mg) increased treatment-emergent adverse events (risk ratio [RR]: 1.20-1.33) but showed no significant difference in serious adverse events compared to placebo.ConclusionsBrexpiprazole 2 mg provides optimal therapeutic benefit while maintaining a favorable safety profile. The findings support initiating treatment at lower doses with careful titration to 2 mg based on individual response and tolerability. Future research should focus on long-term outcomes and real-world effectiveness.

RevDate: 2025-12-08

Seixas-Lima B, Rosa-Neto P, Phillips NA, et al (2025)

Peripheral inflammation in a Canadian cohort of neurodegenerative conditions: Occurrence, determinants, and impact.

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

Background"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration.ObjectiveTo assess blood inflammatory markers in older adults. We hypothesized that elevated inflammation would be found in some cognitively normal older adults but would be more prevalent in individuals with cognitive impairment.MethodsInterleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.ResultsWe found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts-36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.ConclusionsPeripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.

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

Nashiro K, Cahn BR, Choi P, et al (2025)

A Randomized Clinical Trial Reveals Effects of Mindfulness and Slow Breathing on Plasma Amyloid Beta Levels.

Psychophysiology, 62(12):e70182.

Prior research suggests that meditation may slow brain aging and reduce the risk of Alzheimer's disease (AD). However, we lack research systematically examining what aspect(s) of meditation may drive such benefits. In particular, it is unknown how breathing patterns during meditation might influence health outcomes associated with AD. In this study, we examined whether two types of mindfulness meditation practice-one with slow breathing and one with normal breathing-differently affect plasma amyloid beta (Aβ) relative to a no-intervention control group. One week of daily mindfulness practice with slow breathing decreased plasma Aβ levels whereas one week of daily mindfulness practice with normal breathing increased plasma Aβ levels. The no-intervention control group showed no changes in plasma Aβ levels. Slow breathing appears to be a factor through which meditative practices can influence pathways relevant for AD.

RevDate: 2025-12-08

Xue D, Yu DS, Yue L, et al (2025)

Home-based, caregiver-assisted multimodal exercise and cognitive training via videoconferencing for older adults with mild dementia: A mixed-methods pilot study.

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

BackgroundEvidence on the effects of caregiver-assisted combined exercise and cognitive interventions for persons with dementia (PwD) is inconsistent.ObjectiveThis study aimed to evaluate the feasibility and preliminary effects of a home-based Caregiver-Assisted Multimodal Exercise and Cognitive Training (CA-MECT) intervention via videoconferencing for persons with mild dementia in comparison with exercise or cognitive training alone and the control condition.MethodsThirty-three participants were randomized into a combined intervention, exercise, cognitive training, or control group. The combined intervention was a 12-week caregiver-assisted home-based sequentially combined multimodal exercise and cognitive training via videoconferencing. The exercise and cognitive training groups received a 12-week home-based Caregiver-Assisted Multimodal Exercise (CA-ME) and Caregiver-Assisted Cognitive Training (CA-CT), respectively, while the control group received health education. Validated instruments were used to evaluate cognitive, psychological, functional, and health-related quality of life (HRQoL) outcomes.ResultsCA-MECT was feasible, safe, and highly acceptable for PwD and their caregivers. Exploratory analyses suggested that compared with the control group, the CA-MECT participants showed potential improvements in global cognition, immediate recall, attention, number and severity of neuropsychiatric symptoms (NPS), and caregivers' distress, though no clear benefits were observed in functional ability or HRQoL. When compared with single-component interventions, CA-MECT appeared to yield more favorable outcomes for immediate recall (versus CA-CT) and NPS severity (versus CA-ME), whereas its effects on processing speed were less favorable than both comparators.ConclusionsCA-MECT is feasible and shows promise in improving cognition and NPS among PwD. Future studies are warranted to fully explore its efficacy and sustainability.

RevDate: 2025-12-08

Luo R (2025)

Chaperone-mediated autophagy as a sex-specific modulator of synaptic proteostasis and neural function.

Autophagy [Epub ahead of print].

Chaperone-mediated autophagy (CMA), once considered a secondary or auxiliary degradation pathway, is now recognized as a central regulator of synaptic proteostasis. A recent study by Khawaja et al. (2025) in Nature Cell Biology provides compelling evidence that CMA actively remodels the synaptic proteome in a sex-specific manner. Using a conditional knockout strategy based on Lamp2a-floxed mice crossed with a Camk2a-Cre driver line to achieve excitatory neuron-specific deletion of Lamp2a in adult mice, the authors revealed sexually divergent synaptic phenotypes: females exhibit enhanced presynaptic neurotransmitter release and GRIN/NMDAR-mediated plasticity, while males show increased postsynaptic GRIA/AMPAR activity due to impaired receptor endocytosis. These changes are driven by sex-specific degradation of synaptic proteins such as SYN1 (synapsin I) in females and AP2A/α-Adaptin in males. Importantly, reactivation of CMA - either genetically or pharmacologically - rescues synaptic dysfunction, seizure susceptibility, and memory deficits in aged mice and Alzheimer disease models. This commentary contextualizes these findings within the broader framework of activity-dependent proteostasis, sex-specific autophagy modulation, and therapeutic potential of CMA in brain aging and neurodegeneration.

RevDate: 2025-12-08

Lv L, Aly A, McKay C, et al (2025)

Real-world analysis of medication adherence and cost of care for comorbid conditions in patients with early Alzheimer's disease in the U.S.

Neurodegenerative disease management [Epub ahead of print].

AIM: To understand medication adherence and associated healthcare costs of patients with early Alzheimer's disease (AD).

METHODS: This retrospective cohort study used the Axon Registry® linked with claims data to examine medication adherence of U.S. patients with early AD (mild cognitive impairment [MCI] and mild dementia due to AD) from 2015 to 2022. Medication adherence was quantified by the proportion of days covered (PDC) over a one-year follow-up, and adherence rate was defined at a PDC ≥ 80%. Patient comorbidities and healthcare costs were described.

RESULTS: Of 333 patients included, 213 (64%) were female with a median (IQR) age 79 (72-83) years. Patients had a mean (SD) of 2.3 (2.1) comorbidities and took a mean (SD) of 3.0 (1.5) medications. Weighted-average PDC across medications was 74.4% with 7 out of 10 medication classes having a medication adherence rate lower than 60%. DPP-4 inhibitors had the highest medication adherence rate (66.67% of patients), and memantine had the lowest (39.13% of patients). Annual median (IQR) medical and pharmacy costs per-patient were $5,268 ($1,808-$14,651) and $658 ($187-$2,736), respectively.

CONCLUSION: Patients with early AD had multiple comorbidities and took multiple medications. Suboptimal medication adherence and high healthcare costs were observed.

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

Lohman T, Kapoor A, Engstrom AC, et al (2025)

Low frequency BOLD oscillations, APOE4, and plasma pTau217.

medRxiv : the preprint server for health sciences pii:2025.11.25.25340991.

BACKGROUND: Intrinsic low frequency oscillations in BOLD signal (BOLD LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD LFOs may shed light on cerebrovascular dysfunction and early Alzheimers disease pathophysiology, but the mechanisms remain unclear. No investigations to date have assessed the relationship between BOLD LFOs and plasma pTau217, or how this relationship differs in apolipoprotein e4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and genetically predisposed to AD pathophysiology.

METHODS: Independently living older adults (N=118) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain functional MRI and venipuncture. Total BOLD LFOs were quantified as signal power within the 0.01 to 0.10 Hz frequency range. Plasma level of pTau217 was assessed and linear regression was used to quantify the interactive effect of APOE4 carrier status and BOLD LFOs on plasma pTau217. 2x2 ANCOVA was used to compare BOLD LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau217 cutoffs.

RESULTS: The interactive effect of APOE4 carrier status and BOLD LFO power was significantly associated with plasma pTau217 (β=-.65, p=.004). This relationship was driven by an inverse relationship between BOLD LFOs and plasma pTau217 in APOE4 carriers (β=-.49, p=.003). Amyloidβ positive APOE4 carriers displayed lower BOLD LFOs than amyloidβ negative APOE4 carriers (p=.02) and amyloid-β positive APOE4 non carriers (p=.04). All models were adjusted for age and sex.

CONCLUSION: Present study findings suggests that BOLD LFOs are implicated early in AD pathophysiology in an APOE4 dependent manner, adding support for the continued study of BOLD LFOs in the context of cerebrovascular contributions to AD genetic risk.

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

Li R, Feng R, Liu A, et al (2025)

Neuroimaging-derived brain endophenotypes link molecular mechanisms to Alzheimer's disease and aging.

medRxiv : the preprint server for health sciences pii:2025.11.25.25340884.

Alzheimer's disease (AD) genome-wide association studies (GWAS), typically based on clinical phenotypes, have identified numerous risk loci, yet linking these variants to brain changes and molecular processes remains challenging. We developed a DNE-xQTL framework integrating deep learning-derived dimensional neuroimaging endophenotypes (DNEs) with comprehensive brain molecular quantitative trait loci (xQTL) to dissect genetic pathways underlying AD- and aging-related brain variation. By performing GWAS on seven DNEs and applying integrative computational analyses, we biologically annotated each DNE and prioritized xQTL-supported gene targets. This approach both enhanced interpretation of established AD loci through DNE-mediated annotations and revealed underexplored regulatory pathways, organizing 209 candidate genes into evidence-based tiers. We highlight three regulatory clusters: glutamate-receptor and mitochondrial pathways implicating excitatory-neuron vulnerability, SREBP2-associated cholesterol homeostasis linked to vascular dysfunction, and primary-cilia-associated transport implicated in aging. By connecting pre-symptomatic brain alterations to molecular targets and relevant cell types, this framework may inform earlier risk stratification before clinical neurodegeneration occurs.

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

Liu GH, Huang YH, Yuan TC, et al (2025)

Associations of Wearable-Measured Sleep and Physical Activity With Memory Performance in Older Adults: Cross-Sectional Study With Actigraphy and MRI.

JMIR aging, 8:e80584 pii:v8i1e80584.

BACKGROUND: Cognitive decline is a common aspect of aging, and identifying modifiable lifestyle factors, such as physical activity and sleep, is crucial for promoting healthy brain aging. While both are individually linked to cognition, few studies have simultaneously assessed their independent and combined effects using objective wearable-based data, particularly in older Asian populations.

OBJECTIVE: This study aimed to examine the independent and interactive effects of wearable-assessed sleep and physical activity parameters on memory performance in healthy older adults. We also explored whether age and hippocampal volume moderated these associations.

METHODS: This prospective cross-sectional analysis included 88 cognitively healthy community-dwelling adults (≥60 years of age) from the Integrating Systematic Data of Geriatric Medicine to Explore the Solution for Healthy Aging cohort in Taiwan. Participants underwent 12-day wrist-worn actigraphy, brain magnetic resonance imaging, and neuropsychological assessments. Light-intensity physical activity (LPA) and wake after sleep onset (WASO) were selected based on age-adjusted partial correlations with Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery memory scores. Multivariate regressions, age-stratified models (cutoff=72 years), and PROCESS moderation and mediation analyses were conducted, adjusting for age, education, daytime sleepiness, and hippocampal volume.

RESULTS: Partial correlation analyses adjusting for age showed that higher LPA (r=0.260; P=.02) and lower WASO (r=-0.251; P=.02) were significantly associated with better memory scores. Age significantly moderated both effects: LPA was beneficial beyond 73.8 years of age, and WASO was detrimental beyond 71.1 years of age. Multivariate regression models confirmed that both WASO (β=-.044; P=.04) and LPA (β=.042; P=.01) were significant predictors of memory. In subgroup analyses (age ≥72 years), both LPA (β=.054; P=.04) and WASO (β=-.111; P=.01) remained significant predictors. Moderated mediation analyses showed that WASO was associated with reduced LPA (β=-.325; P=.03), but the indirect effect on memory via LPA was not significant. Instead, WASO exerted a direct and age-moderated effect on memory performance. Hippocampal volume moderated both associations, supporting the brain reserve hypothesis.

CONCLUSIONS: Our findings highlight WASO and LPA, as measured by wearable devices, as modifiable behavioral factors linked to memory function in older adults. The impact of these factors intensifies with advancing age and may be influenced by hippocampal reserve. Promoting daily light physical activity and maintaining sleep continuity may serve as accessible, age-tailored strategies for preserving cognitive health in aging populations.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04207502; https://classic.clinicaltrials.gov/ct2/show/NCT04207502.

RevDate: 2025-12-09

Anonymous (2025)

Erratum.

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