@article {pmid42819539,
year = {2026},
author = {Takahashi, R and Kashibayashi, T and Fujita, J and Yoshida, K and Hashiramoto, A and Kowa, H and Mizuta, E},
title = {Baseline CSF tau and short-term clinical change during lecanemab therapy: A prospective real-world cohort study in Japan.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70487},
pmid = {42819539},
issn = {2352-8729},
abstract = {INTRODUCTION: Real-world prognostic evidence for cerebrospinal fluid (CSF) biomarkers during lecanemab therapy remains limited. We examined whether baseline CSF phosphorylated tau 181 (pTau181), total tau, and amyloid beta (Aβ) 42/Aβ40 were associated with 6-month clinical change.

METHODS: This prospective single-center cohort included 50 patients with early Alzheimer's disease spectrum treated with lecanemab. CSF biomarkers were measured using the Lumipulse G system. The primary outcome was 6-month change in Clinical Dementia Rating Sum of Boxes (CDR-SB). Models were adjusted for age, sex, and baseline Mini-Mental State Examination; sensitivity analyses included APOE ε4 status.

RESULTS: CDR-SB worsening occurred in 19 participants (38.0%). Higher pTau181 (β per SD = 0.408; 95% CI: 0.106 to 0.709; p = 0.0091) and total tau (β = 0.341; 95% CI: 0.032 to 0.651; p = 0.0314) were associated with worsening. Aβ42/Aβ40 was not.

DISCUSSION: Baseline CSF pTau181 and total tau were associated with 6-month clinical trajectories, supporting cautious cohort-level risk stratification.},
}

@article {pmid42819642,
year = {2026},
author = {Yang, X and Hu, P and Han, W and Dong, L and Zhang, H and Wang, J and Chen, H},
title = {Research advances in red ginseng polysaccharides: preparation, structural characteristics and immunomodulatory effect.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1929729},
pmid = {42819642},
issn = {1663-9812},
abstract = {Red ginseng is a processed product of ginseng through steaming. Its polysaccharides differ in structure and biological activity from those of ginseng. Red ginseng polysaccharides are mostly acidic polysaccharides and have various biological activities. It is worth noting that its immunomodulatory effect has become an important area of research. Pharmacological studies have shown that polysaccharides from red ginseng can enhance immunity through various pathways, such as affecting immune cell activity, regulating cytokine levels, promoting immune organ development, and regulating gut microbiota. In addition, red ginseng polysaccharide has other pharmacological effects, such as anti-diabetic effect, anti-Alzheimer's disease effect, health benefits for the skin, anticancer effect, and cardioprotective effect. This article reviews the extraction, purification, structural characterization, and biological activity of polysaccharides from red ginseng to elucidate their pharmacological effects and potential molecular mechanisms. In addition, this review also discusses the current research status of red ginseng polysaccharides, pointed out the existing gaps, and proposed innovative perspectives for better development of red ginseng polysaccharides.},
}

@article {pmid42819698,
year = {2026},
author = {Khawar, M and Bakthavatchalam, P},
title = {The Promise of Blood-Based Biomarkers in Early Detection and Care of Alzheimer's Disease.},
journal = {Nepal journal of epidemiology},
volume = {16},
number = {2},
pages = {1436-1437},
pmid = {42819698},
issn = {2091-0800},
}

@article {pmid42820100,
year = {2026},
author = {Le, LNN and Wheeler, GJ and Blockley, NP and Fletcher, E and Jung, Y and Farias, SET and Gavett, B and DeCarli, C and Fan, AP},
title = {Oxygen extraction fraction mapping between normal cognition and mild cognitive impairment in older adults using quantitative BOLD.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42820100},
issn = {2837-6056},
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology ; *Magnetic Resonance Imaging/methods ; *Oxygen/metabolism/blood ; Aged ; Female ; *Cognition/physiology ; Male ; *Brain/diagnostic imaging/metabolism ; *Aging/physiology/metabolism ; Brain Mapping/methods ; Bayes Theorem ; Aged, 80 and over ; },
abstract = {Oxygen extraction fraction (OEF) represents the proportion of oxygen utilized by the brain from the blood and is a sensitive biomarker in understanding the vascular interplay between oxygen supply and demand. Alterations in OEF are increasingly recognized in normal aging and the pathophysiology of many neurological disorders, including Alzheimer's disease and cognitive impairment. Here, we aimed to assess regional OEF MRI in older adults and investigate its relationship with mild cognitive impairment (MCI) and normal aging using a Variational Bayesian quantitative BOLD (qBOLD) framework. The qBOLD model leverages a biophysical relationship between OEF, deoxygenated blood volume (DBV), and the reversible transverse relaxation rate (R2 [']) to extract parameter values from asymmetric spin echo (ASE) MRI scans. The reliability of these parameter estimates was enhanced by Variational Bayesian inference, which incorporates prior distributions that we optimized in numerical simulation. We then applied this model to a cohort of older adults (N = 70) from the Alzheimer's Disease Research Center (ADRC) at the University of California, Davis, including 58 cognitively normal (CN) and 12 amnestic mild cognitive impaired (MCI) participants. Our findings revealed a trend of elevated OEF across many cortical brain regions in the MCI group. Additionally, we identified regional positive associations between OEF and age in the MCI group, significantly in the left inferior parietal region (β = 0.88 ± 0.23 , T = 3.75 , P = 0.0004). Furthermore, the relationship between OEF and episodic memory in the right parahippocampal region differed significantly between two diagnostic groups (negative for CN and positive for MCI) (β = 0.09 ± 0.02 , T = 3.77 , P = 0.0004). This work adopts a novel qBOLD MRI framework for studying OEF changes in cognitive impairment as a potential biomarker for monitoring pathophysiology in aging and dementia.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology
*Magnetic Resonance Imaging/methods
*Oxygen/metabolism/blood
Aged
Female
*Cognition/physiology
Male
*Brain/diagnostic imaging/metabolism
*Aging/physiology/metabolism
Brain Mapping/methods
Bayes Theorem
Aged, 80 and over

@article {pmid42820135,
year = {2026},
author = {Zaraska, M},
title = {Our Tears Can Help Diagnose Cancer, Parkinson's, and Alzheimer's.},
journal = {ACS central science},
volume = {12},
number = {9},
pages = {1273-1276},
doi = {10.1021/acscentsci.6c01440},
pmid = {42820135},
issn = {2374-7943},
abstract = {Eye swabs, bioassays, and even smart contact lenses can "pick up" biomarkers for various conditions.},
}

@article {pmid42820145,
year = {2026},
author = {Weng, Q and Goldstein, BA and Engelhard, MM},
title = {Censoring-Aware Reinforcement Learning to Optimize Early Risk Alerts from Longitudinal Clinical Data.},
journal = {Proceedings of machine learning research},
volume = {340},
number = {},
pages = {2151-2174},
pmid = {42820145},
issn = {2640-3498},
abstract = {Early recognition of chronic conditions is critical to ensure patients receive timely interventions and support. Passive surveillance of routine electronic health records (EHRs) provides information about longitudinal health trajectories that can support prompt recognition and inform associated early actions. However, relevant information is acquired at a different rate for each patient, and there is an inherent trade-off between the earliness versus the specificity of diagnosis and related actions. Therefore, determining when to alert providers about a likely chronic condition requires us to weigh the predicted risk at the given time against the anticipated value of future information. To address this challenge, we analyze the optimal timing of early alerts using a Partially Observable Markov Decision Process (POMDP) with asymmetric reward. To learn an optimal alerting policy, we then propose a model-free reinforcement learning (RL) framework tailored to long-term clinical event surveillance from EHRs. Our proposed framework overcomes the pervasive issue of right-censoring in offline EHRs by leveraging a pseudo-label imputation approach. We also analytically demonstrate that entropy-regularized RL enables post-hoc threshold calibration to adapt the learned policy to specific preferences regarding the importance of earliness versus specificity without retraining. Systematic evaluations in synthetic data reveal that the advantage of RL-based look-ahead planning is maximized when diagnostic evidence emerges in predictable information bursts. Finally, real-world validations on two clinical cohorts show that our policy achieves an actionable lead time of 20.9 months prior to Alzheimer's disease diagnosis and 8.7 months prior to autism diagnosis in a pediatric cohort, both at 90% specificity. Our method and results provide a generalizable blueprint for optimal surveillance of chronic disease processes.},
}

@article {pmid42820327,
year = {2026},
author = {Lin, Y and Cho, I and Zhu, X and Wang, K and Zhu, L and Wong, W and Murray, M and Zhou, F},
title = {Potential of Ginkgo biloba Extract to Intervene in Chronic Inflammation-Related Diseases.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70467},
pmid = {42820327},
issn = {1099-1573},
support = {//USYD-Wepon and Faculty of Health and Medicine Scholarship of the University of Sydney/ ; },
abstract = {Chronic inflammation is a pathological mechanism of central importance that underpins a wide range of diseases, including neurodegenerative, cardiovascular, respiratory, gastrointestinal, and dermatological disorders. Ginkgo biloba extract (GBE), a standardized formulation derived from Ginkgo biloba leaves, has attracted growing attention due to its anti-inflammatory, antioxidant, and neuroprotective properties. This review comprehensively summarizes the current preclinical and clinical evidence regarding the therapeutic potential of GBE and its active constituents in inflammation-related diseases. GBE has been shown to attenuate pro-inflammatory cytokine production, suppress nuclear factor kappa B (NF-κB) activation, restore redox homeostasis, and modulate disease-relevant pathways in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, atherosclerosis, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, inflammatory skin conditions and rheumatoid arthritis. While these findings highlight the promising multi-targeted anti-inflammatory actions of GBE, limitations remain regarding the identification of specific active compounds, standardization of formulations, and the availability of robust clinical evidence. Further research is warranted to clarify the mechanisms of action and optimize delivery of GBE, and to validate the efficacy and safety of GBE in large-scale clinical trials.},
}

@article {pmid42820818,
year = {2026},
author = {Dillon, EC and Bailey, C and Alsamawi, A and Aasaavari, A and Fabian, T and Robison, J},
title = {"I Wanted to Get Back Out There": In-depth Interviews With Older Adults and Family Caregivers About Moving Out of Nursing Homes Using Medicaid's Money Follows the Person Program and How Dementia Influences Transitions.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261491313},
doi = {10.1177/07334648261491313},
pmid = {42820818},
issn = {1552-4523},
abstract = {Medicaid's Money Follows the Person (MFP) Program enables nursing home residents to return to community living, yet people living with dementia (PLWD) less often transition to the community through MFP, for unclear reasons. To understand mechanisms underlying this disparity, we conducted in-depth interviews with 44 older adults in Connecticut eligible for MFP and 44 family caregivers (41% PLWD/PLWD family members). Desire to move, program awareness, ability to self-advocate, personal care needs, family support, housing and home and community-based services (HCBS) resources all influenced moves. PLWD less often desired to move, typically required more assistance to move, were less able to self-advocate and manage logistics, had higher personal care needs, needed more family/informal support, and had additional safety and supervision needs. Better support for PLWD is needed in transition and HCBS programs as the population grows, nursing homes beds decrease, and the desire to live in the community persists.},
}

@article {pmid42820819,
year = {2026},
author = {Zhang, Q and Yu, J and Zhai, X and Zhang, L and Peng, J and Deng, C and Liu, Y and Zhou, Q and Niu, T and Luo, F and Chen, C},
title = {Mosaic Loss of the Y Chromosome: Mechanisms and Diseases.},
journal = {Protein & cell},
volume = {},
number = {},
pages = {},
doi = {10.1093/procel/pwag073},
pmid = {42820819},
issn = {1674-8018},
abstract = {Mosaic loss of the Y chromosome (mLOY) is a male‑specific somatic loss of the Y chromosome that is predominantly observed in peripheral blood leukocytes, but can also be found in other tissue types. It represents one of the most common male-specific somatic mutations, particularly prevalent in aging individuals. Accumulating evidence shows that mLOY markedly increases the incidence, progression, and adverse prognosis of multiple diseases, including, but not limited to, myocardial fibrosis, lung and bladder cancers, and Alzheimer's disease. Mechanistically, for extrinsic effects of mLOY, hematopoietic mLOY affect other cell populations, thereby promoting disease initiation and progression. From an intrinsic effects, mLOY within cells reprograms autosomal gene expression and reshapes interactions with the immune microenvironment, jointly driving malignant evolution. In this review, we summarize the current understanding of both intrinsic and extrinsic mLOY effects on immune regulation and disease pathogenesis, highlighting its multifaceted roles across cancer, cardiovascular disorders, infections, and other mLOY-associated conditions.},
}

@article {pmid42821427,
year = {2026},
author = {Lévesque, M and Akzam-Ouellette, MA and Joubert, S and Arguin, M},
title = {Altered temporal features of visual processing in subjective cognitive decline.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001128},
pmid = {42821427},
issn = {1931-1559},
support = {//Hope for Dementia/ ; },
abstract = {OBJECTIVE: Subjective cognitive decline (SCD) is possibly the earliest known stage of Alzheimer's disease. Individuals with SCD report perceiving a decline in their cognitive functioning and express concern about it. However, when assessed with standard neuropsychological tests, they perform within normal limits.

METHOD: The present study focuses on the temporal features of visual processing in SCD using the random temporal sampling technique. This method reveals the perceptual oscillations which occur during a visual task by presenting stimuli with randomly varying signal-to-noise ratio through time. Fourteen individuals with SCD and 15 others without (i.e., controls), aged between 60 and 85 years old, took part in the study.

RESULTS: Participants with SCD performed within normal limits on neuropsychological tasks, as did the control group. In the experimental task, participants had to recognize briefly presented five-letter French words. The results take the form of classification images, which depict how visual processing efficiency fluctuates over time and across different frequency bands of signal-to-noise ratio oscillations. The classification images reveal significant differences between groups on the temporal patterns of visual processing. A machine learning classifier was used to categorize the data of individual participants according to group membership. The classifier achieved 79.3% classification accuracy using 18.0% of the available features.

CONCLUSIONS: Even though SCD individuals show no detectable cognitive impairment in neuropsychological testing, random temporal sampling can reveal anomalies in their perceptual function. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42821606,
year = {2026},
author = {Xu, MY and Bai, YD and Zeng, XQ and Tan, CR and Lai, YJ and Wang, YJ},
title = {Bazedoxifene restores myelin changes and attenuates cognitive deficits in a mouse model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490479},
doi = {10.1177/13872877261490479},
pmid = {42821606},
issn = {1875-8908},
abstract = {BackgroundDemyelination and remyelination are critical processes in the pathogenesis of Alzheimer's disease (AD). The selective estrogen receptor modulator bazedoxifene (BZA) has been shown to promote remyelination, suggesting its potential therapeutic efficacy.ObjectiveThis study aimed to evaluate the therapeutic efficacy of BZA in addressing demyelination and associated cognitive deficits in a mouse model of AD.MethodsThe changes in myelin and oligodendrocyte-related indicators in the brains of APP/PS1 mice were assessed via immunostaining. 5 × FAD transgenic mice received oral administration of BZA or vehicle for 3 months. The therapeutic outcomes were evaluated through behavioral tests, immunostaining and western blotting.ResultsAD mice exhibited pronounced myelin loss and oligodendrocytes depletion. BZA treatment attenuated cognitive decline, restored myelin changes and mitigated neurodegeneration in the brain. These effects were observed independently of alterations in amyloid-β deposition.ConclusionsThese findings provide compelling evidence supporting the involvement of demyelination in AD and suggest that BZA may represent a promising therapeutic agent for AD by targeting myelin repair mechanisms.},
}

@article {pmid42821639,
year = {2026},
author = {Schwaninger, I and Ighanian, P and Borga, L and Giraitis, M and Hoogendoorn, P and Klucken, J},
title = {Value in app store metadata and user reviews: A dual perspective on quality of Parkinson's and dementia apps.},
journal = {PLOS digital health},
volume = {5},
number = {10},
pages = {e0001730},
pmid = {42821639},
issn = {2767-3170},
abstract = {App stores provide a range of health applications for people living with Alzheimer's disease (AD) and Parkinson's disease (PD). Users like patients can access information from both manufacturer-provided app descriptions and metadata, as well as from user reviews. However, navigating this information to identify value-generating apps of high quality remains challenging. From a health technology assessment (HTA) standpoint, quality is defined by evidence-based medicine, safety, and user-centeredness. To explore the potential value of app store information available to patients, we conducted a descriptive, mixed-methods analysis of unstructured app metadata and user feedback from the Apple App Store and Google Play Store (as of May 2024). We analyzed 1,237 AD/PD-related apps which included 50 duplicates (resulting in 1,187 apps), utilizing descriptive statistics, content analysis, large language model-supported exploratory classification, and a topic modeling approach. In total, only about 2% of the apps claimed to be certified medical devices. Moreover, 24% of Apple apps and 14% of Google apps were in the "Medical" app store genre, among which we found that 63% of Apple and 54% of Google apps were patient-facing. We manually categorized patient-facing apps predominantly under "Care Support," followed by "Health & Wellness" and "Patient Monitoring." Importantly, user feedback provided exploratory, potentially valuable patient-reported outcome and experience information but is derived from personal opinions on "user experience," "health improvement," and "costs." As quality information on DHTs could be identified in unstructured app metadata, this information should be improved in trustworthiness and more accessible to users like patients, supporting the public to find high-quality health apps. Furthermore, as user opinions contained information with potential value for patients, these should be explored as complementary value-generating indicators of health apps in future work.},
}

@article {pmid42821808,
year = {2026},
author = {Costa, N and Marcélo Fleuret, C and Gombault, E and Soto Martin, M and De Mauleon, A},
title = {Longitudinal Impact of Agitation and Aggression Symptoms on Societal Costs in Alzheimer's Disease: A Focus on Informal Care and Socioeconomic Disparities.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {10},
pages = {e70257},
pmid = {42821808},
issn = {1099-1166},
support = {//Ethypharm/ ; //Center Hospitalier Universitaire de Toulouse/ ; },
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/economics/psychology ; Aged ; *Psychomotor Agitation/economics ; *Aggression/psychology ; France ; Longitudinal Studies ; Prospective Studies ; Aged, 80 and over ; Caregivers/economics ; *Cost of Illness ; Middle Aged ; *Health Care Costs/statistics & numerical data ; Socioeconomic Disparities in Health ; *Patient Care/economics ; Long-Term Care/economics ; },
abstract = {BACKGROUND: To date, no longitudinal study has assessed the effect of agitation on societal costs-particularly informal care costs-over time in Alzheimer's Disease (AD) patients with Agitation and Aggression (A/A) symptoms.

OBJECTIVES: This study estimates the impact of A/A symptoms evolution on longitudinal care costs including informal care costs in moderate-to-severe AD, considering patient and caregiver socioeconomic characteristics.

DESIGN: A longitudinal trajectory clustering method was used on this longitudinal, prospective, multicenter observational cohort study.

SETTING AND PARTICIPANTS: 262 community-dwelling and long-term care facility (LTCF) patients of both sexes, aged 60 years and older, with clinically significant A/A symptoms were recruited from memory centers in southwest France.

METHODS: Patients were followed for 12 months. A/A data was recorded by clinicians using the Neuropsychiatric Inventory (NPI-c). Costs were estimated from a societal perspective, including healthcare and informal care, using the RUD questionnaire. K-means longitudinal method identified A/A evolution profiles. Cost differences across A/A evolution profiles were analyzed using Generalized Linear Models.

RESULTS: Two A/A evolution profiles were identified: mild symptoms at baseline with improvement (A) and moderate symptoms at baseline with limited improvement or stability (B). Annual costs were €22,959 in group A and €23,625 in group B excluding supervision, and €52,111 and €56,149, respectively, including supervision. In LTCF residents, higher A/A severity was associated with increased medical visits and medication costs, though overall cost differences were smaller. Informal care neared 70% of total costs for community-dwelling patients, with supervision covering the majority of these costs.

CONCLUSIONS: Evolution of A/A symptoms significantly increases both healthcare and informal care costs, particularly in at-home settings. Integrating systematic monitoring of behavioral symptoms into routine care would enable personalized, cost-effective strategies. Informal care costs, often undervalued and overlooked in economic analyzes, underscores the need for improvement in resource allocation and quality of life, for both patients and caregivers.

CLINICAL TRIAL NUMBER: NCT03554226.},
}

Humans
Female
Male
*Alzheimer Disease/economics/psychology
Aged
*Psychomotor Agitation/economics
*Aggression/psychology
France
Longitudinal Studies
Prospective Studies
Aged, 80 and over
Caregivers/economics
*Cost of Illness
Middle Aged
*Health Care Costs/statistics & numerical data
Socioeconomic Disparities in Health
*Patient Care/economics
Long-Term Care/economics

@article {pmid42821845,
year = {2026},
author = {Shir, D and Algeciras-Schimnich, A and Piura, YD and Bornhorst, JA and Figdore, DJ and Elgenidi, A and Lachner, C and Graff-Radford, NR and Day, GS},
title = {Clinical Factors Associated With Discordant Plasma P-Tau217 and Established Alzheimer Disease Biomarkers.},
journal = {Neurology},
volume = {107},
number = {8},
pages = {e218591},
doi = {10.1212/WNL.0000000000218591},
pmid = {42821845},
issn = {1526-632X},
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; Biomarkers/blood ; Male ; Retrospective Studies ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Aged, 80 and over ; Middle Aged ; Phosphorylation ; Positron-Emission Tomography ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau (p-tau) 217 is increasingly used for Alzheimer disease (AD) diagnosis and treatment decisions but may be discordant with established AD biomarkers. False-positive (FP) plasma results may lead to overtreatment and false-negative (FN) results to missed or delayed disease-modifying therapies. We evaluated factors associated with discordant results.

METHODS: This retrospective study included participants enrolled in memory and aging studies at Mayo Clinic with "positive" (>0.324 pg/mL) or "negative" (<0.186 pg/mL) plasma p-tau217 results and confirmatory AD biomarkers. Plasma results were classified as true positive (TP), true negative (TN), FP, or FN, referencing amyloid-PET and CSF p-tau181/β-amyloid (Aβ) 42. Clinical and laboratory variables were compared using univariate analyses; multivariable logistic regression evaluated independent associations with discordance.

RESULTS: Among 706 participants (median 70.0 [interquartile range 15.8] years; 54% male), 60 (8.5%) had discordant plasma p-tau217 results. FN results (5.6%) were more frequent than FP results (2.8%; p = 0.007). Discordance was associated with older age (odds ratio [OR] 1.61 per decade, 95% CI 1.23-2.14) and obstructive sleep apnea (OR 1.94, 95% CI 1.08-3.49). FN (vs TP) results were associated with milder clinical stage (global Clinical Dementia Rating [CDR] ≤0.5 vs CDR ≥1; p < 0.001), higher Mini-Mental State Examination scores (OR 1.20 per point, 95% CI 1.05-1.36), obstructive sleep apnea (OR 2.01, 95% CI 1.01-4.3), higher body mass index (OR 1.11/kg/m[2], 95% CI 1.03-1.20), and higher estimated glomerular filtration rate (eGFR: OR 1.33/10 mL/min/1.73 m[2], 95% CI 1.05-1.69). In age-adjusted models, body mass index (OR 1.14, 95% CI 1.03-1.25), eGFR (OR 1.63/10 mL/min/1.73 m[2], 95% CI 1.22-2.16), and earlier clinical stage (CDR ≤0.5) were independently associated with FN results. FP (vs TN) results were associated with older age (OR 2.37, 95% CI 1.36-4.09), thyroid disease (OR 4.41, 95% CI 1.36-14.3), lower eGFR (OR 0.48/10 mL/min/1.73 m[2], 95% CI 0.31-0.66), and advanced disease stage (CDR ≥1). In age-adjusted models, eGFR (OR 0.54/10 mL/min/1.73 m[2], 95% CI 0.35-0.82) and advanced disease stage (CDR ≥ 1 vs CDR 0: OR 11.11, 95% CI 2.0-50.0; vs CDR 0.5: OR 4.55, 95% CI 1.12-16.67) were independently associated with FP results.

DISCUSSION: Plasma p-tau217 results and established AD biomarkers were discordant in 8.5% of participants. Clinical stage and factors related to brain amyloid clearance, renal clearance, and volume of distribution were associated with discordant results. These insights may inform mechanisms of discordance and identify patients requiring confirmatory biomarker measures.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/diagnosis
Female
Biomarkers/blood
Male
Retrospective Studies
Aged
Amyloid beta-Peptides/cerebrospinal fluid/blood
Aged, 80 and over
Middle Aged
Phosphorylation
Positron-Emission Tomography

@article {pmid42821881,
year = {2026},
author = {Güntert, L and Taeymans, J and Baur, H and Van Dyck, M and Lutz, N},
title = {Physical inactivity attributable burden of disease on morbidity and mortality across Swiss language regions: a population-based modelling study.},
journal = {Swiss medical weekly},
volume = {156},
number = {},
pages = {5162},
doi = {10.57187/5162},
pmid = {42821881},
issn = {1424-3997},
mesh = {Humans ; Switzerland/epidemiology ; Female ; *Sedentary Behavior ; Male ; Middle Aged ; Aged ; Adult ; *Cost of Illness ; Prevalence ; Language ; Risk Factors ; *Noncommunicable Diseases/epidemiology ; Morbidity ; Exercise ; },
abstract = {UNLABELLED: BACKGROUND: Physical inactivity is a major risk factor for noncommunicable diseases, contributing to both substantial morbidity and premature mortality. In Switzerland, the prevalence of physical inactivity varies across language regions. This study aimed to quantify differences across Swiss language regions in the physical inactivity-attributable burden of disease, expressed as Years Lived with Disability (YLD) and Years of Life Lost (YLL) for 2022. The analysis focuses on YLD and YLL attributable to physical inactivity across 15 physical inactivity-associated diseases.

METHODS: This study employed the Population Attributable Fraction approach to estimate the proportion of YLD and YLL attributable to physical inactivity in Switzerland. The analysis included individuals aged >20 years and was stratified by disease, age, sex and language region (German-, French- and Italian-speaking). Physical inactivity was defined according to WHO guidelines as not meeting at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week. Prevalence data on physical inactivity were derived from the 2022 Swiss Health Survey. Prevalences were combined with relative risks (RR) of corresponding diseases, identified through a systematic literature search to derive Population Attributable Fractions. Estimates of YLD and YLL for Switzerland for 2022 were derived from the Global Burden of Disease study. YLD and YLL estimates attributable to physical inactivity are presented as rates per 100,000 people aged >20 years. Uncertainty was assessed using parametric bootstrapping.

RESULTS: Overall, the physical inactivity-attributable burden of disease was estimated at 227.08 (95% CI: 214.74-240.08) YLD and 424.23 (95% CI: 383.15-479.23) YLL per 100,000 people aged >20 years. This corresponds to approximately 2% of total DALYs in Switzerland in 2022. Clear regional differences were observed. Estimated physical inactivity-attributable YLD rates were highest in the Italian-speaking region (134.90; 95% CI: 122.04-148.25) followed by the French-speaking region (130.72; 95% CI: 120.78-141.50) and German-speaking region (96.26; 95% CI: 88.81-104.01). Similarly, estimated YLL rates attributable to physical inactivity were highest in the Italian-speaking region (287.74; 95% CI: 245.82-349.99), followed by the French-speaking region (221.56; 95% CI: 192.54-264.55) and German-speaking region (186.67; 95% CI: 162.64-222.27). Disease-specific analysis indicated that depression (93.38; 95% CI: 85.46-101.80) and low back pain (52.01; 95% CI: 45.90-58.47) contributed most to physical inactivity-attributable YLD rates, whereas coronary heart disease (132.12; 95% CI: 115.60-149.55) and Alzheimer's disease and dementia (83.61; 95% CI: 51.90-134.97) were the main contributors to physical inactivity-attributable YLL rates. Women showed consistently higher burden of disease than men, with physical inactivity-attributable YLD rates of 286.06 (95% CI: 264.58-308.90) versus 166.32 (95% CI: 155.06-178.44) and physical inactivity-attributable YLL rates of 475.23 (95% CI: 404.85-577.64) versus 371.69 (95% CI: 337.50-414.96).

CONCLUSION: Results of this analysis suggest that physical inactivity significantly contributes to YLD and YLL rates in Switzerland, with pronounced regional and sex-specific disparities. The higher burden of disease observed in the Italian- and French-speaking regions highlights the need for regionally tailored prevention strategies that address cultural and contextual differences.},
}

Humans
Switzerland/epidemiology
Female
*Sedentary Behavior
Male
Middle Aged
Aged
Adult
*Cost of Illness
Prevalence
Language
Risk Factors
*Noncommunicable Diseases/epidemiology
Morbidity
Exercise

@article {pmid42822260,
year = {2026},
author = {d'Orsi, G},
title = {Epilepsy phenotypes and Alzheimer's disease biomarkers in adults with down syndrome: beyond diagnostic codes.},
journal = {Seizure},
volume = {143},
number = {},
pages = {39-40},
doi = {10.1016/j.seizure.2026.09.024},
pmid = {42822260},
issn = {1532-2688},
}

@article {pmid42822579,
year = {2026},
author = {Zhang, X and Tao, T and Liu, W and Xie, A and Liang, Y and Zhu, X},
title = {Mitochondria and associated complexes as therapeutic targets in aging: From biomacromolecular structure-function insights to clinical translation.},
journal = {Mitochondrion},
volume = {},
number = {},
pages = {102221},
doi = {10.1016/j.mito.2026.102221},
pmid = {42822579},
issn = {1872-8278},
abstract = {Mitochondria and their biomacromolecular complexes-such as the electron transport chain (ETC), mitochondrial permeability transition pore (mPTP), and protein quality control systems-play pivotal roles in aging and age-related diseases. This review integrates recent insights into how structural and functional disruptions of these complexes drive cellular senescence and systemic decline. We outline the architecture of mitochondrial assemblies (e.g., oxidative phosphorylation (OXPHOS) complexes, mtDNA-protein interactions) essential for energy production and organelle stability. Age-related alterations in stoichiometry, conformational states (e.g., mPTP opening), and post-translational modifications (e.g., SIRT3-mediated acetylation) compromise mitochondrial integrity, fueling metabolic dysfunction and chronic inflammation ("inflammaging"). Therapeutic strategies include small-molecule stabilizers of ETC supercomplexes, peptide-based mPTP inhibitors, and CRISPR-mediated correction of mtDNA-protein mismatches. Tissue-specific models (e.g., Complex I in skin aging, Bcl-2 protein imbalance in ovarian aging) exemplify the clinical relevance. We also categorize nine age-associated diseases-neurodegenerative, cardiovascular, and cancer types-based on their dependence on distinct mitochondrial complexes, such as ATP synthase in cancer resistance and the TIM/TOM import machinery in Alzheimer's disease. By linking structural findings (e.g., cryo-EM studies) with therapeutic innovation, this review offers a framework for targeting mitochondrial complexes to mitigate aging and its related pathologies.},
}

@article {pmid42822589,
year = {2026},
author = {Saleki, S and Wabant, C and Loriot, A and Stanga, S and Masquelier, J and Muccioli, GG and Suelves, N and Kienlen-Campard, P},
title = {Alzheimer's disease-associated presenilin 2 N141I mutation impairs neuronal lipid homeostasis and mitochondrial dynamics through selective downregulation of the Golgi exchange factor Gbf1.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116045},
doi = {10.1016/j.expneurol.2026.116045},
pmid = {42822589},
issn = {1090-2430},
abstract = {Presenilin 2 (PS2) mutations cause familial Alzheimer's disease, yet their effects beyond amyloid processing remain poorly understood. Here, we investigated how PS2 deletion and the N141I mutation affect neuronal lipid homeostasis and mitochondrial dynamics in mouse primary neurons. Both PS2 deletion and N141I mutation reduced neuronal lipid content. However, exogenous lipid supplementation rescued this deficit only in N141I-expressing neurons, indicating a partial loss-of-function effect. N141I neurons also displayed reduced OPA1, a mitochondrial fusion regulator, restored by lipid supplementation. RNA-sequencing identified Gbf1, a Golgi-specific guanine nucleotide exchange factor, as selectively downregulated in N141I but not knockout tissue, which was confirmed at the protein level in mouse brain and primary neurons. Gbf1 knockdown in mouse embryonic fibroblasts (MEFs) recapitulated the N141I lipid profile. Together, these findings reveal a PS2-GBF1-lipid-mitochondria axis disrupted specifically by the N141I mutation, suggesting an amyloid-independent pathway contributing to neurodegeneration and identifying potential therapeutic targets for familial Alzheimer's disease.},
}

@article {pmid42822590,
year = {2026},
author = {Yagihara, H and Saito, Y and Takeuchi, T and Seki, K and Minakawa, EN},
title = {Fluid amyloid-β (Aβ) biomarkers reflect early β-sheet-rich Aβ deposition during the preclinical stage in Alzheimer's disease model 5XFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116044},
doi = {10.1016/j.expneurol.2026.116044},
pmid = {42822590},
issn = {1090-2430},
abstract = {Early detection of disease progression using clinically-relevant biomarkers in animal models is important for mechanistic studies and for developing therapeutics in neurodegenerative diseases including Alzheimer's disease (AD). The preclinical stage of AD, when amyloid-β (Aβ) starts to accumulate before cognitive decline, provides a critical window for disease modification. In humans, decreases in cerebrospinal fluid (CSF) Aβ42 and the Aβ42/Aβ40 ratio in preclinical AD are considered to reflect the preferential sequestration of aggregation-prone Aβ42 into β-sheet-rich deposition in the brain, with corresponding changes being detectable in plasma. However, the extent to which these biomarker-pathology relationships are recapitulated in AD model mice remains incompletely defined. Here we show that CSF and plasma Aβ42 and the Aβ42/Aβ40 ratio decline with age in parallel with the progression of β-sheet-rich Aβ deposition in preclinical 5XFAD mice, one of the most widely used AD mouse models, as assessed through monthly profiling of these biomarkers. Notably, the CSF Aβ42/Aβ40 ratio showed a negative correlation with β-sheet-rich Aβ deposition in the brain, whereas CSF Aβ40 did not show a comparable association. In addition, the plasma Aβ42/Aβ40 ratio showed a positive correlation with the CSF Aβ42/Aβ40 ratio, suggesting that the plasma Aβ42/Aβ40 ratio may also reflect brain Aβ deposition in this model. The strength of these correlations differed by sex, suggesting that sex-dependent differences in the Aβ kinetics in this model may influence how closely fluid biomarkers reflect pathological progression. These findings support the potential utility of fluid Aβ as a pathology-linked, translatable biomarker in preclinical 5XFAD mice.},
}

@article {pmid42822610,
year = {2026},
author = {Arayesh, MJ and Ataellahi, F and Masoudi, R},
title = {Differential effects of amyloid-β and tau on UCH gene expression in Drosophila models of Alzheimer's disease.},
journal = {Gene},
volume = {},
number = {},
pages = {150431},
doi = {10.1016/j.gene.2026.150431},
pmid = {42822610},
issn = {1879-0038},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive impairments in learning and memory. Substantial evidence indicates that dysfunction of the ubiquitin-proteasome system (UPS) in the AD brain leads to aberrant protein aggregation, ultimately resulting in synaptic dysfunction and neuronal loss. In this study, we investigated the effects of pan-neuronal expression of Tau[WT] or Aβ42-key pathological hallmarks of AD-on the expression of UCH, a critical UPS component, in Drosophila melanogaster at three time points: 5, 15, and 25 days after eclosion.

METHODS AND RESULTS: UCH mRNA levels were quantified using real-time RT-PCR. UCH expression showed an age-dependent downregulation in Aβ42 transgenic flies over all three post-eclosion intervals. While UCH transcription witnessed no significant change in 5-day-old Tau[WT] transgenic flies, there was a considerable decline in UCH mRNA levels in 15- and 25-day-old flies. Notably, Aβ42 had a more prominent impact on UCH gene expression than Tau[WT] across all three time points.

CONCLUSION: Tau[WT] and Aβ42 exert independent adverse effects on UCH expression. An apparent age-related trend was observed in the fly models, whereby Aβ42 showed a relatively stronger influence on UCH transcription compared with Tau[WT]. Accordingly, therapeutic strategies that target both Tau and amyloid-β may warrant consideration.},
}

@article {pmid42822752,
year = {2026},
author = {Xuan, Z and Rahman, MU and Ilyas, M and Alioui, Y and Xin, Y and Cao, X and Ullah, H},
title = {Gut bacterial isolates from individuals with Alzheimer's disease induce strain-specific intestinal, inflammatory, and neurobehavioral phenotypes in mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150569},
doi = {10.1016/j.brainres.2026.150569},
pmid = {42822752},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which alterations in the microbiota-gut-brain axis has been increasingly investigated. However, the effects of individual cultivable bacterial isolates recovered from individuals with AD on host intestinal and neurobehavioral phenotypes remain insufficiently characterized. In this study, three bacterial isolates, Escherichia coli, Klebsiella pneumoniae, and Citrobacter pasteurii, were recovered from fecal samples collected from individuals diagnosed with AD and evaluated in healthy BALB/c mice following long-term oral administration. The effects of the isolates on physiological parameters, intestinal morphology and barrier-associated markers, inflammatory responses, gut microbial community composition, and neurobehavioral outcomes were assessed. The three isolates produced strain-specific effects, with C. pasteurii producing the most pronounced overall phenotype. Mice receiving C. pasteurii showed reduced body weight gain, increased spleen index, and shortened colon length, accompanied by elevated circulating inflammatory cytokines. Alterations in goblet cells, MUC2 expression, and tight-junction-associated proteins, including ZO-1 and claudin-1, were also observed, indicating alterations in intestinal barrier-associated structures. Gut microbiota analysis revealed strain-specific changes in microbial diversity and community composition, with the most pronounced alterations observed in the C. pasteurii group. In addition, C. pasteurii administration was associated with increased hippocampal inflammatory responses and astrocytic activation, whereas no apparent hippocampal neuronal loss was detected. Neurobehavioral testing revealed reduced locomotor activity and altered exploratory and behavioral responses, particularly in the C. pasteurii group. However, because reduced locomotor activity may influence performance in the novel object recognition and tail suspension tests, these findings should be interpreted cautiously. K. pneumoniae produced intermediate effects, whereas E. coli showed comparatively limited effects under the experimental conditions used. Collectively, these findings indicate that the tested bacterial isolates recovered from individuals with AD can produce strain-specific intestinal, inflammatory, microbial, and neurobehavioral alterations in healthy mice, with C. pasteurii producing the strongest overall phenotype. Importantly, the observed changes in gut microbial composition do not establish specific bacterial functions or pathogenicity, as microbial functional activity was not directly assessed. The present study does not establish that these bacteria are specifically associated with AD or that they cause AD progression; rather, it provides experimental evidence that individual cultivable bacterial isolates recovered from individuals with AD may differentially influence host phenotypes relevant to processes implicated in neurodegenerative disease. Further studies using larger human cohorts with appropriate healthy controls, validated AD models, and direct functional and mechanistic investigations are required to clarify the relevance of these observations to AD pathophysiology.},
}

@article {pmid42823347,
year = {2026},
author = {Bravo-Risi, F and Alburquerque Orta, G and Kim, PJ and Wylie-Young, H and Stimming, TH and Soto, P and Estrada, L and Jankowsky, JL and Morales, R},
title = {The Progression of Prion Diseases Is Not Altered in the Absence of TMEM106B.},
journal = {eNeuro},
volume = {13},
number = {10},
pages = {},
doi = {10.1523/ENEURO.0043-26.2026},
pmid = {42823347},
issn = {2373-2822},
mesh = {Animals ; *Membrane Proteins/genetics/deficiency/metabolism ; Female ; *Nerve Tissue Proteins/genetics/deficiency/metabolism ; Male ; Disease Progression ; *Prion Diseases/pathology/metabolism/genetics ; Disease Models, Animal ; Prions/metabolism ; Mice, Knockout ; Brain/pathology/metabolism ; Mice, Inbred C57BL ; Mice ; },
abstract = {Transmembrane protein 106B (TMEM106B) is a type II transmembrane glycoprotein localized in late endosomes and lysosomes. This protein has been attributed to relevant roles in disease risk and progression of multiple neurodegenerative disorders. In experimental models, TMEM106B has been linked with the prion-like spread of misfolded tau proteins responsible for Alzheimer's disease and other tauopathies. The role of this protein in the spread of other misfolded proteins, like prions, has not been explored. Here, we tested whether the removal of TMEM106B altered the progression of prion diseases using animal mouse models (male and female). This was carefully tested using different prion dosages, strains, and routes of administration. Our results demonstrate that the absence of TMEM106B does not alter the progression of prion diseases in any of the tested conditions. This data provides supportive evidence on the specificity of TMEM106B in neurodegenerative conditions.},
}

Animals
*Membrane Proteins/genetics/deficiency/metabolism
Female
*Nerve Tissue Proteins/genetics/deficiency/metabolism
Male
Disease Progression
*Prion Diseases/pathology/metabolism/genetics
Disease Models, Animal
Prions/metabolism
Mice, Knockout
Brain/pathology/metabolism
Mice, Inbred C57BL
Mice

@article {pmid42823476,
year = {2026},
author = {Rittmo, J and Franzmeier, N and Strandberg, O and Chauveau, L and Satterthwaite, TD and Wisse, LEM and Spotorno, N and Behjat, HH and Dehsarvi, A and van Westen, D and Anijärv, TE and , and Landau, SM and Palmqvist, S and Janelidze, S and Stomrud, E and Ossenkoppele, R and Mattsson-Carlgren, N and Hansson, O and Vogel, JW},
title = {Different functional connectivity gradients reflect aging and Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42823476},
issn = {1546-1726},
support = {KAW 2020.0239//Science for Life Laboratory (SciLifeLab)/ ; KAW 2020.0239//Science for Life Laboratory (SciLifeLab)/ ; 2024-03642//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2024-03642//Vetenskapsrådet (Swedish Research Council)/ ; 23074CB//Alzheimer Forschung Initiative (Alzheimer Forschung Initiative e.V.)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; },
abstract = {Aging and Alzheimer's disease (AD) are accompanied by alterations to large-scale communication patterns in the brain, which can be tracked in vivo using functional connectivity. The location, direction and relevance of these changes remain widely debated, although they are rarely studied in the context of whole-cortex communication dynamics. Here, in two independent cohorts (BioFINDER-2, N = 973; Alzheimer's Disease Neuroimaging Initiative, N = 129), we show that functional connectivity changes associated with aging and AD are strongly aligned with separate fundamental axes of hierarchical brain communication. Early accumulation of AD pathology and subsequent cognitive decline are both linked to functional change along the sensory-association axis. Meanwhile, age-related functional changes occur along the representation-executive axis consistently throughout the adult lifespan. These findings together suggest that both AD and aging alter major but orthogonal functional pathways in the brain. More broadly, our findings position whole-brain connectivity dynamics as a unifying framework for interpreting functional changes across the adult lifespan.},
}

@article {pmid42823573,
year = {2026},
author = {Nguyen, N and Yuan, M and Wang, Y},
title = {From Design to Bedside: Brain-Targeted Engineered Nanoparticles and Predictive Modeling for Neurodegenerative Diseases Therapeutics.},
journal = {Pharmaceutical research},
volume = {},
number = {},
pages = {},
pmid = {42823573},
issn = {1573-904X},
support = {CMMI 1851635//National Science Foundation/ ; ECCS 2021081//National Science Foundation/ ; },
abstract = {Nanoparticle (NP)-based drug delivery systems offer promising solutions for neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, which have no cure due to the brain's structural complexity and the restrictive nature of the blood-brain barrier (BBB). Conventional therapeutics, despite strong in vitro efficacy, often fail clinically due to poor brain penetration. Recent advances in NP engineering, including optimization of size (10-100 nm), surface charge (-10 to -20 mV), and targeted ligand decoration, have improved BBB crossing and reduced premature clearance. In parallel, predictive in silico approaches, such as physiologically based pharmacokinetic (PBPK) modeling, computational fluid dynamics, and machine learning models, enable quantitative prediction of NP biodistribution, residence times, and region-specific uptake. By simulating key determinants, including blood flow dynamics, vasculature heterogeneity, permeability, and retention, these computational tools accelerate lead selection, reduce experimental burden, and inform design before in vivo testing. This review integrates recent progress in NP design with advanced computational modeling, highlighting how their convergence provides a rational framework for developing next-generation brain-targeted therapeutics. We further discuss regulatory and translational challenges, including safety, biocompatibility, and the need for humanized preclinical benchmarks. Together, these innovations offer a roadmap for advancing NP-based strategies toward clinical impact in neurodegenerative disease.},
}

@article {pmid42823667,
year = {2026},
author = {Kavlak, Y and Yıldız, S and Yıldız, P and Kar, F},
title = {Effects of an eight-week combined exercise program on functional and sarcopenia-related outcomes in institutionalized older adults with and without Alzheimer's disease: a comparative intervention study.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42823667},
issn = {1471-2318},
mesh = {Humans ; *Sarcopenia/therapy/physiopathology/psychology/diagnosis/epidemiology ; Aged ; Female ; Male ; *Alzheimer Disease/therapy/psychology/physiopathology/diagnosis/epidemiology ; Aged, 80 and over ; Muscle Strength/physiology ; *Exercise Therapy/methods ; Treatment Outcome ; *Institutionalization/trends/methods ; Activities of Daily Living/psychology ; Time Factors ; Nutritional Status ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a major cause of disability in older adults and is frequently accompanied by sarcopenia and functional decline, contributing to loss of independence. To investigate the effects of an eight-week combined exercise program on physical and cognitive function, sarcopenia-related outcomes and nutritional status in institutionalized older adults with and without AD.

METHODS: Twenty-three participants aged ≥ 65 years (12 with moderate AD and 11 cognitively healthy controls) completed supervised combined aerobic and resistance exercise three times per week for eight weeks. Muscle strength, physical performance, nutritional status, cognition, and activities of daily living were assessed before and after the intervention. Sarcopenia status was classified according to Working Group on Sarcopenia in Older People 2018 (EWGSOP2) criteria using strength and gait speed measures.

RESULTS: Comparison of quadriceps muscle strength before and after exercise showed significant improvement in both Alzheimer's patients (p = 0.013) and the healthy group (p < 0.001). Significant improvement was found in MNA values ​​after exercise in Alzheimer's patients (p = 0.021) and in instrumental activities of daily living in healthy individuals (p = 0.002). After the intervention, quadriceps strength improved significantly in both groups (p < 0.001). When the relationships between parameters were examined, it was found that the relationships between physical function and daily living activities were significant in individuals with Alzheimer's disease (p < 0.05).

CONCLUSIONS: Short-term combined exercise is a versatile intervention method applicable to improve muscle strength, mobility, and nutritional status in older adults living in institutions, including those with Alzheimer's disease.},
}

Humans
*Sarcopenia/therapy/physiopathology/psychology/diagnosis/epidemiology
Aged
Female
Male
*Alzheimer Disease/therapy/psychology/physiopathology/diagnosis/epidemiology
Aged, 80 and over
Muscle Strength/physiology
*Exercise Therapy/methods
Treatment Outcome
*Institutionalization/trends/methods
Activities of Daily Living/psychology
Time Factors
Nutritional Status

@article {pmid42823730,
year = {2026},
author = {Rotter, J and Kirmann, T and Brendler, J and Anthofer, L and Wilpert, NM and Hallermann, S and Biebermann, H and Bechmann, I},
title = {Multiscale characterization and distribution of the thyroid hormone transporter MCT8 in the adult and aged human brain.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42823730},
issn = {2051-5960},
mesh = {Humans ; *Monocarboxylic Acid Transporters/metabolism/genetics ; Symporters ; Aged ; *Brain/metabolism/pathology ; Female ; Male ; Adult ; Middle Aged ; *Aging/metabolism/pathology ; *Thyroid Hormones/metabolism ; Aged, 80 and over ; },
abstract = {The local availability of thyroid hormones (TH) depends on TH transporters such as monocarboxylate transporter 8 (MCT8, encoded by SLC16A2). Mutations of SLC16A2 cause Allan-Herndon-Dudley syndrome (AHDS), a disorder characterized by severe neurodevelopmental and motor deficits. While MCT8's importance in foetal brain development is well-established, its precise topographical, cellular, and subcellular distribution in the adult human brain has remained largely uncharacterized, limiting our understanding of which structures depend on MCT8-mediated TH transport throughout life and whether neurodegenerative processes such as Alzheimer's disease (AD) affect local transporter availability. In this study, we systematically mapped MCT8 expression across eight functionally distinct brain regions from 14 aged human body donors. Our multiscale approach combined immunostaining, automated whole-slide image analysis of over 13 million cells, multiplex RNAscope in situ hybridization, stimulated emission depletion (STED) microscopy, and single-nucleus RNA sequencing data analysis. We additionally applied standardized Braak staging to investigate whether AD progression correlates with alterations in MCT8 expression. We demonstrate robust MCT8 expression across brain barriers, glial cells, and in distinct neuronal populations. RNAscope confirmed a strong concordance between SLC16A2 mRNA presence and MCT8 immunoreactivity. STED and confocal microscopy localized MCT8 to plasma membranes, perinuclear regions, and axonal/dendritic compartments, indicating roles in both trans- and intracellular TH transport. MCT8 expression was preserved across Braak stages, with no significant difference between donors with varying degrees of neurofibrillary pathology. Our findings establish a comprehensive cellular and regional framework for MCT8-mediated transport in the human brain, mapping its specific anatomical distribution across regions crucial for motor control and cognitive processing. Stable MCT8 expression across Braak stages suggests that cerebral TH dysregulation in AD likely reflects altered hormone metabolism rather than transporter loss.},
}

Humans
*Monocarboxylic Acid Transporters/metabolism/genetics
Symporters
Aged
*Brain/metabolism/pathology
Female
Male
Adult
Middle Aged
*Aging/metabolism/pathology
*Thyroid Hormones/metabolism
Aged, 80 and over

@article {pmid42823800,
year = {2026},
author = {Kharitonova, EV and Chen, B and Sun, Q and Ockerman, F and Chen, C and Zhou, LY and Tian, S and Cao, H and Ober, C and Cox, NJ and Tao, R and Li, Y},
title = {EndoPRS-SS: Summary-statistic based incorporation of endophenotypes to improve risk prediction.},
journal = {HGG advances},
volume = {},
number = {},
pages = {100677},
doi = {10.1016/j.xhgg.2026.100677},
pmid = {42823800},
issn = {2666-2477},
abstract = {Endophenotypes are critical biological markers with genetic links to disease progression. We previously developed endoPRS, a multi-trait polygenic risk score (PRS) method that leverages endophenotype data to improve disease risk prediction. However, endoPRS requires individual-level genotype-phenotype data for model fitting, restricting its broader use. To address this, we introduce endoPRS-SS, an extension which enables PRS inference using genome-wide association study (GWAS) summary statistics and LD reference panels. Through simulation and real data analysis, we demonstrate that endoPRS-SS maintains the predictive accuracy of endoPRS, while increasing computational efficiency up to 90-fold. We also extend the endoPRS framework to support the incorporation of multiple endophenotypes simultaneously and find that multi-endophenotype PRS outperform single-endophenotype PRS. Notably, incorporating both monocyte count and executive function scores significantly improves Alzheimer's disease prediction for Europeans in the UK Biobank cohort. These extensions expand the scope of endoPRS and strengthen its utility for large-scale genetic risk assessment.},
}

@article {pmid42823958,
year = {2026},
author = {Lanata, S and Windon, C and Tee, BL and de Leon, J and Aguirre, GA and Jackson, AJ and Lieu, K and Diaz, V and Escudero, SP and Hill-Jarrett, TG and Weng, A and Adewale, K and Amiuri, A and Archila, J and Calderon, LM and Chen, A and Chen, Y and Ching, A and Colverson, A and Lopera, CC and Dorsman, K and Fuentes-Juarez, B and Garcia, A and Guevarra, A and Joo, YM and Kaczmarska, M and Erismas, KR and Klein, J and Kornhuber, A and Lay, S and Leng, F and Light, SW and Li, K and Lopez, L and Macri, D and Mamuyac, E and Martinez Roman, L and Mei, D and Caipa, MP and Prioleau, C and Dionisio Reyes, RJ and Robles-Archila, O and Rodriguez, D and Shibiru, I and Suntay, JM and Thomas, K and Tucker, M and Wang, YT and Wu, J and Zhao, X and Smith, K and Gorno-Tempini, ML and Seeley, WW and Rosen, HJ and Valcour, V and Kramer, JH and Possin, K and Rabinovici, G and Miller, BL},
title = {From neighborhoods to brain health: an outreach model linking health literacy, cognitive care, research, and the arts, in San Francisco.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1930344},
pmid = {42823958},
issn = {2296-2565},
mesh = {Humans ; San Francisco ; *Health Literacy ; *Community-Institutional Relations ; *Residence Characteristics ; Aged ; *Brain ; Cognition ; Aging ; },
abstract = {Traditional community outreach, research recruitment, and engagement strategies in aging neuroscience often fail to target and capture the diversity of structural and environmental conditions that shape the risk of age-related neurocognitive disorders (NCDs), including Alzheimer's disease. In this manuscript, we describe the rationale, implementation, and outcomes of the Community Outreach Program (COP) of the UCSF Fein Memory and Aging Center (MAC), emphasizing its neighborhood-based initiative designed to engage vulnerable populations to improve brain health literacy, access to cognitive care, and research inclusion among older adults living in underserved San Francisco neighborhoods. Guided by a social and environmental determinants of brain health framework, the program used neighborhood-level vulnerability and research representation mapping to identify neighborhoods with high vulnerability and low engagement in research, then implemented a multilingual, community-engaged model centered on four pillars: brain health education, arts- and movement-based programming, community-based cognitive clinics, and multilingual media outreach. Delivered in partnership with community organizations and safety-net providers in Mandarin, Cantonese, Spanish, Tagalog, and English, this model has generated durable partnerships across vulnerable neighborhoods, expanded access to culturally responsive cognitive care, improved inclusion in brain aging and NCDs research, and fostered innovative research projects. From 2019 to 2025, representation of individuals from vulnerable and underrepresented San Francisco neighborhoods in UCSF Fein MAC observational research increased substantially compared to previous years. These findings support place-based, multilingual, and reciprocity-centered community engagement as a promising framework for reducing and studying disparities in brain health.},
}

Humans
San Francisco
*Health Literacy
*Community-Institutional Relations
*Residence Characteristics
Aged
*Brain
Cognition
Aging

@article {pmid42824080,
year = {2026},
author = {Privšek, E and Marseglia, A and Košutić, I and Rosenberg, A and Granberg, T and Kramberger, MG and Kivipelto, M and Westman, E},
title = {Cerebral microbleed assessment on MRI in a memory clinic: Reliability, prevalence, and implications for anti-amyloid therapy.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70472},
pmid = {42824080},
issn = {2352-8729},
abstract = {INTRODUCTION: Cerebral microbleeds (CMBs) represent an important magnetic resonance imaging (MRI) marker of cerebral small vessel pathology in memory-clinic populations, where vascular and neurodegenerative pathologies frequently overlap.

METHODS: This cross-sectional study included 747 patients from a Swedish memory clinic who underwent 3T MRI with susceptibility-weighted imaging. Two readers assessed CMBs using standardized criteria. Inter- and intra-observer agreement were evaluated before and after protocol refinement. CMB prevalence and burden were analyzed across diagnostic groups and by cerebrospinal fluid amyloid status.

RESULTS: CMBs were present in 28.6% of patients and frequently observed in subjects with mild cognitive impairment or dementia. Inter-observer agreement improved from κ = 0.71 to κ = 0.82 after protocol refinement. Among amyloid-positive patients with cognitive impairment, 11.2% exceeded proposed CMB thresholds for anti-amyloid therapy eligibility.

DISCUSSION: Standardized CMB assessment improves reliability in memory-clinic populations. Given its growing impact on treatment eligibility and safety, consistent evaluation is essential for patient management.},
}

@article {pmid42824090,
year = {2026},
author = {Schwartz, NU and Ellingson, T and Nguyen, H and Lin, Z and Ashton, NJ and Dage, JL and Deniz, K and Dietz, CD and Ljubenkov, PA and Miller, BL and Nael, K and Possin, K and Rojas, JC and Rosen, HJ and Saloner, R and Soleimani-Meigooni, DN and Staffaroni, AM and Stephens, ML and Tammewar, G and Wang, Y and La Joie, R and Rabinovici, GD and Boxer, AL and VandeVrede, L},
title = {Evaluation of plasma neurofilament and glial fibrillary acidic protein to predict or detect amyloid related imaging abnormalities.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70446},
pmid = {42824090},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid-targeting therapies (ATT) require frequent magnetic resonance imaging monitoring to detect vasogenic edema and hemorrhage, i.e., amyloid-related imaging abnormalities (ARIA). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are potential blood-based biomarkers (BBM) of ARIA.

METHODS: Plasma NfL and GFAP were longitudinally collected in an ATT clinic and natural log transformed. Baseline, pre-ARIA, and trajectories were compared between patients with (N = 15) and without (N = 45) ARIA.

RESULTS: Baseline NfL and GFAP did not differ between patients with or without ARIA (ln[NfL] ECLIA 1.24 ± 0.38 pg/mL vs 1.25 ± 0.40 pg/mL, p = 0.77; ln[NfL] Simoa 2.87 ± 0.47 pg/mL vs 2.98 ± 0.40 pg/mL, p = 0.30, ln[GFAP] ECLIA 4.95 ± 0.36 pg/mL vs 4.88 ± 0.47 pg/mL, p = 0.69). No significant changes were seen at the timepoint preceding ARIA, and ARIA incidence made no detectable impact on biomarker trajectories.

DISCUSSION: Biobanking in treatment clinics can evaluate clinical utility of BBMs as monitoring tools. These findings do not support a strong association between NfL or GFAP and ARIA in the ATT clinic.},
}

@article {pmid42824337,
year = {2026},
author = {Beltrán, ÓG and Angarita-Rodríguez, A and González, J and Hernández, ED and Pinzón, A},
title = {Gut microbiota signatures in mild cognitive impairment: a scoping review of microbial taxa and clinical implications.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1895237},
pmid = {42824337},
issn = {1664-302X},
abstract = {OBJECTIVE: To identify systematically the typical gut microbiota in mild cognitive impairment patients and its association in disease progression. Systematically identify microbial taxa consistently associated with Mild Cognitive Impairment.

DESIGN: A scoping review was performed according to the guidelines of the Joanna Briggs Institute using CoCoPop design.

STUDY SELECTION: Several studies about gut microbiota sequencing in mild cognitive impairment diagnosed patients compared against healthy controls.

METHODS: Searches in PubMed, Embase, Scopus, and Web of Science using MeSH and DeCS terms, were performed up to December 2025. Two reviewers independently screened titles and abstracts. Then, the full texts were reviewed to select documents to be included. When there were disagreements in papers selection, those were resolved after discussions among the reviewers. Relevant data information from selected publications was extracted, and a descriptive analysis was made.

RESULTS: The documents do not show drastic changes in the alpha or beta diversity of the microbiota, but they do identify consistent alterations in the relative abundance of specific taxa that allow patients with MCI to be distinguished from healthy controls. Among the most relevant findings is the decrease in SCFA-producing genera, such as Ruminococcus and Lachnospira, whose reduction is directly associated with the deterioration of key brain functions, including synaptic processes and neuronal oxidative metabolism. On the other hand, there is an increase in proinflammatory taxa such as Bacteroides, a pattern that is similar to that observed in patients with Alzheimer's disease, although generally less pronounced.

CONCLUSION: The results highlight that alterations in the abundance of specific bacteria, characterized by the loss of protective taxa and an increase in proinflammatory bacteria, serve as early biomarkers for detecting and predicting Mild Cognitive Impairment (MCI). This pattern of proinflammatory dysbiosis can be identified even in preclinical stages, and it has been proposed as a potential noninvasive tool for early diagnosis and therapeutic intervention before dementia progresses.},
}

@article {pmid42824359,
year = {2026},
author = {Aversi, MTM and Freitas, PM and Aversi-Ferreira, TA},
title = {New Alzheimer's disease diagnostics and psychological clinical perspectives.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1866853},
pmid = {42824359},
issn = {1664-1078},
abstract = {Recent advances in blood-based biomarkers have transformed the early diagnosis of Alzheimer's disease (AD), enabling the identification of biological risk at preclinical and presymptomatic stages in a noninvasive and accessible manner. Despite this diagnostic progress, the expansion of psychological clinical services in dementia care has not kept pace, representing a critical gap in the current management of AD. This theoretical paper critically discusses the role of psychological clinical practice in the prevention and management of AD in light of these diagnostic advances, particularly from the perspective of the International Working Group (IWG), which defines AD as a clinical-biological entity and recommends that cognitively normal individuals with positive biomarkers be considered at risk rather than diagnosed. Based on this framework and on evidence from the 2024 Lancet Commission on dementia prevention, we propose a three-phase roadmap for the integration of psychological care into multidisciplinary AD management. Phase 1 encompasses universal prevention through psychoeducation, cognitive reserve promotion, and emotional education. Phase 2 targets at-risk individuals with elevated biomarker profiles, focusing on neuropsychological evaluation, risk disclosure support, and early cognitive intervention. Phase 3 addresses individuals with established AD through cognitive rehabilitation and caregiver support. We further argue that government policies must integrate psychologists into multidisciplinary neurological and geriatric teams, and that psychology training programs must be updated to prepare professionals for preventive roles. More research on standardized psychological protocols for pre-dementia contexts is urgently needed.},
}

@article {pmid42824632,
year = {2026},
author = {Miao, J and Xue, C and Yan, X and Gu, J and Chu, D and Sun, H},
title = {From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1927017},
pmid = {42824632},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, pathologically defined by extracellular amyloid-β plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The Braak staging system established that tau pathology spreads in a stereotypical pattern across the brain, supporting the "prion-like" hypothesis: misfolded tau aggregates serve as seeds, inducing the misfolding and aggregation of normal tau, and thereby driving disease progression along neuroanatomical pathways. In the past 5 years (2021-2026), substantial advances have elucidated the molecular mechanisms underlying tau seeding activity. This review summarizes recent progress in tau seeding research, highlighting both intrinsic and extrinsic regulators of tau prion-like activity. Intrinsic factors include the structural basis of tau strains, MAPT mutations, alternative splicing (3R/4R isoforms), post-translational modifications, and liquid-liquid phase separation. Extrinsic factors encompass cofactors, molecular chaperones, non-coding RNAs, epigenetic mechanisms, environmental exposures, and the emerging concept of trans-seeding by heterologous protein fibrils. We also review therapeutic strategies targeting tau pathology, focusing on their mechanisms and clinical development. Integrating these mechanistic insights and therapeutic advances will inform future research and clinical strategies for AD and related tauopathies.},
}

@article {pmid42824777,
year = {2026},
author = {Taherkhani, AM and Şenol, H and Valizadeh, Y and Ghafouri, SN and Dastyafteh, N and Aktaş, A and Sadeghian, N and Moradkhani, F and Larijani, B and Biglar, M and Taslimi, P and Mohammadi-Khanaposhtani, M and Mahdavi, M},
title = {Design and synthesis of carbazole-acrylamide-pyridinium hybrids as dual acetylcholinesterase/butyrylcholinesterase inhibitors and evaluation of their cytotoxic profile on SH-SY5Y and HEK293 cell lines.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42824777},
issn = {2632-8682},
abstract = {A novel series of seventeen carbazole-acrylamide-pyridinium-N-phenylacetamide hybrids (12a-q) was designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for potential Alzheimer's disease therapy. Their inhibitory activity was evaluated against both enzymes using tacrine and galantamine as reference standards. Tacrine exhibited IC50 values of 58.34 nM against AChE and 160.50 nM against BChE, while galantamine showed 124.72 nM and 216.23 nM, respectively. The synthesized derivatives demonstrated IC50 values ranging from 6.41 to 74.93 nM against AChE and from 38.05 to 191.96 nM against BChE. All compounds were more potent than galantamine, and most outperformed tacrine as well. Compound 12i was the most potent AChE inhibitor (IC50 = 6.41 nM), showing 9.1-fold and 19.5-fold higher potency than tacrine and galantamine, respectively. Compound 12g was the strongest BChE inhibitor (IC50 = 38.05 nM), with 4.2-fold and 5.7-fold higher activity than tacrine and galantamine. Kinetic analysis revealed that all of the most potent compounds act as competitive inhibitors. Cytotoxicity evaluation revealed that compounds 12i and 12g exhibited lower toxicity toward HEK293 cells than sorafenib, with favorable selectivity toward SH-SY5Y cells. These results establish the carbazole-acrylamide-pyridinium scaffold as a promising lead for developing safer cholinesterase inhibitors for Alzheimer's disease.},
}

@article {pmid42824999,
year = {2026},
author = {Bai, Y and Zhao, J and Zhang, S and Yan, C and Chen, Y and Du, G and Liu, A},
title = {Machine Learning-Guided Discovery of Natural BACE1 Inhibitors with Enzymatic and Cellular Validation.},
journal = {ACS omega},
volume = {11},
number = {38},
pages = {58100-58111},
pmid = {42824999},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by excessive accumulation of β-amyloid (Aβ) peptides in the brain. Beta-secretase 1 (BACE1), the rate-limiting enzyme in the amyloidogenic processing pathway of amyloid precursor protein (APP), has been widely recognized as an important therapeutic target for reducing Aβ production. In the present study, nine machine learning-based predictive models for BACE1 inhibitors were constructed using Naïve Bayes (NB) and Recursive Partitioning (RP) algorithms. Subsequently, internal and external validations were conducted to evaluate predictive performance. The optimized models were subsequently applied to screen an in-house natural product library containing 452 compounds. Based on consensus prediction criteria, 171 compounds were identified as potential BACE1 inhibitors and subjected to fluorescence resonance energy transfer (FRET)-based enzymatic assays. Among them, 33 compounds exhibited inhibitory rates greater than 50% at an initial concentration of 50 μg/mL. Further dose-response evaluation identified five compounds with IC50 values below 50 μM, including Theaflavin-3,3'-digallate, γ-mangostin, Licoagrochalcone B, Chicoric acid, and Resveratrol. Cell-based validation using APPswe-HEK293T cells demonstrated that Theaflavin-3,3'-digallate significantly reduced extracellular Aβ1-42 secretion. Molecular docking analysis further revealed that Theaflavin-3,3'-digallate could stably bind to BACE1 through multiple hydrogen-bond and hydrophobic interactions. Collectively, this study demonstrates that integrating machine learning-assisted virtual screening with natural product libraries is an effective strategy for discovering novel BACE1 inhibitors. Theaflavin-3,3'-digallate was identified as a promising natural BACE1 inhibitor with both enzymatic and cellular activities. This research provides new technology and potential lead compound for the development of future anti-Alzheimer's disease drug.},
}

@article {pmid42825043,
year = {2026},
author = {Wu, M and Cao, Y and Wu, X and Wang, Y and Deng, Z and Zhao, Y and Lu, G and Qu, X and Zhu, F and Cheng, Y and Wang, P and Zhong, L},
title = {Comprehensive metabolite profiling in fruits of different Prunus cultivars.},
journal = {Food chemistry: X},
volume = {39},
number = {},
pages = {104431},
pmid = {42825043},
issn = {2590-1575},
abstract = {Variations in metabolite profiles among Prunus cultivars shape fruit flavor and overall quality, and ultimately determine consumer preference. To comprehensively evaluate the metabolic quality of various Prunus cultivars, we adopted an integrated extraction strategy to obtain distinct metabolite fractions from identical samples. In this work, seven predominant Prunus cultivars from Xinjiang, China were investigated, 382 volatile metabolites and 417 non-volatile metabolites were identified, where phenols were detected as the dominant secondary metabolites and esters were abundant volatile metabolites. 'Black' displayed greater antioxidant activity relative to other cultivars, due to its more than four-fold higher content of pyroglutamic acid, glutamine, and γ-dodecalactone. Additionally, network pharmacology analysis confirmed that the metabolites maybe associated with diabetes, cancer, and Alzheimer's disease. Collectively, this study for the first time elucidates the full metabolite profile in Prunus, and provides practical guidance for consumer choices as well as a solid theoretical foundation for selective breeding of Prunus.},
}

@article {pmid42825245,
year = {2026},
author = {Jia, M and Yang, R and Xu, Y and Wu, Z and Lu, J and Li, Z and Yan, Q and Fan, G and Gui, Y},
title = {Oral microbiome-metabolome axis links glycerophospholipid dysregulation to Alzheimer's disease.},
journal = {Journal of oral microbiology},
volume = {18},
number = {1},
pages = {2732297},
pmid = {42825245},
issn = {2000-2297},
abstract = {INTRODUCTION: This study aimed to evaluate the feasibility of using tongue biofilm as a non-invasive, patient-friendly, and cost-effective biomarker source for identifying early microbial and metabolic disturbances associated with Alzheimer's disease (AD).

MATERIALS AND METHODS: A total of 62 outpatients were enrolled (31 with AD and 31 cognitively normal controls). Tongue biofilm samples were analyzed using 16S rRNA sequencing and untargeted metabolomics via UPLC-Q/TOF-MS. Additionally, cerebrospinal fluid (CSF) samples from 36 individuals (18 per group) were examined under identical untargeted metabolomics processing protocols to validate the metabolomic findings.

RESULTS AND DISCUSSION: Microbiome analysis revealed an increased relative abundance of Proteobacteria in the AD group, while Firmicutes and Bacteroidetes were enriched in controls. Metabolomic profiling identified 88 significantly different metabolites between groups, 64 of which achieved area under the curve (AUC) values > 0.90 in the ROC analysis. Glycerophospholipid metabolism has emerged as a key dysregulated pathway in AD, a finding further corroborated by CSF metabolomic analysis. Tongue biofilm represents a non-invasive, cost-effective, and accessible biomarker source, offering potential for AD diagnosis and research when coupled with microbiome and metabolomic analyses. Moreover, the role of glycerophospholipid metabolism in AD pathogenesis warrants further investigation.},
}

@article {pmid42825350,
year = {2026},
author = {Chen, J and Long, Z and Li, Y and Luo, M and Luo, S and He, G},
title = {[Corrigendum] Alteration of the Wnt/GSK3β/β‑catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model.},
journal = {International journal of molecular medicine},
volume = {58},
number = {5},
pages = {},
doi = {10.3892/ijmm.2026.6003},
pmid = {42825350},
issn = {1791-244X},
abstract = {Following the publication of the above article, a concerned author drew to the authors' attention that they had apparently used an inappropriate antibody in their study: In the Materials and methods section, the authors had reported the use of Abcam's recombinant antibody against plant homeodomain (PHD) finger protein 1 (a.k.a. PHF1; cat. no. ab184951) to probe for the unrelated protein, tau paired helical filaments (PHFs). Based on their search of previous literature, the authors acknowledged that they had made a methodological error in selecting the incorrect antibody; therefore, the western blot assay results shown in Fig. 4A on p. 317 for protein PHF1 should be considered to be invalid. Given that this issue has come to light, the authors have now purchased the correct and specific antibody targeting phosphorylated tau (p‑tau‑S404) from ABclonal Viotech Co., Ltd (cat. no. AP1378) and completely repeated the relevant experiments, in strict accordance with the original experimental protocols and conditions. In addition, the authors provided the Editorial Office with the raw data from the repeated experiments, and also proof of purchase of the correct antibody. The corrected version of Fig. 4, now showing the revised data for the PHF1 blots in Fig. 4A together with re‑quantified bar charts for these data shown in Fig. 4B, is featured on the next page. Additional changes to the text should also be noted: The text in the Materials and methods section, 'Western blot analysis' subsection, on p. 315 (left-hand column, lines 14-15), should read as follows (changes highlighted in bold): '...rabbit anti insulin degrading enzyme (IDE) antibody (ab133561), rabbit anti‑PHF‑1 antibody (ab184951), mouse anti‑GSK3β antibody (ab93926)...'. In addition, revisions have also been made to the legend for Fig. 4. The authors confirm that the error made in performing these experiments has not had a significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 44: 313‑323, 2019; DOI: 10.3892/ijmm.2019.4198].},
}

@article {pmid42813639,
year = {2026},
author = {Singh, AP and Prajapati, S and Yadav, S and Yadav, A},
title = {Lipid-based Nanocarriers for Neurodegenerative Disorders: Bridging Blood-brain Barrier Biology and Translational Drug Delivery.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026478560260909100922},
pmid = {42813639},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, remain difficult to treat because the Blood-brain Barrier (BBB) severely restricts therapeutic access to the central nervous system. This review evaluates BBB biology and the potential of lipid-based nanocarriers to improve brain-targeted drug delivery and facilitate clinical translation.

METHODS: A structured narrative review of peer-reviewed preclinical and clinical literature published between 2000 and 2025 was conducted using PubMed, Scopus, and Web of Science. Evidence concerning BBB structure and transport mechanisms, lipid-based nanocarrier design, physicochemical characteristics, drug-release behavior, computational modelling, therapeutic applications, and translational challenges was critically synthesized.

RESULTS: Liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and lipid-polymer hybrid nanoparticles demonstrated improved drug solubility, stability, controlled release, systemic circulation, and brain targeting. Preclinical evidence indicates enhanced brain bioavailability and therapeutic effects, including reductions in neuroinflammation, oxidative stress, and disease-associated pathological processes. However, clinical translation remains constrained by formulation complexity, scalability, long-term safety, and inconsistent clinical outcomes.

DISCUSSION: Integration of BBB transport biology with surface functionalization, receptormediated targeting, formulation engineering, and computational modelling may enable more rational nanocarrier development. Nevertheless, standardized characterization, reproducible manufacturing, comprehensive safety evaluation, and stronger clinical validation are required to bridge the gap between promising preclinical findings and therapeutic implementation.

CONCLUSION: Lipid-based nanocarriers represent promising platforms for overcoming biological and pharmacokinetic barriers in neurodegenerative disorders. Further optimization and rigorous translational validation are essential to establish their safety, reproducibility, and clinical effectiveness.},
}

@article {pmid42813641,
year = {2026},
author = {Küpeli, E and Mancak, M and Cakirli, E and Bardakci, H and Avci, TB and Ozdemir, S},
title = {Solid and Nanostructured Lipid Carriers for Plant-Derived Neuroprotective Agents: Advances and Future Perspectives.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128509583260914134550},
pmid = {42813641},
issn = {1873-4286},
abstract = {Neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), continue to pose a substantial therapeutic challenge, largely due to progressive neuronal degeneration and the limited effectiveness of currently available treatments. Plant-derived bioactive compounds-including polyphenols, alkaloids, terpenoids, and flavonoids-have shown notable neuroprotective properties. However, their clinical use remains constrained by low bioavailability and limited ability to cross the blood-brain barrier (BBB). Lipid-based nanocarrier systems, especially solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), have emerged as promising alternatives for improving delivery efficiency. This review evaluates recent advances in SLN and NLC formulations developed for phytochemical delivery in neurodegenerative conditions, focusing on formulation approaches, production methods, and the physicochemical factors that govern system performance. Preclinical findings consistently indicate enhanced solubility, improved stability, and more effective brain targeting with these systems. Even so, several challenges continue to impede their clinical translation. In particular, issues related to formulation reproducibility, scalability of production, and long-term safety remain unresolved. Alternative administration routes such as intranasal delivery offer a potential strategy to bypass the BBB, although their practical feasibility still requires further confirmation. SLN- and NLC-based systems offer a promising approach, although their clinical development is still ongoing. Future efforts should focus on establishing standardized formulation protocols, conducting rigorous in vivo studies, and ensuring alignment with regulatory requirements to facilitate successful clinical translation.},
}

@article {pmid42813688,
year = {2026},
author = {Yu, H and Chang, W and Mahmut, D and Huang, C and Zhang, B},
title = {Integrative transcriptomic and regulatory network analysis reveals associations of seven proposed risk genes with immune-related molecular features in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493169},
doi = {10.1177/13872877261493169},
pmid = {42813688},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves neuroinflammation influenced by genetic and immune dysregulation. Seven proposed AD risk genes (CACNA2D3, EPB41L2, INPP5D, MYO1F, RBM47, SSH2, TBXAS1) have been identified, but their associations with the immune microenvironment (IME) remain unclear.ObjectiveThis study investigates associations between these genes and the neuroimmune landscape in AD.MethodsIntegrative transcriptomic and regulatory network analysis was performed using the GSE53697 dataset (9 AD and 8 control samples) from the GEO. Immune cell enrichment scores and pathway activity were evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA), and enriched pathways were identified through Gene Set Enrichment Analysis (GSEA). Upstream regulatory associations were explored by constructing miRNA-mRNA and transcription factor regulatory networks, and correlations between the risk genes and established AD-related genes were assessed using public databases.ResultsAD samples showed immune dysregulation, including reduced dendritic cell ssGSEA scores. All seven risk genes correlated with immune cell subsets and immunomodulatory molecules. Enrichment analysis revealed inflammatory pathways including NF-κB, IL-17, TNF, MAPK, and Notch, suggesting potential links to neuroinflammation and neuronal signaling disruption. Upstream analysis identified 85 miRNAs and several transcription factor motifs annotated to HOXA13, ESRRA, and SNAI1/2/3. Correlation analysis further revealed associations between risk genes and AD-related genes, placing these genes within established AD pathological networks in an exploratory manner.ConclusionsThis exploratory study provides insights into how AD risk genes are associated with the IME and may be linked to neuroinflammatory pathways and neuronal function, providing hypotheses for future studies of immune-genetic crosstalk in AD pathogenesis.},
}

@article {pmid42813805,
year = {2026},
author = {Feng, J and Nanshan, M and Shi, H and Wong, KY and Lam, KF and Cao, J},
title = {A regularized semiparametric cure-rate model with high-dimensional imaging data.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261483498},
doi = {10.1177/09622802261483498},
pmid = {42813805},
issn = {1477-0334},
abstract = {Structural magnetic resonance imaging (MRI) is informative for studying progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), but incorporating high-dimensional images into survival models requires methods that accommodate irregular brain domains and yield interpretable spatial effects. We propose a regularized semiparametric mixture cure-rate model for high-dimensional imaging predictors that separates susceptibility to AD conversion from time to AD among susceptible subjects. Baseline MRI images are represented by bivariate Bernstein spline basis functions over a triangulation of the brain domain, and sparsity-inducing penalties are imposed on imaging effects in both incidence and latency components. This construction enables direct estimation of localized coefficient functions describing how image regions are associated with susceptibility and conversion time. We develop an expectation-maximization algorithm that updates latent susceptibility probabilities and solves penalized logistic and Cox regression subproblems, together with an efficient tuning strategy. Simulations show that the method can recover localized active regions and provide useful incidence and latency discrimination. An application to Alzheimer's Disease Neuroimaging Initiative data demonstrates susceptibility discrimination and interpretable brain-region coefficient maps.},
}

@article {pmid42814409,
year = {2026},
author = {Huang, S and Zhang, Z and Xia, J and Deng, M and Chen, F and Wang, M and Fei, Y and Jiang, Z and Lu, C and Fu, J and Guo, J and Zhou, H},
title = {ZBP1-mediated Treg cell dysfunction exacerbates neuroimmune dysregulation in Alzheimer's disease under metabolic stress.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71896},
pmid = {42814409},
issn = {1552-5279},
support = {81871098//the National Science Foundation of China/ ; 81671392//the National Science Foundation of China/ ; 2021YFE0111800//National Key R&D Program of China/ ; ZY [2021-2023]-0207-01//National Key R&D Program of China/ ; shslczdzk02802//National Key R&D Program of China/ ; 2018SHZDZX01//National Key R&D Program of China/ ; },
mesh = {Animals ; *Alzheimer Disease/immunology/metabolism ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Mice ; *Stress, Physiological/immunology ; *DNA-Binding Proteins/metabolism ; Humans ; *Neuroimmunomodulation ; Male ; Mice, Transgenic ; Disease Models, Animal ; Diet, High-Fat ; Brain/metabolism ; Female ; *RNA-Binding Proteins/metabolism ; },
abstract = {INTRODUCTION: Metabolic stress increases Alzheimer's disease (AD) risk, but mechanisms linking metabolic dysfunction to neuroimmune dysregulation remain unclear.

METHODS: We assessed cognition in community-dwelling participants and used high-fat diet (HFD)-fed 5xFAD mice, high glucose and high palmitate (HGHP)-treated regulatory T cell (Treg) co-cultures, and adoptive Treg transfer to evaluate metabolic stress-associated neuroimmune dysfunction. Flow cytometry, RNA sequencing, positron emission tomography computed tomography, and electrophysiology assessed Treg function, AD pathology, cerebral metabolism, and synaptic plasticity.

RESULTS: Metabolic stress impaired Treg stability and function, accompanied by increased Z-DNA-binding protein 1 (ZBP1) expression and activation of apoptotic and necroptotic signaling. Treg dysfunction was associated with enhanced glial activation and neuronal injury. Under HGHP stress, ZBP1-deficient Tregs showed improved survival and stronger immunosuppressive activity, more effectively limiting glial activation and preserving neuronal integrity. In vivo, ZBP1-deficient Treg transfer conferred greater neuroprotection than wild-type Treg transfer in HFD-fed AD mice.

DISCUSSION: ZBP1 may contribute to metabolic stress-induced Treg dysfunction and represent a candidate target to improve Treg-based therapy in HFD-fed AD mice.},
}

Animals
*Alzheimer Disease/immunology/metabolism
*T-Lymphocytes, Regulatory/immunology/metabolism
Mice
*Stress, Physiological/immunology
*DNA-Binding Proteins/metabolism
Humans
*Neuroimmunomodulation
Male
Mice, Transgenic
Disease Models, Animal
Diet, High-Fat
Brain/metabolism
Female
*RNA-Binding Proteins/metabolism

@article {pmid42814513,
year = {2026},
author = {Jia, H and Wu, S and Xue, X and Li, Z and Li, L and He, H and Wang, Q and Gao, H and Wen, C},
title = {A review on diffusion tensor imaging-based comprehensive intelligent diagnosis of Alzheimer's disease.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42814513},
issn = {2191-0200},
abstract = {AI-assisted early diagnosis of Alzheimer's disease (AD) has substantial clinical value, and diffusion tensor imaging (DTI), which captures white matter microstructural alterations, has considerable potential across the AD continuum. However, major barriers to clinical translation remain. This review systematically evaluated the evolution of algorithmic paradigms, the effectiveness of multimodal fusion, and barriers to clinical generalization in DTI-based AD diagnosis. Using an "Input-Model-Fusion" evaluation framework, we analyzed 98 studies published from 2010 to 2026 and compared sample size, diagnostic task, validation design, and methodological quality. Four findings emerged. 1) Modality selection should be task-driven; single-modality DTI and multimodal fusion have different applicability across diagnostic tasks. 2) Algorithm choice was closely related to sample size: conventional machine learning, particularly support vector machines, predominated in small-sample studies, whereas deep learning architectures, including convolutional neural networks, graph convolutional networks, and Transformers, were more widely used with large datasets. 3) Substantial performance degradation in multicenter or external validation highlighted persistent limitations in clinical generalizability. Data source, sample representativeness, feature processing, validation strategy, acquisition protocol, and software pipeline heterogeneity remain important constraints on clinical translation and cross-study comparability of DTI metrics. 4) Hippocampal pathways, the corpus callosum, fornix, and cingulum showed relatively stable discriminative value. Future research should move beyond "algorithm accuracy competition" toward clinical pragmatism by prioritizing task alignment, standardized DTI acquisition and processing, external validation, and neurobiological interpretability.},
}

@article {pmid42814589,
year = {2026},
author = {Singh, L and Gupta, GD and Singh, S},
title = {Neurobehavioral and Molecular Rescue by Dapagliflozin in Aluminum Chloride-Induced Alzheimer's Model: Possible Relevance of NF-κB and Aβ(1-42).},
journal = {Assay and drug development technologies},
volume = {},
number = {},
pages = {1540658X261486541},
doi = {10.1177/1540658X261486541},
pmid = {42814589},
issn = {1557-8127},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by the deposition of amyloid-β plaques in the hippocampus, leading to cognitive and behavioral impairments. This study investigated the neuroprotective outcome of Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor primarily used for glycemic control, which also exhibits notable anti-inflammatory, antioxidant, and neuroprotective properties. Using an aluminum chloride (AlCl3)-induced rat model of AD, the research evaluates behavioral, biochemical, and neuroinflammatory changes, particularly focusing on the nuclear factor kappa-B protein (NF-κB) signaling pathway. Rats were orally administered AlCl3 to induce AD-like pathology, followed by DAPA treatment (1 and 2 mg/kg, p.o.) over a 28-day period. Behavioral assessments, including the Morris water maze and Elevated Plus Maze, were used to evaluate spatial memory and anxiety. On day 29, hippocampal tissues were collected to assess neurotransmitter levels, oxidative stress markers (LPO, GSH, nitrite), and inflammatory cytokines (interleukin-1 beta, interleukin-6), along with the expression of NF-κB. AlCl3 exposure led to significant alterations in neurotransmitter balance (AChE, GABA, and glutamate), heightened oxidative stress, and increased neuroinflammatory responses. DAPA treatment significantly mitigated these changes, notably downregulating NF-κB, which correlated with decreased amyloid beta and expression in the hippocampus. These findings suggest that beyond its antidiabetic action, DAPA offers promising neuroprotection against AlCl3-induced neurotoxicity, potentially via modulation of the NF-κB signaling pathway.},
}

@article {pmid42814649,
year = {2026},
author = {Liguori, C and Carpi, M},
title = {The orexinergic system in Alzheimer's disease: from sleep disruption to accelerated neurodegeneration.},
journal = {European neurology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ene/acsag009},
pmid = {42814649},
issn = {1421-9913},
abstract = {BACKGROUND: Sleep-wake dysregulation is increasingly recognized as an early and clinically relevant feature of Alzheimer's disease (AD), with growing evidence supporting a bidirectional relationship between disturbed sleep and AD pathophysiology. Sleep fragmentation, reduced slow-wave and REM sleep may contribute to amyloid-β (Aβ) accumulation by increasing Aβ production during wakefulness and diminishing glymphatic clearance during sleep, while emerging amyloid pathology can further disrupt sleep architecture and circadian sleep-wake rhythm, reinforcing a feed-forward cycle.

SUMMARY: Within this framework, the orexinergic system, centered in the hypothalamus and crucial for arousal and sleep-wake stability, has been implicated as a mechanistic link between hyperarousal, impaired sleep consolidation, and altered amyloid dynamics. Preclinical studies suggested that orexin-A signaling can exacerbate Aβ and tau pathology and impair synaptic function, whereas biomarker studies reported high cerebrospinal fluid orexin-A levels in mild cognitive impairment and dementia due to AD. These observations raise the hypothesis that targeting orexin signaling and improving sleep may represent actionable strategies within the AD continuum.

KEY MESSAGES: Clinical evidence indicates that behavioral and pharmacological interventions can improve sleep in at-risk populations, yet robust proof of disease-modifying effects on AD biomarkers or clinical progression remains limited. Ongoing trials of dual orexin receptor antagonists may clarify whether sustained modulation of sleep-wake regulation can influence AD-related biology beyond symptomatic sleep benefits.},
}

@article {pmid42814823,
year = {2026},
author = {Hernandez, H and Pedraza, LK and Santamaria-Garcia, H and Moguilner, S and Legaz, A and Prado, P and Cuadros, J and Amoruso, L and Gonzalez, L and Dellavale, D and Espinoza-Puelles, JP and Espinosa, JP and Jarne, C and Mattiussi, F and Caccia, M and Welford, AS and Pelella, N and Inchauspe, J and Ferrante, FJ and Pérez, G and Maito, MA and Rocatti, G and Godoy, ME and Migeot, J and Orellana, P and Caviedes, A and Bruno, M and Takada, L and Slachevsky, A and Behrens, MI and Bruna, B and Aguillon, D and Zapata, L and Avila-Funes, JA and Custodio, N and Miller, B and Gorno-Tempini, ML and Escudero, SP and Reyes, P and Hu, K and de Oliveira, MO and Coronel-Oliveros, C and Cruzat, J and Cardona, JF and Corley, M and Meier, IB and Narayan, VA and Tagliazucchi, E and Baez, S and Duran-Aniotz, C and García, AM and Ibanez, A},
title = {Speech clocks decode dementia phenotypes, social exposome, and biological aging.},
journal = {Science advances},
volume = {12},
number = {40},
pages = {eaef9864},
pmid = {42814823},
issn = {2375-2548},
mesh = {Humans ; *Aging/physiology ; Female ; Phenotype ; *Speech/physiology ; Alzheimer Disease/physiopathology ; Male ; *Dementia/physiopathology/diagnosis ; Aged ; *Frontotemporal Dementia/physiopathology ; Cognitive Dysfunction/physiopathology ; },
abstract = {Biological aging clocks offer estimations of aging and dementia, yet scalability is limited. We introduce a large-scale, cross-national speech clock derived from 2928 individuals across five Latin American countries, spanning healthy controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-language/language-dominant frontotemporal dementia (nldFTD/ldFTD). Multimodal acoustic and linguistic features were trained with supervised models to estimate chronological age, generating speech age gaps (SAGs) as cross-sectional markers of deviations from chronological age, with positive values interpreted as relatively older-appearing speech profiles. SAGs differentiated diagnostic groups (HCs < patient groups, with AD < nldFTD < ldFTD). This pattern was associated with clinical/cognitive domains. SAGs correlated with phosphorylated tau (p-Tau217) in AD and social exposome in HCs and AD. Brain clocks (structural/functional/combined) were associated with SAG in AD, nldFTD, and ldFTD. Epigenetic age correlated with SAGs in HCs and AD across Hannum, Retroclock, and OMICmAge, whereas ldFTD associations were limited to Retroclock and OMICmAge. These results indicate that SAGs capture cross-sectional multilevel aging-related variation and may offer a scalable, culturally adaptable, low-cost biomarker candidate for research in underrepresented global settings.},
}

Humans
*Aging/physiology
Female
Phenotype
*Speech/physiology
Alzheimer Disease/physiopathology
Male
*Dementia/physiopathology/diagnosis
Aged
*Frontotemporal Dementia/physiopathology
Cognitive Dysfunction/physiopathology

@article {pmid42814956,
year = {2026},
author = {Lu, S and Hu, S and Huang, J and Shi, Y and Yu, D and Cao, W and Yin, M and Petersen, JD and Huang, B},
title = {Electroencephalography in Subjective Cognitive Decline and Mild Cognitive Impairment: Systematic Review of Biomarkers, Classification, and Prognostic Evidence.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e92709},
pmid = {42814956},
issn = {1438-8871},
mesh = {Humans ; *Biomarkers ; *Cognitive Dysfunction/diagnosis/classification/physiopathology ; Disease Progression ; *Electroencephalography ; Prognosis ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are heterogeneous clinical states that may represent early or at-risk stages of Alzheimer disease (AD) and other dementias in some individuals. Improved characterization and risk stratification in these populations may facilitate timely evaluation and intervention. Electroencephalography (EEG), a noninvasive, cost-effective neurophysiological technique with high temporal resolution, holds significant potential for elucidating neural mechanisms and providing candidate neurophysiological markers associated with SCD and MCI.

OBJECTIVE: The study aims to systematically synthesize evidence on group-level EEG biomarkers, EEG-based classification models, the evaluation of EEG in screening or diagnostic pathways, and EEG-based prediction of progression in SCD and MCI.

METHODS: A search was conducted across PubMed, Web of Science, Cochrane Library, MEDLINE (via Ovid), Scopus, Wanfang Data, CQVIP, Yiigle, and CNKI databases to include reports published in English or Chinese, which reported group-level EEG differences, EEG-based classification, screening or diagnostic evaluations, or prognostic outcomes in SCD and MCI. A total of 2 independent reviewers screened the titles and abstracts. Prediction-model reports were assessed using PROBAST+AI (Prediction Model Risk of Bias Assessment Tool and Applicability Assessment for AI), prognostic-factor reports using QUIPS (Quality in Prognosis Studies), and other observational reports using design-specific Joanna Briggs Institute checklists. Certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system.

RESULTS: A total of 20 reports were included, representing a maximum of 3853 confirmed-deduplicated participants after correction of a nested subsample and removal of confirmed duplicate participants across reports, of whom 2927 diagnosed with SCD/MCI/AD or other dementias. Of these, 10 reports were assessed as prediction or AI model reports, 9 as nondiagnostic observational reports, and 1 as a prognostic-factor study. Although potentially informative between-group EEG differences and preliminary model performance were reported, no conventional diagnostic test-accuracy study was identified. The certainty of evidence was very low across all 4 evidence bodies.

CONCLUSIONS: The available evidence suggests that EEG is a promising noninvasive modality for characterizing neurophysiological alterations associated with SCD and MCI. EEG-based classification and prognostic models have also shown encouraging preliminary performance. However, the current evidence is more supportive of biomarker discovery and model development than of established clinical screening or diagnosis. Translation into routine practice will require prospective reports with standardized EEG procedures, representative clinical populations, prespecified thresholds, participant-level data separation, and independent external validation. These findings provide a basis for evaluating EEG as a potential adjunctive or triage tool in future clinical pathways.},
}

Humans
*Biomarkers
*Cognitive Dysfunction/diagnosis/classification/physiopathology
Disease Progression
*Electroencephalography
Prognosis

@article {pmid42815043,
year = {2026},
author = {Shahbaz, S and Shahbaz, MH and Fatima, R and Mansoor, MH and Kharal, M and Bashir, M and Ul Abideen, Z and Nadeem, MS},
title = {Trends in mortality of Alzheimer's disease with comorbid hypertension in patients in the US from 1999-2020.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2739337},
pmid = {42815043},
issn = {1758-2032},
abstract = {AIMS: To examine temporal trends and demographic disparities in Alzheimer's disease (AD)-related mortality among adults aged ≥ 65 years with comorbid hypertension in the United States from 1999 to 2020.

MATERIALS AND METHODS: We conducted a population-based retrospective analysis using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause of Death database. Deaths involving AD (ICD-10 G30) and hypertension (ICD-10 I10-I15) were identified. Age-adjusted mortality rates (AAMRs) were assessed by sex, race/ethnicity, geographic region, urbanization level, and state. Temporal trends were evaluated using Joinpoint regression.

RESULTS: Between 1999 and 2020, 409,112 deaths involving AD and hypertension were recorded. The overall AAMR increased from 14.51 per 100,000 in 1999 to 69.06 in 2020, with a decline from 2007 to 2014 followed by an increase through 2020. Females had higher AAMRs than males, and non-Hispanic Black individuals had the highest AAMR among the racial and ethnic groups examined.

CONCLUSIONS: AD-related mortality among older adults with comorbid hypertension increased substantially during the study period, with notable demographic and geographic disparities.},
}

@article {pmid42815078,
year = {2026},
author = {Cho, Y and Dictus, C and Chan, YN and Teng, CH and Shieu, B and Wang, J and Crowder, V and Plassman, BL and Beeber, A and Bryant, AL and Wu, B and Anderson, RA},
title = {A qualitative comparison of care partner experiences supporting self-care of people living with mild cognitive impairment versus mild dementia: Insights from an oral hygiene intervention.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {74},
number = {Pt A},
pages = {104360},
doi = {10.1016/j.gerinurse.2026.104360},
pmid = {42815078},
issn = {1528-3984},
abstract = {PURPOSE/AIMS: Care partners play a crucial role in supporting people living with mild cognitive impairment (PLwMCI) and mild dementia (PLwMD) in daily tasks and health behaviors. Care partners' experiences may vary depending on the care recipient's degree of cognitive decline. Our objective was to compare the challenges and strategies of care partners supporting PLwMCI versus PLwMD.

METHODS: Guided by the Adaptive Leadership Framework for Chronic Illness, we conducted a qualitative directed content analysis of secondary data from audio recordings of coaching sessions led by a nurse in a pilot of an oral hygiene intervention designed to teach care partners skills to lead behavior change in PLwMCI and PLwMD.

RESULTS: Notable differences included that care partners of PLwMCI expressed concerns about future cognitive decline and engaged in more equal and collaborative communication. In contrast, care partners of PLwMD experienced greater distress when balancing the PLwMD's autonomy with the efficiency of care, and used more tactile cues and directive communication to facilitate new routines.

CONCLUSIONS/IMPLICATIONS: These findings suggest that tailoring interventions to the level of cognitive impairment may enhance the care partners' effectiveness in supporting health behavior change for PLwMCI and PLwMD.},
}

@article {pmid42815425,
year = {2026},
author = {Mohamed, M and Koubeisi, MW and Aljuaid, F and Alosman, K},
title = {CausalEvidentialFuse: A unified framework for trustworthy multimodal clinical data fusion in healthcare diagnosis.},
journal = {Computer methods and programs in biomedicine},
volume = {288},
number = {},
pages = {109647},
doi = {10.1016/j.cmpb.2026.109647},
pmid = {42815425},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Radiomics, the high-throughput extraction of quantitative imaging features from medical images, has transformed healthcare diagnosis by enabling the integration of heterogeneous clinical data sources such as electronic health records and medical imaging. However, existing multimodal fusion approaches suffer from critical trustworthiness limitations, including susceptibility to spurious cross-modal correlations, inadequate uncertainty quantification, and limited interpretability. These shortcomings impede clinical translation, where reliable and transparent predictions are essential. This study aims to develop a unified framework that simultaneously addresses causal robustness, uncertainty calibration, and clinical interpretability in multimodal clinical data fusion. To reflect the heterogeneous modality coverage of the four benchmark datasets used in this study-MIMIC-IV and eICU (structured EHR only), MIMICCXR (chest radiograph imaging plus radiomic features), and ADNI (MRI-derived radiomic features, cognitive scores, and APOE genotype)-we frame the framework as general multimodal clinical data fusion, with the radiomics-clinical fusion setting evaluated on the imaging-bearing cohorts (MIMICCXR and ADNI) and the genomic setting represented by the single APOE marker in ADNI.

METHODS: We propose CausalEvidentialFuse, comprising three synergistic components. First, a Cross-Modal Causal Attention module leverages structural causal models and do-calculus to disentangle genuine cross-modal relationships from confounding factors including scanner variability and demographic biases. Second, an Uncertainty-Aware Evidential Fusion module, built upon Dempster-Shafer evidence theory, quantifies both aleatoric and epistemic uncertainty using Dirichlet evidence distributions. Third, a Clinical Knowledge Graph-Guided Feedback (CKGF) mechanism incorporates domain knowledge from clinical knowledge graphs (SNOMED CT and ICD-10) to regularize predictions; this module does not involve direct clinician participation, prospective clinician feedback, or explicit clinical guideline supervision, and the previous term "Clinical Knowledge Graph-Guided Feedback (CKGF)" (CKGF) has therefore been revised throughout the manuscript to CKGF. The framework was evaluated on four large-scale, de-identified, publicly available benchmark datasets spanning diverse clinical domains: Medical Information Mart for Intensive Care (version IV), its Chest X-Ray collection, the Alzheimer's Disease Neuroimaging Initiative, and the electronic Intensive Care Unit Collaborative Research Database.

RESULTS: CausalEvidentialFuse achieved the highest area under the receiver operating characteristic curve across all four datasets, with an average improvement of 2.5 percentage points (2.9% relative) over the best-performing baseline (EvidentialDL; mean AUC 0.899vs 0.874). The framework attained the lowest Expected Calibration Error of 0.031, indicating substantially better-calibrated uncertainty (a 35.4% relative reduction compared with EvidentialDL's ECE of 0.048, and a 54.4% reduction compared with the best non-evidential baseline MCAGN's ECE of 0.068). Epistemic uncertainty was reduced by 34.2% relative to baseline methods. Cross-dataset generalization demonstrated a performance retention rate of 91.8% (compared with 88.5% for the second-best method, EvidentialDL), and retrospective clinical validation confirmed clinically meaningful sensitivity and specificity across all diagnostic tasks. Inference time remained at 23 milliseconds, within clinical decision support requirements.

CONCLUSIONS: CausalEvidentialFuse establishes a new standard for trustworthy multimodal healthcare diagnosis by integrating causal reasoning, evidential uncertainty quantification, and clinical knowledge guidance within a single unified framework. The results demonstrate that addressing multiple trustworthiness dimensions simultaneously yields complementary benefits-the causal module, evidential fusion module, and knowledge-guided feedback each contribute partially independent improvements that combine favorably-achieving superior diagnostic accuracy while providing the calibrated uncertainty estimates and interpretable reasoning chains required for confident clinical adoption.},
}

@article {pmid42815436,
year = {2026},
author = {Maitri, SN and Chakre, RR},
title = {Mask attention layer modified residual vision transformer with transfer learning based features extraction for Alzheimer disease classification.},
journal = {Psychiatry research. Neuroimaging},
volume = {364},
number = {},
pages = {112341},
doi = {10.1016/j.pscychresns.2026.112341},
pmid = {42815436},
issn = {1872-7506},
abstract = {AD is an advanced neurodegenerative condition that requires precise and prompt examination for clinical involvement. Many deep learning (DL) algorithms for AD classification are computationally complex and unsuitable for real-time clinical applications. Hence, this study proposes a Mask Attention Layer Modified Residual Vision Transformer (MRViT) combined with transfer learning and Hiking Troops Optimization (HkTO) for effectual MRI-based AD classification. MRI images are gathered from the Open Access Series of Imaging Studies (OASIS) and the AD Neuroimaging (ADNI) dataset. Primarily, a Modified Pixel Gaussian filter is applied to eradicate noise and improve image quality. Afterward, deep features are extracted using transfer learning models, namely InceptionResNetV2, DenseEfficientNet-B3, and ConvoGoogleNet, to attain discriminative feature representations. The extracted features are then optimized using the HkTO algorithm to select the most relevant and non-redundant features, thereby dropping feature dimensionality. Also, HkTO is used to optimize the hyperparameters of the proposed MRViT classifier, refining classification accuracy and model robustness. Lastly, the certain optimal features are classified using the proposed MRViT architecture, including a mask attention mechanism to highlight disease-relevant regions while suppressing irrelevant information. Testing on the OASIS and ADNI datasets shows classification accuracies of 99.66 % and 99.89 %, proving the framework's precision and computational efficiency.},
}

@article {pmid42815452,
year = {2026},
author = {Oltra-Cucarella, J and Bonete-López, B and Iñesta, C and Guillén-Torrano, D and Ripoll, O and Obodo-Arroyo, CO and Pérez-Elvira, R and Wöbbeking, D and Sánchez-Sansegundo, M and Tomé, M and Freilich, B and Abellán-Miralles, I and Pérez-Carmona, N and Ruiz-Piñero, M and Sitges-Maciá, E},
title = {Sensitivity and specificity of the attention, memory, and frontal abilities screening test to identify objective cognitive impairment in older adults: a pilot study.},
journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists},
volume = {41},
number = {7},
pages = {},
doi = {10.1093/arclin/acag075},
pmid = {42815452},
issn = {1873-5843},
support = {GV/2021/139//Conselleria Innovación, Universidades, Ciencia i Sociedad Digital, Generalitat Valenciana/ ; CIGE/2023/29//Conselleria Innovación, Universidades, Ciencia i Sociedad Digital, Generalitat Valenciana/ ; },
mesh = {Humans ; Pilot Projects ; Female ; Aged ; Male ; *Neuropsychological Tests ; *Cognitive Dysfunction/diagnosis ; Sensitivity and Specificity ; Middle Aged ; *Attention/physiology ; *Memory/physiology ; Aged, 80 and over ; ROC Curve ; },
abstract = {OBJECTIVE: The use of screening tests is part of the neuropsychological assessment. Recently, the Attention, Memory and Frontal Abilities Screening Test (AMFAST) has been developed and translated to Spanish. However, its diagnostic properties have never been compared to other tests used to identify cognitive impairment. The goal of this pilot study is to compare the diagnostic properties of the AMFAST with those of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-Neuropsychological Battery (CERAD-NB) in their ability to distinguish pre-defined clinical groups in a heterogeneous clinical sample of Spanish older adults.

METHODS: Ninety-four participants (66 cognitively unimpaired - CU; 28 cognitively impaired - CI) aged 50 or older were assessed with the AMFAST and the CERAD-NB, and differences between groups were analyzed with beta-binomial models. The diagnostic properties of both tests were calculated with adjusted-ROC curves, and areas under the curve (AUCs) were compared.

RESULTS: The CU group outperformed the CI group both on the AMFAST (b = -1.67, std. error (SE) = 0.19, p < .001) and on the CERAD-NB (b = -1.02, SE = 0.12, p < .001). The adjusted-ROC curves showed no differences in sensitivity and specificity compared to the model with test scores only, neither for the AMFAST (z = -1.03, p = .305) nor for the CERAD (z = -1.16, p = .246), with no statistically significant differences in the AUC (AMFAST = 0.954, CERAD = 0.954, p = .989).

CONCLUSIONS: Our preliminary results based on a small, diagnostically heterogeneous sample suggest that the AMFAST and the CERAD-NB did not differ significantly to identify objective cognitive impairment. Future studies with larger, more homogenous samples are needed.},
}

Humans
Pilot Projects
Female
Aged
Male
*Neuropsychological Tests
*Cognitive Dysfunction/diagnosis
Sensitivity and Specificity
Middle Aged
*Attention/physiology
*Memory/physiology
Aged, 80 and over
ROC Curve

@article {pmid42815597,
year = {2026},
author = {Kahou Tadah, RB and Bilanda, DC and Ngapout Fifen, JR and Kengne, SF and Owona, PE and Akamba Ambamba, BD and Tcheutchoua, YC and Bidinga A Goufani, CR and Follesa, P and Kamtchouing, P and Dzeufiet Djomeni, PD},
title = {Neuroprotective effects of Isodon ramosissimus (Hook.f.) Codd (Lamiaceae) aqueous extract against scopolamine-induced Alzheimer-like phenotype.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122429},
doi = {10.1016/j.jep.2026.122429},
pmid = {42815597},
issn = {1872-7573},
abstract = {Isodon ramosissimus is traditionally used in folk medicine for the management of neurological disorders. However, its neuroprotective properties against scopolamine-induced cognitive impairments have not yet been scientifically investigated.

AIM OF THE STUDY: This study investigated the anti-amnesic and neuroprotective effects of the aqueous extract of Isodon ramosissimus (IrAE) in a scopolamine-induced Alzheimer's-like phenotype in rats.

MATERIALS AND METHODS: Liquid chromatography-mass spectrometry (LC-MS) and quantitative phytochemical analyses were performed to tentatively identify IrAE bioactive compounds. Forty-eight male Wistar rats were randomly assigned to six groups receiving saline, scopolamine (1 mg/kg), scopolamine plus donepezil (5 mg/kg), or scopolamine plus IrAE (75, 150, or 300 mg/kg) for 14 consecutive days. Learning and memory were evaluated using the novel object recognition and Morris water maze tests. Cholinesterase activity, oxidative stress biomarkers, and histopathological changes in the prefrontal cortex and hippocampus were also assessed.

RESULTS: Scopolamine induced significant cognitive deficits (p < 0.01), increased Acetylcholinesterase activity and oxidative stress (p < 0.01), and caused substantial neuronal damage. IrAE treatment significantly reversed learning and memory deficits (p < 0.01), attenuated acetylcholinesterase activity and oxidative stress (p < 0.01), and preserved cortical and hippocampal neurons from scopolamine's neurotoxic effects. LC-MS analysis tentatively identified oridonin, stigmasterol, chrysoeriol, ferruginol, and corosolic acid, compounds with reported cognitive-enhancing, antioxidant, anti-inflammatory, anticholinesterase, and neuroprotective activities.

CONCLUSION: IrAE exerts marked anti-amnesic and neuroprotective effects, associated with cholinergic and antioxidant modulation. These findings provide preliminary pharmacological support for the traditional use of IrAE, warranting further preclinical investigation of its potential in the management of cognitive disorders.},
}

@article {pmid42815778,
year = {2026},
author = {Sasaguri, H},
title = {Current Status of Models for Alzheimer's Disease and Related Neurodegenerative Diseases.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105126},
doi = {10.1016/j.neures.2026.105126},
pmid = {42815778},
issn = {1872-8111},
}

@article {pmid42815878,
year = {2026},
author = {Zhang, XT and Murphy, M and Riordan, H and Wang, K and Esquivel, R and Xu, W and Zhang, X and Gong, X and Sun, Y and Lu, Y},
title = {Understanding Alzheimer's disease through biomarkers: pathology, progression, and clinical application.},
journal = {Bioanalysis},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/17576180.2026.2740372},
pmid = {42815878},
issn = {1757-6199},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide accounting for an estimated 60% to 80% of cases. Biomarkers play an integral role in AD randomized clinical trials (RCTs), providing objective measures of disease pathology, progression, and therapeutic efficacy. Key biomarkers, including amyloid-beta (Aβ), tau proteins, neuroinflammatory and neurodegeneration markers, as well as various neuroimaging modalities can help to facilitate the assessment of disease-modifying therapies, enable earlier detection of pathological changes before clinical symptoms emerge, and inform regulatory decision-making by demonstrating target engagement and possible treatment efficacy when linked to cognitive outcomes. This review examines the most salient biomarkers in AD RCTs and underlines their importance in advancing diagnostics, guiding therapeutic development, and improving clinical trial design to enable effective disease-modifying treatments. [Relevant literature was identified through searches of PubMed and Google Scholar for studies published through June 2026].},
}

@article {pmid42815901,
year = {2026},
author = {Dai, R and Dai, J and Yan, C and Shi, L and Bi, J and Huang, P and Zhai, Y and Sun, S and Zhu, WH and Guo, Z},
title = {Discriminating Monomers and Fibrils of Amyloid-β1-42 With Site-Ordered Peptide-QMFluors.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e3711838},
doi = {10.1002/anie.3711838},
pmid = {42815901},
issn = {1521-3773},
support = {2023YFA1802000//National Key Research and Development Program/ ; 22225805//NSFC/China/ ; T2522013//NSFC/China/ ; 32121005//NSFC/China/ ; 32394001//NSFC/China/ ; 22378122//NSFC/China/ ; 23J21901600//Shanghai Science and Technology Innovation Action Plan/ ; //Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism/ ; 2021 Sci & Tech 03-28//Shanghai Municipal Education Commission/ ; 24DX1400200//Science and Technology Commission of Shanghai Municipality/ ; },
abstract = {The detection of soluble amyloid-β (Aβ), the most neurotoxic species in early Alzheimer's disease (AD), remains a major analytical challenge. Conventional probes are designed to target the β-sheet structures of mature fibrils and are thus blind to these transient, nonfibrillar species. Here, we introduce "site-ordered engineering" strategy, a peptide-conjugated QMFluors conjugate designed to selectively target Aβ1-42 monomers with high fidelity. We identified the conjugation site order on the fluorophore as the key parameter controlling this molecular topology and self-assembly behavior. This breakthrough is enabled by a hydrogen-bond-driven recognition mechanism, fundamentally departing from classical dyes that target the β-sheets of mature fibrils. This yields an unprecedented "inverted selectivity" with a 20-fold fluorescence enhancement for monomers over fibrils. Using probe N-QM-KLVFF with super-resolution microscopy, we reveal the nanoscale "core-shell" biophysical phase diagram of plaques, visualizing dense fibrillar cores surrounded by monomeric/oligomeric halos. Furthermore, the probe demonstrates a limit of detection of pg/mL level and excellent linearity, meeting the stringent requirements for trace cerebrospinal-fluid-biomarker analysis. This work provides not only a powerful tool for early diagnosis and pathological investigation, but also establishes "aggregation-regulated accessibility" as a generalizable principle for designing probes for other dynamic amyloid protein targets.},
}

@article {pmid42816030,
year = {2026},
author = {Zhu, W and Yuan, N and Tang, M and She, K and Chen, M and Huang, M and Feng, R and Ma, Q and Chen, J},
title = {From bench to beside: luteolin's therapeutic promise in neurological disorders.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1153-1162},
doi = {10.1016/S1875-5364(26)61211-3},
pmid = {42816030},
issn = {1875-5364},
mesh = {*Luteolin/therapeutic use/pharmacology/chemistry ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; *Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Antioxidants ; *Parkinson Disease/drug therapy ; },
abstract = {Luteolin (3',4',5,7-tetrahydroxyflavone) is a naturally occurring flavonoid found in diverse plant families, including Apiaceae, Brassicaceae and Lamiaceae, and is a major bioactive component of Chinese medicines such as Chrysanthemum morifolium and Perilla frutescens. It possesses antidepressant, anti-inflammatory, antioxidant and neuroprotective activities, and has shown therapeutic potential in depression, Alzheimer's disease (AD) and Parkinson's disease (PD). Based on a comprehensive PubMed search, this review examines the shared pathological features-neuroinflammation, oxidative stress and synaptic dysfunction-across these three disorders and elucidates the pharmacological actions of luteolin. Clinical trial data were retrieved from NIH and ICTRP registries. We critically analyze current research limitations, including the lack of validated direct targets beyond PPARγ, the predominance of pathway-based evidence without orthogonal validation, and significant pharmacokinetic defects (low oral bioavailability, rapid glucuronidation, poor BBB penetration). While luteolin holds promise for central nervous system (CNS) disorders, its clinical translation requires advanced drug delivery systems (e.g., nano-formulations, brain-region-specific prodrugs), combination therapies or structural modification, and future cohort studies for prophylactic use. Addressing these priorities will be essential for its therapeutic development.},
}

*Luteolin/therapeutic use/pharmacology/chemistry
Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy
*Alzheimer Disease/drug therapy
Oxidative Stress/drug effects
Antioxidants
*Parkinson Disease/drug therapy

@article {pmid42816032,
year = {2026},
author = {Fan, L and Jiang, H and Yi, M and Peng, W and Zhang, Z},
title = {Icariin enhances PINK1-associated mitophagy to attenuate NLRP3/GSDMD-related microglial pyroptosis and cognitive impairment in Alzheimer's disease.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1176-1190},
doi = {10.1016/S1875-5364(26)61213-7},
pmid = {42816032},
issn = {1875-5364},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Microglia/drug effects/metabolism ; PTEN-Induced Putative Kinase ; Mice ; *Mitophagy/drug effects ; *Flavonoids/pharmacology ; *Pyroptosis/drug effects ; *Protein Kinases/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism/genetics ; Humans ; Mice, Transgenic ; Molecular Docking Simulation ; Male ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which microglia-mediated neuroinflammation contributes to disease progression. Icariin (ICA), a major bioactive flavonoid from Epimedium, has neuroprotective activity, but how it regulates mitochondrial quality control and inflammatory injury in microglia remains unclear. In the present study, APP/PS1 transgenic mice and Aβ1-42-stimulated BV-2 microglia were used to examine the effects of ICA on mitophagy, mitochondrial stress, NLRP3/GSDMD-related pyroptotic changes, and neuroinflammation. Behavioral testing, histological analysis, transcriptomic profiling, immunofluorescence, Western blotting, ELISA, molecular docking, molecular dynamics simulation, cellular thermal shift assay, Mdivi-1 co-treatment, and siRNA-mediated Pink1 knockdown were performed. ICA improved cognitive deficits in APP/PS1 mice and reduced microglial inflammatory activation. Transcriptomic and experimental analyses showed that ICA enhanced mitophagy-related responses, restored mitochondrial membrane potential, and reduced excessive mitochondrial reactive oxygen species accumulation. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay supported potential engagement of ICA with PINK1. ICA also reduced NLRP3 inflammasome-associated inflammatory injury, GSDMD-related pyroptotic changes, and IL-1β and IL-18 release. In APP/PS1 mice, Mdivi-1 co-treatment weakened the anti-inflammatory effects of ICA. In Aβ1-42-stimulated BV-2 microglia, Pink1 knockdown reduced ICA-induced LC3/TOM20 colocalization and partially reversed the inhibitory effects of ICA on NLRP3 inflammasome-associated inflammatory markers. Overall, ICA enhances PINK1-associated mitophagy, alleviates mitochondrial stress, and attenuates NLRP3/GSDMD-related microglial pyroptotic injury in AD-related models. These findings suggest that PINK1-associated mitochondrial quality control contributes to the neuroprotective effects of ICA.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics
*Microglia/drug effects/metabolism
PTEN-Induced Putative Kinase
Mice
*Mitophagy/drug effects
*Flavonoids/pharmacology
*Pyroptosis/drug effects
*Protein Kinases/metabolism/genetics
*Cognitive Dysfunction/drug therapy/metabolism/genetics
Humans
Mice, Transgenic
Molecular Docking Simulation
Male

@article {pmid42816035,
year = {2026},
author = {Zhu, M and Wang, Y and Tang, H and Sun, Y and Feng, X and Wang, Q and Kuang, H},
title = {Data mining and multi-omics profiling to reveal the mechanisms of cold/hot property of traditional Chinese medicine in Alzheimer's disease treatment.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1221-1236},
doi = {10.1016/S1875-5364(26)61216-2},
pmid = {42816035},
issn = {1875-5364},
mesh = {Animals ; Humans ; Rats ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Data Mining ; *Drugs, Chinese Herbal/pharmacology ; Gastrointestinal Microbiome/drug effects ; Medicine, Chinese Traditional ; Metabolomics ; Multiomics ; Oxidative Stress/drug effects ; Proteomics ; },
abstract = {Alzheimer's disease (AD) is a severely debilitating condition that significantly hampers independent living, with no effective treatments currently available. Traditional Chinese medicine (TCM) has shown substantial promise in both preventing and alleviating AD symptoms. The medicinal properties-specifically hot, warm, cool, and cold-serve as a critical link between TCM theory and clinical application. However, the majority of research has concentrated on individual herbs for AD, with relatively few comprehensive studies exploring the biological mechanisms through which these herbs exert their medicinal properties. In this context, data mining, network pharmacology, and multi-omics approaches, including metabolomics, gut microbiota analysis, and proteomics, were employed to elucidate the effects and mechanisms of action of three hot/warm property herbs (THPH) and three cold/cool property herbs (TCPH) in the treatment of AD. Findings indicated that the herbs effective against AD primarily possess warm properties. THPH demonstrated a significant enhancement in cognitive, learning, and memory functions in AD rat models when compared to TCPH, potentially achieving therapeutic effects by boosting the synthesis of the neurotransmitter acetylcholine. Furthermore, THPH modulated energy metabolism, corrected metabolic imbalances in both brain and serum within AD rat models, inhibited oxidative stress, restored synaptic plasticity-related proteins and signaling pathways, and maintained intestinal microbiota homeostasis. Consequently, this study offers valuable insights into the therapeutic implications of the hot (warm) and cold (cool) properties of TCM in the management of Alzheimer's disease.},
}

Animals
Humans
Rats
*Alzheimer Disease/drug therapy/metabolism/genetics
Data Mining
*Drugs, Chinese Herbal/pharmacology
Gastrointestinal Microbiome/drug effects
Medicine, Chinese Traditional
Metabolomics
Multiomics
Oxidative Stress/drug effects
Proteomics

@article {pmid42816467,
year = {2026},
author = {Brunwasser, SJ and McGregor, JN and Bhaskaran-Nair, K and Farris, CA and Elmore, H and Higashikubo, BT and Berriman-Rozen, ZD and Ko, D and Dyer, EL and Grady, JM and Whitesell, JD and Harris, JA and Hengen, KB},
title = {The default mode network exhibits circuit-specific selective vulnerability despite widespread amyloid burden in an animal model of Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42816467},
issn = {2041-1723},
support = {R01AG091773//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 1R01EB029852//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; A2022038S//BrightFocus Foundation (BrightFocus)/ ; R01AG047589//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 NS118442/NS/NINDS NIH HHS/United States ; R01 AG091773/AG/NIA NIH HHS/United States ; R01 EB029852/EB/NIBIB NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology/pathology ; Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; Mice ; Hippocampus/metabolism/physiopathology/pathology ; Mice, Transgenic ; *Default Mode Network/physiopathology/metabolism/pathology ; Plaque, Amyloid/metabolism ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; Neurons/metabolism ; Gyrus Cinguli/physiopathology/metabolism/pathology ; *Nerve Net/physiopathology/metabolism ; Female ; },
abstract = {In Alzheimer's Disease (AD) the default mode network (DMN) exhibits selective vulnerability to functional decline and amyloid beta (Aβ) plaques in early AD. DMN vulnerability may simply be the result of Aβ accumulation. Alternately, Aβ may unmask an intrinsic susceptibility of DMN circuits. Should DMN vulnerability persist amidst global Aβ deposition, this would support the latter hypothesis. We tested this using long-term, multi-region recordings of single units in mice characterized by widespread Aβ (APP/PS1). We tracked a neuronal population within the retrosplenial cortex (a DMN region) and two monosynaptically connected target populations, one within (anterior cingulate) and the other outside the DMN (primary visual cortex). We also recorded in hippocampus and examined interactions between the in-DMN and out-DMN circuits. Our data revealed progressive dysfunction restricted to the in-DMN circuit. In contrast, communication originating within but targeting an out-DMN population was unaffected by disease. Dysfunction was pronounced in sleep.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology/pathology
Disease Models, Animal
*Amyloid beta-Peptides/metabolism
Mice
Hippocampus/metabolism/physiopathology/pathology
Mice, Transgenic
*Default Mode Network/physiopathology/metabolism/pathology
Plaque, Amyloid/metabolism
Male
Amyloid beta-Protein Precursor/genetics/metabolism
Neurons/metabolism
Gyrus Cinguli/physiopathology/metabolism/pathology
*Nerve Net/physiopathology/metabolism
Female

@article {pmid42816521,
year = {2026},
author = {Othman, M and Khedr, E and Fawi, G and Heikal, S and Mostafa, SA and Ibrahim, A and Qayaty, A and Ali, EM and Salama, M},
title = {Blood metal signatures and their association with Alzheimer's disease risk and cognitive decline in an Egyptian cohort.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42816521},
issn = {2730-664X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial disease in which environmental exposures may contribute to disease risk. This study aimed to investigate associations between blood concentrations of arsenic, lead, mercury, and lithium with AD risk and cognitive performance in an Egyptian cohort.

METHODS: We conducted a cross-sectional study in 50 AD patients and 50 cognitively healthy controls recruited across multiple centres in Egypt. Blood metal concentrations were measured by inductively coupled plasma optical emission spectrometry. A tiered analytical strategy addressed variable left-censoring: group-stratified Kaplan-Meier imputation was applied for arsenic, lead, and lithium, followed by logistic and linear regression adjusted for age and sex, with a binary detection sensitivity analysis for lithium, lead, and mercury. Multiple testing was corrected using the Benjamini-Hochberg false discovery rate method.

RESULTS: Here we show that higher arsenic concentrations are strongly associated with increased odds of AD (OR = 1321.61, p = 3.48×10⁻⁶) and lower cognitive scores (β = -16.44, p = 1.46×10⁻⁸), both surviving false discovery rate correction. Higher lithium is associated with reduced disease odds (OR = 0.634, FDR-adjusted p = 0.022) and better cognitive performance (β = 1.21, FDR-adjusted p = 0.020), corroborated in sensitivity analyses. Mercury detection is markedly more frequent in patients than controls (24% vs. 2%, p = 0.002) and associates with lower cognitive scores (β = -7.08, p = 0.0003). Lead shows a borderline association with disease (OR = 1.53, p = 0.046) that does not survive correction.

CONCLUSIONS: These findings support arsenic neurotoxicity and lithium deficiency as potentially important contributors to AD risk in an Egyptian population, with implications for environmental public health in low- and middle-income settings.},
}

@article {pmid42816571,
year = {2026},
author = {Mason-Chalmers, K and Rodriguez, JA},
title = {Harmful tau spreads like self-propagating prion proteins.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42816571},
issn = {1476-4687},
}

@article {pmid42816601,
year = {2026},
author = {Nan, J and Boix, CA and Shi, S and Fan, X and Ni, J and Wang, K and Shuai, X and Ding, K and Wu, P and An, Y and Sun, N and Hou, L and Chen, K and Huang, X and Li, C and Akay, L and Louderback, K and Nawaid, H and Park, YP and Fu, X and Liu, C and Li, X and Yin, Y and Mo, W and Yang, Z and Ma, W and Hu, X and Bennett, DA and Kellis, M and Tsai, LH and Sunyaev, S and Li, J and Xiong, X},
title = {Single-cell profiling and genetic regulation of alternative polyadenylation in the human brain.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42816601},
issn = {1546-1718},
support = {32422017, 92353301, 32370609//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024YFF1207600, 2023YFA1800700//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; LR25C060002//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Alternative polyadenylation (APA) has a central role in regulation of the fate of mRNA and exhibits high variability in the brain and in neurons. However, brain APA regulation has not been mapped at cell type resolution, and the genetic control of APA in brain cell types and its contribution to genetic disease have remained unclear. Here we report a single-cell atlas of APA of the aged human brain across 2 million cells from 379 human postmortem brains across individuals with and without Alzheimer's disease (AD). We show that APA provides an independent mechanistic layer for understanding gene regulatory changes in AD, as genes with APA alterations are distinct from those with expression changes but often converge to similar pathways, including microglial activation and microtubule transport in neurons. We integrate APA variation with whole-genome sequencing to identify cell-type-resolved 3' untranslated region quantitative trait loci (3'aQTLs) for 4,288 genes. We find that 3'aQTLs preferentially colocalize with pQTLs over eQTLs. Across 17 brain traits and diseases, we identify 168 GWAS loci dependent on 3'aQTLs, of which only 17.5% are shared with eQTLs. These include PLEKHA1 and APOC2 for AD, PAK6 and AP3B2 for schizophrenia, NDUFA13 for bipolar disorder, MTCH2 for multiple brain traits, and SNCA, the top locus in Parkinson's disease. We show that 3' untranslated region choice alters SNCA mRNA localization within the cell, consistent with the observation that the SNCA risk locus acts in an eQTL-independent manner in neurons and oligodendrocytes. Our results provide a cell-type-specific foundation to interrogate the cis and trans regulation of APA and to understand the contribution to disease heritability of this key post-transcriptional layer.},
}

@article {pmid42816607,
year = {2026},
author = {Lövestam, S and Shimozawa, A and Tarutani, A and Ohtani, R and Masuda-Suzukake, M and Hasegawa, K and Robinson, AC and Saito, Y and Murayama, S and Yoshida, M and Suzuki, H and Onaya, M and Hasegawa, M and Goedert, M and Scheres, SHW},
title = {Prion-like transmission of human tau strains in the mouse brain.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42816607},
issn = {1476-4687},
abstract = {Most neurodegenerative diseases are thought to spread through the brain by prion-like mechanisms, in which filamentous protein assemblies self-propagate by templated seeding[1]. Distinct conformations of amyloid filaments may provide the physical basis for the strains that lead to different diseases[2]. However, a central pillar of the prion hypothesis, that strains retain their structural identity upon transmission, has not been demonstrated. Here we show that the injection of tau filaments from the brains of individuals with Alzheimer's disease or corticobasal degeneration into the brains of wild-type mice leads to the seeded assembly of amyloid filaments made of mouse tau with the same structures as those of the seeds. Thus, we show that, similar to prion strains, tau filaments propagate through templated seeding, and that the mouse is a suitable model to study the molecular mechanisms by which distinct tau folds drive disease-specific pathology in the brain.},
}

@article {pmid42816815,
year = {2026},
author = {Mar, J and Arrospide, A and Handels, R and Soto-Gordoa, M},
title = {Economic model of Alzheimer's disease that incorporates the uncertainty associated with measuring efficacy in clinical trials.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490543},
doi = {10.1177/13872877261490543},
pmid = {42816815},
issn = {1875-8908},
abstract = {BackgroundClinical trials of Alzheimer's disease (AD) treatments are ongoing, and uncertainty about their efficacy is a key factor in their evaluation.ObjectiveThe objective of this study was to propose a new methodological approach for the economic evaluation of treatments to account for the uncertainty associated with measuring efficacy in clinical trials and the waning effect.MethodsA discrete event simulation model was built using data from a synthetic clinical trial dataset to model typical patient-level natural history trajectories of Clinical Dementia Rating scores from mild cognitive impairment to severe dementia using mixed regression models for repeated measures (MMRM). As the MMRM coefficients are correlated, this variability was incorporated into the model probabilistic sensitivity analysis using Cholesky decomposition. Uncertainty about treatment effect waning was addressed by scenario analysis (optimistic and pessimistic).ResultsAlthough the main contribution of this study is to describe an innovative model, the results of the hypothetical intervention are presented in the standard format of incremental cost-utility ratios (ICURs), cost-effectiveness and acceptability curves. Specifically, the ICUR of the hypothetical treatment ranged from €73,216 to €63,662 per quality-adjusted life year.ConclusionsWe present an innovative approach to the economic evaluation of Alzheimer's disease treatments, applying a Monte Carlo simulation approach (PSA) to two scenarios and shaping individual cognitive trajectories on a continuous scale to fit the target population of clinical trials. Its transparent design allows the economic model to be shared between the pharmaceutical company and the assessment agencies while keeping individuals' clinical trial data confidential.},
}

@article {pmid42816822,
year = {2026},
author = {Li, B and Shi, T and Yang, M and Liu, H},
title = {Nonlinear association between waist-to-height ratio and Alzheimer's disease among middle-aged and older adults: A cross-sectional study from NHANES.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490818},
doi = {10.1177/13872877261490818},
pmid = {42816822},
issn = {1875-8908},
abstract = {BackgroundThe association between waist-to-height ratio (WHtR) and Alzheimer's disease (AD) remains unclear in the general population.ObjectiveThis study aimed to investigate the relationship between WHtR and AD using data from the nationally representative National Health and Nutrition Examination Survey (NHANES).MethodsThis cross-sectional study included participants aged ≥45 years from NHANES. Weighted multivariable logistic regression, restricted cubic spline (RCS), subgroup, and sensitivity analyses were performed to evaluate the association between WHtR (scaled by 10) and AD.ResultsHigher WHtR was significantly associated with greater odds of AD after adjustment for potential confounders (OR = 1.30, 95% CI: 1.18-1.42, p < 0.001). Significant interactions were observed for age (p for interaction = 0.017) and physical activity (p for interaction = 0.02). RCS analysis revealed a significant nonlinear U-shaped association between WHtR and AD (p for nonlinearity = 0.005), with the lowest odds observed at a WHtR value of 5.46 on the 10-fold scale. Sensitivity analyses showed generally consistent results.ConclusionsHigher WHtR was significantly associated with greater odds of AD among middle-aged and older adults. A nonlinear U-shaped association was also observed, suggesting that both lower and higher WHtR levels may be associated with increased odds of AD. Further prospective studies are warranted to confirm these findings.},
}

@article {pmid42816823,
year = {2026},
author = {Zhu, C and Li, H and Gao, J and Li, H and Qiao, Y and Li, J and Wang, Q and Gao, F and Shao, L and Wang, L and Wu, D and Zheng, Y and Gao, Q and Qiao, Y and Du, J and Zhang, J},
title = {Use of multiple post-diagnostic dementia services across healthcare tiers in Beijing, China: A caregiver-reported cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489615},
doi = {10.1177/13872877261489615},
pmid = {42816823},
issn = {1875-8908},
abstract = {BackgroundPost-diagnostic dementia care, including for Alzheimer's disease, is multi-component and requires coordinated access to cognitive assessment, medication management, consultation for behavioral and psychological symptoms of dementia (BPSD), and non-pharmacological interventions. Evidence on service use and tiered distribution in China remains limited.ObjectiveTo characterize the use, tiered distribution, and reasons for non-use of four post-diagnostic dementia services in Beijing, China, and to explore caregiver-related correlates of service use.MethodsFrom July to October 2025, 202 family caregivers were recruited by convenience sampling from three tertiary hospitals and six community health service centers across four Beijing districts. A structured questionnaire was administered through interviews. Four exploratory Firth penalized likelihood logistic regression models were fitted, with Benjamini-Hochberg correction as a supplementary assessment of multiplicity.ResultsService use varied substantially: cognitive assessment 95.5%, medication management 83.7%, BPSD consultation 61.8% (n = 131), and non-pharmacological interventions 25.7%. Only 16.8% of caregivers reporting BPSD accessed all four services. Tiered distribution was heterogeneous: non-pharmacological interventions concentrated in hospitals; medication management more often involved primary care. Higher income was associated with non-pharmacological intervention use, and regular clinic attendance with BPSD consultation. "Unaware" was the leading reason for non-use of BPSD consultation, cognitive stimulation, and cognitive training, whereas "no perceived need" predominated for ADL rehabilitation.ConclusionsPost-diagnostic dementia service use in Beijing was uneven across service types and healthcare tiers. The exploratory associations suggest that informational and economic factors may be relevant to access to underused services within China's tiered healthcare system.},
}

@article {pmid42816829,
year = {2026},
author = {Goncalo, AK},
title = {The role of neuroinflammation in the connections between autism spectrum disorder and Alzheimer's disease and related dementias: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491809},
doi = {10.1177/13872877261491809},
pmid = {42816829},
issn = {1875-8908},
abstract = {Recent evidence suggests a link between autism spectrum disorder (ASD) and early-onset Alzheimer's disease and related dementias (AD/ADRD), yet the mechanisms underlying this association remain poorly understood. This narrative review investigates whether early management of ASD may reduce the risk of developing AD/ADRD by targeting shared biological pathways. A literature search was conducted using PubMed and included English-language studies published from 1996 to 2026. Eligible studies addressed ASD, AD/ADRD, neuroinflammation, aging, or dementia, and included systematic reviews, meta-analyses, narrative reviews, clinical trials, randomized controlled trials, and translational animal studies. Studies lacking discussion of mechanisms relevant to ASD, neuroinflammation, aging, or dementia were excluded. Search terms included AD, dementia, ASD, inflammation, pregnenolone, omega-3, prednisolone, celecoxib, minocycline, N-acetylcysteine, sulforaphane, histamine receptor agonists, and GABA. Additional studies were identified through reference list screening. Of 170 records identified, 133 met the inclusion criteria and formed the basis for the review. Findings indicate that neuroinflammation is a central mechanism linking ASD-related comorbidities with established AD/ADRD risk factors. The evidence suggests that reducing neuroinflammation, particularly through interventions targeting microglial activation during childhood or early adulthood, may lower the likelihood of early-onset AD/ADRD in individuals with ASD. Although current evidence is primarily theoretical and indirect, it supports further investigation of anti-inflammatory strategies as potential preventive interventions. The review concludes by proposing future empirical studies to test whether early neuroinflammation-targeted treatment in ASD can reduce the incidence of early-onset AD/ADRD.},
}

@article {pmid42816830,
year = {2026},
author = {Pintus, M and Valletta, M and Sacchi, L and Carandini, T and Ghezzi, L and Pietroboni, A and Fenoglio, C and Serpente, M and Arcaro, M and Bruno, G and Galimberti, D and Canevelli, M and Arighi, A},
title = {Exploring the interplay between frailty, Alzheimer's disease biomarkers, and cognitive functioning in patients with mild cognitive impairment: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487377},
doi = {10.1177/13872877261487377},
pmid = {42816830},
issn = {1875-8908},
abstract = {BackgroundFrailty is characterized by declining homeostatic reserves and increased vulnerability to stressors, and has been associated with cognitive decline and dementia.ObjectiveTo examine the relationship between frailty, Alzheimer's disease (AD) biomarkers, and cognitive performance in individuals with mild cognitive impairment (MCI).MethodsWe enrolled 183 MCI patients from the Diagnostic Outpatient Service of the Neurodegenerative Diseases Unit at IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan. Cerebrospinal fluid (CSF) biomarkers amyloid-β42, total-tau, and phosphorylated-tau181were analyzed. Frailty was assessed using a 47-item frailty index (FI), and cognitive performance was measured with the Mini-Mental State Examination (MMSE).ResultsHigher FI scores were associated with lower MMSE scores, even after adjusting for amyloid and tau biomarkers (β = -0.72, 95% CI -1.20, -0.24). Compared to robust (FI ≤ 0.11) amyloid-negative subjects, individuals with higher FI (>0.11) and CSF amyloid positivity had significantly lower MMSE scores. Patients with lower FI had twice the odds ratio (OR 2.00, 95% CI 1.02-3.90) of presenting an amyloid-positive (A+) CSF profile compared to those with higher FI; similar trends were found for the amyloid and tau-positive (A + T+) profile (OR 2.29, 95% CI 1.14-4.61).ConclusionsFrailty modulates the phenotypic variability of AD, influencing its clinical expression in MCI. Specifically, it is associated with lower cognitive performance in MCI independently of AD biomarker status and contributes synergistically with amyloid pathology to cognitive decline. Moreover, lower frailty levels are associated with a higher likelihood of an AD-compatible CSF profile, suggesting that frailty assessment may aid in identifying patients at greater risk.},
}

@article {pmid42816862,
year = {2026},
author = {Woudstra, AL and Holtman, L and van Vliet, EA},
title = {Microglia-derived extracellular vesicle content as a biomarker for early detection of Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42816862},
issn = {2047-9158},
support = {20-11//EpilepsieNL/ ; },
mesh = {Humans ; *Microglia/metabolism/pathology ; *Alzheimer Disease/diagnosis/metabolism/pathology ; Biomarkers/metabolism ; *Extracellular Vesicles/metabolism/pathology ; Early Diagnosis ; Animals ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta aggregation, tau pathology, synaptic dysfunction, and neuronal loss. While current biomarker frameworks such as the A/T/N classification have advanced diagnosis, they predominantly reflect relatively late stages of disease, limiting opportunities for early intervention. This underscores the urgent need for biomarkers that are not only accessible and sensitive but also specific to the earliest pathogenic mechanisms of AD. Recent work has underscored the pivotal role of disease-associated microglia (DAM) in the onset and progression of AD. DAM exhibit dual roles: they promote protection by phagocytosing amyloid and debris, metabolizing lipids, and remodelling synapses, yet can also drive pathology through excessive cytokine release, chronic inflammatory signalling, and impaired aggregate clearance. DAM release extracellular vesicles (EVs) that encapsulate proteins, nucleic acids, and lipids, reflective of their state. These vesicles reflect microglial (dys)function and can be detected in cerebrospinal fluid and blood, offering a minimally invasive means to monitor early AD pathology. In this review, we examine the emerging evidence that the content of microglia-derived EVs may fulfil the criteria of ideal biomarkers with a focus on the detectability, sensitivity, specificity, and feasibility for longitudinal monitoring. We discuss their potential to overcome limitations of current fluid and imaging biomarkers by offering more stable cargo protection, cell-type specificity, and accessibility in peripheral fluids. Furthermore, we highlight the opportunities and challenges in isolating microglia-derived EVs, identifying reliable surface and cargo markers, and standardizing methodologies for reproducibility across studies. By integrating insights from microglial biology with EV research, we provide evidence for microglia-derived EV content as biomarkers for early detection of AD and propose a roadmap toward DAM-specific EV signatures that could transform early AD diagnosis and disease monitoring. Such advances hold promise not only for AD but also for broader applications in neurodegenerative and neuroinflammatory disorders.},
}

Humans
*Microglia/metabolism/pathology
*Alzheimer Disease/diagnosis/metabolism/pathology
Biomarkers/metabolism
*Extracellular Vesicles/metabolism/pathology
Early Diagnosis
Animals

@article {pmid42816892,
year = {2026},
author = {Wang, H and Fan, X and Ping, J and Shao, Q and Wang, C and Wang, H and Ji, Q and Su, M and Qian, W},
title = {Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42816892},
issn = {2047-9158},
support = {JC2023042//Nantong Natural Science Foundation/ ; 82607575//National Natural Science Foundation of China/ ; 82473926//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Proto-Oncogene Proteins c-fyn/metabolism ; *Neurodegenerative Diseases/metabolism/enzymology ; *Tauopathies/metabolism/enzymology ; Animals ; tau Proteins/metabolism ; Signal Transduction/physiology ; },
abstract = {Synaptic dysfunction and intracellular accumulation of pathological tau are convergent hallmarks of Alzheimer's disease (AD) and related tauopathies, yet the molecular mechanisms coupling these events to widespread neurodegeneration remain incompletely understood. The Src family kinase Fyn has emerged as a critical signaling hub that integrates upstream pathogenic triggers, such as amyloid-β (Aβ), with downstream neurotoxic cascades. Here, we review the multifaceted roles of Fyn in orchestrating synaptic failure, highlighting how Fyn recruitment by mislocalized tau promotes N-methyl-D-aspartate receptor hyperactivation and calcium dysregulation. We examine the biophysical basis of Fyn-tau interactions, particularly the role of liquid-liquid phase separation in stabilizing toxic signaling complexes. We also discuss how aberrant Fyn signaling in microglia and astrocytes amplifies neuroinflammation. Finally, we evaluate the potential of Fyn as a therapeutic target, emphasizing the necessity of strategies that selectively uncouple pathological signaling from physiological functions to effectively halt disease progression.},
}

Humans
*Proto-Oncogene Proteins c-fyn/metabolism
*Neurodegenerative Diseases/metabolism/enzymology
*Tauopathies/metabolism/enzymology
Animals
tau Proteins/metabolism
Signal Transduction/physiology

@article {pmid42816922,
year = {2026},
author = {Ning, X and Xiao, Y and Wang, N and Jiao, X and Li, X and Zhang, Y and Zhao, Q},
title = {The efficacy of donepezil combination therapy strategies in Alzheimer's disease: A systematic review and network meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491977},
doi = {10.1177/13872877261491977},
pmid = {42816922},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) remains a therapeutic challenge, and adding other agents to donepezil may offer additional benefits.ObjectiveThis network meta-analysis aimed to compare the efficacy of donepezil-based combination therapies versus donepezil monotherapy in patients with AD.MethodsWe searched PubMed, Embase, Cochrane Library and Web of Science up to October 2025 for randomized-controlled trials comparing donepezil plus another drug with donepezil alone. The primary outcomes were cognitive function [Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)], behavioral function (Neuropsychiatric Inventory) and functional ability [Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)]. A frequentist network meta-analysis was performed, and treatments were ranked by SUCRA (Surface under the cumulative ranking curve) values. Time-stratified analyses were also conducted.Results41 trials involving 9822 patients were included. Compared with placebo, several combinations significantly improved MMSE and ADAS-cog scores, with Don (Donepezil) + Mas (Masitinib) (97.5%, 92.9%), Don + NBP (DL-3-n-butylphthalide) (82.5%, 74.5%) and Don + DSC (Dengzhan shengmai capsule) (81.4%) ranking highest. For ADCS-ADL, Don + Mas (92.7%), Don + NBP (74.1%), and Don + DSC (77.1%) showed significant improvements. No combination was statistically superior to donepezil monotherapy for any outcome, but numerical trends favored combination therapy across all time windows. The certainty of evidence was mostly moderate to low.ConclusionsSeveral donepezil-based combination therapies, particularly those with masitinib, NBP, DSC, and memantine, are more effective than placebo in improving cognitive and functional outcomes in AD. Although direct comparisons with donepezil monotherapy did not reach statistical significance, consistent trends support the potential of add-on strategies. Longer-term trials are needed to confirm sustained benefits.},
}

@article {pmid42816923,
year = {2026},
author = {Smith, AN and Johnson, CN and Taylor, MK and Keller, JE and Suzuki, A and Payne, C and Burns, JM and Wilkins, HM and Sullivan, DK},
title = {APOE4 is associated with lower adiposity independent of total energy intake in cognitively normal older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493064},
doi = {10.1177/13872877261493064},
pmid = {42816923},
issn = {1875-8908},
abstract = {BackgroundApolipoprotein E ε4 (APOE4) carriers with cognitive impairment exhibit lower BMI than non-carriers, but whether APOE4 influences body composition in cognitively normal older adults remains unknown.ObjectiveTo examine the association between APOE4 carrier status and body composition in cognitively normal older adults.MethodsCross-sectional analysis of 203 cognitively normal older adults (mean age 71.4 ± 4.8 years). Body composition was assessed via dual-energy x-ray absorptiometry. Linear regression models adjusted for age, sex, total energy intake, and physical activity examined associations between APOE4 status and BMI, body fat percentage, fat mass index (FMI), and lean mass index (LMI).ResultsAPOE4 carriers (32%, n = 65) had lower BMI (β = -1.42 kg/m[2], p = 0.043), body fat percentage (β = -3.56%, p < 0.001), and FMI (β = -1.51 kg/m[2], p = 0.002) compared to non-carriers (68%, n = 138). LMI did not differ between groups (β = 0.18 kg/m[2], p = 0.43).ConclusionsAPOE4 carriers exhibited lower adiposity but not lean mass compared to non-carriers, independent of total energy intake and physical activity. These findings suggest APOE4 influences fat mass through metabolic mechanisms that emerge before cognitive decline. Longitudinal studies are needed to determine whether these differences contribute to AD pathogenesis.},
}

@article {pmid42816925,
year = {2026},
author = {Lopes-Gomes, E and Resende, FFB and Greuel, AM and Marina, CL and de Sant'Ana, FJF and Titze-de-Almeida, SS and Titze-de-Almeida, R},
title = {Clinical and neuropathological aspects of canine cognitive dysfunction syndrome and a translational perspective for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491819},
doi = {10.1177/13872877261491819},
pmid = {42816925},
issn = {1875-8908},
abstract = {Canine cognitive dysfunction syndrome (CCDS) shares notable clinical and molecular similarities with Alzheimer's disease (AD), supporting the value of cross-species translational research to enhance diagnostic and therapeutic approaches for both conditions. These disorders are progressive neurological diseases characterized by abnormal accumulation of neurotoxic proteins, primarily amyloid-β and tau. Their pathological aggregation induces neural injury and cerebral dysfunction, culminating in comparable clinical manifestations in dogs and humans. Exosomal microRNAs represent a promising class of molecular biomarkers for early diagnosis and provide insights into disease progression. Current diagnostic strategies include neurological evaluation, advanced imaging techniques, and, in dogs, behavioral assessments based on owner-reported observations. These assessments employ standardized rating scales such as the Canine Cognitive Dysfunction Rating Scale, the Canine Dementia Scale, and the DISHA questionnaire, which evaluate key signs of CCDS, including disorientation, altered interactions, sleep-wake cycle disturbances, house-soiling, and anxiety. This review highlights advances in understanding AD and canine cognitive dysfunction syndrome, linking veterinary and human medicine to foster translational insights benefiting both fields.},
}

@article {pmid42816931,
year = {2026},
author = {Xiao, H and Wang, J and Wan, S},
title = {WIMOAD: Weighted Integration of Multi-Omics data with meta learning for Alzheimer's Disease diagnosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491975},
doi = {10.1177/13872877261491975},
pmid = {42816931},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD), the most prevalent subtype of dementia, is characterized by a gradual decline in brain cognitive function. Early detection is critical for initiating timely interventions that may delay the severe progression of the disease. Recent advances in next-generation sequencing (NGS) offer promising, non-invasive, and cost-effective strategies for AD screening. However, most current approaches rely on single-omics data, which fail to capture the complex biological heterogeneity among individuals.ObjectiveTo develop a user-friendly and efficient framework that incorporates blood-based multi-omics for stage-specific AD classification and detects genetic markers associated with disease pathology.MethodsWe introduce WIMOAD, a stacking ensemble and weighted multi-omics integration for AD diagnosis. It leverages paired gene expression and methylation data from ADNI and presents a meta learning framework for multi-cognitive stage classification during AD progression.ResultsAcross tasks, WIMOAD consistently outperforms single-omics models and representative integration baselines, and surpasses existing integration methods in AD diagnosis. Its interpretability also facilitates the detection of novel biomarkers across different omics layers. The code is freely available at https://github.com/wan-mlab/WIMOAD.ConclusionsThe study believes WIMOAD is an interpretable, cost-effective and promising integrative framework for accurate AD diagnosis and biomarker discovery across different cognitive stages utilizing blood-based data, which eventually will have consequential impacts on early treatment intervention and personalized therapy design for AD.},
}

@article {pmid42816938,
year = {2026},
author = {Chang, VW and Hayes-Larson, E and Zheng, H and Zhang, YS},
title = {Body mass index and mortality in incident dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491694},
doi = {10.1177/13872877261491694},
pmid = {42816938},
issn = {1875-8908},
abstract = {BackgroundLimited evidence suggests that higher body weight may be associated with improved survival among individuals with dementia relative to those in the normal weight range. The mechanisms underlying this association are uncertain and may include both physiological and methodological factors.ObjectiveTo examine the association between weight status at incident dementia and mortality and to assess potential sources of bias.MethodsWe examined the association between weight status at incident dementia and mortality in a large, U.S. population-based sample with extended follow-up. We also evaluated potential sources of bias affecting this association, including confounding due to weight loss, collider stratification bias, and survivor bias.ResultsCompared with the normal weight category, class I obesity at incident dementia was associated with a 27% lower risk of mortality (HR 0.73, 95% CI: 0.62-0.86). Overweight and class II/III obesity were also associated with lower mortality. Analyses evaluating potential sources of bias did not support these mechanisms as major contributors to the observed associations.ConclusionsIn a large, U.S. population-based sample with extended follow-up, overweight and obesity at incident dementia were associated with lower mortality relative to normal weight. While the underlying mechanisms are not fully understood, these findings suggest that weight status at diagnosis may serve as a useful prognostic indicator alongside other factors.},
}

@article {pmid42816978,
year = {2026},
author = {Anshika, and Tailor, NK},
title = {Cinnamic Acid-based Hybrid Molecules as Multitarget Therapeutic Agents for Cancer, Alzheimer's Disease, and Malaria: A Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575495727260909051459},
pmid = {42816978},
issn = {1875-5607},
abstract = {Molecular hybridization has emerged as a powerful medicinal chemistry approach for address the limitations of conventional single-target therapeutics, particularly in the treatment of complex, multifactorial diseases. This strategy involves integrating two or more pharmacologically active pharmacophores into a single molecular framework, enabling enhanced biological activity, multi-target interactions, and improved pharmacokinetic properties. Among the diverse scaffolds investigated for hybrid drug design, cinnamic acid has attracted considerable attention owing to its structural simplicity, synthetic accessibility, and broad spectrum of biological activities. The incorporation of cinnamic acid into hybrid molecules has generated a wide range of compounds with improved therapeutic potential and selectivity. The pharmacological effects of cinnamic acid hybrids are associated with the modulation of key enzymes, including α-glucosidase, α-amylase, and acetylcholinesterase, as well as important signaling pathways such as NF-κB, COX-2, iNOS, PI3K/Akt/mTOR, and MAPK/ERK. These molecular interactions contribute to their diverse biological activities and therapeutic applications. This review provides a comprehensive overview of recent developments in cinnamic acid-based molecular hybrids, emphasizing design strategies, structure- activity relationships, pharmacological properties, and underlying mechanisms of action. Particular attention is given to their anticancer, neuroprotective, and antimalarial therapeutic applications. Furthermore, the review critically examines the advantages and current challenges of cinnamic acid hybridization and highlights future research directions. Overall, cinnamic acid-based molecular hybrids represent a promising platform for the development of multifunctional therapeutic agents with enhanced efficacy and broader clinical potential.},
}

@article {pmid42816980,
year = {2026},
author = {Pal, T and Singh, P},
title = {Oleandrin and PBI-05204 for Neuroprotection in Alzheimer's Disease, Parkinson's Disease, and Stroke: Preclinical Mechanisms, Blood-brain Barrier Penetration, and Clinical Translation Perspectives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575485020260907153210},
pmid = {42816980},
issn = {1875-5607},
abstract = {INTRODUCTION: Alzheimer's disease, Parkinson's disease, and ischemic stroke are increasingly becoming one of the major health concerns across the globe due to the scarcity of effective treatments for these conditions. Natural compounds like oleandrin and PBI-05204 that are extracted from Nerium oleander have been recognised for their promising qualities in the treatment and prevention of these conditions due to their ability to provide protection to the neurons in the brain.

METHODS: A systematic review was conducted to identify preclinical research articles related to oleandrin and PBI-05204 in the treatment of Alzheimer's disease, Parkinson's disease, and ischemic stroke. Searches were conducted on articles from January 2021 to March 2026 in Pub- Med/MEDLINE, Scopus, and Web of Science using the terms "oleandrin," "PBI-05204," "Nerium oleander," "blood-brain barrier," "neuroprotection," "Alzheimer," "Parkinson," and "stroke." Original in vitro or in vivo preclinical studies providing information on neuroprotective results, mechanistic information (BDNF, Nrf2-ARE, apoptosis, mitochondria), or information on blood-brain barrier permeability were included. Non-original articles (reviews, editorials), preclinical research not involving any neurobiological parameters, and articles in languages other than English were excluded.

RESULTS: Preclinical studies suggest that both oleandrin and PBI-05204 can diffuse across the BBB and provide neuroprotection. These molecules were shown to increase the expression levels of BDNF, promote ARE-dependent transcription, rehabilitate mitochondrial function, and regulate apoptosis. Though these results are highly hopeful, the major translational gap is in the ability to reproduce preclinical success in the clinical environment.

DISCUSSION: There is sufficient cellular-molecular evidence for the potential use of these compounds, namely oleandrin, as well as PBI-052040. Some challenges may arise when attempting to apply such observations as a new treatment modality at the clinical research stage. This is true for bioavailability, toxicity, and regulatory factors that need to be addressed.

CONCLUSION: Oleandrin and PBI-05204 make for very interesting compounds to consider for their neuroprotective properties in the context of neurodegeneration. Although there is promise in the preliminary human data from these compounds, there are also significant translational hurdles that must be cleared before their final application for human benefit.},
}

@article {pmid42817119,
year = {2026},
author = {Verma, A and Kushwaha, SKS and Kushwaha, N and Dutta, S and Nigam, P},
title = {Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273459017260922073618},
pmid = {42817119},
issn = {1996-3181},
abstract = {Neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal dysfunction and loss, often accompanied by toxic protein aggregation and chronic neuroinflammation. Increasing evidence indicates that dysregulated autophagy and persistent inflammatory responses are central drivers of disease onset and progression. Autophagy, a fundamental cellular degradation and recycling process, is essential for maintaining neuronal homeostasis by removing damaged organelles and misfolded proteins through mechanisms such as macroautophagy and mitophagy. However, key regulators of this pathway, including ULK1, Beclin-1, LC3, and p62/SQSTM1, are frequently impaired in neurodegenerative conditions, leading to the accumulation of pathogenic proteins such as tau, α-synuclein, and amyloid-β. Concurrently, aberrant activation of microglia and inflammasomes promotes the sustained release of pro-inflammatory cytokines, creating a neurotoxic environment that exacerbates neuronal injury. This review examines the molecular crosstalk between autophagy and neuroinflammation, with particular emphasis on disease-specific mechanisms, including LC3-associated endocytosis (LANDO) in Alzheimer's disease, tau-mediated pathology, and dopaminergic neurodegeneration in Parkinson's disease. Importantly, this review introduces a unifying conceptual framework in which neuroinflammation and autophagy are integrated as a dynamic, stagedependent immune-autophagy axis that governs neurodegenerative disease progression and therapeutic responsiveness. In addition, emerging multimodal therapeutic strategies targeting both autophagic flux and immune modulation are discussed, including mTOR inhibitors, mitophagy enhancers, GLP-1 receptor agonists, and nanomedicine-based delivery systems. Advances in three-dimensional organoids, induced Pluripotent Stem Cell (iPSC) models, and biomarker-driven clinical trials are further enhancing translational potential. In conclusion, understanding the interplay between autophagy and neuroinflammation provides critical insights into the pathophysiology of neurodegeneration and offers promising avenues for the development of targeted, disease-modifying therapies.},
}

@article {pmid42817127,
year = {2026},
author = {Wang, S and Wang, S and Sun, Y and Zhang, S and Wu, J and Xie, D},
title = {Beyond Fuel: Metabolic Intermediates as Signaling Molecules in Neuroinflammation and Neurodegeneration.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X486332260921110838},
pmid = {42817127},
issn = {1875-6190},
abstract = {Historically, research has viewed substantial brain metabolic activity through the lens of energy production, primarily treating metabolites as substrates and products in bioenergetic pathways. However, this paradigm is now evolving. Key metabolic intermediates are recognized not only as components of Adenosine Triphosphate (ATP) synthesis, but also as potent signaling molecules that establish intricate communication networks. This "metabolic signaling language" profoundly influences inflammation, epigenetics, and cell fate by translating cellular metabolic conditions into certain functional outcomes. In this review, three prototypical metabolites, namely succinate, itaconate, and α-Ketoglutarate (α-KG), were discussed. We investigated succinate accumulation during ischemia and mitochondrial stress, which serves as an early alarm that drives inflammation through both intracellular and extracellular receptor-mediated mechanisms. Conversely, itaconate, an inducible metabolite produced by myeloid cells, exerts inhibitory effects and actively alleviates inflammation by covalently modifying proteins. Finally, we highlighted α-KG, a central metabolic hub that links metabolic status to cellular identity and aging by epigenetically regulating DNA and histone demethylase activity. By summarizing the functions of these metabolites across neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, we delineate a fundamental layer of biological regulation. Deciphering and therapeutic modulation of this metabolic language represent a frontier in neuroscience, offering novel targets for intractable neurological diseases.},
}

@article {pmid42817129,
year = {2026},
author = {Tian, W and Hao, Y and Qiu, S and Chen, Z and Wu, X and Yang, Y},
title = {Genetic Evidence of Association Between Plasma Cathepsin L2 and Alzheimer's Disease: A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050504771260920194040},
pmid = {42817129},
issn = {1875-5828},
abstract = {BACKGROUND: Recent studies have suggested cathepsins, lysosomal cysteine proteases, are associated with Alzheimer's DISEASE (AD). This study conducted Mendelian Randomization (MR) analysis to systematically assess the causal effect of genetically predicted plasma cathepsins levels on AD and AD endophenotypes (cognition and brain structure).

METHOD: Recent large-scale Genome-Wide Association Studies (GWAS) in Europe provided summary statistics on plasma cathepsins, AD, cognition, and brain structure. The primary statistical estimate was employed by Inverse Variance Weighting (IVW). Various sensitivity analysis was performed to draw robust results, including Cochran's Q test, MR-Egger intercept test, and MR PRESSO.

RESULTS: Genetically predicted plasma cathepsin levels were not significantly associated with AD risk. Higher genetically predicted cathepsin L2 levels were associated with better fluid intelligence (β = 0.081, 95% CI 0.029 to 0.133, P = 0.00230, adjusted P = 0.0207). The associations of cathepsin L2 with general cognitive function (β = 0.081, 95% CI 0.010 to 0.152, P = 0.0247, adjusted P = 0.2226) and white matter hyperintensity volume (WMH, β = -0.068, 95% CI -0.134 to -0.002, P = 0.0433, adjusted P = 0.3898) were considered exploratory. Cathepsin L2 was also associated with monocyte count after correction across the three evaluated immune-cell traits (nominal P = 0.0133, FDR-adjusted P = 0.0285); the estimated indirect effect through monocyte count was -0.0016.

DISCUSSION: These findings identify cathepsin L2 as the most consistently associated candidate with fluid intelligence and additional exploratory signals across cognitive, neuroimaging, and peripheral immune-cell phenotypes. The association with monocyte count raises a testable hypothesis regarding a peripheral immune-related pathway. Further studies using larger protein GWAS datasets, stronger genetic instruments, and independent populations are required to validate these findings.

CONCLUSION: Genetically predicted plasma cathepsin L2 levels were associated with fluid intelligence after multiple comparisons. Although the immune-cell analyses raised the possibility of a monocyte-related peripheral pathway, the present findings did not establish a statistically supported mediating effect or a direct protective effect of cathepsin L2 against AD.},
}

@article {pmid42817135,
year = {2026},
author = {Chen, H and Xia, C and Li, Y and Sun, W and Wang, Y},
title = {ZhiXiaoSanZheng Decoction Ameliorates HGPA-induced HK-2 Cell Injury and Mitochondrial Metabolic Imbalance by Regulating the AMPK/PPARα/CPT1A Pathway.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128525206260914061658},
pmid = {42817135},
issn = {1873-4286},
abstract = {INTRODUCTION: ZhiXiaoSanZheng Decoction (ZXSZD) is a modern clinical Traditional Chinese Medicine (TCM) formula that exerts favorable clinical efficacy in the treatment of Diabetic Kidney Disease (DKD). However, its potential renal tubular protective mechanism remains unclear.

METHODS: Ultra-high-performance liquid chromatography-tandem mass spectrometry was employed to analyze and characterize the chemical ingredients of ZXSZD. An in vitro cell model was established by stimulating HK-2 cells with High Glucose-Palmitic Acid (HGPA) to mimic the metabolic microenvironment of DKD. Oil Red O staining was performed to assess intracellular lipid accumulation. Western blot and immunofluorescence assays were used to determine the protein expression levels of key molecules in the AMPK/ PPARα/CPT1A signaling pathway. Additionally, mitochondrial membrane potential, intracellular ATP content, activities of mitochondrial respiratory chain complexes (I and IV), oxidative stress levels, and concentrations of inflammatory cytokines were quantified.

RESULTS: A total of 141 chemical ingredients were preliminarily identified in ZXSZD. In HGPA-induced HK- 2 cells, ZXSZD significantly attenuated intracellular lipid accumulation, upregulated the protein expression of p-AMPK, PPARα, and CPT1A, ameliorated energy metabolism impairment and mitochondrial dysfunction, and suppressed oxidative stress as well as inflammatory responses.

DISCUSSION: The results indicate that ginkgolide effectively binds and stabilizes the ApoE4 N-terminal domain, supporting its potential role in modulating a key pathological factor in Alzheimer's disease. Its superior pharmacokinetic profile and interaction dynamics compared with those of curcumin and resveratrol suggest broader therapeutic relevance. These in silico insights provide a mechanistic basis for further investigation into ginkgolide's neuroprotective effects.

CONCLUSION: ZXSZD ameliorates energy metabolism impairment and mitochondrial dysfunction in HGPAinduced HK-2 cells by activating the AMPK/PPARα/CPT1A signaling pathway, while also inhibiting oxidative stress and inflammation.},
}

@article {pmid42817632,
year = {2026},
author = {Redeker, V and Melki, R},
title = {Differential proteostasis imbalance and the molecular basis of distinct synucleinopathies and tauopathies.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817632},
issn = {1471-2970},
support = {//European Union Joint Programme on Neurodegenerative Disease/ ; //EraPerMed/ ; ANR-23-JPW2-0006//Agence Nationale de la Recherche/ ; ANR-21-HBPR-0003-01//Agence Nationale de la Recherche/ ; ANR-22-PERM-0006//Agence Nationale de la Recherche/ ; },
mesh = {*Proteostasis ; *Tauopathies/physiopathology/genetics/metabolism ; Humans ; *Synucleinopathies/physiopathology/genetics/metabolism ; *alpha-Synuclein/metabolism/genetics/chemistry ; *tau Proteins/metabolism/chemistry/genetics ; Proteotoxic Stress ; },
abstract = {This short review discusses the structural and molecular events at the origin of diverse debilitating neurodegenerative diseases. The pathological consequences owing to the primary, secondary, tertiary and quaternary structural diversity of alpha-synuclein and tau proteins and the aggregates they form are presented. The crosstalk between alpha-synuclein and tau proteins aggregates structural heterogeneity and cellular homeostasis, and more precisely the proteostasis network is next considered. Overall, the proteostasis network appears as the master regulator of distinct synucleinopathies and tauopathies progression depending on its capacity to clear and/or disassemble to completion structurally diverse alpha-synuclein or tau fibrillar aggregates or not. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
*Tauopathies/physiopathology/genetics/metabolism
Humans
*Synucleinopathies/physiopathology/genetics/metabolism
*alpha-Synuclein/metabolism/genetics/chemistry
*tau Proteins/metabolism/chemistry/genetics
Proteotoxic Stress

@article {pmid42817633,
year = {2026},
author = {Morley, JF},
title = {Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817633},
issn = {1471-2970},
mesh = {*Proteostasis ; Humans ; *Neurodegenerative Diseases/physiopathology/pathology ; Animals ; Proteotoxic Stress ; Protein Folding ; },
abstract = {Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
Humans
*Neurodegenerative Diseases/physiopathology/pathology
Animals
Proteotoxic Stress
Protein Folding

@article {pmid42817639,
year = {2026},
author = {Czyż, DM and Brown, BM},
title = {The microbiota-proteostasis axis: implications in neurodegenerative diseases.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817639},
issn = {1471-2970},
support = {//American Federation for Aging Research/ ; //Glenn Foundation for Medical Research/ ; },
mesh = {*Proteostasis ; *Neurodegenerative Diseases/microbiology/physiopathology ; *Microbiota ; Humans ; Animals ; },
abstract = {Disruption of protein homoeostasis, or proteostasis, is a hallmark of protein conformational diseases (PCDs), including Alzheimer's and Parkinson's disease. These disorders are characterized by progressive protein aggregation and cellular dysfunction, yet no effective therapies exist. Emerging evidence indicates that microbial communities influence host proteostasis, giving rise to the concept of the microbiota-proteostasis axis. Microbes and their products can modulate host proteins by engaging with host proteostasis. As such, microbial dysbiosis has been linked to proteostasis disruption through the production of metabolites, extracellular vesicles, functional amyloids, and toxins or effector proteins capable of seeding or destabilizing host proteins associated with PCDs. These microbial factors have been shown in experimental models to converge on key proteostasis pathways, including protein synthesis, folding and clearance, thereby potentially reducing cellular buffering capacity and lowering the threshold for proteotoxic collapse. In parallel, microbiota-driven influence on inflammatory responses and immune signalling further amplifies systemic proteostasis disruption. In this review, we synthesize emerging evidence defining the microbiota-proteostasis axis and highlight how microbial factors influence host proteostasis. Importantly, these host-microbe interactions often precede neurodegeneration, suggesting potential for early detection and intervention. Together, these insights support targeting the microbiota as a potential strategy to enhance proteostasis and delay or prevent neurodegenerative disease. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
*Neurodegenerative Diseases/microbiology/physiopathology
*Microbiota
Humans
Animals

@article {pmid42817879,
year = {2026},
author = {Zheng, W and Ma, Y and Su, C and Qiu, Z and Yan, Z and Xu, G and Geng, D and Wang, A},
title = {Non-invasive neuromodulation in Alzheimer's disease: toward brain-heart coupling as a candidate framework for biomarker-guided adaptive intervention.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42817879},
issn = {2191-0200},
abstract = {Alzheimer's disease (AD) has entered an era of biologically informed, disease-modifying therapy, yet durable clinical benefit remains limited, highlighting the need for complementary interventions. Noninvasive neuromodulation has emerged as a promising strategy, but the field is still largely organized by device categories, stimulation targets, and short-term cognitive outcomes. This framing alone does not readily account for the marked heterogeneity, stage dependence, and limited durability reported across studies. This narrative review synthesizes clinical, preclinical, and mechanistic evidence across repetitive transcranial magnetic stimulation, transcranial electrical stimulation, sensory gamma entrainment, focused ultrasound, photobiomodulation, and transcutaneous vagus nerve stimulation. We propose that device classification is a useful starting point but an incomplete explanatory framework, because different modalities have been linked, with varying levels of evidence, to overlapping processes involving network reconfiguration, autonomic regulation, neurovascular function, inflammatory signaling, and clearance-related biology. Against this background, we examine the brain-heart axis and the central autonomic network (CAN) as a candidate intermediate level at which central neural and peripheral physiological responses to stimulation might be jointly characterized. Building on this view, we propose a biomarker hierarchy that extends from heart rate variability to directional and time-varying brain-heart coupling measures, which could be tested as candidate markers of physiological state, target engagement, and treatment responsiveness. At present, however, there is no prospective evidence that brain-heart coupling causally mediates the therapeutic effects of neuromodulation in AD. We, therefore, present brain-heart coupling as a testable candidate framework for studying state dependence, target engagement, and, ultimately, biomarker-guided adaptive neuromodulation.},
}

@article {pmid42817897,
year = {2026},
author = {Fisher, L and Hoang, MN and DuBose, L and Fan, Q},
title = {Psychological and Contextual Factors of AI Acceptance Among Informal Caregivers of People Living With Dementia: Cross-Sectional Pilot Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e104072},
pmid = {42817897},
issn = {2561-326X},
mesh = {Humans ; Cross-Sectional Studies ; *Caregivers/psychology/statistics & numerical data ; Female ; Male ; Middle Aged ; *Dementia/psychology/complications/nursing ; Pilot Projects ; Aged ; *Artificial Intelligence/standards/statistics & numerical data ; Adult ; Surveys and Questionnaires ; Aged, 80 and over ; },
abstract = {BACKGROUND: Informal caregivers make up a large share of the care provided to people living with dementia, and experience an elevated risk for anxiety, depression, and caregiving burden. Technology-based interventions, such as mobile apps, aim to support informal caregivers by providing information, training, and mental or social support. Considering the diverse nature of the caregiver experience, AI is being incorporated into such interventions to create more tailored and specific support; however, AI hesitancy may serve as a significant barrier to usage.

OBJECTIVE: The study aimed to preliminarily assess the levels of AI acceptance in adult informal caregivers of people living with dementia, and generate hypotheses regarding the psychological and contextual factors of AI acceptance.

METHODS: Adult, unpaid caregivers were recruited through social media and community partners. A cross-sectional, web-based survey was administered through Qualtrics (Qualtrics, LLC) to evaluate AI acceptance and psychological flexibility (PF). AI acceptance was measured using the Attitude Towards Artificial Intelligence (ATTARI-12) scale, while PF was measured using the Personalized Psychological Flexibility Index (PPFI). Social needs were assessed by the 'Accountable Health Communities Health Related Social Needs (AHC-HRSN) tool (Centers for Medicare and Medicaid Services). Descriptive, correlational, and regression analyses were performed to examine the associations between these factors and AI acceptance.

RESULTS: Overall, 31 informal caregivers of people living with dementia completed the survey. With an average age of 60 (SD 10.6) years old, the majority of caregivers were women (29/31, 94%), Caucasian (25/31, 81%), highly educated (24/31, 77% completed some form of higher education), and currently serving in a caregiver role (21/31, 68%). Mean PPFI and ATTARI-12 scores were moderate (66.4, SD 10.3, and 3.01, SD 0.55, respectively), demonstrating a neutral attitude regarding AI use. In bivariate analyses, ATTARI-12 differed by the caregiver-perceived illness severity (P<.001). Linear regression suggested trends that the PPFI acceptance subscale (β=.05, 95% CI 0.002-0.097; P=.04) was associated with ATTARI-12 scores.

CONCLUSIONS: This study suggests that caregivers' acceptance of such technology may vary according to their care recipient's disease severity and the acceptance subscale of the PPFI. Additionally, the study provides justification for using the ATTARI-12 and PPFI scales to assess AI acceptance and PF in informal caregivers of people living with dementia, respectively. Future research should explore these factors across a larger and more diversified cohort to further generalize and confirm our findings.},
}

Humans
Cross-Sectional Studies
*Caregivers/psychology/statistics & numerical data
Female
Male
Middle Aged
*Dementia/psychology/complications/nursing
Pilot Projects
Aged
*Artificial Intelligence/standards/statistics & numerical data
Adult
Surveys and Questionnaires
Aged, 80 and over

@article {pmid42817909,
year = {2026},
author = {LeBlang, S and Mehta, RI and D'haese, PF and Grinspan, A and Sokolov, A and Frazzetta, G},
title = {Focused ultrasound blood-brain barrier opening: a review of post-procedure MRI outcomes.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2737272},
pmid = {42817909},
issn = {1744-8360},
abstract = {INTRODUCTION: Focused ultrasound (FUS) blood-brain barrier opening (BBBo) is an incisionless technique that facilitates cerebral drug delivery by temporarily increasing BBB permeability. Clinical trials have shown that FUS produces reversible BBBo and is feasible in humans. There are currently no standardized imaging protocols for assessing the safety of FUS-BBBo, although MRI is commonly performed.

AREAS COVERED: This structured narrative review summarizes neuroimaging techniques used to assess FUS-BBBo safety in clinical trials of participants with neurological disorders that reported post-procedural MRI findings. A search of PubMed from September 2014 to April 2026 was undertaken to identify clinical trials of FUS-BBBo (13 in patients with brain tumors and 16 in neurodegenerative diseases).

EXPERT OPINION: Localized T2* hypointense signals and T2 hyperintense signals are relatively common after FUS-BBBo. While these findings have been thought to be related to transient microhemorrhage or edema, no consistent association has been found between such findings and clinically significant adverse events. Further work incorporating standardized post-FUS-BBBo MRI safety assessments is needed to clarify the biological significance of these signal alterations, and to determine whether they indicate a potential long-term safety concern, are a harmless finding associated with the BBBo procedure, or are associated with the underlying diseases and/or concomitant drugs.},
}

@article {pmid42817939,
year = {2026},
author = {Karaahmet, B and Lama, T and Wang, A and Cao, W and Menon, V and Klein, HU and Bennett, DA and De Jager, PL and Zhang, Y and Taga, M},
title = {High-Dimensional Multi-Omic Mapping of Post-Mortem Human Brain Using Iterative Indirect Immunofluorescence Imaging on Xenium-Processed Tissues.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.16.751033},
pmid = {42817939},
issn = {2692-8205},
abstract = {UNLABELLED: Spatial transcriptomics approaches provide crucial insights into gene expression distribution within intact tissue architecture, but they encounter limitations in detecting morphologically complex cell types, assessing their spatial associations with pathology, and accurately annotating cell types using RNA data alone. Therefore, we developed a robust post-processing workflow integrating Xenium spatial technology with iterative indirect immunofluorescence imaging (4i) on formalin-fixed paraffin-embedded (FFPE) human brain tissue. The post-Xenium 4i protocol presented here allows multi-omic tissue mapping, enabling deeper investigation of pathological microenvironments defined by the spatial distribution of neuropathological hallmarks and enrichment of specific cell populations. We applied this workflow on calcarine cortex tissue sections where cerebral amyloid angiopathy (CAA) burden is present, in addition to amyloid plaques and tau pathology, generating a 15-plex image that captures the complexity of the pathological microenvironment.

MOTIVATION: The expansion of spatial transcriptomics (ST) technologies has enhanced our ability to dissect the complexity and diversity of the molecular organization of the human brain. Among these techniques, the Xenium platform enables high-plex, in situ gene expression profiling at subcellular resolution while preserving tissue architecture, thereby offering powerful insights into tissue organization. However, transcriptomic data can be greatly enriched by the inclusion of morphological, anatomical, pathological, and cellular markers at the protein level. Here, we report a post-spatial profiling workflow that combines the Xenium platform with iterative indirect immunofluorescence imaging (4i) on formalin-fixed paraffin-embedded (FFPE) human brain tissue to capture key pathological features for Alzheimer's disease (AD) and facilitate cell segmentation. This approach enables cost-effective and flexible multiplexed, multi-omic mapping of the same tissue section by registering Xenium transcript data with subsequent 4i immunostaining, which maximizes the RNA quality. Incorporating immunofluorescence (IF)-based cell-type markers alongside RNA profiles enables cell types to be annotated using robust protein markers rather than relying solely on transcriptomic information, thus reducing an important source of noise in downstream analyses. Immunofluorescence staining of FFPE tissue following Xenium processing also preserves cellular morphology, allowing the morphological complexity of distinct cell types to be captured and quantitated, especially for glial cells with highly ramified processes. To demonstrate the practical application of this workflow to AD studies, we developed a proof-of-concept deep learning framework to classify nuclei into specific major cell types of the brain using the IF data. Thus, we present an integrated experimental and analytic workflow optimized for the multi-omic characterization of human brain tissue in an AD context; these pipelines provide spatially resolved insights into pathological microenvironments found in the older human brain and can readily be adjusted to detect other proteins of interest or other pathological features. Altogether, this approach provides a comprehensive view of spatial architecture within pathologically affected regions and enables accurate transcript-independent cell-type annotation.

HIGHLIGHTS: Integrate Xenium and 4i to build a multi-omic map on the same FFPE brain tissueImprovement of cell-type annotationIdentify pathologic features and cross-register them into the transcriptomic and proteomic spatial matrix.},
}

@article {pmid42817989,
year = {2026},
author = {Aceituno, K and Granger, K and Leon, J and Godoy-Lugo, JA and Young, KE and Joseph, T and Liu, K and Kruijff, I and Morales, E and Hakian, M and Birnbaum, A and van der Kant, R and Hill, CM and Cortes, CJ},
title = {Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.16.752181},
pmid = {42817989},
issn = {2692-8205},
abstract = {Physical exercise promotes systemic and neural adaptations that support healthy brain aging and may mitigate Alzheimer's disease (AD) progression. However, the capacity of the AD-afflicted brain to mount and translate exercise-responsive molecular adaptations into neuroprotection remains unclear. Here, we examined the effects of long-term voluntary wheel running (VWR) on molecular, neuropathological, and behavioral outcomes in independently studied male and female 5xFAD mice. VWR elicited expected metabolic and transcriptional remodeling of inguinal white adipose tissue, confirming engagement of exercise-responsive peripheral biology. In contrast, hippocampal transcriptional responses were modest, with few differentially expressed genes and coordinated changes emerging primarily at the pathway level. These responses involved synaptic, neuroimmune, mitochondrial, neurotrophic, and monoaminergic processes and differed qualitatively between the two groups. Several components of the canonical hippocampal exercise response also failed to converge into coordinated cellular adaptations: synaptic protein abundance changed without altering synapse density, while neurotrophic, neurogenic, and vascular responses showed little correspondence across molecular and cellular measures. VWR also produced little change in hippocampal amyloid pathology or behavioral function despite sustained exercise engagement. Together, these findings demonstrate that the 5xFAD brain retains modest molecular responsiveness to prolonged voluntary exercise but may be unable to mount a sufficiently robust or coordinated response to produce broad neuroprotective effects. These findings highlight disease context as an important determinant of the efficacy of exercise-based interventions in neurodegenerative disease.},
}

@article {pmid42818016,
year = {2026},
author = {Springer, KS and Driver, FC and Wang, X and Soh, H and Moulema, CD and Flynn, WF and Robson, P and Tzingounis, AV and Jackson, AC},
title = {Spatial organization of voltage-gated ion channel expression across molecularly defined neuronal populations in the mouse mammillary bodies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.15.751911},
pmid = {42818016},
issn = {2692-8205},
abstract = {The mammillary bodies (MB) are a hypothalamic component of the limbic Papez circuit that plays a critical role in spatial and episodic memory in mammals. Degeneration of the MB occurs in disorders associated with cognitive impairment, including Korsakoff's syndrome and Alzheimer's disease, yet the molecular organization and intrinsic properties of MB neurons remain poorly understood. Recent single-cell RNA sequencing identified multiple transcriptionally distinct neuronal populations within the MB and suggested that they differentially express voltage-gated ion channels that regulate neuronal excitability. Here, we used fluorescence in situ hybridization (FISH) to define the anatomical organization of cluster-enriched molecular markers and determine the spatial distribution of transcripts encoding voltage-gated sodium (Na V), potassium (K V), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels among defined subregions of the mouse MB. We found that marker transcripts occupy characteristic but partially overlapping spatial domains that broadly correspond to classical anatomical subdivisions. In addition, several ion channel transcripts, including Scn1a, Scn2a, Kcnq2, Kcnq3, and Hcn1 , exhibited distinct patterns of enrichment across molecularly defined neuronal populations and MB subregions. Multiplex FISH further revealed unexpected co-expression of Scn1a and Scn2a within Pvalb -enriched neuronal populations, while whole-cell recordings demonstrated distinct intrinsic firing properties of neurons in the lateral and medial mammillary nuclei. Together, these findings establish a molecular framework linking neuronal population identity with voltage-gated ion channel expression in the MB and provide a foundation for future studies investigating how cell type-specific differences in intrinsic excitability contribute to memory function and neurological disease.},
}

@article {pmid42818075,
year = {2026},
author = {Bhatt, NN and Tabrizi, Z and Janulis, J and Chakraborty, S and Weick, M and Franciosa, SA and Rodriguez Moore, G and Agatemor, C and Galvin, JE and Bracko, O},
title = {Reducing Neutrophil Sialic Acid Residues Alleviates Cerebral Hypoperfusion in Alzheimer's Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.23.753660},
pmid = {42818075},
issn = {2692-8205},
abstract = {OBJECTIVE: Dysregulation of the immune system is increasingly recognized as a contributor to Alzheimers disease (AD) progression, partly through neutrophil adhesion to the cerebral vasculature, which promotes hypoperfusion in AD. Because sialic acid (SA) residues on membrane glycoproteins regulate neutrophil-endothelial interactions, we investigated whether neutrophil sialylation is altered in AD and whether reducing it improves cerebral vascular function.

APPROACH AND RESULTS: Lectin blots of isolated neutrophils showed increased SA levels in two AD mouse models, 5xFAD and APP-SAA. We identified α2,3 sialyltransferase-IN-1 as a small-molecule inhibitor that reduces sialylation in vivo. Treating 5xFAD mice with this inhibitor decreased SA on neutrophil membranes, increased cerebral blood flow, and reduced capillary stalling. Leukocytes from patients with preclinical AD and mild cognitive impairment also had higher SA levels than those from age-matched healthy controls.

CONCLUSIONS: Elevated terminal sialylation of neutrophil glycoproteins contributes to capillary stalling and cerebral hypoperfusion in AD. Neutrophil sialylation may serve as both a biomarker and a therapeutic target for improving cerebral blood flow and slowing disease progression.},
}

@article {pmid42818084,
year = {2026},
author = {Babtie, AC and Blake, GET and Consortium, YG and Clifton, NE and Hawes, T and Barroso, I and Mill, J},
title = {A single-nuclei multiomics resource across four brain regions prioritises human neural cell types influencing brain-related traits.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.24.754059},
pmid = {42818084},
issn = {2692-8205},
abstract = {Genetic studies have identified thousands of variants associated with brain-related traits. However, the majority of these map to non-coding regions and their causal roles and functional consequences are unclear. In this study, we profiled gene expression and chromatin accessibility in ∼140,000 individual nuclei from 40 post-mortem adult human brain samples from 11 donors spanning four brain regions (amygdala, hippocampus, hypothalamus and prefrontal cortex). Integrating these data with genome-wide association study statistics allowed us to prioritise specific neural cell populations relevant for complex traits. Concordant with epidemiological evidence, we prioritise similar neuronal cell populations for BMI, schizophrenia, bipolar disorder and age at menarche associated variants. Our paired multiomic data also provides support for putative enhancer-gene relationships relevant to Alzheimer's disease. These data provide a valuable resource to help interpret trait-associated genetic variation and nominate effector transcripts and cellular pathways relevant to brain-related phenotypes.},
}

@article {pmid42818091,
year = {2026},
author = {Sharma, A and Aylar, D and Lapin, D and Marambaud, P and Wang, P},
title = {Extracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.18.752724},
pmid = {42818091},
issn = {2692-8205},
abstract = {Extracellular cold-inducible RNA-binding protein (eCIRP) is a crucial neuroinflammatory mediator in ischemic stroke and alcohol-induced memory impairment. We have recently discovered that amyloidβ causes microglia to release eCIRP, prompting us to investigate its role in Alzheimer's disease (AD). We found that eCIRP levels were significantly elevated in the cerebrospinal fluid (CSF) and plasma of AD patients compared with age-matched non-AD subjects, as well as in hTau.P301S mice (a model of AD tauopathy) compared with wildtype control mice. Plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients. eCIRP induced neurotoxic astrocyte-specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8-D1a cells, primary murine astrocytes and intracerebroventricular eCIRP-injected C57BL/6 mice brains. In particular, eCIRP increased Complement 3, an astrocytic marker involved in neuroinflammation-associated neurodegeneration. Primary astrocytes from TREM-1 knockout mice were resistant to eCIRP induction of neurotoxic astrocytes. eCIRP increased TREM-1 expression and activation in astrocytes. Blocking CIRP/TREM-1 interaction using peptide M3, effectively attenuated eCIRP's induction of neurotoxic astrocytes. Thus, eCIRP strongly correlates with astrocyte reactivity in AD patients, and eCIRP induces neurotoxic astrocytes via TREM-1, which is attenuated by M3, suggesting a novel therapeutic opportunity to target neurotoxic astrocytes in AD.},
}

@article {pmid42818094,
year = {2026},
author = {Endresz, N and Fafouti, ME and Arbabi, K and Zhou, X and DeLong, T and Gonzalez-Burgos, G and Duncan, L and Sibille, E and Tripathy, SJ},
title = {Selective depletion of upper-layer somatostatin interneuron subtypes in schizophrenia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.18.752621},
pmid = {42818094},
issn = {2692-8205},
abstract = {Schizophrenia (SCZ) is associated with cortical GABAergic dysfunction, but whether inhibitory interneurons are lost or persist in an altered molecular state remains unresolved. Here, we harmonized seven prefrontal post-mortem single-nucleus RNA-seq datasets onto a fine-grained taxonomy of cortical cell types and meta-analyzed their gene expression and abundance changes in SCZ (298 controls, 171 SCZ). First, we find a subclass-wide reduction of SST mRNA within somatostatin (Sst) neurons. Second, we find reduced abundance (depletion) of a subset of upper-layer Sst interneurons and increased abundance of L6b excitatory neurons, with both changes confirmed in spatial transcriptomics (12 controls, 12 SCZ). Notably, SCZ genetic risk is enriched in the most depleted Sst cells. Depleted Sst subtypes highly express HCN1 , partially correspond to primate-specialized CALB1 -expressing double-bouquet cells, and are among the cells lost earliest in Alzheimer's disease. These upper-layer Sst interneurons constitute an intrinsically vulnerable population and a promising target for neuroprotective and compensatory therapies.},
}

@article {pmid42818102,
year = {2026},
author = {Huang, Y and Toga, AW and Zhao, L and , },
title = {White Matter Slow-4 fALFF as a Complementary Marker in the Multimodal Alzheimer's Disease Biomarker Landscape.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.17.752468},
pmid = {42818102},
issn = {2692-8205},
abstract = {INTRODUCTION: White matter (WM) functional activity, quantified as slow-4 fractional amplitude of low-frequency fluctuations (fALFF; 0.027-0.073 Hz), may reflect Alzheimer's disease (AD) pathology, but its utility relative to established structural imaging markers remains poorly characterized.

METHODS: We analyzed 369 ADNI-3 participants with baseline resting-state fMRI. Global WM slow-4 fALFF (JHU-20 atlas) was compared against hippocampal volume, entorhinal cortical thickness, FA, and MD across 11 outcomes: plasma biomarkers (pTau217, Aβ42/40, NfL, GFAP; n = 108), PET (amyloid Centiloid, tau SUVR, FDG; n = 66-207), and cognition (MEM, EF, mPACC, MMSE; n ≈ 222-225) using head-to-head benchmarking and variance decomposition.

RESULTS: WM fALFF was significantly associated with GFAP (partial RZ = 5.35%), amyloid PET (partial RZ = 2.17%), tau PET (partial RZ = 3.52%), executive function (partial RZ = 2.61%), and mPACC (partial RZ = 3.53%). In trimmed models, fALFF explained unique variance in NfL and GFAP beyond FA and MD (unique ΔRZ: 3.65% and 4.45%) - nearly 8-fold greater than DTI's unique contribution for NfL. Gray matter markers showed larger associations with cognition and PET pathology. The incremental value of fALFF was modality-specific: it persisted beyond DTI markers (NfL, GFAP, amyloid PET, executive function, mPACC) and beyond gray matter markers (NfL, GFAP), but in every domain - plasma included - fALFF was no longer significant when all five imaging markers were entered simultaneously.

DISCUSSION: WM slow-4 fALFF captures neurodegeneration-related variance - particularly astroglial reactivity and axonal injury - incremental to DTI microstructure and partially independent of gray matter atrophy. These findings position WM functional activity as a complementary, non-invasive imaging marker in the multimodal AD biomarker landscape.

RESEARCH IN CONTEXT: Evidence before this study: White matter (WM) resting-state BOLD signals carry physiologically valid functional information. WM slow-4 fALFF is reduced in preclinical Alzheimer's disease (AD) and correlates with amyloid burden and cognition. Direct benchmarking against established structural imaging markers within matched samples has remained scarce.Added value of this study: In 369 ADNI-3 participants, we conducted a direct same-sample head-to-head comparison of global WM slow-4 fALFF versus hippocampal volume, entorhinal thickness, global FA, and MD across 11 pre-specified AD biomarker and cognitive outcomes. WM fALFF showed the largest covariate-adjusted association with GFAP (partial RZ = 5.35%) and uniquely explained ∼8× more NfL variance than DTI in trimmed models, contributing non-redundant functional information.Implications of all the available evidence: Global WM slow-4 fALFF, derived from standard resting-state fMRI, is a non-invasive complement to structural imaging that showed associations with markers of astroglial reactivity and neuroaxonal injury, and could augment multimodal AD biomarker panels without additional scanning cost.},
}

@article {pmid42818178,
year = {2026},
author = {Hu, M and Kershaw, A and Brunson, S and Li, Y and Zhao, D and Liu, S},
title = {Cell Type-Specific Structural and Functional Signatures of APOE4, Age and Sex in the Mouse Anterior Olfactory Nucleus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.21.753183},
pmid = {42818178},
issn = {2692-8205},
abstract = {As the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the human APOE ε4 allele alters neuronal physiology before overt pathology. However, how aging and sex modify these effects in the anterior olfactory nucleus (AON), an early AD-affected brain region, remains unclear. Here, we performed whole-cell recordings and post hoc morphological reconstructions of pyramidal cells (PCs) and interneurons (INs) in acute AON slices from adult and aged humanized APOE3 (E3) and APOE4 (E4) knock-in mice of both sexes with identification of context-dependent remodeling across structural, intrinsic, and synaptic domains. In PCs, morphology was broadly susceptible to APOE genotype x age x sex and their interactions. Functionally, aged E4 PCs exhibited a more depolarized resting membrane potential than aged E3 PCs. Additionally, afterhyperpolarization amplitude displayed a marked age x genotype interaction, reversing the direction of the E4 - E3 difference from adulthood to aging. Excitatory synaptic event frequency showed a complex genotype and age and sex interaction, whereas inhibitory synaptic event amplitude was elevated in E4 mice. In contrast, INs displayed far more restricted alterations. Morphological changes were limited to dendritic length, which was modulated by age and sex specifically in E4 mice. Physiologically, genotype effects were confined to action potential amplitude, while aging primarily altered membrane properties and excitatory synaptic inputs. Together, these findings demonstrate that APOE genotype cell-specifically shapes AON neuronal properties through interactions with age and sex, suggesting that APOE4 establishes altered cellular states that influence how this circuit responds to subsequent disease-related stress.},
}

@article {pmid42818216,
year = {2026},
author = {Falvey, A and Palandira, SP and Chaudhry, S and Strohl, JJ and Huerta, PT and Tsaava, T and Tynan, A and d'Abramo, C and Giliberto, L and Koppel, J and Al-Abed, Y and Brines, M and Marambaud, P and Chavan, SS and Chang, EH and Tracey, KJ and Pavlov, VA},
title = {Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.19.752906},
pmid = {42818216},
issn = {2692-8205},
abstract = {Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain-to-periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.},
}

@article {pmid42818221,
year = {2026},
author = {Blanc, V and Griffiths, SJ and Haas, J and Davidson, NO and Lathe, R},
title = {mRNA editing of the Alzheimer's risk gene APOE.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.03.749263},
pmid = {42818221},
issn = {2692-8205},
abstract = {UNLABELLED: Variants in the human APOE gene govern the risk of Alzheimer's disease and other disorders. Three major APOE variants in humans reflect C→T replacements at two positions in a single exon: an upstream variant (AE4 site) that differs between the ancestral APOE ε4 allele (APOE4) (C) and human-specific APOE2 / E3 (T), and a downstream variant (AE2 site) that differentiates APOE3 / E4 (C)from APOE2 (T). It has long been assumed that APOE allelotypes are genomically encoded, but here we report that multiple individuals express brain APOE C or U/T variant transcripts that differ from genomically templated versions. We demonstrate up to 10% C→U or U→C nucleotide replacement at AE4 and AE2, but not at other sites, and with no corresponding changes in genomic DNA. Single-cell transcriptomic datasets from brain microglia revealed sporadic (up to ∼8%) C→U replacement at AE2. We found 0.4-1.6% of brain transcripts in human APOE knock-in mice harbor selective C→U changes at either AE4 or AE2 sites. Transfection of HepG2 or Huh7 cells with either mouse or human APOBEC1 led to efficient (>90%) C→U editing of APOE4 mRNA at the AE4 but not AE2 site, with lower (<10%) C→T editing of genomic DNA at the AE4 site by mouse, but not human, APOBEC1. Furthermore, interrogation of proteomic datasets revealed up to 4% of non-genomically encoded APOE peptides in human plasma, indicating that the edited APOE transcripts are functional in vivo . These data suggest that APOE mRNA is subject to RNA editing that interconverts the different allelic forms of APOE .

AUTHOR SUMMARY: Human APOE gene variants govern the risk of Alzheimer's disease (AD) and other disorders. Three alleles are widespread: ancestral E4 and human-specific E3 and E2 . AD risk declines in the order E4 > E3 > E2 . It has been assumed that the APOE allotype we inherit is laid down at birth, but we report that APOE mRNA is enzymatically edited to convert E4 to E3 / E2 , and/or E2 to E3 / E4 . Up to ∼10% conversion was seen in brain, and up to 100% in vitro driven by the RNA-editing enzyme APOBEC1. Proteomic analysis of human plasma argues that edited APOE transcripts are functional in vivo .},
}