@article {pmid42520619,
year = {2026},
author = {Zhao, H and Zhang, T and Liu, L and Zhang, S and Ma, W},
title = {The management of daily topics in conversations with individuals with Alzheimer's disease in Chinese residential care.},
journal = {Social science & medicine (1982)},
volume = {406},
number = {},
pages = {119617},
doi = {10.1016/j.socscimed.2026.119617},
pmid = {42520619},
issn = {1873-5347},
abstract = {BACKGROUND: Individuals with Alzheimer's Disease (AD) often experience difficulties managing topics in daily interactions, which can hinder their participation in interactions and affect their social engagement. There is a gap in exploring the interactional dynamics and the maintenance of personhood when interacting with individuals with AD in asymmetric institutional settings.

OBJECTIVES: This study aims to examine the interactional competence of individuals with AD and how their vulnerabilities are managed in daily-topic interactions within institutional healthcare settings.

METHODS: This study adopts Conversation Analysis (CA) to examine video-recorded conversations between a trained researcher and individuals with mild cognitive impairment due to AD residing in two residential care facilities in China.

FINDINGS: Individuals with mild AD demonstrate agency within asymmetric interactions by reshaping conversational frames, preserving face, and situating themselves within relational contexts to maintain their personhood. This agency emerges only when interlocutors actively engage, providing validation and recognition while accommodating temporary incoherence. These findings underscore the collaborative nature of sustaining identity in dementia care and highlight the particular significance of such interactional practices within the Chinese cultural context.

IMPLICATIONS: Conversation partners can support agency in individuals with AD by ratifying frame reconfigurations, sustaining topics, acknowledging repetitions, and responding flexibly to disengagement. Care facilities are also expected to create more opportunities for residents to engage in casual conversation.},
}

@article {pmid42520739,
year = {2026},
author = {Jafari, M and Tang, Z and Acharya, UR and Li, Y},
title = {Applications of quantum AI in brain disorder diagnosis: A systematic review.},
journal = {Computer methods and programs in biomedicine},
volume = {286},
number = {},
pages = {109565},
doi = {10.1016/j.cmpb.2026.109565},
pmid = {42520739},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Brain disorder diagnosis and prediction remain challenging because neuroimaging, electrophysiological, behavioral, and multimodal data are high-dimensional, noisy, heterogeneous, and limited by small clinical cohorts. This systematic review synthesised applications of quantum artificial intelligence (QAI) for brain disorder diagnosis, prediction, detection, and monitoring.

METHODS: Following PRISMA guidelines, studies published from 2016 to 13 January 2026 were retrieved from Scopus, Web of Science, and IEEE Xplore. After screening, 36 studies met the eligibility criteria and were qualitatively analysed according to disorder category, data modality, QAI method, implementation setting, validation strategy, and performance.

RESULTS: At the broader disease-group level, neurodegenerative disorders were the most frequently investigated, followed by mental health and psychiatric disorders. At the individual level, Parkinson's disease and schizophrenia were the leading applications, followed by depression, anxiety, Alzheimer's disease, and stress-related tasks. MRI-based modalities were the most frequently used data source, followed by multimodal data and EEG. Methodologically, primary QAI approaches were dominated by quantum neural and QDL architectures, followed by quantum-inspired optimization or feature-selection methods and quantum-kernel/conventional QML classifiers. Qiskit/IBM Quantum and PennyLane were the most frequently reported quantum software frameworks. However, most studies relied on simulators, classical quantum-inspired implementations, or unclear implementation settings, with limited real-hardware evaluation.

CONCLUSIONS: QAI shows emerging potential for brain disorder analysis, particularly through hybrid quantum-classical learning, quantum neural architectures, quantum-kernel methods, and quantum-inspired optimization. Nevertheless, current evidence remains preliminary and requires larger datasets, subject-level and external validation, fair classical benchmarking, noise-resilient circuits, real quantum hardware evaluation, explainability, and clinical validation.},
}

@article {pmid42520782,
year = {2026},
author = {Persson, J and Voss, G},
title = {Anti-Amyloid Therapies for Early Alzheimer's Disease: Evidence-Based Recommendations.},
journal = {South Dakota medicine : the journal of the South Dakota State Medical Association},
volume = {79},
number = {1},
pages = {35-39},
pmid = {42520782},
issn = {0038-3317},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; Evidence-Based Medicine ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older adults and represents a growing public health burden. Traditional therapies offer only symptomatic relief without modifying disease progression. Recently approved anti-amyloid monoclonal antibodies, donanemab and lecanemab, represent a shift toward disease-modifying treatment in patients with mild cognitive impairment (MCI) or mild AD with confirmed amyloid pathology.

METHODS: This review synthesizes current evidence from key clinical trials, real-world safety considerations, and expert-driven appropriate use recommendations (AURs) to guide the safe and effective use of donanemab and lecanemab.

RESULTS: Both agents demonstrate statistically significant and clinically meaningful slowing of cognitive and functional decline in early symptomatic AD. Key differences exist in their mechanisms of action, dosing schedules, and treatment duration. Safety monitoring, particularly for amyloid-related imaging abnormalities (ARIA) and apolipoprotein E (APOE) ε4 genotyping, is an essential component of care.

CONCLUSION: Anti-amyloid therapies offer a meaningful step forward in AD management, but their use requires careful patient selection, biomarker confirmation, and adherence to safety protocols. As long-term outcomes and comparative effectiveness remain uncertain, continued surveillance, patient education, and equitable access will be important in optimizing the clinical impact of anti-amyloid therapies.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal/therapeutic use
Evidence-Based Medicine
Cognitive Dysfunction/drug therapy

@article {pmid42520805,
year = {2026},
author = {Savignac, C and St-Onge, F and Villeneuve, S and Badhwar, A and Gagliano Taliun, SA and Farhan, S and Geddes, M and Iturria Medina, Y and Poirier, J and Spreng, RN and Bzdok, D and , },
title = {Parent-of-origin effects in Alzheimer's liability dissociate neurocognitive and cardiovascular traits in at-risk individuals.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102943},
doi = {10.1016/j.xcrm.2026.102943},
pmid = {42520805},
issn = {2666-3791},
abstract = {Alzheimer's disease (AD) has a higher prevalence in women than men and is more frequently inherited from mothers than fathers. Yet, while neuroimaging and biomarker studies link maternal family history to stronger AD-related alterations, epidemiological studies suggest that paternal history confers comparable or even greater risk. Here, we leverage the deeply profiled PREVENT-AD cohort to derive three intermediate phenotypes of AD susceptibility. Drawing on nearly 1,000 individual study visits, we quantify how these intermediate phenotypes vary as a function of maternal versus paternal AD lineage. We show that lineage-specific differentiation, including both maternal and paternal biases, is reflected in the brain structure and phenome of adult children of AD patients. Cognitive and cardiovascular risk markers, together with associated genetic variants, show the strongest differentiation along the parental-lineage spectrum of disease susceptibility relative to other correlates of AD burden. Our cross-generational analysis ultimately delineates multidimensional parent-of-origin effects in AD genealogy.},
}

@article {pmid42520915,
year = {2026},
author = {Xing, S and Ren, P and Chen, Z and Fu, Y},
title = {Non-transgenic rodent models associated with Alzheimer's disease: applications, evaluation, and perspectives.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.063},
pmid = {42520915},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Familial AD accounts for less than 1% of cases, while sporadic AD (SAD) accounts for over 95%. Mild cognitive impairment (MCI) is the critical transition phase from normal aging to AD dementia. Understanding the pathological progression from MCI to AD and the mechanisms underlying SAD is essential. Rodent models, including transgenic and non-transgenic models, are vital tools for developing effective AD therapies. However, transgenic models primarily mimic familial AD and poorly replicate MCI and the complex pathological features of SAD. Non-transgenic models address these limitations by incorporating genetic, environmental, and aging factors, thereby better simulating SAD complexity. In addition, non-transgenic models are valuable for studying the compensatory mechanisms within neural networks that preserve cognitive function despite early pathology during MCI. In this review, we provide a comprehensive summary of non-transgenic rodent models used in AD and MCI research. First, we detail modeling strategies, including agents, administration routes, and dosages. Next, we discuss evaluation methods, such as behavioral and molecular assessments. We emphasize the importance of electrophysiological data, such as long-term potentiation, for evaluating cognition. Finally, we discuss the advantages and limitations of these non-transgenic models. This review may serve as a reference for selecting models to study the progression from MCI to AD and to develop related therapeutics. Combining non-transgenic and transgenic models more accurately replicates the complex, multifactorial pathology of the disease.},
}

@article {pmid42521027,
year = {2026},
author = {de Sevilla, LP and Majumdar, S and Recio, B},
title = {The Human Retina in Alzheimer's Disease: Pathology, Mechanisms, and Biomarkers.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103275},
doi = {10.1016/j.arr.2026.103275},
pmid = {42521027},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and synaptic dysfunction that begins decades before clinical symptoms emerge. While AD research has traditionally focused on the brain, increasing evidence suggests that the retina undergoes pathological remodeling that shares features with cerebral changes. Advances in retinal imaging, including optical coherence tomography (OCT), OCT angiography, and hyperspectral approaches, have identified structural, vascular, and functional abnormalities in individuals with mild cognitive impairment (MCI) and early-stage AD. This supports the potential utility of the retina as a non-invasive biomarker for detecting neurodegenerative processes. Furthermore, postmortem studies have demonstrated accumulation of amyloid-β and phosphorylated tau, increased vulnerability of retinal ganglion cells (RGC), synaptic alterations in the inner plexiform layer (IPL), and significant activation of glial cells and complement-mediated inflammatory pathways. Melanopsin RGCs appear to be selectively affected, suggesting a mechanistic link between retinal pathology and the circadian or sleep disturbances commonly observed in AD. This review synthesizes human clinical data from imaging, histopathological, and proteomic studies supporting retinal involvement in AD, with emphasis on convergent mechanisms, including mitochondrial dysfunction, oxidative stress, microglial activation, and synaptic degeneration. Key limitations and sources of variation in current retinal biomarker studies, including cohort heterogeneity, comorbid ocular disease, and methodological variability, are discussed, and future directions are outlined to strengthen retinal diagnostics and therapeutic monitoring of visual system dysfunction in AD.},
}

@article {pmid42521029,
year = {2026},
author = {Virlley, M and Spooner, RK and Wilson, TW and Pruitt, T and Davenport, EM and Maldjian, JA and Proskovec, AL},
title = {Gating of Somatosensory Neural Oscillations Across the Lifespan: A Narrative Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103276},
doi = {10.1016/j.arr.2026.103276},
pmid = {42521029},
issn = {1872-9649},
abstract = {Healthy and pathological aging are associated with progressive changes in cortical inhibition, yet the underlying neural mechanisms remain incompletely understood. Somatosensory gating (SG), the brain's suppression of redundant tactile input, provides a pre-attentive marker of inhibitory function. Paired-pulse paradigms concurrent with noninvasive magnetoencephalography (MEG) provide a millisecond portrayal of the neural dynamics underlying somatosensory processing and the gating of such responses with excellent spatial resolution. This narrative review synthesizes SG research focusing on neural oscillations, with a particular emphasis on gamma-band activity which is linked to GABAergic inhibitory processes. SG oscillatory metrics are sensitive to both healthy chronological aging and biological stressors such as allostatic load and epigenetic aging and offer insight beyond neural evoked responses. We also examine aberrant presentations of SG oscillatory metrics in age-related neuropathologies, including Alzheimer's disease and HIV-associated neurocognitive disorder, sensorimotor pathologies, and psychiatric conditions. Finally, we outline methodological considerations and propose future directions to refine SG oscillatory metrics as markers of inhibitory decline or potential compensatory mechanisms, situating the existing findings within prominent theories of neurocognitive aging. Collectively, this review underscores how an oscillatory perspective to brain function reveals frequency-specific somatosensory and inhibitory mechanisms, highlighting their differential sensitivity to healthy aging and pathology.},
}

@article {pmid42521030,
year = {2026},
author = {Kechko, OI and Moskalev, AA and Franceschi, C and Mitkevich, VA and Makarov, AA},
title = {Is amyloid beta peptide a driver of inflammaging?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103280},
doi = {10.1016/j.arr.2026.103280},
pmid = {42521030},
issn = {1872-9649},
abstract = {Inflammaging, the chronic subclinical systemic inflammation accompanying aging, represents a critical pathogenetic mechanism underlying age-related neurodegenerative diseases. While amyloid beta (Aβ) peptides are established contributors to neuroinflammation in Alzheimer's disease, their role in aging-related subclinical inflammation remains insufficiently elucidated. In humans, Aβ exhibits dual functions: it supports neuronal activity, survival, and protection against neurotrauma, while also promoting inflammation and central nervous system dysfunction. This review highlights the beneficial effects of Aβ, including its antioxidant and antipathogenic properties, and synthesizes current knowledge of the molecular mechanisms driving Aβ-associated inflammaging. We structure this analysis across distinct brain cell types - microglia, astrocytes, oligodendrocytes, neurons, pericytes, and endothelial cells - and consider additional factors influencing Aβ-related neuroinflammation. Finally, we examine strategies to counteract the detrimental effects of Aβ, focusing on Aβ physiological clearance via the blood-brain barrier and glymphatic system, as well as therapeutic interventions. Understanding Aβ-driven inflammaging mechanisms offers new therapeutic avenues for early intervention in age-related neurodegenerative diseases, particularly in genetically susceptible populations. Targeting Aβ-associated inflammaging reframes Aβ not solely as a pathological marker but also as a context-dependent contributor to inflammatory processes during brain aging.},
}

@article {pmid42521309,
year = {2026},
author = {Moncion, K and Rodrigues, L and Bon, A and Sutoski, A and Sikorska, K and Allison, EY and Abreu, J and Golchi, S and Arbour, N and Gauthier, C and Paquette, C and Rosa-Neto, P and Leppert, I and Rowley, C and Tardiff, CL and Thiel, A and Al-Khazraji, B and Tang, A and Roig, M},
title = {Protecting the brain from post-stroke cognitive impairment and dementia with multimodal exercise training: study protocol for a Bayesian adaptive trial (PROTECT).},
journal = {BMJ open},
volume = {16},
number = {7},
pages = {e123336},
doi = {10.1136/bmjopen-2026-123336},
pmid = {42521309},
issn = {2044-6055},
mesh = {Humans ; *Stroke/complications ; *Stroke Rehabilitation/methods ; *Cognitive Dysfunction/prevention & control/etiology ; *Dementia/prevention & control/etiology ; Bayes Theorem ; *Exercise Therapy/methods ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; Resistance Training/methods ; Brain ; Multicenter Studies as Topic ; Biomarkers/blood ; Cognition ; Neuroimaging ; },
abstract = {INTRODUCTION: Stroke triggers acute vascular and inflammatory mechanisms that predispose the brain to rapid neurodegeneration. Up to 52% of stroke survivors develop cognitive impairment within 6 months and 20% receive a clinical diagnosis of dementia within 5 years. The subacute phase (<6 months) represents a critical window in which the brain may be most responsive to neuroprotective interventions. Multimodal aerobic and resistance training improves cognition in chronic stroke, but whether it improves cognition, neuroimaging markers and blood biomarkers of dementia risk when delivered during this early window remains unknown. The PROTECT trial will compare the effects of 12 weeks of multimodal exercise (moderate-to-high-intensity resistance and aerobic training) versus a low-intensity exercise comparator on cognition, neuroimaging outcomes, blood biomarkers of cognitive decline and dementia risk in people with subacute stroke.

METHODS AND ANALYSIS: The PROTECT trial is a 12-week, Phase 3, assessor-blinded, multisite Bayesian adaptive randomised controlled trial (RCT) following a two-arm parallel group sequential design with 6-month and 12-month follow-up (NCT07445841). Participants will be randomised to multimodal training or the comparator using concealed allocation with permuted blocks of varying sizes. The primary outcome is cognition, measured using the 13-item Alzheimer's Disease Assessment Scale-Cognitive assessment (ADAS-Cog-13). Secondary outcomes include ADAS-Cog-Plus, structural and perfusion neuroimaging and blood biomarkers of inflammation and neurodegeneration. Tertiary outcomes include cardiorespiratory fitness, functional mobility, muscle strength, body composition, neuropsychological status, patient-reported cognition, quality of life, fatigue and healthcare utilisation. Outcomes will be assessed at baseline, post-intervention (primary endpoint) and at 6-month and 12-month follow-up. Sample size was estimated via 20 000 Monte Carlo simulations using an ADAS-Cog effect size of Cohen's d=0.63 from a previous exercise RCT. The target was ≥80% power to detect this treatment effect at a one-sided type I error rate of 2.5%, using a weakly informative prior centred at zero with a variance of 100. The minimum required was 45 completers per arm (N=90) and accounting for 25% attrition, up to 120 participants (60 per arm) will be enrolled. Pre-planned adaptive features include: (1) two interim analyses at 50% and 75% of completers; (2) early stopping for efficacy and futility; and (3) sample size re-estimation.

ETHICS AND DISSEMINATION: Ethical approval to conduct this study has been granted by the Centre de recherche interdisciplinaire en réadaptation du Montréal métropolitain (CRIR MP-50-2025-2294) and Hamilton Integrated Research Board (HIREB 19222). Any protocol amendments will be submitted to the appropriate ethics boards. Written informed consent to participate in this study will be obtained from all participants by study coordinators or assistants. Study results will be published and reported in peer-reviewed journal following Adaptive Designs Consolidated Standards of Reporting Trials extension guidelines.

TRIAL REGISTRATION NUMBER: NCT07445841.},
}

Humans
*Stroke/complications
*Stroke Rehabilitation/methods
*Cognitive Dysfunction/prevention & control/etiology
*Dementia/prevention & control/etiology
Bayes Theorem
*Exercise Therapy/methods
Randomized Controlled Trials as Topic
Clinical Trials, Phase III as Topic
Resistance Training/methods
Brain
Multicenter Studies as Topic
Biomarkers/blood
Cognition
Neuroimaging

@article {pmid42521490,
year = {2026},
author = {Jung, WH and Oh, ST and Choe, MS and Kwon, YJ and Kim, SJ and Jeon, YS and Baek, KM and Chang, W and Lim, KS and Kim, JS and Yun, SP and Lee, MY},
title = {A Cerebral Organoid Model of Familial Alzheimer's Disease Using Amyloid Precursor Protein Mutation, Val669Leu (APP[Seoul]).},
journal = {International journal of stem cells},
volume = {},
number = {},
pages = {},
doi = {10.15283/ijsc25044},
pmid = {42521490},
issn = {2005-3606},
abstract = {Various animal and cellular Alzheimer's disease (AD) models harboring familial AD (fAD) mutations have been developed and widely used for AD research. In this study, we established an AD cerebral organoid (CO) model using a novel Val669Leu (APP[Seoul]) mutation in the APP gene. We generated a human embryonic stem cell (hESC) line overexpressing APP[Seoul], referred to as the fAD-S hESC line. Using this line, we produced COs and confirmed robust AD-associated pathologies, including amyloid-β (Aβ) accumulation and tau phosphorylation. In addition, increased expression of β-secretase was observed in this model. Based on these findings, we investigated the effects of BACE1 inhibitor IV, a β-secretase inhibitor, in the CO model. Treatment with BACE1 inhibitor IV significantly reduced Aβ levels and tau phosphorylation. Furthermore, we differentiated the fAD-S hESC line into cortical neurons (fAD-S neurons) to establish a 2D cellular AD model. Consistent with the CO results, fAD-S neurons exhibited elevated levels of Aβ and phosphorylated tau, which were also significantly attenuated by BACE1 inhibitor IV treatment. Collectively, these results demonstrate the successful establishment of hESC-derived 2D and 3D AD models based on the APP[Seoul] fAD mutation.},
}

@article {pmid42521537,
year = {2026},
author = {da Silva, AMP and Haddad-Santos, D and de Siqueira Lima, DV and Cardoso, LJC and Moura, CB and Høilund-Carlsen, PF and Perry, G and Kishi, T and Barbosa, BJAP and Anghinah, R},
title = {Bayesian Reanalysis of a Pilot Randomized Clinical Trial of Low-Dose Lithium in Mild Cognitive Impairment: A Probabilistic Re-Expression of the LATTICE Trial.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.014},
pmid = {42521537},
issn = {1545-7214},
abstract = {OBJECTIVE: The LATTICE pilot randomized clinical trial found no statistically significant effect of low-dose lithium on 6 coprimary outcomes in mild cognitive impairment (MCI). We aimed to re-express these results in Bayesian terms and estimate the probability of benefit, negligible difference, or harm across cognitive, neuroimaging, biomarker, and safety outcomes.

METHODS: We conducted a Bayesian reanalysis of published aggregate data from LATTICE, a single-site, randomized, double-blind, placebo-controlled 2-year trial of low-dose lithium carbonate versus placebo. The trial randomized 83 older adults with MCI, of whom 80 initiated treatment. Outcomes included verbal and visuospatial delayed recall, Preclinical Alzheimer Cognitive Composite, hippocampal and cortical volume measures, brain-derived neurotrophic factor, and serious adverse events. Posterior means, 95% credible intervals (CrI), and posterior probabilities were estimated using weakly informative priors.

RESULTS: Lithium was associated with a posterior mean standardized effect of 0.38 SD for CVLT-II delayed recall (95% CrI, -0.03 to 0.80), corresponding to a 96.5% probability of benefit and an 80.6% probability of exceeding 0.20 SD. The raw between-group difference was 1.47 points (95% CrI, 0.18-2.75). Bayesian re-expression of the intention-to-treat model showed an annualized CVLT-II treatment-by-time effect of 0.69 points per year (95% CrI, 0.02-1.35). BVMT-R remained near null. Hippocampal outcomes were directionally favorable but imprecise. Other cognitive, biomarker, imaging, and safety outcomes showed no robust signal.

CONCLUSIONS: This Bayesian reanalysis supports an inconclusive interpretation of LATTICE, while identifying a probabilistic signal for verbal delayed recall-not seen in the other outcomes-that warrants testing in adequately powered trials.},
}

@article {pmid42521539,
year = {2026},
author = {Bassiouni, W and Ye, E and Colson, TL and Ferguson, SSG and Abd-Elrahman, KS},
title = {M1 muscarinic receptor modulation drives sex-specific alterations of Alzheimer's pathophysiology in APPswe/PSEN1ΔE9 mice.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {},
number = {},
pages = {104980},
doi = {10.1016/j.jpet.2026.104980},
pmid = {42521539},
issn = {1521-0103},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, where females account for 60% of diagnosed cases. AD is featured by β-amyloid deposition, which influences the activity of M1 muscarinic acetylcholine receptors (M1 mAChRs) that are essential for memory and learning. We previously demonstrated that VU0486846, a M1 mAChR positive allosteric modulator, improves cognitive function in AD mice by ameliorating β-amyloid pathology. However, it remains unclear how changes in M1 mAChR signaling and subcellular localization in AD brain influences its mechanism and how this differs between sexes. Nine-month-old male and female APPswe/PSEN1ΔE9 (APP/PS1) and wild-type mice were treated with VU0486846 (10 mg/kg/day) or vehicle via drinking water for 8 weeks. Elevated extracellular signal-regulated kinase 1/2 signaling, a plausible driver for β-amyloid pathology, was observed in female but not male APP/PS1 mice cortices, whereas VU0486846 mitigated this change. Additionally, VU0486846 enhanced the phosphorylation of the neuronal transcription factor cAMP response element-binding protein and increased the level of c-Fos, which regulate neuronal survival, in female wild-type and APP/PS1 mice only. In contrast, only male APP/PS1 mice exhibited increased levels of p62/SQSTM1 and decreased glycogen synthase kinase-3β activity, indicative of impaired autophagic flux, a change that was ameliorated by VU0486846 treatment. In subcellular fractions obtained from mice cortices, VU0486846 only increased cytosolic M1 mAChR level in female wild-type and APP/PS1 mice but not in males. Our findings indicate that M1 mAChR signaling is disrupted in APP/PS1 mice in a sex-dependent manner. VU0486846 enhances prosurvival signaling in females, potentially by increasing the cytosolic pool of M1 mAChRs, while modulating autophagy pathways in males, highlighting a sex-specific mechanism of action and underscoring its therapeutic potential. SIGNIFICANCE STATEMENT: The study highlights the sex-specific role of M1 muscarinic acetylcholine receptor (M1 mAChR) in Alzheimer's disease (AD) pathophysiology, providing evidence that the ability of M1 mAChR positive allosteric modulation to alleviate β-amyloid pathology occurs through distinct mechanisms. It rescues neuronal activity in females, which could be linked to enhanced cytosolic receptor pooling, while restoring autophagic flux in males. The study also reinforces the therapeutic potential of M1 mAChR positive allosteric modulators and supports the development of sex-tailored interventions for AD.},
}

@article {pmid42521649,
year = {2026},
author = {Na, HK and Sun, Y and Park, CW and Lee, JH and Choi, YY and Vo, QP and Chung, SJ and Yoo, HS and Lyoo, CH and Sohn, YH and Hong, JY and Lee, PH},
title = {Greater Motor and Nonmotor Burden at Diagnosis Is Associated With Amyloid Copathology in Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70446},
pmid = {42521649},
issn = {1531-8257},
support = {2024ER100200//Korean National Institute of Health/ ; RS-2026-25498013//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: Concurrent Alzheimer's disease pathology is increasingly recognized as a poor prognostic factor in Parkinson's disease (PD), yet reliable clinical indicators for early identification of AD copathology remain poorly established.

OBJECTIVE: To investigate baseline motor and nonmotor symptom profiles associated with amyloid-β (Aβ) copathology in newly diagnosed PD.

METHODS: Among patients with PD who underwent Aβ imaging, we retrospectively identified 152 patients who completed the Cross-Cultural Smell Identification Test (CC-SIT), autonomic function tests, neuropsychological assessment, and Neuropsychiatric Inventory Questionnaire (NPI-Q) at drug-naive state. Predictors of Aβ positivity were identified using stepwise multivariable logistic regression and validated with Random Forest classifiers employing Boruta feature selection.

RESULTS: Compared with Aβ-negative counterparts (n = 93), Aβ-positive (Aβ + PD, n = 59) patients demonstrated greater olfactory dysfunction (CC-SIT, P = 0.002), dysautonomia (Composite Autonomic Severity Scale [CASS], P < 0.001), and mood disturbance (NPI-Q-mood, P < 0.001) and higher prevalence of probable rapid eye movement sleep behavior disorder (P = 0.009) and neurogenic orthostatic hypotension (P = 0.006). Aβ + PD patients showed greater motor disability (Unified Parkinson's Disease Rating Scale Part III [UPDRS-III], P < 0.001) despite comparable striatal dopamine transporter uptake. Logistic regression identified lower CC-SIT scores (odds ratio [OR] = 0.821, 95% confidence interval [CI95%]: 0.703-0.959), higher CASS scores (OR = 1.380, CI95%: 1.144-1.666), higher NPI-Q-mood scores (OR = 1.057, CI95%: 1.005-1.111), higher UPDRS-III (OR = 1.080, CI95%: 1.030-1.132), and APOE ε4 carrier status (OR = 3.643, CI95%: 1.479-8.969) as independent predictors of Aβ positivity, which were also confirmed as important variables by Boruta feature selection.

CONCLUSIONS: Our findings suggest that greater motor and nonmotor symptom burden at diagnosis, characterized by olfactory/autonomic dysfunction, mood disturbance, and motor deficits disproportionate to dopaminergic denervation, was associated with Aβ positivity in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42521874,
year = {2026},
author = {Vanderlip, CR and Stark, CEL},
title = {Modernizing cognitive assessment in Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42521874},
issn = {2662-8465},
support = {T32AG00096//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG066683/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; },
}

@article {pmid42521895,
year = {2026},
author = {Abidar, S and Nhiri, M and Bianchi, V},
title = {Suicide in neurodegenerative diseases: a systematic review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42521895},
issn = {1590-3478},
mesh = {Humans ; *Neurodegenerative Diseases/psychology ; *Suicide/psychology/statistics & numerical data ; Amyotrophic Lateral Sclerosis/psychology ; Multiple Sclerosis/psychology ; },
abstract = {BACKGROUND AND OBJECTIVE: Suicide is a public health issue, which differs from suicidality, the continuum from suicidal ideation to the suicidal act, including suicide attempts and completed suicide. The main goal of the present study is to determine the relationship between Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with suicidality.

METHODS: This is a systematic review aiming to determine the relationship between AD, PD, ALS, and MS with suicidality following PRISMA 2020 guidelines by collecting cross-sectional, case-control, and cohort studies; case series; case reports; and retrospective and prospective studies from Google Scholar, PubMed, and Cochrane Library. The protocol of this systematic review was registered on PROSPERO; the registration number is CRD420261422354.

RESULTS: From 2247 records identified from electronic databases, only 24 articles were included: three studies focusing on AD, nine on PD, and six studies focusing on ALS and MS, respectively. These studies exhibited moderate to low risk of bias. Despite the broad differences regarding the neurochemistry, pathophysiology, diagnosis, symptoms, and treatments of the selected diseases, patients are at a higher risk of suicidality. Depression and low social connectivity are the most prevalent risk factors. Suicidality is mainly detected during the first years post-diagnosis in PD, ALS, and MS patients, while the results in AD are confusing.

CONCLUSIONS: Data about this topic is scarce and largely varying. Further research is required to elucidate this paradigmatic realm, fostering awareness, enhancing therapies, and providing explanations and interpretations of the mechanisms involved.},
}

Humans
*Neurodegenerative Diseases/psychology
*Suicide/psychology/statistics & numerical data
Amyotrophic Lateral Sclerosis/psychology
Multiple Sclerosis/psychology

@article {pmid42522048,
year = {2026},
author = {Wang, QQ and Sun, QQ and Guo, YS and Yin, S and Zhou, JW},
title = {Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42522048},
issn = {2047-9158},
support = {82301629//National Natural Science Foundation of China/ ; ZR2024MH129//Natural Science Foundation of Shandong Province/ ; 2021ZD0200900//STI2030-Major Projects/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/therapy/metabolism/immunology ; *Parkinson Disease/pathology/therapy/metabolism/immunology ; *Neuroinflammatory Diseases/pathology/therapy/metabolism ; Animals ; Inflammation/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neuroinflammation is increasingly recognized as a key contributor and amplifier associated with the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Neuroinflammation occurs throughout various stages of these diseases with expanding complexity. Currently, no effective therapies exist that specifically target neuroinflammatory processes in these disorders. In this review, we synthesize current understanding of central and peripheral inflammatory mechanisms implicated in both diseases. We illustrate how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration. Additionally, peripheral factors, including systemic inflammation, environmental exposures, and gut-brain axis interactions, are discussed for their roles in modulating neuroinflammatory responses. Notably, the underappreciated roles of oligodendrocyte precursor cells and oligodendrocytes in neuroimmune crosstalk are also highlighted. Advanced methodologies, including glial cell imaging, single-cell transcriptomics, and human induced pluripotent stem cell-derived organoid models, are providing unprecedented insights into the molecular and cellular mechanisms underlying neuroinflammation. Finally, we evaluate emerging therapeutic strategies and ongoing clinical trials targeting neuroinflammatory pathways and analyze the potential of immunomodulatory approaches to slow disease progression. This comprehensive review emphasizes that precise targeting of neuroinflammation represents a tractable strategy for developing effective disease‑modifying treatments for AD and PD.},
}

Humans
*Alzheimer Disease/pathology/therapy/metabolism/immunology
*Parkinson Disease/pathology/therapy/metabolism/immunology
*Neuroinflammatory Diseases/pathology/therapy/metabolism
Animals
Inflammation/pathology
Amyloid beta-Peptides/metabolism

@article {pmid42522051,
year = {2026},
author = {Souza, MR and Alvarenga, TA and Mazaro-Costa, R and Tufik, S and Andersen, ML},
title = {Reproductive neuroendocrine pathways as modulators of sleep-related sex differences in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71699},
doi = {10.1002/alz.71699},
pmid = {42522051},
issn = {1552-5279},
support = {2020/13467-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Associação Fundo de Incentivo à Pesquisa/ ; },
}

@article {pmid42522056,
year = {2026},
author = {Wear, D and Morrone, CD and Yu, WH},
title = {Refining our understanding of sleep impairment and connection to Alzheimer's disease in preclinical models.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71700},
doi = {10.1002/alz.71700},
pmid = {42522056},
issn = {1552-5279},
support = {A2022016F//BrightFocus Foundation/ ; //Ontario Ministry of Colleges and Universities/ ; 11020222023Q2412//Natural Sciences and Engineering Research Council of Canada/ ; AG080781//Foundation for the National Institutes of Health/ ; },
}

@article {pmid42522059,
year = {2026},
author = {Okorie, M and Jonson, C and Oddi, AP and Castruita, PA and Fulton-Howard, B and Yaffe, K and Yokoyama, JS and Udeh-Momoh, C and Andrews, SJ and , },
title = {Cross-ancestry polygenic risk scores enhance Alzheimer's disease risk prediction in multiethnic cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71529},
doi = {10.1002/alz.71529},
pmid = {42522059},
issn = {1552-5279},
support = {ZIAAG000534//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; R01AG062588//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; R01AG057234//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; P30AG062422//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; P01AG019724//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; U19AG079774//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; U24AG072122//National Alzheimer's Coordinating Center/ ; U54NS123985/NS/NINDS NIH HHS/United States ; U19AG079774/AG/NIA NIH HHS/United States ; //Rainwater Charitable Foundation/ ; //Bluefield Project to Cure Frontotemporal Dementia/ ; /ALZ/Alzheimer's Association/United States ; //Global Brain Health Institute/ ; //Genentech/ ; //French Foundation/ ; //Mary Oakley Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genetic Risk Score ; Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Amyloid beta-Peptides/cerebrospinal fluid ; Bayes Theorem ; *Multifactorial Inheritance/genetics ; Female ; Cohort Studies ; tau Proteins/cerebrospinal fluid ; White People/genetics ; Male ; },
abstract = {INTRODUCTION: Genome-wide association studies (GWAS) have identified 80+ genetic loci associated with Alzheimer's disease (AD), enabling the development of polygenic risk scores (PRS). However, the predictive accuracy of PRS in diverse populations remains low. Here, we evaluated the predictive accuracy of single-, multi-, and cross-ancestry AD-PRS models across multi-ancestral populations.

METHODS: We used AD GWAS summary statistics from European, African, Admixed American, and East Asian populations to construct AD-PRS for each target population. Model performance was assessed by estimating odds ratios, R[2], and area under the curve.

RESULTS: The cross-ancestry Bayesian PRS model demonstrated the highest predictive performance in non-European populations. It was significantly associated with poorer cognitive function, lower Aβ42 cerebrospinal fluid levels, and the most severe category of Aβ and tau neuropathological burden.

DISCUSSION: Inclusive genetic datasets and cross-ancestry PRS models are needed to enhance the transportability of AD-PRS across multi-ancestral populations.},
}

Humans
*Alzheimer Disease/genetics
Genetic Risk Score
Genome-Wide Association Study
*Genetic Predisposition to Disease
Amyloid beta-Peptides/cerebrospinal fluid
Bayes Theorem
*Multifactorial Inheritance/genetics
Female
Cohort Studies
tau Proteins/cerebrospinal fluid
White People/genetics
Male

@article {pmid42522069,
year = {2026},
author = {Okorie, M and Jiang, X and Yaffe, K and Yokoyama, JS and Andrews, SJ and , },
title = {Associations of dementia polyexposure scores to Alzheimer's disease endophenotypes in a diverse population.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71567},
doi = {10.1002/alz.71567},
pmid = {42522069},
issn = {1552-5279},
support = {U24AG072122//National Alzheimer's Coordinating Center/ ; //Mary Oakley Foundation/ ; //French Foundation/ ; //Genentech/ ; //Global Brain Health Institute/ ; /ALZ/Alzheimer's Association/United States ; //Rainwater Charitable Foundation/ ; U54NS123985/NS/NINDS NIH HHS/United States ; U19AG079774/AG/NIA NIH HHS/United States ; R01AG057234/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P01AG019724/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Endophenotypes ; *Alzheimer Disease/epidemiology/diagnosis/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Female ; Male ; Aged ; tau Proteins/metabolism ; *Dementia/epidemiology/diagnosis ; Risk Factors ; Positron-Emission Tomography ; Aged, 80 and over ; Peptide Fragments ; },
abstract = {INTRODUCTION: Dementia clinical risk scores (CRSs) provide accessible tools for identifying individuals at risk for Alzheimer's disease (AD) and related dementias, yet their performance across diverse populations and relationships to AD endophenotypes remains unclear.

METHODS: We evaluated four CRSs, modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (mCAIDE), Washington Heights-Inwood Columbia Aging Project (WHICAP), Lifestyle for Brain Health (LIBRA), and Cognitive Dementia Risk (CogDRisk), in relation to cognitive impairment (CI) and AD endophenotypes, including tau phosphorylated at threonine 217 (pTau217)/amyloid beta 42 (Aβ42) positivity defined using a Youden index-derived cutoff for amyloid positron emission tomography (PET) positivity. Logistic and linear regression models stratified by self-reported race/ethnicity were used to assess the associations of CRS with endophenotypes and CI and to evaluate predictive performance.

RESULTS: CogDRisk showed the strongest and most consistent performance across endophenotypes, pTau217/Aβ42 positivity, and CI, with mCAIDE performing the worst and lacking associations with plasma biomarkers. Higher CRS were consistently associated with increased odds of dementia across all races/ethnicities.

CONCLUSIONS: CRSs capture AD-related risk across diverse populations and modestly reflect underlying biological endophenotypes, supporting their utility in community-based risk assessment.},
}

Humans
*Endophenotypes
*Alzheimer Disease/epidemiology/diagnosis/diagnostic imaging
Amyloid beta-Peptides/metabolism
Female
Male
Aged
tau Proteins/metabolism
*Dementia/epidemiology/diagnosis
Risk Factors
Positron-Emission Tomography
Aged, 80 and over
Peptide Fragments

@article {pmid42522110,
year = {2026},
author = {Quigley, DD and Walsh, S and Kassner, CT and Dhingra, L and Dick, AW},
title = {Private Equity Ownership in Hospice Care: A Systematic Review (2012-2026).},
journal = {The American journal of hospice & palliative care},
volume = {},
number = {},
pages = {10499091261471107},
doi = {10.1177/10499091261471107},
pmid = {42522110},
issn = {1938-2715},
abstract = {Hospice care is associated with improved end-of-life outcomes. Recent shifts in hospice utilization highlight several key trends. Alzheimer's disease and related dementias (ADRD) (25%) have surpassed cancer (23%) as the leading primary diagnosis. Concurrently, industry ownership has transitioned from predominantly nonprofit to for-profit (70%) and private equity (PE) ownership has grown dramatically from 3% to 15%. To date, no study has synthesized evidence on PE ownership in hospice care. We conducted a systematic review of English-language, peer-reviewed studies published 2012-2026, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 630 screened articles, 114 underwent full-text review and 6 met inclusion criteria. All studies used national data; sample sizes ranged from 80 to 536 PE-owned hospices. Three studies examined PE prevalence and market trends; two assessed caregiver-reported care experiences, and one evaluated financial outcomes by PE ownership. The evidence regarding PE ownership of hospices remains limited. It highlights the increasing role of PE in hospice markets. It consistently found (across two studies) worse care experiences at PE-owned hospices vs nonprofit hospices, except for emotional and religious support which was similar across ownership type. The evidence suggests PE ownership is associated with complex, often worse patterns related to market structure, care experiences, and financial allocation. Additionally, it underscores the limited evidence base to inform policy development. Research is needed to examine associations between PE ownership and hospice care quality, both overall and among vulnerable populations. Research should clarify modifiable factors influencing hospice quality and better characterize evolving ownership structures.},
}

@article {pmid42522301,
year = {2026},
author = {Ishak, NI and Siran, R and Mohamad Zain, WNIW and Azme, N},
title = {Endothelial-to-mesenchymal Transition at the Blood-brain Barrier: Molecular Mechanisms and Pathological Roles Across Brain Diseases.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273485479260721072747},
pmid = {42522301},
issn = {1996-3181},
abstract = {Endothelial-to-Mesenchymal Transition (EndMT) is a significant contributor to Blood- Brain Barrier (BBB) dysfunction in various brain diseases. The majority of current therapies, aimed at reducing BBB dysfunction, focus on preventing inflammation or stabilizing tight junctions. In most cases, these therapies do not provide adequate or long-lasting vascular protection. Endothelial cells undergo phenotypic programming, losing their barrier-forming capacity and developing features of mesenchymal and extracellular matrix-producing cells as the disease progresses. The change leads to chronic vascular leakage, neuroinflammation, microvascular fibrosis, and dysfunctional neurovascular coupling. Several upstream stimuli, including inflammatory cytokines, TGF-β/BMP-Smad signaling, and oxidative damage, converge to drive EndMT within the distinctive, specialized environment of the brain endothelium. Ischemic stroke, multiple sclerosis, cerebral cavernous malformations, arteriovenous malformations, glioblastoma, brain metastasis, and Alzheimer's disease indicate that EndMT is not a rare or unique process but a shared and common pathologic process that may result in disease progression and eventual resistance to treatment. Recent single-cell and spatial transcriptomic data have shown that partial EndMT states exist and may be precursors to irreversible microvascular remodeling. It is necessary to identify therapeutic approaches that go beyond short-term stabilization of the BBB and target the molecular programs underlying the loss of endothelial identity. This review synthesizes mechanistic, disease-related, and therapeutic evidence indicating that EndMT is a leading cause of BBB failure and highlights therapeutic opportunities for targeting this endothelial plasticity in brain diseases.},
}

@article {pmid42522305,
year = {2026},
author = {Paliwal, D and Thakur, A},
title = {Exploring the Therapeutic Potential of Chalcones in Alzheimer's Disease: Mechanistic Insights and SAR Perspectives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575457432260717112508},
pmid = {42522305},
issn = {1875-5607},
abstract = {Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by amyloid- β aggregation, oxidative stress, neuroinflammation, tau hyperphosphorylation, and cholinergic dysfunction. The limited efficacy of current therapies has driven the development of multitargetdirected ligands (MTDLs). Chalcones represent a versatile scaffold for modulating multiple ADrelated targets. This review provides a concise analysis of the structure-activity relationship (SAR) of chalcone derivatives, highlighting the effects of hydroxylation, methoxylation, halogenation, and heterocyclic hybridization on biological activity. Electron-withdrawing substituents (e.g., halogens, -CF3) enhance enzyme inhibition and MAO-B selectivity, whereas electron-donating groups (e.g., hydroxyl and methoxy groups) contribute to antioxidant activity, metal chelation, and hydrogen bonding interactions. Scaffold hybridization and optimized linker design further improve multitarget engagement, including AChE/BuChE inhibition, MAO-B modulation, and anti-amyloid activity. However, despite promising in vitro and in silico findings, translational limitations remain due to insufficient in vivo validation and pharmacokinetic constraints. Overall, chalcone-based MTDLs provide a rational framework for the development of next-generation anti-Alzheimer agents.},
}

@article {pmid42522313,
year = {2026},
author = {Tian, J and Yao, R and Shen, L and Jiao, B and Luo, SL},
title = {PP2A: Decoding Its Structure, Regulation and Therapeutic Applications in Neurological Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X482496260716074148},
pmid = {42522313},
issn = {1875-6190},
abstract = {Protein phosphatase 2A (PP2A) is a highly conserved serine/threonine phosphatase that plays a pivotal role in maintaining cellular homeostasis by counterbalancing kinase activity. As a heterotrimeric enzyme composed of scaffolding, regulatory, and catalytic subunits, PP2A achieves extraordinary functional diversity through the dynamic assembly of more than 80 holoenzyme variants. This structural versatility allows PP2A to regulate a wide range of biological processes, including cell cycle progression, apoptosis, DNA damage response, and major signaling pathways such as MAPK and Wnt. Dysregulation of PP2A, through altered subunit expression, post-translational modification, or inhibition by endogenous suppressors like CIP2A and SET, has been implicated in diverse diseases, notably neurodegenerative disorders, cancers, and metabolic syndromes. In neurological disorders such as Alzheimer's and Parkinson's diseases, impaired PP2A activity contributes to pathogenic protein hyperphosphorylation, neurofibrillary tangle formation, and neuroinflammation. Recent advances have fundamentally reshaped our understanding of PP2A biology. High-resolution structural studies have revealed the molecular basis of holoenzyme assembly and substrate recruitment, while accumulating evidence suggests that PP2A activity is dynamically regulated across tissues and cell types, largely driven by differential expression of regulatory subunits and post-translational modifications. Despite these advances, current knowledge remains fragmented, and a comprehensive synthesis linking PP2A structural dynamics, regulatory mechanisms, and its roles in pathophysiology, particularly in the context of neurological disorders, is still lacking. This review deciphers the structural complexity and regulatory mechanisms of PP2A, elucidates its multifaceted roles in neural physiology and pathology, and examines current and emerging therapeutic strategies targeting PP2A modulation to intervene in neurological disease.},
}

@article {pmid42522580,
year = {2026},
author = {Park, CW and Choi, Y and Lee, HS and Jeong, SH and Lee, PH and Kim, YJ and Sohn, YH and Lee, J and Chung, SJ},
title = {Amyloid-linked trajectories of cerebral hypoperfusion and dopamine loss in dementia with Lewy bodies.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag264},
pmid = {42522580},
issn = {1460-2156},
abstract = {Dementia with Lewy bodies (DLB) is clinically heterogeneous, and the evolutionary trajectories of cortical dysfunction, nigrostriatal dopaminergic degeneration, and amyloid accumulation, as well as the interactions among them, remain poorly understood. This study enrolled 83 patients with DLB who underwent dual-phase 18F-FP-CIT PET and 18F-FBB PET scans at initial assessment. Fifteen standardised imaging biomarkers capturing cerebral perfusion (early-phase 18F-FP-CIT PET images), striatal dopamine depletion (late-phase 18F-FP-CIT PET images), and amyloid burden (18F-FBB PET images) were entered into a Subtype and Stage Inference (SuStaIn) model. The SuStaIn analysis delineated two subtypes of DLB with distinct evolutionary trajectories: Subtype 1 (n = 37) was characterized by early amyloid accumulation, followed by cerebral hypoperfusion progressing from the posterior cingulate cortex to other cortical and limbic regions, and later diffuse striatal dopamine depletion; Subtype 2 (n = 36) initially presented with selective dopamine loss in the putamen, with subsequent dopaminergic deficits in other striatal subregions, followed by amyloid accumulation and cerebral hypoperfusion progressing from the precuneus to other cortical and limbic regions. The remaining 10 patients with DLB did not have sufficiently abnormal imaging findings to be categorized into a defined subtype (Subtype 0). Subtype 1 exhibited more severe Alzheimer's disease (AD)-like cortical atrophy and lower cingulate island sign ratios on early-phase 18F-FP-CIT PET images. Patients in Subtype 2 had a higher prevalence of rapid eye movement sleep behavior disorder and visual hallucinations than those in Subtype 1. In conclusion, we delineate two distinct multimodal imaging progression patterns in DLB: an early nigrostriatal dopamine depletion-linked trajectory with more typical DLB characteristics and an early amyloid deposition-linked trajectory characterised by an inverse cingulate island sign and AD-like cortical atrophy. These findings highlight the clinical and biological heterogeneity within DLB.},
}

@article {pmid42522648,
year = {2026},
author = {Wei, Z and Qian, H and Dai, C and Wu, J and Li, Y and Yin, K and Li, M and Yang, H},
title = {Global Research Trends of Protein Post-translational Modifications in Alzheimer's Disease: A Bibliometric Analysis.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X457922260717112524},
pmid = {42522648},
issn = {1875-6190},
abstract = {BACKGROUND: In recent years, a considerable body of research has increasingly underscored the critical roles that protein Post-Translational Modifications (PTMs) play in the pathogenesis of Alzheimer's Disease (AD). However, a comprehensive bibliometric analysis of this field is still lacking. This study aims to systematically map research trends and hotspots and to identify promising directions for future work.

METHODS: The data in this study were extracted from the Web of Science Core Collection (WOSCC) and visualized using CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel 2016 to analyze bibliometric indicators including countries, institutions, authors, journals, citations, production categories, and keywords.

RESULTS: A collection of 1,170 articles was retrieved, spanning the publication period from January 1, 1990, to December 31, 2024. The top three countries in terms of publications were the United States, China, and Germany. The most productive institution was the University of California System in the United States, contributing 57 articles. The leading authors identified were Mitkevich Vladimir, Perry George, and Makarov Alexander A. The Journal of Alzheimer's Disease was the top-ranked journal in terms of published papers. The most frequently cited article was "The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation," published in the International Journal of Molecular Sciences. Finally, the most prolific research category was neuroscience, with 432 papers published. High-frequency keywords included Alzheimer's disease, phosphorylation, tau, and neurodegeneration.

DISCUSSION: The study's findings suggest that PTM research in AD continues to revolve around the core pathological hallmarks represented by Aβ and tau protein. At the same time, some studies have reported aberrant modifications of α-synuclein and its potential role in AD. By systematically cataloging diverse PTM types and the molecular mechanisms involving Aβ and tau throughout AD progression, this analysis paves the way for a reassessment of AD pathogenesis from a "modification-function-pathology" perspective and provides a basis for identifying potential PTM-related targets and intervention strategies.

CONCLUSION: This bibliometric analysis highlights the growing scholarly attention devoted to the relationship between PTMs and AD. The significant contributions and emerging trends emphasize the pivotal role of PTMs in the pathogenesis of AD, which may guide future biomarker discovery.},
}

@article {pmid42522708,
year = {2026},
author = {Li, H and Khang, TF},
title = {SIEVEseq: Unified differential expression, variability, and skewness analyses using RNA-Seq data.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {},
number = {},
pages = {},
doi = {10.1093/dnares/dsag012},
pmid = {42522708},
issn = {1756-1663},
abstract = {RNA-Seq data analysis is commonly biased towards detecting differentially expressed genes and insufficiently conveys the complexity of gene expression changes between biological conditions. This bias arises because discrete count models cannot fully and independently parameterize the mean, variance, and skewness of gene expression distributions. Therefore, a unified statistical framework that simultaneously tests differential expression, variability, and skewness is needed. We present SIEVEseq, a statistical methodology that provides such a framework. SIEVEseq embraces a compositional data analysis strategy to transform discrete RNA-Seq counts into continuous form with a distribution well-fitted by the skew-normal distribution. Both parametric and nonparametric simulations show that SIEVEseq better controls the false discovery rate and Type II error than existing differential expression methods. Analysis of the Mayo RNA-Seq dataset for Alzheimer's disease demonstrates that gene sets with significant differences in mean, variance, and skewness between control and disease groups strongly predict disease state. Furthermore, functional enrichment analysis indicates that relying solely on differentially expressed genes identifies only part of the biological spectrum, whereas incorporating genes with differential variability and skewness reveals additional disease-related aspects. Cross-data and cross-methodology validation suggest the detected biological signals are genuine. The SIEVEseq R package is available at https://cran.r-project.org/web/packages/SIEVEseq.},
}

@article {pmid42523103,
year = {2026},
author = {Dey, C and Pal, P and Khan, A and Dey, SG},
title = {Heme-copper-Aβ mediated dopamine oxidation through self-sustaining redox cycling.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03615e},
pmid = {42523103},
issn = {1364-548X},
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration, with Aβ peptides playing a critical role in disease pathology. Beyond their aggregation into plaques, Aβ peptides can interact with redox-active cofactors such as copper and heme, forming complexes capable of catalyzing ROS generation. While Cu-Aβ is known to oxidise catecholamines like dopamine through redox cycling, the functional implications of ternary heme-Cu-Aβ assemblies remain poorly understood. In this study, we demonstrate that the heme-Cu-Aβ complex catalyzes dopamine oxidation more efficiently than Cu-Aβ alone, driven by a self-sustaining cooperative redox cascade involving Cu-mediated H2O2 generation and subsequent heme-mediated peroxidase-like activity in the presence of the endogenously produced H2O2. Moreover, kinetic analysis and mutant studies reveal the critical contributions of Arg5 in modulating the redox behavior of the complex. These findings establish the heme-Cu-Aβ complex as a potent catalytic assembly capable of altering dopamine homeostasis under oxidative stress, offering new insights into Aβ-mediated neurotoxicity in Alzheimer's disease.},
}

@article {pmid42523146,
year = {2026},
author = {Vellone, D and Leon, R and Goodarzi, Z and Forkert, ND and Smith, EE and Ismail, Z},
title = {Mild behavioral impairment-apathy and Alzheimer's disease plasma phosphorylated tau biomarker levels.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470257},
doi = {10.1177/13872877261470257},
pmid = {42523146},
issn = {1875-8908},
abstract = {BackgroundMild behavioral impairment (MBI), characterized by later-life emergence of persistent neuropsychiatric symptoms (NPS), is an early clinical indicator of dementia risk. Global MBI has been associated with Alzheimer's disease (AD) pathology; studies have also explored MBI domains. Prior work has linked MBI-apathy to AD cerebrospinal fluid (CSF) biomarkers, but whether associations are detectable using plasma-based biomarkers such as phosphorylated tau (p-tau) is unknown. Establishing such relationships is critical, as plasma biomarkers are more accessible than CSF.ObjectiveTo explore cross-sectional and longitudinal associations between MBI-apathy and plasma p-tau181 levels using Alzheimer's Disease Neuroimaging Initiative data.MethodsOlder adults with normal cognition or mild cognitive impairment were categorized as MBI-apathy (n = 69), non-MBI NPS (n = 112), and no-NPS (n = 215) based on Neuropsychiatric Inventory scores and symptom persistence over one year. Linear regression modelled cross-sectional associations between NPS group and plasma p-tau181, adjusting for age, sex, education, apolipoprotein E4 status, and Mini-Mental State Examination score. Hierarchical linear mixed-effects modelling assessed associations over two and three years, including time-by-NPS group interactions.ResultsMBI-apathy was associated with significantly higher plasma p-tau181 levels at baseline (24.05% [6.06-45.08%]; adjusted p = 0.014), and over two (26.46% [7.24-49.12%]; adjusted p = 0.012) and three years (29.28% [10.17-51.72%]; adjusted p = 0.004) compared to no-NPS. No significant associations were observed for non-MBI NPS. In sensitivity analyses, non-MBI apathy was not associated with plasma p-tau181 at baseline (-9.96% [-32.69-20.44%]; unadjusted p = 0.478).ConclusionsMBI-apathy is associated with elevated plasma p-tau181 cross-sectionally and longitudinally, supporting MBI-apathy as a potential proxy marker of tau pathology for early AD detection.},
}

@article {pmid42523149,
year = {2026},
author = {Mosquera-Heredia, MI and Vidal, OM and Barceló, E and Morales, LC and Silvera-Redondo, C and Bolívar, DA and Allegri, R and Arcos-Burgos, M and Garavito-Galofre, P and Vélez, JI},
title = {Novel blood lncRNA biomarkers associated with clinical severity and specific cognitive dimensions in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470430},
doi = {10.1177/13872877261470430},
pmid = {42523149},
issn = {1875-8908},
abstract = {BackgroundDifferential expression of long non-coding RNAs (lncRNAs) in brain, serum, and blood show strong potential to distinguish Alzheimer's disease (AD) from healthy controls.ObjectiveTo explore whether lncRNA signatures delineate AD pathology and map to distinct, multidimensional cognitive domains, enhancing specificity in assessing AD severity and progression.MethodsWe profiled 29,603 lncRNAs transcripts in blood samples from 15 AD patients and 15 healthy controls, alongside comprehensive neuropsychological assessments. Generalized Linear Models and Predictive Power Score analyses, with statistical prioritization, identified lncRNAs associated to AD neuropsychological architecture.ResultsSeveral lncRNAs share strongly associated with cognitive performance and AD severity, mapping to genes involved in key AD-related molecular processes, including synaptic and neurotransmitter regulation (e.g., EPHB1, CHRNA4, TEAD1), protein homeostasis and Aβ pathology (e.g., FBXL2, FAM221A, APP), mitochondrial function and cellular stress (e.g., VDAC3, PPT2-EGFL8), neuroinflammation and immune regulation (e.g., TEAD1, EMX2OS, LY6E-DT), epigenetic and transcriptional control (e.g., PRDM2, DLEU1, FIRRE), neuronal excitability (e.g., KCNJ14), and neuroprotection and synaptic plasticity (e.g., SIL1). Novel associations included ferroptosis, DNA stability, microtubule dynamics, and dendritic orientation (e.g., BTB3, DICER1, GNG7, IBA57, NEAT1, POT1, SRD5A3).ConclusionsWe identify candidate lncRNA signatures that may serve as potential biomarkers and enhance our understanding of the molecular basis of the cognitive architecture in AD, opening new avenues for biomarker identification and targeted therapeutic strategies development. Validation in larger, diverse cohorts is essential to confirm their mechanistic contributions to AD.},
}

@article {pmid42523152,
year = {2026},
author = {Oliveira, MPB and Da Silva, SLA and Cezar, NOC and Lima-Truax, CR and Truax, BD and Brito-Costa, S and Takahashi, ACM and Serrão, PRMDS and Andrade, LP},
title = {Exploring the relationship between Alzheimer's disease and lower extremity isokinetic muscle strength in community-dwelling older adults: A cross-sectional observational study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471888},
doi = {10.1177/13872877261471888},
pmid = {42523152},
issn = {1875-8908},
abstract = {BackgroundOlder adults diagnosed with Alzheimer's disease (AD) often experience diminished muscle strength, highlighting the continued importance of evaluating muscle function in this population.ObjectiveTo examine the relationship between AD and isokinetic lower limb muscle strength in older adults.MethodsA cross-sectional observational study was conducted to examine the association between AD and lower limb isokinetic muscle strength in community-dwelling older adults. AD diagnosis was the independent variable; dependent variables included peak torque, average peak torque, and total work. A standardized isokinetic protocol adapted for older adults with cognitive impairment was used to assess knee (flexion/extension at 60°/s and 180°/s) and ankle (dorsiflexion/plantar flexion at 30°/s) strength. Crude and adjusted linear regression models evaluated statistical associations, with significance set at p ≤ 0.05.ResultsA total of 80 older adults were included, 50% of whom had a diagnosis of AD. The crude model's analysis showed an association between AD and all knee and ankle isokinetic measurements. When the models were adjusted, the association was maintained only for ankle peak torque (β1 = -16.23; p < 0.048) and ankle average peak torque (β1 = -13.65; p < 0.049) at 30°/s (plantar flexion).ConclusionsAlzheimer's disease is associated with lower ankle plantar flexors isokinetic muscle strength in community-dwelling older adults. No significant associations between AD and knee (flexors and extensors) and ankle (dorsiflexors) isokinetic muscle strength were found.},
}

@article {pmid42523300,
year = {2026},
author = {Flores, S and Wilpitz, A and Ojeda-Juarez, D and Wang, J and Danque, G and Sumowski, P and Funk, G and Malik, A and Pizzo, D and Richards, E and Iliff, JJ and Sigurdson, CJ},
title = {Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.732468},
pmid = {42523300},
issn = {2692-8205},
abstract = {Aquaporin 4 (AQP4) water channels are polarized to astrocytic endfeet at blood vessel interfaces, and lose polarity in vascular diseases, including stroke, chronic traumatic encephalopathy, and Alzheimer's disease. AQP4 modulates water influx and efflux in the interstitial fluid, yet how AQP4 localization impacts cerebral amyloid angiopathy (CAA) remains poorly understood. Here we show that astrocytic end feet and AQP4 are displaced from amyloid-bearing vessels in a prion-CAA mouse model that expresses GPI-anchorless PrP [C] . Displacing AQP4 genetically through deleting alpha-syntrophin (Snta1 [-/-]) led to a marked prolongation in survival, together with reduced microglial inflammation and C1q, in prion-CAA-affected mice. Additionally, synaptic structural proteins were better maintained. Finally, the level and distribution of prion aggregates were similar among the mice, indicating that prion conversion and spread was not affected. These results suggest that reducing AQP4 water channel function slows the decline in a vascular amyloid disease by reducing neuroinflammation.},
}

@article {pmid42523318,
year = {2026},
author = {Wisch, JK and Jiao, Z and Millar, PR and McKay, NS and Beric, A and Lin, W and Baker, B and Stauber, J and Preminger, S and Jucker, M and R Barthélemy, N and Chhatwal, J and Ryan, NS and Schindler, SE and Morris, JC and Cruchaga, C and Benzinger, TLS and Karch, CM and Bateman, RJ and McDade, E and Llibre-Guerra, J and , and , and Gordon, BA and Ances, BM and Ibanez, L},
title = {Biomarker Variability Limits Individualized Amyloid Time Estimation in Alzheimer Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.08.737258},
pmid = {42523318},
issn = {2692-8205},
abstract = {OBJECTIVE: Disease progression modeling (DPM) or "amyloid time" is increasingly used to stage Alzheimer disease (AD). DPM performance depends on within-individual heterogeneity in rates of pathological accumulation as well as test-retest reliability of the biomarker. The relative contributions of these variabilities have not been systematically assessed. This would be particularly relevant if extrapolations from DPM were to be used to make individual-level predictions for research, clinical trials, or potentially future clinical practice.

METHODS: We conducted simulation studies incorporating empirically-derived noise properties from amyloid biomarkers to assess the contributions of inter- and intra-individual variability. Findings generalized in an autosomal dominant AD cohort with amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma biomarkers and in a sporadic AD cohort with both amyloid PET and plasma biomarkers. We assessed group level DPM performance via mean average error (MAE) and root mean squared error (RMSE). At the individual level, we evaluated distinctness of distributions of biomarker levels associated with specific disease timings.

RESULTS: Inter-individual variability was the dominant source of error in temporal estimates. Intra-individual variability reduced estimate stability. Optimal performance occurred in biomarkers with positive average accumulation rates where a subset of individuals had exceptionally high levels of accumulation. In research study data, amyloid PET outperformed CSF and plasma biomarkers.

INTERPRETATION: DPM is fundamentally constrained by dynamic range, variability, and test-retest reliability of the biomarker of interest. Current DPM approaches are more robust at the group level, particularly when applied to biomarkers with more than 10-15% variability like fluid biomarkers.

FUNDING: National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korean Ministry of Health & Welfare and Ministry of Science and ICT, Spanish Institute of Health.},
}

@article {pmid42523335,
year = {2026},
author = {Vrba, SM and Limkar, AR and Keil-Steitz, K and Nirschl, JJ and Laaker, CJ and Bansal, D and Ordonez, SFW and Brooks, EG and Helgager, J and Pehar, M and Sandor, M and Ricke, WA and Fabry, Z},
title = {Amyloid-beta is present in the spinal cord of APP/PS1 mice and may contribute to neuropathology manifesting as lower urinary tract dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.09.737006},
pmid = {42523335},
issn = {2692-8205},
abstract = {Urinary incontinence (UI) is a common and debilitating comorbidity in Alzheimer's disease (AD), yet its underlying pathophysiology remains poorly defined. While UI in dementia has traditionally been attributed to functional impairment, emerging clinical and urodynamic data suggest that neurologic mechanisms may contribute to lower urinary tract dysfunction in this population. Here, we investigated urinary function and neuropathological changes in aged APP/PS1 mice (AD mice), a widely used model of amyloid pathology. Using functional voiding assays, we identified a pattern of urinary dysfunction characterized by increased urinary frequency, small-volume voiding, shortened void duration, and reduced bladder compliance in the absence of bladder outlet obstruction or gross changes in bladder or prostate morphology. These findings are most consistent with a storage-phase abnormality accompanied by impaired voiding coordination rather than classic detrusor overactivity or underactivity. We examined spinal cord and peripheral components involved in bladder innervation and identified amyloid-beta deposition throughout the thoracolumbar and lumbosacral spinal cord, dorsal root ganglia, ventral roots, cauda equina, and associated meningeal structures in AD mice. Importantly, amyloid deposition was accompanied by reduced expression of vesicular acetylcholine transporter and decreased neuronal activation in bladder-innervating pathways, without evidence of increased apoptosis. Taken together, these data demonstrate that AD mice develop a mixed lower urinary tract dysfunction phenotype associated with amyloid-beta deposition and altered neuronal signaling within the spinal cord and peripheral micturition pathways. These findings support a neurogenic contribution to urinary dysfunction in AD and highlight the spinal cord as a novel site of pathology that may influence urinary symptoms in Alzheimer's dementia.},
}

@article {pmid42523338,
year = {2026},
author = {Gutierrez-Kuri, E and Marie Garcia-Rogers, JL and Perez, J and Smith, S and Kenwood, MR and Archuleta, KS and Xiao, Y and Campos, G and Barannikov, S and Wang, H and Pardo, S and Romsdahl, TB and Miller, H and Stowe, AM and William, R and Goldberg, M and Han, X and Bieniek, KF and Weintraub, ST and Griffith, AV and Hopp, SC and Palavicini, JP},
title = {PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.738356},
pmid = {42523338},
issn = {2692-8205},
abstract = {BACKGROUND: Phospholipase C gamma-2 (PLCγ2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP 2) to form diacylglycerol (DAG) and inositol trisphosphate (IP 3), feeding into diverse downstream signaling pathways. PLCG2 polymorphisms have been associated with reduced and/or increased risk of Alzheimer's disease (AD) and related dementias, longevity, autoinflammation, and immune disorders. In the brain, PLCγ2 is expressed in microglia, and other neuroimmune and vascular interface populations, yet its role in brain homeostasis remains incompletely defined.

METHODS: We analyzed the brains of three-month-old Plcg2 wild-type (WT), heterozygous (Het KO) and homozygous knockout (Homo KO) littermate mice modeling human PLCG2 loss-of-function risk alleles linked to AD risk using a multiomic approach that included lipidomics, metabolomics, proteomics, and transcriptomics, together with immunofluorescence, as well as flow-cytometric profiling of peripheral and brain-draining immune compartments.

RESULTS: Plcg2 deficiency substantially impaired early survival and produced splenomegaly without increasing total spleen cellularity, instead shifting spleen composition toward myeloid/innate-enriched cells and away from B cells, with expansion of age-associated B-cell (ABC-like) subsets and parallel reductions in CD4 and CD8 regulatory T cells in spleen and cervical lymph nodes. Brain lipidomics revealed selective depletion of PIP 2 , despite very low bulk PLCγ2 protein abundance relative to other PLC family members. PLCγ2 loss led to significant reductions in myelin-enriched lipid classes and myelin/paranode-associated proteins, accompanied by compensatory upregulation of oligodendrocyte/myelin genes, and modest shifts in microglial, lysosomal, complement, and oxidative metabolism pathways by NanoString and DIA-MS. Targeted acylcarnitine profiling demonstrated reprogramming of brain oxidative metabolism, with increased short-, medium-, and long-chain acylcarnitines and enrichment of mitochondrial matrix fatty-acid and amino-acid catabolic enzymes in Homo KO brains.

CONCLUSIONS: Loss of PLCγ2 installs a coordinated program that compromises systemic immune tolerance and subtly erodes central myelin and phosphoinositide homeostasis while enhancing brain oxidative metabolism, effects that extend beyond microglial phagocytic signaling and may underlie increased vulnerability to AD pathology and aging, providing a mechanistic framework for how PLCG2 variation may link systemic immune regulation, white-matter integrity, and neurodegenerative risk.

LIMITATIONS: Because constitutive Plcg2 Homo KO mice display high early mortality and intestinal vascular abnormalities, observed phenotypes may reflect developmental compensation and may not fully recapitulate protective human PLCG2 variants.},
}

@article {pmid42523383,
year = {2026},
author = {Matsumoto, N and Choi, H and Freda, PJ and Hernandez, ME and Wang, ZP and Moore, JH},
title = {EcoXAI: Autonomous Agentic Ecosystem for Explainable Artificial Intelligence and Biomedical Discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.08.737358},
pmid = {42523383},
issn = {2692-8205},
abstract = {MOTIVATION: As biomedical datasets and knowledge graphs continue to grow in size, complexity, and heterogeneity, navigating and extracting actionable insights from them presents a major bottleneck for researchers. There is a clear need for autonomous analytical solutions that can utilize recent advancements in agentic AI such as agent harnessing and loop engineering without introducing hallucination or workflow fragmentation. Researchers, regardless of technical expertise, need tools that streamline complex data analysis and deliver meaningful, actionable insights grounded in both data and established biomedical knowledge. EcoXAI addresses this by introducing a modular, customizable, containerized multi-agent system that structures analysis into explicit pipeline execution stages, lowering the computational barrier for clinical and translational researchers.

RESULT: EcoXAI replaces monolithic AI text interfaces with an autonomous execution-driven framework with specialized bioinformatics agents for delivering proactive, data-driven insights grounded in established biological knowledge. Unlike purely LLM-driven or less integrated AI solutions prone to hallucinations or biologically implausible outcomes, EcoXAI's multi-agent framework, which leverages modern agentic management and explicit knowledge graph integration, provides greater transparency and verifiability in its reasoning. In our use case in drug repurposing for Alzheimer's Disease, EcoXAI evaluated 103 drug candidates and identified 79 novel candidates whose predictive models exceeded a randomized baseline, including the CCR5 antagonist Maraviroc, whose generated hypothesis was subsequently supported by the literature. These results demonstrate the potential of knowledge graph-grounded AI agents to accelerate hypothesis-driven biomedical research.

EcoXAI is available on GitHub at: https://github.com/EpistasisLab/EcoXAI .

CONTACT: jason.moore@csmc.edu.},
}

@article {pmid42523480,
year = {2026},
author = {Goate, A and Romero-Molina, C and Gomez-Gutierrez, R and See, WY and Patel, T and Davtyan, H and Ma, J and Xu, Q and Sewell, M and Allton, K and McReynolds, M and Calderon, O and Lightfoot, Y and Bommer, G and Cruchaga, C and Blurton-Jones, M and Ray, W and Marcora, E},
title = {Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine and reduced Alzheimer's disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10216155/v1},
pmid = {42523480},
issn = {2693-5015},
abstract = {Lactamase β (LACTB) is a serine β-lactamase-like mitochondrial enzyme genetically associated with obesity, kidney disease, and hyperlipidemia. LACTB is located in an Alzheimer's Disease (AD) risk locus and its expression in the brain has been genetically associated with AD susceptibility. The aim of this study was to investigate LACTB function and genetic link to AD in myeloid cells, due to their central role in modulating AD risk. Our Mendelian randomization analyses revealed that lower LACTB expression in myeloid cells is genetically associated with reduced disease susceptibility and increased succinylcarnitine, a metabolite independently associated with AD risk. We identified LACTB as a primary enzyme responsible for succinylcarnitine hydrolysis. In human macrophages and microglia, LACTB loss promoted enhanced oxidative phosphorylation, reduced protein synthesis and altered lipid homeostasis. LACTB expression was upregulated following interferon or TNF stimulation, and LACTB loss modified efferocytosis-related functions under inflammatory conditions. In vivo , xenotransplanted human LACTB knockout microglia showed enhanced association with amyloid plaques in the mouse brain. Together, these findings experimentally validated the genetic association between reduced LACTB expression and elevated succinylcarnitine and identified LACTB as an inflammation-responsive regulator of myeloid cell metabolism and function that may contribute to its protective genetic association with AD. Given its druggability and potential to use succinylcarnitine as a genetically-validated endophenotype and target engagement biomarker, LACTB represents a promising therapeutic target for AD.},
}

@article {pmid42523500,
year = {2026},
author = {Kim, Y and Heo, W and Park, SJ and Kim, Y and Cho, YE},
title = {Astrocytic lactate shuttle disruption and the energy-starved lysosome in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523500},
issn = {2693-5015},
abstract = {Lysosomal dysfunction is central to Alzheimer's disease (AD), yet why structurally intact vacuolar H[+]-ATPase (V-ATPase) proton pumps fail to maintain lysosomal pH remains unresolved. Because V-ATPase activity depends on continuous ATP supply, we hypothesized that disruption of the astrocyte-neuron lactate shuttle imposes a cross-cellular energy deficit-an "energy-starved lysosome" (ESL) state. Integrating single-nucleus transcriptomics (SEA-AD; 1.3 million nuclei, 84 donors) with cerebrospinal fluid proteomics (ADNI Emory; n = 1,105), we found that astrocytic lactate-export genes, led by MCT4 (- 43%), declined far faster than V-ATPase, and that astrocytic MCT4 was coupled to neuronal V-ATPase independently of disease stage (donor-level partial r = + 0.466). At the protein level, V-ATPase V1A abundance was preserved across diagnostic groups-consistent with structural pump integrity-while, at the individual level, glycolytic capacity (hexokinase-1, HK1) tracked Tau pathology; this glycolysis-Tau coupling reproduced on an independent proteomic platform and against immunoassay Tau, whereas an apparent CSF V1A-Tau correlation did not survive distribution-robust analysis or validation against immunoassay Tau and is not interpreted as an individual-level marker. These findings position cross-cellular metabolic decoupling, rather than structural pump loss, as a candidate upstream constraint on lysosomal acidification, defining a candidate intervention window.},
}

@article {pmid42523505,
year = {2026},
author = {Salomón-Cruz, ID and Agudelo-Castrillon, SC and Barbosa-Carvajal, JP and Lozano-Trujillo, LA and Ríos, MH and Trujillo-Chacón, LM and Villegas, A and Osorio, E and Fernandez, GJ and Area-Gómez, E and Cardona-Gómez, GP},
title = {APOE3 Christchurch is associated with sphingolipids recycling and glial lipid remodeling in autosomal dominant Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10297182/v1},
pmid = {42523505},
issn = {2693-5015},
abstract = {Alzheimer's disease is characterized by profound disturbances in brain lipid metabolism, which regulate membrane integrity, connectivity, immune response, and cell survival. However, the mechanisms by which the protective APOE3 Christchurch variant modulates lipid homeostasis in autosomal dominant AD remain poorly understood. Here, we investigated lipid changes in postmortem brains carriers of PSEN1-E280A mutation, including APOE3Ch variant. Using a multimodal approach integrating thin-layer chromatography lipid profiling, enzymatic activity assays, digital PCR, immunofluorescence, flow cytometry, and single-nucleus RNA sequencing, we characterized lipid composition and transcriptional expression in the cerebral cortex. Familial and sporadic AD brains exhibited extensive remodeling of lipid pathways, including depletion of structural phospholipids and marked alterations in sphingolipid metabolism. Notably, APOE3Ch carriers displayed reduced cholesterol and phospholipid content, preservation of ceramide pools, and enrichment of specific ganglioside fractions, accompanied by increased sphingomyelinase activity and coordinated downregulation of genes involved in sphingolipid biosynthesis and remodeling. Single-nucleus transcriptomic analyses further revealed cell-type-specific alterations across glial populations, including reduced pruning of differentiated oligodendrocytes and suppression of lipid metabolic process in astrocytes and microglia. Together, these findings suggest that APOE3Ch promotes a reduced de novo biosynthesis of cholesterol and a distinct sphingolipid metabolic state characterized by enhanced lipid recycling, potentially attenuating lipid-driven neuroinflammatory responses.},
}

@article {pmid42523517,
year = {2026},
author = {Diaz, CS and Baghirova, N and Vu, DT and Can, DC and Allali, G and Ryvlin, P and Chén, OY},
title = {Imputation-free transformer learning enables robust Alzheimer's disease prediction and calibrated uncertainty quantification across heterogeneous clinical cohorts.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42523517},
issn = {2331-8422},
abstract = {Accurate diagnostic classification and disease-severity prediction for Alzheimer's disease are hampered by the incompleteness and heterogeneity of real-world clinical data. Left unaddressed, these barriers prevent reliable disease modelling and hinder effective clinical evaluation. Conventional imputation strategies introduce systematic bias, distort inter-feature relationships, and yield overconfident predictions, limitations especially consequential in diagnostic settings. Here, we propose NITROGEN, an imputation-free transformer that jointly models within-patient feature dependencies and between-patient relational structure through masked and intersample attention, enabling robust multimodal learning directly from partially observed records. We trained NITROGEN on ADNI (N=7858 scans), and evaluated it on two independent cohorts: OASIS-3 (N=2675 scans) and AIBL (N=1286 scans). Across cohorts and diagnostic and cognitive score prediction tasks, NITROGEN showed robust calibration and uncertainty quantification advantages over tree-based ensemble methods, while maintaining competitive discriminative performance. Cross-cohort and cross-method analyses identified cortical thickness in the temporal pole, age, and APOE genotype as important, though not individually sufficient, features for AD classification. We further introduced a modality-aware uncertainty adjustment that augments predictive uncertainty proportionally to the importance of absent modalities, enabling calibrated confidence when diagnostic information is unavailable. Together, our results show that imputation-free attention learning preserved meaningful discrimination under cohort shift, revealing expected degradation on more distributionally different cohorts, and demonstrate that evaluating models along calibration, interpretability, and cross-cohort reliability, not accuracy alone, is essential for clinical deployment.},
}

@article {pmid42523519,
year = {2026},
author = {Chen, X and Munoz-Mayorga, D and Lyu, X and Jati, S and Zhang, J and Rossitto, LA and Tao, Y and Zhao, S and Hui, E and Kauffman, A and Zhu, B},
title = {A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523519},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) disproportionately affects women, who exhibit greater vulnerability to Tau pathology and neuroinflammation. The precise mechanisms underlying this vulnerability remain elusive, although sex hormones are thought to play a pivotal role. Here, we report that supplementation with the non-aromatizable androgen dihydrotestosterone (DHT) exacerbates Tau pathology in female tauopathy models, with microglia as the main driver of this effect. DHT treatment upregulates proinflammatory gene expression in microglia and promotes the disease-associated microglia (DAM) phenotype in a Trem2-dependent manner. Surprisingly, these effects are independent of the canonical androgen receptor (AR) and instead depend on the orphan nuclear receptor TR4, which mediates DHT-driven effects by transcriptionally regulating Trem2 in microglia. Moreover, TR4 protein levels are elevated in postmortem brain tissue from Braak stage 6 female AD patients and correlate with p-Tau levels. Together, our findings uncover a non-canonical DHT-TR4- Trem2 signaling axis in microglia and identify TR4 as a key regulator of neuroinflammation in female neurodegeneration, providing mechanistic insight into female-specific vulnerability to AD.},
}

@article {pmid42523523,
year = {2026},
author = {Estrella, LD and Dasgupta, S and Gundavelli, A and Li, H and Yang, SH and Chancellor, S and Pastika, T and Abdourahman, A and Tamm, J and Yanamandra, K and Romanul, N and Liao, F and Zhao, K and Lin, G and Srinivasa, P and Wang, X and Martin, A and Asque, E and Doering, A and Ried, JS and Talanian, RV and Kwon, T and Woodbury, ME and Grinberg, YY and Agastra, E and Oakley, DH and Hyman, BT and Serrano-Pozo, A and Zwang, T and Das, S and Bennett, RE},
title = {Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523523},
issn = {2693-5015},
abstract = {Cerebrovascular alterations are widely observed in both Alzheimer's Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Pick's disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.},
}

@article {pmid42523541,
year = {2026},
author = {Ambekar, A and Zielinski, R and Eloyan, A},
title = {TRAECR: A Tool for Preprocessing Positron Emission Tomography Imaging for Statistical Modeling.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42523541},
issn = {2331-8422},
abstract = {Positron emission tomography (PET) imaging is widely used in a number of clinical applications, including cancer and Alzheimer's disease (AD) diagnosis, monitoring of disease development, and treatment effect evaluation. Statistical modeling of PET imaging is essential to address continually emerging scientific questions in these research fields, including hypotheses related to evaluation of effects of disease modifying treatments on amyloid reduction in AD and associations between amyloid reduction and cognitive function, among many others. In this paper, we provide background information and tools for statisticians interested in developing statistical models for PET imaging to pre-process and prepare data for analysis. We introduce our novel pre-processing and visualization tool TRAECR (Template registration, MRI-PET co-Registration, Anatomical brain Extraction and COMBAT/RAVEL harmonization) to facilitate data preparation for statistical analysis.},
}

@article {pmid42523631,
year = {2026},
author = {Ding, X and Hu, X and Xue, W and An, Y and Cheng, W and Zhang, S and Lei, A and Zhang, J},
title = {Anti-inflammatory CAR-microglia targeting Aβ for Alzheimer's disease therapy.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1820099},
pmid = {42523631},
issn = {1664-3224},
mesh = {*Alzheimer Disease/therapy/metabolism/immunology ; Animals ; *Microglia/metabolism/immunology/transplantation ; *Amyloid beta-Peptides/metabolism/immunology ; Humans ; Mice ; Axl Receptor Tyrosine Kinase ; Receptor Protein-Tyrosine Kinases/genetics/metabolism ; Disease Models, Animal ; *Induced Pluripotent Stem Cells/metabolism ; c-Mer Tyrosine Kinase/genetics/metabolism ; Efferocytosis ; Mice, Transgenic ; Proto-Oncogene Proteins/genetics/metabolism ; Phagocytosis ; Cytokines/metabolism ; Anti-Inflammatory Agents ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and chronic neuroinflammation, which together drive progressive neuronal loss and cognitive decline. In recent years, monoclonal antibodies targeting Aβ have demonstrated encouraging clinical benefits in Alzheimer's disease (AD). However, their therapeutic efficacy remains limited by insufficient and unsustained clearance of Aβ, as well as treatment-associated neuroinflammatory responses. These limitations highlight the need for alternative strategies that can achieve efficient Aβ elimination while maintaining immune homeostasis. To overcome these challenges, we developed a novel anti-inflammatory CAR-Microglia (CAR-Mic) incorporating a construct based on the TAM receptor family (TYRO3, AXL, and MERTK), which are key regulators of efferocytosis and anti-inflammatory responses. The resulting Aβ-targeted CAR-Mics showed enhanced Aβ engulfment and reduced proinflammatory cytokines release. Among the constructs tested, AXL-CAR demonstrated the most favorable overall performance and was therefore selected for the generation of human induced pluripotent stem cell (iPSC)-derived CAR microglia-like cells (CAR-iMGLs). In an AD mouse model, AXL-CAR-iMGLs exhibited enhanced Aβ clearance without evidence of severe adverse effects. Collectively, these findings establish TAM receptor-based CAR-iMGLs as a promising cell therapy model for AD and potentially other neurodegenerative disorders characterized by chronic neuroinflammation and defective pathological protein clearance.},
}

*Alzheimer Disease/therapy/metabolism/immunology
Animals
*Microglia/metabolism/immunology/transplantation
*Amyloid beta-Peptides/metabolism/immunology
Humans
Mice
Axl Receptor Tyrosine Kinase
Receptor Protein-Tyrosine Kinases/genetics/metabolism
Disease Models, Animal
*Induced Pluripotent Stem Cells/metabolism
c-Mer Tyrosine Kinase/genetics/metabolism
Efferocytosis
Mice, Transgenic
Proto-Oncogene Proteins/genetics/metabolism
Phagocytosis
Cytokines/metabolism
Anti-Inflammatory Agents

@article {pmid42523676,
year = {2026},
author = {Cai, H and Wang, Y and Che, S and Hou, Z},
title = {Transcranial low-intensity pulsed ultrasound in neurological disorders: mechanisms, therapeutic applications, and translational challenges.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1850924},
pmid = {42523676},
issn = {1664-2295},
abstract = {Transcranial low-intensity pulsed ultrasound (LIPUS) is an emerging non-invasive modality with high spatial precision, substantial tissue penetrability, and favorable biosafety. Acting predominantly through mechanical rather than thermal bioeffects, LIPUS modulates mechanosensitive ion channels, intracellular calcium signaling, synaptic transmission, glial activation, neurovascular coupling, and, in selected settings, blood-brain barrier permeability. These features support its growing application in neurological disorders. In this review, we summarize the mechanistic basis of transcranial LIPUS and discuss its therapeutic applications in Alzheimer's disease, Parkinson's disease, epilepsy, ischemic stroke, and major depressive disorder. Across these conditions, LIPUS has been associated with neuroprotection, enhanced synaptic plasticity, suppression of pathological neural activity, attenuation of neuroinflammation, promotion of vascular remodeling, and facilitation of targeted delivery through reversible blood-brain barrier opening. We further highlight the major barriers to clinical translation, including heterogeneity of stimulation parameters, incomplete mechanistic understanding, limited comparability across studies, and insufficient large-scale clinical validation. Current evidence supports transcranial LIPUS as a promising ultrasound-based platform for neuromodulation and brain repair, while emphasizing the need for standardized protocols and rigorous translational studies.},
}

@article {pmid42524115,
year = {2026},
author = {Raikes, AC and Bhattrai, A and Wang, T and Wiegand, JP and Brinton, RD},
title = {Humanized APOE mouse brain volume increases over age irrespective of sex and APOE genotype: implications for translational validity to the human.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1843319},
pmid = {42524115},
issn = {1662-4548},
abstract = {BACKGROUND: Humanized APOE mouse models are widely used to study late-onset Alzheimer's disease (LOAD) risk, yet it remains unclear whether they reproduce the macrostructural brain changes observed in human aging and disease.

METHODS: We performed ex vivo magnetic resonance imaging to quantify total and voxelwise brain volumes in male and female mice across APOE genotypes (ε3/ε3, ε3/ε4, ε4/ε4) and ages spanning 6-25 months.

RESULTS: Total brain volume increased with age (cross-sectional estimate: 2.12 mm[3]/month) and was greater in APOE-ε4 carriers, with no effect of sex. Voxelwise analyses revealed regionally specific changes independent of total volume, characterized by cortical volume decreases and subcortical preservation or increases, as well as sex-dependent spatial patterns. No localized volumetric effects of APOE genotype were detected.

CONCLUSION: These findings indicate that, despite incorporating a major genetic risk factor for LOAD, this model does not reproduce the atrophy phenotype characteristic of human aging and Alzheimer's disease. Instead, the observed pattern is more consistent with non-pathological or vulnerable aging, suggesting that humanized APOE alone is insufficient to induce MRI-detectable macrostructural atrophy within this cross-sectional comparison, though this finding does not preclude other APOE-dependent pathological mechanisms.},
}

@article {pmid42524118,
year = {2026},
author = {Rafiey, M and Nosrati, R and Pourgholaminejad, A and Ahangaran, S and Babaei, P},
title = {Histone Deacetylase Inhibitor Combined with Rosiglitazone Improves Cognitive Function Via Microglial Polarization and Increased Mature/Pro-BDNF in Alzheimer's Disease.},
journal = {Advanced pharmaceutical bulletin},
volume = {16},
number = {1},
pages = {157-165},
pmid = {42524118},
issn = {2228-5881},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by diminished brain metabolism, cognitive impairments, neural loss, astrogliosis, and microgliosis. We hypothesized that co-administration of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist and a histone deacetylase (HDAC) inhibitor would enhance cognitive function in an AD model of rats.

METHODS: Forty adult male Wistar rats were randomly assigned into five groups (n=8 per group): (1) Control group receiving saline, (2) AD model group (induced by i.c.v injection of Streptozocin), (3) AD+Rosiglitazone (ROSI) (4) AD+MS-275, and (5) AD+combined ROSI and MS-275 group. Cognitive functions were evaluated using the passive avoidance test and the Morris water maze (MWM). Microglial polarization was assessed by flow cytometry, and protein expression was analyzed by western blotting.

RESULTS: Data analyzed by one-way ANOVA and post hoc Tukey for (MWM) showed a significant decrease in latency to the target quadrant both in working and reference memories, and a significant increase in total time spent (TTS) in the target quadrant for reference memory in the group of STZ+ROSI+MS-275 (P<0.000). Kruskal-Wallis H test revealed a significant increase in the M2/M1 ratio for ROSI+MS-275+STZ group compared with the STZ+Saline group (P=0.001). Also an increased mature brain-derived neurotrophic factor (BDNF)/pro-BDNF ratio was found in treated groups compared with STZ+saline (P<0.001).

CONCLUSION: These findings suggest that co-administration of Rosiglitazone and MS-275 improves cognitive function in AD rats, potentially through shifting microglial polarization from the M1 to the M2 phenotype and enhancing synaptic strength via an increased mature BDNF/pro-BDNF ratio.},
}

@article {pmid42524288,
year = {2026},
author = {Yu, F and Salisbury, DL and Todd, M and Chow, LS and Porsteinsson, AP and Maxfield, M and Joseph, RP and LoVecchio, F and Heffner, KL and Lin, FV},
title = {Efficacy of sequential aerobic exercise and cognitive training in older adults with amnestic mild cognitive impairment.},
journal = {Aging and health research},
volume = {6},
number = {2},
pages = {},
pmid = {42524288},
issn = {2667-0321},
abstract = {BACKGROUND: Multi-component interventions may be critical for reducing Alzheimer's disease (AD) risk since AD pathogenesis is multi-factorial. Combined Aerobic exercise and Cognitive Training (ACT) may have synergistic effects, but studies are limited with mixed findings.

METHODS: A 3-site, single-blinded Stage II 2 × 2 factorial trial aimed to test the effects of 6-month ACT on cognition in older adults with amnestic mild cognitive impairment in academic research facilities and gyms. Among 325 participants consented, 146 were enrolled and randomized equally to 6-month ACT, cycling only, speed of processing (SOP) cognitive training only, or control. Primary outcomes, executive function and episodic memory, were measured with alternating EXAMINER and Brief Visuospatial Memory Test-Revised (BVMT-R) forms at baseline, 3, 6, 12, and 18 months, and global cognition with the Montreal Cognitive Assessment (MoCA) and EXAMINER/BVMT-R composite.

RESULTS: Executive function improved significantly from baseline to 6 months (ds = 0.58-1.18, adjusted Ps < 0.001-0.026) in all groups except SOP. Global cognition composite increased in cycling only (d = 0.73; adjusted P = 0.012). MoCA decreased over 18 months (adjusted P = 0.030) in the control group only. Between-group comparison was significant between ACT and SOP groups at 6 months (adjusted P = 0.029), but sensitivity analyses showed ACT being superior to both cycling- and SOP-only groups (Ps = 0.030 and 0.002, respectively) among in-person interventions (48.6% of all sessions were delivered in person as designed due to COVID-19).

CONCLUSIONS: ACT's synergistic effects remain to be determined. All interventions are feasible for clinical practice.

TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03313895; date of registration: 10/18/2017).},
}

@article {pmid42524328,
year = {2026},
author = {Miaja, P and Martinez-Baños, M and Martin-Bermejo, MJ and Moreno, I and Dominguez, M and Bovolenta, P},
title = {Pharmacodynamic and stage-dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70301},
pmid = {42524328},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid beta (Aβ) accumulation, neuroinflammation, and cognitive decline. We previously identified secreted frizzled-related protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD-like traits in mice. Here we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an anti-SFRP1 monoclonal antibody (α-SFRP1) in double transgenic amyloid precursor protein (APP) and presenilin-1 (PS1) mice (APP/PS1).

METHODS: Pharmacokinetics and target engagement of α-SFRP1 were assessed in groups of both male and female APP/PS1 mice using biotinylated or Zirconium-89 labeled ([89]Zr) antibodies, with tissue distribution and α-SFRP1 levels quantified by in-house enzyme-linked immunosorbent assay (ELISA) or positron emission tomography/computed tomography (PET/CT). Therapeutic efficacy was evaluated by administering α-SFRP1 or the SFRP1 inhibitor WAY-316606 at different stages of disease progression via retro-orbital injection, followed by analysis of AD-like pathology using ELISA and quantitative immunofluorescence assays and statistical analysis.

RESULTS: Using [89]Zr-labeled antibodies, we show that intravenously administered α-SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24-h clearance. Treatment with α-SFRP1 had no apparent systemic side effects or sex-dependent differences, but its therapeutic efficacy against AD-like brain pathology was strongly dependent on disease stage. Although early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality. Pharmacological inhibition of SFRP1 using a small-molecule inhibitor similarly failed to ameliorate pathology at intermediate stages.

DISCUSSION: Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain-targeted delivery strategies.},
}

@article {pmid42524462,
year = {2026},
author = {Sungted, S and Rangubpit, W and Phongphanphanee, S and Yoshida, N and Dias, CL and Wong-Ekkabut, J},
title = {Aggregation of Amyloid-like Peptides in Different Solvents.},
journal = {Journal of molecular liquids},
volume = {457},
number = {},
pages = {},
pmid = {42524462},
issn = {0167-7322},
abstract = {The aggregation of amphipathic peptides into β-sheet rich structures is a hallmark of several neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. At the molecular level, the toxic mechanism of these peptides involves an increase in the permeation of the cellular membrane, which starts with the partition of nonpolar and polar residues at the water-lipid interface that facilitates aggregation. Here, we study this process using all-atom molecular dynamics simulations in four model peptides composed of 4 phenylalanine (F), 2 lysine (K), and 2 glutamic acid (E) under three solvent conditions. In two sequences, nonpolar and charged amino acids alternate along the chain (FKFEFKFE and FFKKFFEE), and, in the other two sequences (FFFKFEKE and FFFFKKEE), they are segregated to the N- and C-terminals. Peptides are solvated in water and octane to study aggregation in hydrophilic and hydrophobic solvents, respectively. In all simulations, peptides aggregate promptly, adopting mostly random coil conformations; except for FKFEFKFE, which spontaneously forms β-sheet conformations in water that resemble the cross-beta structures found in amyloid diseases. Aggregation takes place with a lower free energy of dimerization in octane compared to water. Simulations are also performed in a water-octane to mimic the water-lipid interface where amyloid peptides aggregate before damaging cell membranes. All peptides are spontaneously attracted to this polar-nonpolar interface which corresponds to a minimum in the free energy profile. At the interface, peptides generally exhibit low backbone interaction energies with a high content of secondary structure. The types of secondary structure formed in the system depend on the sequence pattern. In addition, the arrangement of polar and nonpolar residues modulates the free energy profile of peptide transfer from water to octane, and monomers adsorb at the interface more preferentially than the β-sheet dimer. These findings provide insights into how sequence pattern and solvent environment influence peptide aggregation, secondary structure formation, and interfacial behavior.},
}

@article {pmid42524625,
year = {2025},
author = {Fernandez, F and Reyes-Reyes, E and Chinnasamy, D and Trial, M and Rodgers, KE},
title = {Aging shapes baseline immunity in sterile-housed female hAPOE mouse genotypes.},
journal = {Journal of cellular and molecular immunology},
volume = {4},
number = {1},
pages = {33-39},
pmid = {42524625},
issn = {2833-1141},
abstract = {The Apolipoprotein E ε4 allele (APOE4) is a major risk factor in the development of late-onset Alzheimer's Disease (LOAD; AD) and has been associated with altered immunological responses, particularly under inflammatory challenge. Whether APOE genotype shapes baseline peripheral immunity across aging remains unclear. Because experimental context can influence immune phenotypes, we focus here on baseline profiles under specific-pathogen-free barrier housing (sterile housing) and discuss their implications. To this end, we highlight the peripheral immune profile in female humanized APOE mice (APOE3/3, APOE3/4, APOE4/4) maintained under sterile housing at 6, 9, and 15 months of age. Immunophenotyping of blood and spleen revealed significant age-related changes in B and T cell subpopulations and cytokine levels. Significant increases in activated and effector CD4[+] and CD8[+] T cells, as well as plasma cells, were observed at 15 months of age, particularly in the spleen. These shifts were primarily driven by ageing rather than APOE genotype. The only genotype-related differences detected were an increase in plasma TNF-α and IL-1β levels at 15 months and 9 months, respectively, in APOE4 compared with APOE3. Overall, aging exerts a stronger influence than APOE genotype on baseline peripheral immunity in female hAPOE mice under sterile housing, establishing an age-stratified baseline and providing a context-dependent rationale for future challenge-based studies to define genotype-by-inflammation interactions relevant to LOAD.},
}

@article {pmid42524732,
year = {2026},
author = {Ruiz Piñero, M and Pérez Carmona, N and Piñol Ferrer, B and Pérez Sempere, Á and Abellán Miralles, I},
title = {Minor hallucinations as an early marker to differentiate dementia with Lewy bodies from Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468798},
doi = {10.1177/13872877261468798},
pmid = {42524732},
issn = {1875-8908},
abstract = {BackgroundEarly differentiation between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) remains clinically challenging, particularly in the initial stages, when cognitive profiles largely overlap. Accurate diagnosis is increasingly relevant given disease-specific therapeutic implications.ObjectiveTo compare clinical, neuropsychological, and perceptual features of early-stage AD and DLB, with a particular focus on minor hallucinations (MH), and to assess their diagnostic utility in differentiating both conditions.MethodsThis prospective, cross-sectional study included 121 patients with probable AD (n = 60) or DLB (n = 61), all in mild stages (GDS 3-4) and supported by disease-specific biomarkers. Participants underwent standardized clinical assessment, comprehensive neuropsychological evaluation, structured evaluation of psychotic symptoms, and perceptual testing, including the Pareidolia Test. Group comparisons and ROC analyses were performed to assess discriminative accuracy.ResultsGlobal cognition, attention, executive functions, language, and visuospatial abilities largely overlapped between groups. Episodic memory impairment was significantly more severe in AD across all recall measures. In contrast, DLB patients showed a higher prevalence of core clinical features and a markedly higher frequency of MH (54.1% versus 13.3% in AD). Pareidolic responses were significantly more frequent in DLB and showed the highest discriminative accuracy among perceptual measures. The presence of MH demonstrated a high positive predictive value for DLB.ConclusionsIn early disease stages, MH and susceptibility to perceptual distortions differentiate DLB from AD more effectively than standard cognitive testing. Systematic assessment of these phenomena may improve early diagnostic accuracy in routine clinical practice.},
}

@article {pmid42524837,
year = {2026},
author = {Li, J and Ma, H and Wang, G},
title = {Accelerated Biological Aging, Neurodegenerative Disease, and Mortality in Cardiovascular Disease Patients: Mediation and Modification Analysis.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {8},
pages = {e71059},
doi = {10.1002/cns.71059},
pmid = {42524837},
issn = {1755-5949},
support = {2026-2G-20111//Capital's Funds for Health lmprovement and Research (CFH)/ ; QNPY202518//Scientific Research Project of Xuanwu Hospital, Capital Medical University/ ; },
mesh = {Humans ; *Cardiovascular Diseases/mortality/epidemiology ; Male ; Female ; *Aging ; Aged ; *Neurodegenerative Diseases/mortality/epidemiology ; Middle Aged ; Aged, 80 and over ; Nutrition Surveys ; Risk Factors ; },
abstract = {AIMS: Cardiovascular disease (CVD) patients exhibit increased neurodegenerative diseases and mortality risks, implying a shared heart-brain aging pathway. As a composite biological aging predictor, the association of Phenotypic age (PhenoAge) with mortality and the mediating role of brain health remain unclear in CVD patients.

METHODS: In 4104 CVD patients (57.3% male, mean age 67.3 years) from the National Health and Nutrition Examination Survey (median follow-up of 7.2 years), weighted regression models examined associations of PhenoAge and its acceleration with Alzheimer's disease (AD), Parkinson's disease (PD), and mortality. Mediation effects of the association between PhenoAge and mortality explained by AD and PD were quantified.

RESULTS: The mean PhenoAge was 69.9 years, and AD and PD prevalences were 7.6% and 1.8%. Each 5-year increment of PhenoAge acceleration independently increased risks of AD (OR = 1.24; 95% CI:1.13,1.36), PD (OR = 1.22; 95% CI:1.02,1.46), and all-cause mortality (HR = 1.30; 95% CI:1.24,1.36). AD and PD mediated 20.46%-33.18% of the association between PhenoAge and mortality. Early-onset CVD amplified biological aging-related mortality risk, while a healthier lifestyle attenuated the CVD mortality risk (Pinteraction < 0.05).

CONCLUSION: Accelerated biological aging was associated with adverse brain health outcomes and mortality in CVD patients, with AD and PD as significant mediators. PhenoAge assessment may identify high-risk individuals for personalized heart-brain aging prevention.},
}

Humans
*Cardiovascular Diseases/mortality/epidemiology
Male
Female
*Aging
Aged
*Neurodegenerative Diseases/mortality/epidemiology
Middle Aged
Aged, 80 and over
Nutrition Surveys
Risk Factors

@article {pmid42524884,
year = {2026},
author = {Sa, Y and Yuan, H and Ma, J and Yang, Z and Wang, M and Wang, W and Yang, L and Ma, F and Zhang, W and Mening'oo, GW and Chen, G and Ma, X},
title = {Innovative Test Strip-Based Colorimetric Sensors Integrated With Affinity Chromatography: Acetylcholinesterase Inhibitor Screening Breakthrough in Lycium Barbarum Leaves.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76863},
doi = {10.1002/advs.76863},
pmid = {42524884},
issn = {2198-3844},
support = {2023BEG02014//Key Research and Invention Program of Ningxia/ ; 82360684//National Natural Science Foundation of China/ ; 2024AAC02043//Natural Science Foundation of Ningxia/ ; 2026AAC030216//Natural Science Foundation of Ningxia/ ; XJKF240324,XJKF240330//Key Research Projects of Ningxia Medical University/ ; },
abstract = {Current Alzheimer's drugs exhibit limited effectiveness, highlighting the necessity for multi-target treatments. This study developed an innovative and efficient screening platform combining hydrogen peroxide test strip-based colorimetric sensing with affinity chromatography for rapid identification of acetylcholinesterase (AChE) inhibitors from complex herbal medicines. Applying this strategy, from Lycium barbarum leaves, we identified three potent inhibitors: chlorogenic acid, N-acetyl-N'-caffeoylputrescine (NANCP), and N-caffeoylputrescine (NCP), with IC50 ranging from 55.7 to 143.2 µm. Molecular analyses confirmed their stable binding to AChE. In a D-galactose and AlCl3-induced Alzheimer's disease (AD) mouse model, NCP treatment significantly rescued cognitive deficits in AD mice, with the spontaneous alternation rate in the Y-maze test improved by up to 50%. It markedly reduced cerebral Aβ levels (by 54%) and pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, alleviated oxidative stress, and attenuated hippocampal neuronal damage. Mechanistically, NCP modulated glycerophospholipid metabolism, reshaped gut microbiota, and targeted the proteasome-autophagy pathway, revealing a multi-faceted synergistic mechanism. The research offers a new screening tool for AChE inhibitors and highlights a promising natural multi-target candidate, NCP, for AD therapy.},
}

@article {pmid42525141,
year = {2026},
author = {Zheng, M and Hou, B and Ma, R and Wang, K and Xia, J and Tan, Z},
title = {SOX9 knockdown alleviates Aβ1‑42‑induced neuroinflammation by regulating microglial polarization via inactivation of the ASK1/JNK signaling pathway.},
journal = {Journal of molecular histology},
volume = {57},
number = {4},
pages = {},
pmid = {42525141},
issn = {1567-2387},
mesh = {*Microglia/metabolism/pathology ; Humans ; *MAP Kinase Kinase Kinase 5/metabolism/genetics ; *SOX9 Transcription Factor/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Inflammation/metabolism/pathology ; Female ; Animals ; *MAP Kinase Signaling System ; Male ; Gene Knockdown Techniques ; Alzheimer Disease/metabolism/pathology/genetics ; *Peptide Fragments/metabolism ; Mice ; *Cell Polarity ; Aged ; Cell Line ; },
abstract = {Neuroinflammation driven by microglial polarization imbalance plays a key role in Aβ-induced neuronal injury, a core pathological feature of Alzheimer's disease (AD). The transcription factor SOX9 has been linked to AD progression, but its mechanism remains unclear. SOX9 expression was measured in peripheral blood mononuclear cells from 24 patients with AD and 24 age-matched healthy controls and correlated with Montreal Cognitive Assessment scores. An Aβ1-42-stimulated BV-2 cell model was used to investigate the effects of SOX9 and apoptosis signal-regulating kinase 1 (ASK1) on microglial polarization. Neuronal injury was evaluated in a BV-2/SH-SY5Y co-culture system. The transcriptional regulation of ASK1 by SOX9 was examined using dual-luciferase reporter and chromatin immunoprecipitation assays. ASK1 overexpression and the ASK1 inhibitor GS-4997 were used for mechanistic validation. SOX9 expression was increased in peripheral blood mononuclear cells from patients with AD and was negatively correlated with cognitive function. SOX9 was also upregulated in Aβ1-42-stimulated BV-2 cells. SOX9 overexpression enhanced M1-associated inflammatory markers and reduced M2-associated markers, whereas SOX9 knockdown produced the opposite effects. In the co-culture system, SOX9 knockdown increased SH-SY5Y cell viability, reduced LDH release and apoptosis, increased Bcl-2 expression, and decreased Bax and cleaved caspase-3 expression. SOX9 bound to the ASK1 promoter and promoted ASK1 transcription. SOX9 silencing suppressed ASK1, JNK, and p38 phosphorylation, while ASK1 overexpression reversed the effects of SOX9 knockdown on microglial polarization and neuronal injury. Consistently, GS-4997 blocked the pro-inflammatory and neurotoxic effects induced by SOX9 overexpression. SOX9 exacerbates AD neuroinflammation by promoting microglial M1 polarization via the ASK1/JNK signaling axis.},
}

*Microglia/metabolism/pathology
Humans
*MAP Kinase Kinase Kinase 5/metabolism/genetics
*SOX9 Transcription Factor/metabolism/genetics
*Amyloid beta-Peptides/metabolism
*Inflammation/metabolism/pathology
Female
Animals
*MAP Kinase Signaling System
Male
Gene Knockdown Techniques
Alzheimer Disease/metabolism/pathology/genetics
*Peptide Fragments/metabolism
Mice
*Cell Polarity
Aged
Cell Line

@article {pmid42525165,
year = {2026},
author = {Tahir, MM and Liu, X and Yi, LS and Hou, XQ and Liao, Q and Yu, HL},
title = {From astrocyte cholesterol synthesis to synaptic dysfunction: mechanisms of neuron-glia lipid coupling.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42525165},
issn = {1573-4978},
support = {32371039//National Natural Science Foundation of China/ ; YDZJ202201ZYTS620//Project supported by Jilin Province and Central Government Guides Local Science and Technology Development Fund/ ; },
mesh = {*Astrocytes/metabolism ; *Cholesterol/metabolism/biosynthesis ; Humans ; *Neurons/metabolism ; Animals ; *Synapses/metabolism/pathology ; *Neuroglia/metabolism ; Apolipoproteins E/metabolism ; Sterol Regulatory Element Binding Proteins/metabolism ; Lipid Metabolism ; },
abstract = {BACKGROUND: The brain contains a large proportion of the body's cholesterol, highlighting its importance in central nervous system function. Cholesterol supports neuronal membrane structure, synapse formation, synaptic vesicle activity, receptor signaling, and myelin integrity. Because the blood-brain barrier limits the entry of peripheral lipoproteins, the brain relies mainly on local cholesterol synthesis, transport, recycling, and turnover.

OBJECTIVE: This review examines the mechanisms that regulate astrocyte-to-neuron cholesterol transfer and explains how defects in SREBP-dependent synthesis, ApoE lipidation, ABC transporter-mediated export, neuronal uptake, intracellular trafficking, and cholesterol turnover contribute to synaptic dysfunction and neurodegeneration.

MECHANISMS: In the adult brain, astrocytes are an important source of cholesterol for neurons. Astrocytic cholesterol synthesis is regulated by sterol regulatory element-binding proteins, which control the expression of key cholesterol-biosynthetic genes. Astrocytes release cholesterol in ApoE-containing lipoprotein particles through ATP-binding cassette transporters. Neurons acquire astrocyte-derived cholesterol through LDLR/LRP1, redistribute it via NPC1/NPC2, and eliminate excess cholesterol as 24 S-hydroxycholesterol through CYP46A1.

CONCLUSION: Disruption of this pathway impairs membrane organization, lipid raft signaling, synaptic function, and neuronal survival. These disturbances are associated with Alzheimer's disease, Huntington's disease, and multiple sclerosis.},
}

*Astrocytes/metabolism
*Cholesterol/metabolism/biosynthesis
Humans
*Neurons/metabolism
Animals
*Synapses/metabolism/pathology
*Neuroglia/metabolism
Apolipoproteins E/metabolism
Sterol Regulatory Element Binding Proteins/metabolism
Lipid Metabolism

@article {pmid42525186,
year = {2026},
author = {Bao, YW and Ji, YQ and Wang, LN and Zhou, Y and Wang, F and Shen, DM and Pylypenko, D and Tong, Q and Mak, KF and Guo, LL},
title = {Topography of Juxtaventricular white matter hyperintensities and cognitive associations in Alzheimer's disease: a dual-cohort study.},
journal = {European radiology experimental},
volume = {10},
number = {1},
pages = {},
pmid = {42525186},
issn = {2509-9280},
support = {HABL202235//the special funds for the Science and Technology Programs of Huai'an/ ; NMUB20220204//Science and Technology Development Programs of Nanjing Medical University/ ; HAKY202400205//Northern Jiangsu Clinical Medicine Research Institute's 2024 Projects/ ; GQ202202//Start-up Grant for High-Level Talents of Huai'an No.1 People's Hospital/ ; BK20240307//Basic Research Program of Jiangsu/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Cohort Studies ; Female ; Male ; Aged ; Positron-Emission Tomography ; *Cognition ; Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction/diagnostic imaging ; Aged, 80 and over ; },
abstract = {OBJECTIVE: White matter hyperintensities (WMHs), a hallmark of cerebral small vessel disease, frequently coexist with Alzheimer's disease (AD) and facilitate cognitive deterioration. Juxtaventricular WMH (JVWMH) is hypothesized to reflect pathological processes at the cerebrospinal fluid (CSF)-parenchyma interface and hold particular clinical significance. Therefore, this study specifically investigated associations between JVWMH burden and cognitive performance, CSF volume (CSFV), and amyloid-β (Aβ) pathology.

MATERIALS AND METHODS: Automated WMH segmentation was applied in two cohorts: 295 from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and 82 from a memory clinic. All participants underwent 3-T magnetic resonance imaging, amyloid-positron emission tomography, and cognitive assessment. Analyses evaluated JVWMH associations with Aβ, its discriminative value for cognitive impairment (CI) versus cognitively normal (CN), prediction of longitudinal decline, and mediation of CSFV-cognition relationships.

RESULTS: JVWMH volume significantly discriminated CI from CN participants in both cohorts and predicted cognitive decline in longitudinal AIBL data. JVWMH volume showed strong correlations with CSFV in both cohorts. Notably, JVWMH partially mediated the associations between CSFV and cognition in the AIBL cohort. Non-juxtaventricular WMHs and Fazekas scores demonstrated no significant diagnostic or predictive power.

CONCLUSION: JVWMH volume provides diagnostic and prognostic information beyond conventional WMH metrics in AD. Its correlation with CSFV implicates CSF-parenchyma interface processes, though causality remains unproven. These findings highlight the importance of incorporating spatially stratified WMH metrics in AD research to better capture disease-relevant white matter pathology.

KEY POINTS: Question: JVWMH volume provides diagnostic and prognostic value beyond conventional WMH metrics in AD.

FINDINGS: JVWMH volume discriminated CI from normal cognition, predicted longitudinal decline, correlated with CSF volume, and partially mediated CSF volume-cognition associations.

RELEVANCE STATEMENT: JVWMH volume provides diagnostic and prognostic information beyond conventional WMH metrics in AD, highlighting the value of spatially stratified WMH analysis in AD research to better capture disease-relevant white matter pathology.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*White Matter/diagnostic imaging/pathology
*Magnetic Resonance Imaging/methods
Cohort Studies
Female
Male
Aged
Positron-Emission Tomography
*Cognition
Amyloid beta-Peptides/metabolism
Cognitive Dysfunction/diagnostic imaging
Aged, 80 and over

@article {pmid42525245,
year = {2026},
author = {Santiago, J and Pocevičiūtė, D and Sällberg, T and Önnerfjord, P and , and Vogel, JW and Wennström, M},
title = {Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42525245},
issn = {1432-0533},
support = {2025-337//Stiftelsen för gamla tjänarinnor/ ; KAW 2020.0239//SciLifeLab & Wallenberg Data Driven Life Science Program/ ; 2024-03642//Swedish Research Council/ ; 2024-02875//Swedish Research Council/ ; FO2023-0113//Brain Foundation/ ; 20230519//Crafoord Foundation/ ; 243007//Åhlén Foundation/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *Proteome/metabolism ; *Retina/metabolism/pathology ; Female ; *Synapses/pathology/metabolism ; *Cytoskeleton/pathology/metabolism ; Male ; *Hippocampus/pathology/metabolism ; Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; Proteomics ; },
abstract = {Visual dysfunction is increasingly recognized as an important feature of Alzheimer's disease, and substantial retinal changes have been documented across multiple studies. Yet the molecular changes underlying retinal neurodegeneration and which retinal protein signatures best track cerebral pathology remain incompletely defined. Here, we performed comprehensive mass spectrometry-based proteomics on paired retinal and hippocampal tissue from the same postmortem donors (8 AD, 8 non-demented controls) to identify disease-associated molecular signatures and assess their overlap between these tissues. Using a sequential dual-extraction protocol, we identified 372 differentially abundant retinal proteins in AD, including established APP-processing regulators (SORL1, BACE1) and synaptic proteins. Retinal proteomes clearly separated AD from controls in principal component analysis, indicating robust AD-related molecular differences in the retina. Notably, 87% of proteins were detected in both retina and hippocampus, with 64 differentially abundant proteins shared between tissues, some of which showed strong cross-tissue correlation. Several retinal proteins also correlated with neuropathological disease stage. Functional enrichment analysis revealed convergent alterations in synaptic organization, cytoskeletal dynamics, mitochondrial function, cell adhesion, and APP metabolism in both tissues. Cell-type mapping using single-cell retinal reference data indicated that most proteomic changes were broadly distributed across cell types, though some proteins showed enrichment in specific populations, such as SORL1 in microglia and EYS in photoreceptors. The molecular changes identified here offer a potential basis for the retinal alterations previously documented through in vivo imaging and histological studies. Their similarities with brain pathology further support the retina as a promising window for assessing cerebral disease.},
}

*Alzheimer Disease/pathology/metabolism
Humans
*Proteome/metabolism
*Retina/metabolism/pathology
Female
*Synapses/pathology/metabolism
*Cytoskeleton/pathology/metabolism
Male
*Hippocampus/pathology/metabolism
Aged
Aged, 80 and over
*Brain/pathology/metabolism
Proteomics

@article {pmid42525250,
year = {2026},
author = {Sitdikova, K and Tsoy, A and Chaprov, KD and de Munter, J and Svirin, E and Torosyan, H and Yenkoyan, K and Askarova, S and Steinbusch, HW and Anthony, DC and Strekalova, T},
title = {Large amyloid plaques associate with early behavioral alterations in 6-month-old APPswe/PS1dE9 mice.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag078},
pmid = {42525250},
issn = {1554-6578},
support = {AP23485236//Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; //COBRAIN Center/ ; 21T-3A327//the Higher Education and Science Committee of the Republic of Armenia/ ; 26YSMU-CON-S-3A//the Higher Education and Science Committee of the Republic of Armenia/ ; 101007642//the Higher Education and Science Committee of the Republic of Armenia/ ; 101086453//Aqua-Synapse/ ; EP/Y000420/1//Aqua-Synapse/ ; //EU frameworks/ ; //European Union's HORIZON 2020/ ; //European Commission/ ; },
abstract = {Understanding the earliest pathological changes in Alzheimer disease (AD) is critical for improving early intervention strategies. However, the relationship between amyloid plaque characteristics and early behavioral and molecular alterations remains unclear. We used 6-month-old female APPswe/PS1dE9 mice, a model of early amyloid-dominant pathology, to assess cognition and emotionality across a battery of behavioral tests. Amyloid plaques were quantified using Congo red staining; RT-qPCR and GFAP immunoreactivity were used to assess molecular and glial changes. APPswe/PS1dE9 mice exhibited increased anxiety-like behavior without significant changes in overall locomotor activity. Small plaques (<100 μm2) predominated across all regions; however, behavioral measures of hyperactivity and anxiety correlated specifically with the density and size of large (>200 μm2) plaques. Gene expression changes, including altered SYP, IGF1, TNF, and IL6 expression, were observed primarily in the midbrain and did not correlate with amyloid plaque characteristics. These findings demonstrate that large amyloid plaques, rather than total plaque burden, are selectively associated with early behavioral alterations in APPswe/PS1dE9 mice. Moreover, the midbrain emerges as an early site of molecular dysregulation despite limited plaque deposition. Together, these results support the use of 6-month-old APPswe/PS1dE9 mice as a model of early, amyloid-dominant stages of AD.},
}

@article {pmid42525347,
year = {2026},
author = {Kumari, A and Aran, KR},
title = {KLF4 in Parkinson's Disease: Decoding the Molecular Puzzle of Neuroinflammation, Oxidative Stress, and Emerging Therapies.},
journal = {Current medical science},
volume = {},
number = {},
pages = {},
pmid = {42525347},
issn = {2523-899X},
abstract = {Parkinson's disease (PD) is the most prevalent neurodegenerative movement condition. Tremors, stiffness, bradykinesia/akinesia, and postural instability are its primary motor symptoms; nevertheless, the clinical features also include non-motor and additional motor symptoms. Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is present in several human tissues and performs a range of cell-dependent regulatory actions. Various neurological diseases, such as PD, Alzheimer's disease (AD), and Huntington's disease (HD), have been linked to KLF4, which regulates some neurophysiological and neuropathological processes in the brain. Recent data indicate that KLF4 plays a crucial regulatory role in the neurophysiological and neuropathological processes underlying PD, suggesting that it might be a viable therapeutic target for neurodegenerative diseases. This review focuses on the potential molecular mechanism underlying KLF4-mediated neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. KLF4-mediated pathways are clarified by the information gathered here, and targeting them appears to be a viable therapeutic strategy for treating PD. Nevertheless, there is insufficient information on this subject, and more investigations are needed to fully understand the translational significance of the KLF4-oriented therapeutic strategy in PD.},
}

@article {pmid42508312,
year = {2026},
author = {Peng, M and Shao, L and Zhai, J and Yao, Y and Mei, X and Zhu, S},
title = {Simultaneous and ultrasensitive detection of Alzheimer's disease blood biomarkers using magnetic SERS-encoded tags-based LFIA assay.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130348},
doi = {10.1016/j.talanta.2026.130348},
pmid = {42508312},
issn = {1873-3573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder requiring early diagnosis for effective intervention. The combination of blood Aβ42/Aβ40 ratio and p-tau-181 is recognized as a promising core biomarker panel for AD diagnosis. However, conventional detection methods suffer from limitations including time-consuming procedures, lack of multiplexing capability, and insufficient sensitivity. Herein, we developed a magnetic surface-enhanced Raman scattering (SERS)-encoded tags-based lateral flow immunoassay (LFIA) for simultaneous detection of Aβ42, Aβ40, and p-tau-181 on a single test line. Magnetic Fe3O4@Au nanoparticles were synthesized and modified with three distinct Raman reporters (DTNB for Aβ42, 4-MBA for Aβ40, and 2-MPY for p-tau-181) and corresponding detection antibodies. Under optimal conditions, the assay achieved rapid detection (∼28 min) and high sensitivity, with limits of detection of 93.33 fg/mL for Aβ42, 218.78 fg/mL for Aβ40, and 56.23 fg/mL for p-tau-181. The method exhibited excellent specificity against interfering substances (BSA, human IgG) and closely related species (Aβ38, p-tau-217), as well as good reproducibility (RSD <5%) and stability (≥4 weeks). In clinical plasma samples (n = 40), the combined score (p-tau-181/(Aβ42/Aβ40)) progressively increased with disease severity and correlated well with MMSE scores and MRI MTA grades, capturing both cognitive decline and hippocampal atrophy. This magnetic SERS-encoded LFIA platform offers a rapid, sensitive, user-friendly, and multiplex-capable approach for early AD diagnosis and progression monitoring, showing promise for future point-of-care applications.},
}

@article {pmid42508316,
year = {2026},
author = {Wang, D and Huang, W and Wang, X and Zhang, L and Tao, X and Qin, F and Guo, S and Han, G and Zhang, Z},
title = {Fluorescence lifetime imaging of G-quadruplex RNA dynamics in Alzheimer's disease using a novel nucleic acid-sensitive probe.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130351},
doi = {10.1016/j.talanta.2026.130351},
pmid = {42508316},
issn = {1873-3573},
abstract = {Real-time monitoring of G-quadruplex (G4) RNA dynamics is vital for understanding their biological roles in the progression and treatment of Alzheimer's disease. However, this remains challenging due to two key difficulties. First, current fluorescent probes lack sufficient selectivity for G4 RNA over G4 DNA and other non-G4 secondary structures in live-cell competitive environments. Second, fluorescence intensity-based imaging cannot detect subtle changes in G4 RNA because of variations in fluorophore uptake and photobleaching. Herein, we report a novel thiazole orange derivative (TOGR) for fluorescence lifetime imaging of G4 RNA in living cells. Structural modifications of thiazole orange enhance RNA-binding affinity and G4 selectivity. TOGR exhibits a unique fluorescence lifetime when bound to G4 structures, enabling sensitive detection of G4 formation independent of local probe concentration via FLIM. FLIM imaging reveals that TOGR primarily colocalizes with RNA in the cytoplasm and nucleoli. Due to its preferential RNA-binding affinity in competitive cellular environments, TOGR enables selective monitoring of G4 RNA dynamics, facilitating the exploration of novel roles of G4 RNA in cells without interference from G4 DNA. Importantly, the dynamic behavior of G4 RNA during Alzheimer's disease pathology and the effects of glucocorticoids on G4 RNA dynamics were successfully revealed using this lifetime-sensitive and RNA-selective imaging probe. This research not only paves the way for advanced probe design for detailed G4 RNA imaging but also lays the foundation for exploring G4 RNA-related pathological mechanisms in Alzheimer's disease.},
}

@article {pmid42508318,
year = {2026},
author = {Christifano, DN and Kelly, E and Sands, SA and Honea, RA and Morris, JK and Burns, JM and Taylor, MK},
title = {Omega-3 fatty acids and Alzheimer's disease-related brain biomarkers in older adults enriched for preclinical Alzheimer's disease.},
journal = {Prostaglandins, leukotrienes, and essential fatty acids},
volume = {210},
number = {},
pages = {102762},
doi = {10.1016/j.plefa.2026.102762},
pmid = {42508318},
issn = {1532-2823},
abstract = {BACKGROUND: Preclinical and limited human data suggest long-chain omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may be protective of brain volume and amyloid-beta (Aβ) accumulation, hallmarks of Alzheimer's disease (AD), which may be modulated by Apolipoprotein E ε4 (APOE4) carriage.

METHODS: This cross-sectional study was conducted using baseline data from a clinical trial at the University of Kansas Medical Center that included cognitively normal older adults, enriched for preclinical AD. We investigated serum DHA+EPA's (% total triacylglycerol fatty acids) relationship with MRI-derived gray matter volume and PET-derived Aβ burden (Florbetapir F18) overall and by APOE4 carriage status.

RESULTS: Among all participants (n = 104, 67.3% female, 69.2% preclinical AD, 44.2% APOE4), higher DHA+EPA was related to larger gray matter volume in a left precuneus/postcentral gyrus cluster, with similar relationships between APOE4 carriers and non-carriers. Higher DHA+EPA was also related to lower brain Aβ in the frontoparietal cortex, bilaterally. In APOE sensitivity analyses, higher DHA+EPA was related to lower global and AD-related regional brain Aβ among APOE4 carriers .

CONCLUSIONS: Higher DHA+EPA was associated with larger gray matter volume and lower Aβ in AD-susceptible regions, especially among APOE4 carriers. These findings are consistent with the hypothesis that omega-3 fatty acids influence brain volume and Aβ. Well-designed DHA+EPA supplementation RCTs are needed as DHA supplementation RCTs have inconsistently impacted brain volume and no RCTs investigating the impact of omega-3 on brain Aβ have been reported.

TRIAL REGISTRATION: NCT02000583 (https://clinicaltrials.gov/study/NCT02000583?term=NCT02000583&viewType=Card&rank=1) registered on November 26, 2013.},
}

@article {pmid42508388,
year = {2026},
author = {Gilson, KM and Higueras, AF and Walters, WM and Sanchez-Molano, J and Almeida, VW and Zeier, Z and Dietrich, WD and Bramlett, HM and Kerr, NA},
title = {Intestinal Organoids from Alzheimer's Disease Transgenic Mice Reveal Structural and Molecular Gut Pathology.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0233},
pmid = {42508388},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the most common form of dementia, and early alterations in the gut may contribute to disease progression. The current study focused on generating intestinal organoids from 3xTg-AD transgenic and Wild Type (WT) mice to investigate the role of the gut-brain axis in AD. Intestinal organoid cultures were produced through isolation of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) crypt cells from 4-5-month-old or 1-year-old intestinal tissue. Transmission electron microscopy (TEM) analysis of aged 3xTg organoids demonstrated evidence of impaired gut epithelial viability compared to WT controls. In aged 3xTg organoids, enlarged intercellular spaces, disrupted cell adhesions, diminished tight junction complexes, cellular debris, and amyloid-like fibrils were prominent findings. Immunostaining also demonstrated decreased E-Cadherin and ZO1 expression, along with increased cellular and luminal Aβ in aged 3xTg organoids compared to young 3xTg and WT organoids and p-tau protein accumulation in aged 3xTg organoids compared to all other experimental groups. In the aged 3xTg cohort, increased immunoreactivity of inflammasome components, including IL-1β, ASC, and GSDMD, implicated pyroptosis as a potential mechanism of cell death. These results support the hypothesis that familial AD pathology includes pronounced effects on gut organoid viability, junctional integrity, and abnormal protein accumulation within the intestinal epithelium. This study provides early evidence of gut organoid abnormalities occurring independently of alterations in the AD brain. These findings suggest that the gut epithelium may warrant further investigation as a potential target for future therapeutic strategies in AD.},
}

@article {pmid42508391,
year = {2026},
author = {Gao, W and Lee, HY and Min, KJ},
title = {Aging-Related Metaflammation and Mitochondrial Dysfunction in Neurodegenerative Diseases.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0366},
pmid = {42508391},
issn = {2152-5250},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are increasingly recognized as manifestations of aging-associated systemic dysfunction, rather than isolated brain disorders. Central to this dysfunction is the interplay among metaflammation, mitochondrial breakdown, and chronic neuroinflammation. Metaflammation, driven by peripheral metabolic stress, may prime the brain's immune environment through cytokine signaling and blood-brain barrier compromise. This metabolic-inflammatory crosstalk is thought to impair mitochondrial integrity in neurons and glial cells, promoting oxidative stress and the release of pro-inflammatory mitochondrial components. These mitochondrial signals, in turn, may activate microglial and astrocytic innate immune responses, creating a potentially self-reinforcing cycle of neuroinflammation and energy failure that may contribute to neuronal loss. This review outlines a proposed framework linking metaflammation to neurodegeneration, emphasizing shared mechanisms across AD, PD, and ALS. We further examine preclinical and clinical advances in therapeutic strategies that target this axis including anti-inflammatory agents, caloric restriction, mitophagy enhancers, mitochondrial antioxidants, and senescence-targeted therapies. Together, these interventions reflect a shift from symptom management to systemic metabolic and immune modulation, offering a unified framework for understanding and potentially influencing age-related neurodegeneration.},
}

@article {pmid42508392,
year = {2026},
author = {Kumar, V and Jang, S and Choi, Y and Kim, S and Nam, Y and You, M and Moon, M},
title = {Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0606},
pmid = {42508392},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.},
}

@article {pmid42508514,
year = {2026},
author = {Shang, Y and Zhai, Z and Cong, L and Dong, X},
title = {Corrigendum to 'Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy' [Pharmacological Research (2026), YPHRS_108339].},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108355},
doi = {10.1016/j.phrs.2026.108355},
pmid = {42508514},
issn = {1096-1186},
}

@article {pmid42508529,
year = {2026},
author = {Chatterjee, A and Singh, TG and Singh, S and Kaur, A and Vishwas, S},
title = {Interplay between RNA m[6]A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104748},
doi = {10.1016/j.drudis.2026.104748},
pmid = {42508529},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) involves amyloid-β aggregation, tau hyperphosphorylation and mitochondrial dysfunction with defective mitophagy. Emerging evidence implicates RNA N6-methyladenosine (m[6]A) modification and transglutaminase 2 (TG2) as critical regulators of mitochondrial quality control in AD. Downregulation of METTL3/METTL14 and upregulation of fat mass and obesity-associated protein reduce m[6]A methylation, impair PTEN-induced putative kinase 1/Parkinson protein 2-mediated mitophagy and promote reactive oxygen species accumulation and synaptic loss. Conversely, TG2 overexpression exacerbates mitochondrial stress by crosslinking Aβ and tau, disturbing dynamin-related protein 1- and mitochondrial fission 1 protein-mediated dynamics and suppressing mitophagy. Crosstalk between TG2-induced oxidative stress and m[6]A dysregulation amplifies neuronal damage. Pharmacological modulation, using TG2 inhibitors (e.g. Z-DON) and m[6]A enhancers (e.g. METTL3 overexpression), restores mitophagic flux and mitigates pathology in preclinical models, suggesting dual m[6]A-TG2 targeting as a promising disease-modifying approach in AD.},
}

@article {pmid42508631,
year = {2026},
author = {Alanazi, SM and Al-Kuraishy, HM and Alexiou, A and Papadakis, M and Faheem, SA and Batiha, GE},
title = {Isoform-selective HSP90 inhibition as a precision therapeutic strategy for neurodegenerative and metabolic diseases.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {149},
number = {},
pages = {111834},
doi = {10.1016/j.pnpbp.2026.111834},
pmid = {42508631},
issn = {1878-4216},
abstract = {Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis, coordinating the folding, stabilization, and turnover of a wide range of client proteins in the cytosol, endoplasmic reticulum, and mitochondria. Accumulating evidence indicates that the four HSP90 paralogs HSP90α, HSP90β, GRP94, and TRAP1 have distinct pathological roles in neurodegenerative and metabolic diseases. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, aberrant HSP90 activity contributes to the persistence of toxic protein conformers, defective autophagy, mitochondrial dysfunction, and chronic neuroinflammation. In metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, GRP94- and TRAP1-dependent signaling promotes endoplasmic reticulum stress, impaired mitochondrial metabolism, insulin resistance, and inflammatory remodeling. These mechanistic insights have accelerated the development of a new generation of HSP90 inhibitors with improved selectivity, tissue targeting, and brain penetration. Unlike earlier pan-HSP90 inhibitors, these compounds are designed to exploit paralog-specific vulnerabilities and may enable safer long-term modulation of disease-relevant chaperone networks. This review summarizes current advances in the biology and pharmacology of HSP90 paralogs and proposes isoform-selective HSP90 targeting as a promising therapeutic strategy at the intersection of neurodegeneration and metabolic dysfunction.},
}

@article {pmid42508695,
year = {2026},
author = {Azimzadeh, M and Azimzadeh, M},
title = {From Gut Microbiota to Synaptic Plasticity: Mechanisms Shaping Cognitive Function and Brain Disorders.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116404},
doi = {10.1016/j.bbr.2026.116404},
pmid = {42508695},
issn = {1872-7549},
abstract = {The gut microbiota has emerged as a key regulator of central nervous system development and function. Accumulating experimental and clinical evidence demonstrates that microbial signals influence brain activity through integrated neural, immune, neuroendocrine, and metabolic pathways. These pathways converge on core mechanisms of synaptic plasticity, including neurotrophic signaling, glutamatergic transmission, dendritic remodeling, and adult neurogenesis, thereby shaping learning, memory, executive function, and emotional regulation. Disruption of microbiota-brain communication is implicated in a range of neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting shared systems-level vulnerabilities across conditions and highlighting the translational potential of microbiota-targeted interventions such as probiotics, dietary modulation, postbiotics, and precision microbiome-based strategies. Overall, the gut microbiota functions as a dynamic regulator of brain plasticity and cognitive resilience across the lifespan. Future progress will require identification of causal mechanisms at the level of specific microbial metabolites, neural circuits, and developmental windows using integrated multi-omics and spatially resolved approaches, alongside translation into targeted therapeutic strategies.},
}

@article {pmid42508744,
year = {2026},
author = {Datta, D and Arnsten, A and Sukoff Rizzo, SJ and Silva, AC and Joyce, MK and Tripathy, SJ and Roberts, A and Lewis, DA},
title = {Dorsolateral prefrontal cortex circuitry at the intersection of cognition and disease.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.012},
pmid = {42508744},
issn = {1873-2402},
abstract = {Schizophrenia, major depressive disorder (MDD), and Alzheimer's disease (AD) involve dysfunction of distributed cortical-subcortical networks that support complex cognitive processes and emotion regulation. Convergent evidence identifies the dorsolateral prefrontal cortex (dlPFC) as a critical site of molecular, cellular, and circuitry alterations in these disorders. The primate dlPFC contains recurrent, excitatory microcircuits in layer III that sustain working memory and top-down control through specialized forms of neurotransmission and intracellular signaling. Specifically, NMDA receptor and cholinergic modulation, as well as tightly regulated calcium-cAMP signaling within dendritic spines, support task-specific firing of layer III pyramidal neurons, but may also increase vulnerability to genetic risk, stress, inflammation and aging. This review integrates findings from human postmortem studies, neuroimaging, and genetics to examine how dlPFC circuitry is altered in these disease states. In schizophrenia, layer III pyramidal neurons exhibit altered synaptic and cytoskeletal signaling, lower dendritic spine density, and compensatory shifts in inhibitory inputs that likely weaken recurrent excitation and network synchrony. In MDD, dysfunction of dlPFC pathways regulating subgenual cingulate cortex contributes to impaired top-down control of emotion and motivation. In AD and frontotemporal lobar degeneration, tau pathology and neurodegeneration target association cortices, including layer III dlPFC circuits, contributing to progressive cognitive decline and impaired executive function. The review also highlights how studies in rhesus macaques and genetically engineered marmosets have provided important insight into the organization, physiology, and disease vulnerability of primate dlPFC circuits. Together, these findings inform the development of emerging therapeutic strategies aimed at strengthening prefrontal network function.},
}

@article {pmid42508750,
year = {2026},
author = {Zhang, X and Zhuang, D and Lai, C and Zheng, C and Soh, ZD and Wagner, S and Cai, VY and Yang, Z and Wang, S and Geng, X and Wang, Z and Feng, S and Qu, Y and Wang, L and Tang, S and Mok, VCT and Cheung, C and Chen, C and Zhu, Z and Cheng, CY and Yu, H},
title = {Retinal Manifestations of Alzheimer's Disease: Insights from Animal Models, Clinical Detection, and Future Translation.},
journal = {Progress in retinal and eye research},
volume = {},
number = {},
pages = {101504},
doi = {10.1016/j.preteyeres.2026.101504},
pmid = {42508750},
issn = {1873-1635},
abstract = {The retina, as an extension of the central nervous system, shares a common embryological origin with the brain. In Alzheimer's disease (AD), studies of human tissue and animal models have revealed that hallmark AD pathologies, including amyloid-β (Aβ) deposits and pathological tau protein tangles, also appear in the retina. These findings, coupled with advances in high-resolution retinal imaging techniques, suggest the potential to detect and characterize AD-related molecular and structural changes in the retina. However, retinal findings across different AD mouse models have significant discrepancies and show limited concordance with human phenotypes, complicating the identification of AD-specific alterations and the selection of optimal models for translational research. Moreover, the temporal sequence and functional significance of retinal abnormalities across the AD continuum, from preclinical stages to mild cognitive impairment and overt dementia, remain poorly defined. Addressing these knowledge gaps is essential to establish the retina as a reliable, non-invasive screening and monitoring approach. This review synthesizes current evidence on the spectrum of retinal alterations in AD, including vascular dysfunction, neuroinflammation, impaired Aβ clearance, and neurodegeneration, as observed in diverse mouse models. We compare these manifestations across species and between different models, highlighting findings along the disease continuum to delineate convergent and divergent pathways. We further discuss how emerging technologies enable the identification of AD-specific retinal alterations, and advocate for a paradigm shift from non-specific morphological assessment ("seeing shapes") toward molecular-level interrogation ("seeing components"). Interdisciplinary efforts and technological integration are crucial to establish retina as a dynamic mirror of pathology in AD.},
}

@article {pmid42508872,
year = {2026},
author = {Zhou, K and Cohn, M and Novik, R and Batur, P and Just, C},
title = {Menopause and Brain Health: Neurobiological Changes, Cognitive Implications, and the Role of Estrogen.},
journal = {Obstetrics and gynecology clinics of North America},
volume = {53},
number = {3},
pages = {449-461},
doi = {10.1016/j.ogc.2026.04.001},
pmid = {42508872},
issn = {1558-0474},
abstract = {The menopausal transition is characterized by significant hormonal fluctuations, culminating in a decline in estrogen levels. This decline impacts synaptic plasticity, neurotransmitter regulation, the blood brain barrier, cerebral blood flow, and metabolism, leading to cognitive symptoms often described as brain fog. Menopause-related cognitive changes, often transient, differ from the progressive decline seen in Alzheimer's Disease (AD). Research continues to explore estrogen's role in AD risk, but current evidence does not support using exogenous estrogen solely for dementia prevention. Hormone therapy can help manage menopausal symptoms and should be personalized based on factors like age, timing, and overall brain health.},
}

@article {pmid42508906,
year = {2026},
author = {de Souza, ID and Queiroz, MEC and Pichon, V and Combès, A},
title = {Online aptamer-based solid-phase extraction coupled with high-performance liquid chromatography-mass spectrometry for the determination of Alzheimer's disease biomarkers.},
journal = {Analytica chimica acta},
volume = {1417},
number = {},
pages = {345809},
doi = {10.1016/j.aca.2026.345809},
pmid = {42508906},
issn = {1873-4324},
abstract = {BACKGROUND: Reliable quantification of amyloid-β (Aβ) peptides in biological fluids is of major clinical and research interest in Alzheimer disease context. Conventional offline extraction approaches often involve labor-intensive manual steps and high solvent consumption, limiting throughput routine applications, reproducibility, and sustainability. To address these limitations, this study reports the development of an online coupling between a monolithic oligosorbent (mOS) in capillary and high-performance liquid chromatography-mass spectrometry (HPLC-MS) method for selective Aβ peptide analysis.

RESULTS: A mOS was incorporated online in a set up including a C18 trap column coupled with an HPLC-MS analytical system. Systematic optimization of mOS loading/elution conditions, trapping column desalting/preconcentration, and chromatographic mobile phase composition enabled efficient retention, transfer, and separation of Aβ40 and Aβ42 in a fully automated method. This method achieved lower limits of quantification down to 0.03 ng mL[-1] with good precision and accuracy (CV ranging from 1.1 to 6.2% for Aβ40 and from 4.3 to 10.9% for Aβ42). Comparative evaluation of offline and online extraction using the same mOS capillary demonstrated improved reproducibility and enhanced sensitivity for the online configuration. The method's applicability to a controlled CSF-like matrix was demonstrated using artificial cerebrospinal fluid (aCSF) diluted 1:2 (v/v) in binding buffer (BB), yielding recoveries of 60% for Aβ40 and 34% for Aβ42.

SIGNIFICANCE: The online coupling of the mOS capillary with HPLC-MS also represents a strategic advance toward environmentally responsible bioanalysis. Indeed, the superior AGREEprep score (0.7) for the online configuration compared to offline mode (0.59), underscores its alignment with green analytical chemistry principles, reflecting reductions in solvent use, manual intervention, and overall environmental burden.},
}

@article {pmid42509195,
year = {2026},
author = {Reichert, L and Delparente, A and Hipfinger, IR and Reininger, L and Castro, AP and Hubin, DJ and Schibli, R and Fraley, AE and Mu, L},
title = {Identification of Pyrazolidine-3-One Derivatives as a Novel Structural Scaffold for ATP Synthase Inhibitors.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70399},
pmid = {42509195},
issn = {1860-7187},
support = {205321_192409/1//Swiss National Fundation/ ; #22A047//Novartis Stiftung für Medizinisch-Biologische Forschung/ ; },
abstract = {In a recent study, the oxadiazin-5-one-based compound CJ1-34 was identified as a partial ATP synthase inhibitor, which was found to bind the F1 region of the ATP synthase. These findings were used as a starting point for the design and synthesis of smaller heterocycles, such as pyrazolidine-3-ones and pyrazol-3-ones, as novel structural scaffolds for potential ATP synthase inhibitors. Among the newly synthesized compounds, pyrazolidin-3-one derivatives 9a and 10a outperformed the lead compound CJ1-34 in vitro by inhibiting ATP hydrolytic activity and decreasing ATP levels in HT-22 cells. Subsequent dose-dependent studies identified compound 9a as the most promising ATP synthase inhibitor. Molecular docking revealed similar binding modes for all compounds in the F1-binding site and the calculated docking scores aligned with the measured IC50 values of the tested compounds. This study identified pyrazolidine-3-ones as promising structural scaffolds for ATP synthase inhibition, opening avenues for further biomedical applications in central nervous system diseases such as Alzheimer's and Parkinson's.},
}

@article {pmid42509403,
year = {2026},
author = {Anand, A and Sania, A and Singh, SK and Bajad, N},
title = {Targeting Histone Deacetylase 2 in Alzheimer's Disease: From Molecular Insights to Epigenetic Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42509403},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive impairment, memory loss, and nerve cell dysfunction. Despite substantial research efforts, effective AD therapies remain limited. Histone deacetylase 2 (HDAC2) is a principal epigenetic regulator that is essential for controlling gene expression and neuronal connectivity. Recently, HDAC2 has attracted significant attention as a potential therapeutic target in AD owing to its involvement in key disease hallmarks, including neuroinflammation, Aβ accumulation, and abnormal tau phosphorylation. We have outlined and discussed the molecular insights into HDAC2 in AD and its recently emerged inhibitors. Inhibiting HDAC2 has demonstrated potential in lowering neuroinflammatory signalling and reestablishing synaptic and neuroprotective gene expression patterns in preclinical AD models. Current preclinical evidence indicates that HDAC2 may play a significant role in AD development and may represent a target for therapeutic intervention. Recent progress in HDAC2 inhibitor development offers a rationale for this approach, although further mechanistic and clinical investigations are required. Resolving the precise roles of HDAC2 dysregulation in AD and determining the utility of combination strategies remain important priorities. Whether HDAC2-targeted inhibitors can yield disease-modifying benefits in AD remains to be demonstrated in clinical studies.},
}

@article {pmid42509523,
year = {2026},
author = {Neller, SA and Fernandez Cajavilca, M and Wong, B and Johnson, J and Ellington, L and Eaton, J},
title = {Identifying and Mapping Levels of Active Engagement Within an Arts-Based Intervention: A Qualitative Analysis and Conceptual Development.},
journal = {International journal of behavioral medicine},
volume = {},
number = {},
pages = {},
pmid = {42509523},
issn = {1532-7558},
abstract = {BACKGROUND: Active engagement is crucial in psychoeducational interventions for care partners of persons living with dementia, yet measurement is limited. This manuscript explores participant engagement in an arts-based intervention designed to increase engagement in addressing dementia-related behavioral symptoms. The intervention uses multisensory activities, including caregiver-informed vignettes, to foster engagement and process caregiving experiences.

METHODS: Care partners of persons living with dementia (n = 9) participated in six focus groups. Focus group data were analyzed using process coding to define and map patterns of active engagement across 27 intervention activities. The findings informed development of a conceptual model of active engagement.

RESULTS: Four levels of engagement were identified-Participating, Clarifying, Contributing, and Applying-and explored across participants, time points, and activities. The conceptual model illustrates that (1) antecedents contribute to (2) levels of engagement, leading to (3) the intervention's hypothesized mechanisms of action, proximal outcomes (capacity to adapt, appraisal of caregiving demands), and distal outcomes (perceived stress, caregiver well-being).

CONCLUSION: This manuscript provides a clear framework for operationalizing and measuring active engagement and demonstrates how engagement patterns can be conceptually linked to the intervention's proposed mechanisms of action and outcomes. These findings provide transparency in reporting engagement patterns within an intervention, offering valuable insight into the components of active engagement and how these may be measured. The ability to track active engagement during intervention development and testing has the potential to improve our understanding of intervention dose and fidelity and how active engagement interacts with these to improve outcomes for participants.},
}

@article {pmid42509652,
year = {2026},
author = {Mielke, MM and Gaussoin, SA and Casanova, R and Latham, LA and Manson, JE and Mouton, CP and Ng, TKS and Rapp, SR and Resnick, SM and Sachs, BC and Saquib, N and Shadyab, AH and McEvoy, LK and LaCroix, AZ and Wallace, RB and Espeland, MA and Chen, JC and Hayden, KM},
title = {Alzheimer's blood-based biomarkers, incident dementia, and interactions with age, APOE status, and hormone therapy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71704},
doi = {10.1002/alz.71704},
pmid = {42509652},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; },
abstract = {INTRODUCTION: Cognitive impairment among older adults is often due to multiple pathologies and heterogenous risk factors. We assessed whether Alzheimer's blood-based biomarkers (BBMs) were associated with incident mild cognitive impairment (MCI)/probable dementia, and whether associations were modified by age, apolipoprotein E (APOE), and hormone therapy (HT).

METHODS: Analyses included 2467 Women's Health Initiative Memory Study women (≥65 years of age) randomized between 1995 and 1998 to 3-5-years of HT or placebo. Cox regression (mean 18-year follow-up) assessed associations between the z-scored BBMs and MCI/dementia.

RESULTS: Lower baseline amyloid beta (Aβ)42/40 ratio and higher phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were associated with an increased risk of MCI and dementia; GFAP was most strongly associated. The p-tau181 and NfL associations were stronger among APOE ε4 carriers; BBMs varied non-linearly by age. The associations of BBMs with the cognitive outcomes also varied inconsistently between HT groups.

DISCUSSION: BBMs for AD and related dementias (ADRD) are associated with incident MCI/dementia in older women. Interactions between the BBMs and HT were inconsistent and require further investigation.},
}

@article {pmid42509698,
year = {2026},
author = {Wang, X and Li, J and Wei, Z and Rong, C and Zhao, D and Wang, Y},
title = {Integrating Multi-Omics and Mendelian Randomization Reveals the Role of Epstein-Barr Virus Infection in Alzheimer's Disease and the Therapeutic Potential of Resveratrol.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050463115260708111634},
pmid = {42509698},
issn = {1875-5828},
abstract = {INTRODUCTION: The pathogenesis of Alzheimer's disease (AD) is complex, with immune system dysregulation playing a critical role. However, the specific molecular mechanisms linking peripheral immune responses to central pathologies in AD remain unclear. This study aims to systematically screen for reliable plasma biomarkers of AD by integrating transcriptomics, Mendelian randomization (MR) of plasma proteomics, and bioinformatics analyses, and to explore their potential pathogenic mechanisms and therapeutic drugs.

MATERIALS AND METHODS: Transcriptomic sequencing of plasma samples from three AD patients and three healthy controls was first performed to identify differentially expressed genes (DEGs) and perform functional enrichment analyses. The aim of this study is to provide a preliminary indication of gene expression changes based on real patient samples for subsequent MR and bioinformatics analyses, rather than serving as confirmatory evidence. Following this, two-sample MR was performed to explore the potential causal relationship between plasma proteins and AD in genetic prediction, and MR-positive results were intersected with transcriptome DEGs to identify highconfidence targets. After that, protein-protein interaction (PPI) analysis, functional enrichment (GO/KEGG), and transcription factor (TF) target network analysis were conducted. Based on the KEGG pathway analysis, the causal association between antibodies related to Epstein-Barr virus and AD in genetic prediction was further evaluated. In the end, the diagnostic power of core biomarkers was validated in the GEO dataset. Potential therapeutic drugs were screened in the CTD database, followed by verification through molecular docking and molecular dynamics simulation.

RESULT: Our transcriptomic enrichment analysis of DEGs indicates that AD is significantly correlated with viral infection and immune and inflammatory pathways. According to the results of MR analyses, 36 plasma proteins have a causal effect on AD in genetic prediction. Among these 36 targets, two pathways are identified as enriched: "EBV Infection" and "Efferocytosis". Seven core targets are CR2, ICAM1, TAPBP, TNFAIP3, THBS1, SCARF1, and SIRPG. Also, the concentration of antibodies against EBV EBNA-1 and VCA p18 was confirmed by MR analyses to be risk factors for AD. According to drug predictions, molecular docking, and molecular dynamics simulations, resveratrol can stabilize CR2.

DISCUSSION: This study systematically identifies major plasma immune biomarkers associated with AD and proposes a mechanism by which EBV infection regulates plasma proteins CR2, TNFAIP3, and THBS1, which may affect AD risk. Resveratrol is thought to have preventive and protective effects, as predicted computationally.

CONCLUSION: This study systematically identified key plasma markers associated with AD. Resveratrol is likely to become a potentially effective preventive and protective drug in the prevention and treatment of AD, providing new ideas and targets for immune intervention of AD.},
}

@article {pmid42509699,
year = {2026},
author = {Barczak, A and Krempa-Kowalewska, A and Golan, M},
title = {Cognitive Profiles in Early- and Late-Onset Alzheimer's Disease: The Role of Dementia Severity in Typical Amnestic Presentations Using the Addenbrooke's Cognitive Examination III.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050489392260702044957},
pmid = {42509699},
issn = {1875-5828},
abstract = {INTRODUCTION: Early-Onset (EOAD) and Late-Onset Alzheimer's Disease (LOAD) are often described as presenting distinct cognitive phenotypes. However, reported differences are inconsistent and may reflect demographic and severity-related confounding rather than stable etiological distinctions.

MATERIALS AND METHODS: A retrospective analysis was conducted in 776 patients with clinically diagnosed Alzheimer's disease (EOAD, n = 175; LOAD, n = 601). Cognitive performance was assessed using the Addenbrooke's Cognitive Examination III (ACE-III) and the Mini-Mental State Examination (MMSE). Dementia severity was staged using the Functional Assessment Staging Tool (FAST). Cognitive outcomes were analysed using age- and severity-adjusted ANCOVA models including a diagnosis × age interaction. Severity-stratified and domain-level analyses were also performed.

RESULTS: Unadjusted analyses revealed limited EOAD-LOAD differences in the Attention and Visuospatial domains, with small effect sizes. After adjustment for demographic variables and dementia severity, no cognitive measure reliably differentiated EOAD from LOAD. Cognitive performance showed similar cross-sectional patterns across groups and was primarily determined by dementia severity.

DISCUSSION: Small, stage-dependent differences observed at mild and moderate stages did not persist in more advanced dementia and did not indicate stable cognitive dissociation between EOAD and LOAD.

CONCLUSIONS: After adjustment for demographic factors and dementia severity, EOAD and LOAD do not exhibit distinct cognitive profiles on ACE-III. Cognitive performance reflects disease stage rather than age at onset, supporting the use of ACE-III for staging cognitive impairment rather than for differentiating EOAD from LOAD in typical amnestic presentations.},
}

@article {pmid42509706,
year = {2026},
author = {Shen, Z and Cheng, J and Wang, L and Hou, Q},
title = {Molecular Mechanisms and Therapeutic Strategies in Parkinson's Disease: From Pathogenic Signaling to Drug Development.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X457429260706102249},
pmid = {42509706},
issn = {1875-6190},
abstract = {Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD), yet no effective disease-modifying therapy is currently available. Its pathogenesis is highly complex, involving multiple interacting pathological processes, which poses substantial challenges for therapeutic intervention. Moreover, PD often has a prolonged prodromal phase and lacks sufficiently sensitive and specific diagnostic methods for early-stage detection, further limiting timely identification and treatment. Current pharmacological therapies mainly provide symptomatic relief, but their long-term use is frequently associated with reduced efficacy and motor complications. Therefore, the development of novel therapeutic strategies and potential disease-modifying agents remains an urgent priority. This review systematically summarizes the molecular mechanisms and biomarkers associated with PD, outlines current symptomatic treatments, and discusses emerging therapeutic candidates in clinical development, with particular emphasis on disease-modifying strategies. By integrating pathogenic mechanisms, diagnostic advances, and therapeutic progress, this review aims to provide a comprehensive perspective to support the development of more effective interventions for PD.},
}

@article {pmid42509708,
year = {2026},
author = {Liu, Y and Zhang, Y and Zheng, W and Shi, X and Yao, W and Zhang, J and Bai, F},
title = {Cortico-white Matter Functional Coupling as a Biomarker of Alzheimer's Disease Progression and rTMS Therapeutic Efficacy.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X470892260706231913},
pmid = {42509708},
issn = {1875-6190},
abstract = {INTRODUCTION: Alzheimer's disease (AD) spectrum disorders are characterized by progressive cognitive decline, with white matter degeneration and disrupted cortico-cortical connectivity as early features. Cortico-white matter functional coupling integrates neuronal activity with axonal conduction, yet its natural trajectory across the AD spectrum and ability to be modulated by repetitive transcranial magnetic stimulation (rTMS) remain unclear.

METHODS: Longitudinal resting-state fMRI from the ADNI cohort (n = 160: 59 cognitively normal, CN; 65 mild cognitive impairment, MCI; 36 AD) was used to assess baseline and 1-year changes in mean Fisher's z-transformed coupling between 82 cortical seeds (AAL-90 atlas, excluding subcortical nuclei) and a probabilistic group white matter mask. Specifically, 54 patients with amnestic MCI (aMCI) from the rTMS cohort were allocated to active (n = 40) or sham (n = 14) groups and received four weeks of neuronavigated rTMS targeting the left angular gyrus. Cortico-white matter functional coupling was calculated identically in both cohorts. Changes in coupling strength and their associations with changes in neuropsychological performance were examined across all cortical seeds.

RESULTS: At baseline, mean cortico-white matter functional coupling followed a nonlinear pattern (MCI > AD and CN). One-year follow-up revealed that the CN group exhibited a slight decrease in coupling, and the MCI and AD groups showed a pathological increase. Compared with the sham group, active rTMS significantly attenuated this increase in coupling. After adjusting for covariates, coupling changes were strongly correlated with cognitive decline. The AD group demonstrated the most significant associations (n = 104), whereas the active rTMS group showed 71 associations, predominantly linked to objective memory improvement.

DISCUSSION: This abnormal overcoupling, leading to compensation and decompensation, is associated with the progression of Alzheimer's disease. rTMS effectively moderates this pathological surge by enhancing neural efficiency and stabilizing large-scale network integration. Our findings position cortico-white matter functional coupling as an effective indicator of disease intensity and a measurable link in the chain of rTMS effectiveness for early-stage AD.

CONCLUSION: Overall, cortico-white matter functional coupling may serve as a novel scan-based biomarker for tracking AD progression and evaluating rTMS treatment efficacy in patients with MCI.},
}

@article {pmid42509738,
year = {2026},
author = {Wali, Z and Neha, and Shahwan, M and Dinislam, K and Shamsi, A and Anwar, S},
title = {Network Biology of Alzheimer's Disease and Related Neurodegenerative Disorders: Molecular Mechanisms and Therapeutic Strategies.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070944},
pmid = {42509738},
issn = {2218-273X},
support = {NA//Ajman University/ ; },
abstract = {The most persistent biomedical challenges of the 21st century are neurodegenerative disorders (NDs), where molecular alterations lead to devastating clinical consequences and progressive neuronal loss. The prevalence of neurodegeneration is continuously rising and becoming the main contributor to chronic disability and mortality. Despite their clinical differences, many conditions share pathogenic processes, including oxidative stress, protein misfolding and aggregation, mitochondrial dysfunction, and neuroinflammation. Instead of functioning independently, these processes cooperate to form a self-reinforcing network that gradually weakens synapses and ultimately leads to neuronal death. This study redefines neurodegeneration as a disorder of system-level failure by emphasizing poor cellular stress integration. In addition to demonstrating how gut microbiome gene networks impact inflammation and amyloid production, new research highlights the relationships between mitochondrial-lysosomal interactions, endoplasmic reticulum stress responses, and transcriptionally driven synaptic vulnerability. A key molecular topic is the interaction and pathogenic convergence of the JAK/STAT, HIF-1α, and Notch signaling pathways. Under ongoing metabolic stress, prolonged stimulation of this triad increases inflammation, hinders the regenerative processes, and maintains pseudo-hypoxic conditions, explaining why single-target treatments have mostly been unsuccessful. This review also explores progress in fluid, digital, and imaging biomarkers that facilitate early diagnosis and patient stratification, and assesses new disease-modifying approaches such as antisense oligonucleotides, immunomodulators, gene therapies, and small-molecular agents. Artificial intelligence is emphasized as an essential tool for integrating multimodal data, drug discovery and predictive modeling.},
}

@article {pmid42509739,
year = {2026},
author = {Narita, A and Nakano-Doi, A and Nishiyama, R and Sawano, T and Fukushima, K and Matsuyama, T and Nakagomi, T},
title = {Mirtazapine Induces Lipocalin-Type Prostaglandin D Synthase Expression in Brain Pericytes.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070945},
pmid = {42509739},
issn = {2218-273X},
abstract = {The brain maintains homeostasis partially by scavenging waste products. Failure of this function is closely associated with the onset and pathogenesis of various brain diseases, such as Alzheimer's disease, sleep disorder, and the delay of the reparative process after brain injuries. We recently demonstrated that brain pericytes (BPCs) are sources of lipocalin-type prostaglandin D synthase (L-PGDS), a waste scavenger, in the brain. Based on the above, chemical compounds which promote L-PGDS production could have potential against brain diseases, such as dementia, sleep disorders, and brain injuries. However, the specific chemical compounds that may enhance L-PGDS production in BPCs have not yet been identified. In this study, we explored 158 chemical compounds from FDA-approved drug libraries with these activities. qPCR analysis showed that mirtazapine (MTZ), a noradrenergic and specific serotonergic antidepressant, can increase L-PGDS expression in BPCs as well as in mouse- (m-BPCs) and human-derived BPCs (h-BPCs) in a dose-dependent manner. Since L-PGDS is a secretory protein, m-BPCs and h-BPCs were treated with various MTZ doses and L-PGDS levels in the culture supernatant were investigated. Western blot analysis showed that L-PGDS levels were significantly increased in a dose-dependent manner in both cell types, indicating that MTZ promoted L-PGDS secretion from m-BPCs and h-BPCs. Thus, MTZ may have the potential to be applied as drug repositioning for various brain diseases other than depression by activating L-PGDS production in BPCs, highlighting the importance of BPCs as the source to maintain brain homeostasis.},
}

@article {pmid42509786,
year = {2026},
author = {Guo, L and Grimaldi, N and Wang, M and Ho, L and Shackleton, B and Neff, R and Wang, E and Tu, Z and Gandy, S and Haroutunian, V and Ehrlich, ME and Mobbs, C and Zhang, B},
title = {Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070992},
pmid = {42509786},
issn = {2218-273X},
support = {5R01AG057907-05/NH/NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is an aging-related neurodegenerative disease characterized by an initial memory impairment that progresses to a widespread cerebrocortical failure, culminating in death. Understanding the molecular mechanisms that protect brain function during aging may help reveal novel targets for the development of effective treatments for the memory and cognitive deficits associated with AD. In this study, we analyzed a gene expression dataset generated from the prefrontal cortices of individuals showing no neurological or cognitive abnormalities. The gene expression profiles were used to identify candidate protective genes. We then compared the expression patterns of these genes in aging with their expression patterns in AD, thereby enabling us to pinpoint the genes that potentially contribute to brain resilience that delays or prevents aging-related dementia. We selected seven genes that are potentially protective for aging and AD, and have known homologues in Caenorhabditis elegans (C. elegans). Among these genes, SRPK2, AAK1, EFR3A and MAPK10 were previously implicated in attenuating AD-related cognitive decline. Our experiments demonstrated that all seven genes prioritized by our resilience model significantly extended the lifespan of C. elegans. Given the important relationship between neuronal functional integrity and lifespan (i.e., lifespan vs. brain health span), this work suggests the predicted AD resilience genes could serve as important candidate targets for therapeutic intervention.},
}

@article {pmid42509845,
year = {2026},
author = {De Oliveira, LF and Karunarathne, K and Zona, D and Muschol, M and Ullah, G},
title = {Shrinking of Extracellular Space During Metabolic Stress Accelerates Amyloid-β Aggregation.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16071053},
pmid = {42509845},
issn = {2218-273X},
support = {R21AG087910/NH/NIH HHS/United States ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *Extracellular Space/metabolism ; *Stress, Physiological ; Humans ; Alzheimer Disease/metabolism/pathology ; Protein Aggregates ; Kinetics ; Neurons/metabolism ; Animals ; *Peptide Fragments/metabolism/chemistry ; *Protein Aggregation, Pathological/metabolism ; },
abstract = {Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer's disease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here, we determine how metabolic stress associated with spreading depolarization (SD)-a hallmark of stroke, hypoxia, TBI, and migraine-modulates amyloid β (Aβ42) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different Aβ42 aggregate species depends on Aβ42 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and Aβ42 aggregation kinetics. Our model predicts that neuronal swelling during SD accelerates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis.},
}

*Amyloid beta-Peptides/metabolism/chemistry
*Extracellular Space/metabolism
*Stress, Physiological
Humans
Alzheimer Disease/metabolism/pathology
Protein Aggregates
Kinetics
Neurons/metabolism
Animals
*Peptide Fragments/metabolism/chemistry
*Protein Aggregation, Pathological/metabolism

@article {pmid42509854,
year = {2026},
author = {Alessio, M and Giulia, N and Annagrazia, A and Francesco, A and Raffaele, M and Massimo, C and Giacinto, B and Carlo, N and Romano, E and Rossella, R},
title = {Lithium as a Potential Neuroprotective Strategy in Glaucoma: Mechanisms and Therapeutic Perspectives.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16071062},
pmid = {42509854},
issn = {2218-273X},
abstract = {Glaucoma is a major global health concern, identified as the foremost cause of irreversible blindness, affecting nearly 95 million individuals. It is characterized by the progressive degeneration of retinal ganglion cells (RGCs), leading to significant vision-related disabilities and an extensive socio-economic impact. The concept that glaucoma should be viewed not solely as an ocular condition but also as a neurodegenerative disorder, sharing pathophysiological features with diseases like Alzheimer's and Parkinson's, is now widely accepted. This review examines the convergence of molecular mechanisms, including the roles of amyloid precursor proteins and neuroinflammation, that contribute to RGC loss. Notably, lithium, traditionally used as a mood stabilizer, has emerged as a potential neuroprotective agent for the treatment of Alzheimer's disease. In light of the common neurodegenerative mechanisms linking glaucoma with central neurodegenerative diseases, here, we review the current evidence supporting lithium's therapeutic potential in glaucoma, emphasizing the need for further clinical studies to determine its effectiveness in preserving optic nerve health and improving patient outcomes.},
}

@article {pmid42510415,
year = {2026},
author = {Li, R and Wu, M},
title = {Multidimensional Prosodic and Semantic Coherence Modeling for Mandarin Mild Cognitive Impairment Detection.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
doi = {10.3390/bioengineering13070748},
pmid = {42510415},
issn = {2306-5354},
support = {2025J01001//Fujian Provincial Department of Science and Technology/ ; 32071057, 61673322, 31200769//National Natural Science Foundation of China/ ; Not applicable (Xiamen University Undergraduate Innovation and Entrepreneurship Training Program)//Undergraduate Innovation and Entrepreneurship Training Program of Xiamen University/ ; },
abstract = {Early detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains critically important, yet conventional neuroimaging and biomarker-based approaches are costly, invasive, and poorly scalable for population screening. Speech offers a non-invasive, cost-effective alternative cognitive biomarker, but existing systems rarely integrate its multiple linguistic dimensions. We present Multi-Spec MCI-Net, a multimodal framework for HC/MCI classification that jointly models three complementary speech representations: token-level semantics via dVAE and BERT operating on Mel spectrograms; temporal prosodic dynamics via a 1D-CNN with attention; and discourse-level semantic coherence via a graph convolutional network. A gated fusion mechanism adaptively weights these modalities, yielding clinically interpretable predictions tailored to individual phenotypic profiles. Evaluated on the Chinese NCMMSC2021_AD challenge dataset and the DementiaBank Mandarin subset, the model achieves 89.29% accuracy and 0.9584 ROC AUC on NCMMSC2021_AD, with 92.31% MCI recall-critical for minimizing false negatives in screening contexts. Evaluation on the combined NCMMSC2021_AD and DementiaBank Mandarin dataset attains 77.46% accuracy and 0.8280 AUC, demonstrating robustness across spontaneous dialog and picture description tasks. Ablation studies confirm that multimodal fusion outperforms the semantic-only baseline by 5.16 percentage points, with each branch contributing non-redundant diagnostic information. These results establish an effective, interpretable approach for scalable, speech-based early MCI screening.},
}

@article {pmid42510516,
year = {2026},
author = {Song, C and Deng, C and Zhang, T and Yao, W and Li, D and Wang, X},
title = {Rhodopseudomonas pseudopalustris Mitigates Alzheimer's Disease-Related Pathology in C. elegans Models by Enhancing Antioxidant Defense Capacity and Immune Activity.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070785},
pmid = {42510516},
issn = {2076-3921},
support = {32571125//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapeutics. Probiotics, promising neuroprotective candidates, exert benefits mainly by modulating gut-brain-axis (GBA) signaling. This study explored the anti-AD effects and mechanisms of Rhodopseudomonas pseudopalustris (R. pse). Using Caenorhabditis elegans (C. elegans) AD models, we evaluated AD-related phenotypes (learning deficits, paralysis) after R. pse administration, and performed genetic analysis and metabolomic profiling to clarify its regulatory pathways and metabolites. Mechanistically, R. pse significantly alleviated AD-related phenotype in C. elegans. It upregulated γ-glutamylcysteine synthetase (GCS-1) to enhance the glutathione (GSH)-dependent antioxidant defense. Knockout of the oxidation repair enzyme methionine sulfoxide reductase A-1 (MSRA-1) abolished the neuroprotective effects of R. pse, which was rescued by methionine. R. pse also activated activating transcription factor 7 (ATF-7)-mediated innate immunity and transforming growth factor β (TGF-β) signaling, with pantothenic acid as its functional metabolite. Collectively, R. pse is a potential anti-AD bacterium that mitigates AD model pathogenesis by enhancing the cellular antioxidant capacity, providing experimental evidence for bacteria-based AD interventions.},
}

@article {pmid42510529,
year = {2026},
author = {Vietri, M and Napolitano, E and Miranda, MR and Marino, C and Musella, S and Di Sarno, V and Ostacolo, C and Manfra, M and Campiglia, P and Tecce, MF and D'Ursi, AM and Moltedo, O and Bertamino, A and Ciaglia, T and Vestuto, V},
title = {Metabolic Reprogramming Associated with Ferroptosis Protection by an Indole-Based Antioxidant in Aβ(25-35)-Treated SH-SY5Y Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070798},
pmid = {42510529},
issn = {2076-3921},
support = {J97G22000400006//Ministero dell'università e della ricerca/ ; },
abstract = {Ferroptosis has emerged as a critical mechanism linking iron dysregulation, oxidative stress, and neurodegeneration in amyloid-associated pathologies. Building on our previous work, which identified compound 20 as a promising antioxidant and neuroprotective agent, the present study investigates the molecular mechanisms underlying its protective activity against amyloid-induced ferroptosis in human neuroblastoma SH-SY5Y cells exposed to Aβ(25-35). Compound 20 (3-(((4-hydroxybenzyl)(methyl)amino)methyl)-1-methyl-N-(2-(piperazin-1-yl)ethyl)-1H-indole-5-carboxamide) markedly counteracted Aβ(25-35)-induced ferroptotic damage by restoring intracellular glutathione levels, depleting the labile iron pool, and suppressing lipid peroxidation. In parallel, the compound significantly rescued mitochondrial membrane potential and attenuated endoplasmic reticulum (ER) expansion associated with ER stress, thereby preserving cellular homeostasis under oxidative challenge. These protective effects were further corroborated by real-time PCR analysis, which revealed the modulation of key genes involved in the oxidative stress response, endoplasmic reticulum stress, and inflammatory pathways. To gain a systems-level insight into these mechanisms, untargeted [1]H-NMR metabolomic profiling was performed. This analysis confirmed the activation of antioxidant pathways and disclosed a significant modulation of energy metabolism and GABA-related pathways, both of which are closely linked to redox balance and neuronal resilience. Overall, these findings demonstrate that compound 20 drives metabolic reprogramming that orchestrates its multifactorial protective effect against Aβ(25-35)-induced ferroptosis by coordinating antioxidant defense, iron homeostasis, and ER stress mitigation.},
}

@article {pmid42510588,
year = {2026},
author = {Ciccone, L and Petrarolo, G and D'Agostino, I and Scianò, F and Bernardoni, BL and Leri, M and Ann, J and Nencetti, S and Lee, J and Bucciantini, M and La Motta, C},
title = {Polyphenolic Imidazopyridines as Multifunctional Modulators of Oxidative Stress, Metal Dyshomeostasis, and β1-42 Amyloid Aggregation in an In Vitro Model of Alzheimer's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070857},
pmid = {42510588},
issn = {2076-3921},
abstract = {Alzheimer's disease (AD) involves oxidative stress, metal dyshomeostasis, and toxic oligomers of the amyloid-β peptide (Aβ1-42), calling for multifunctional agents. We investigated a panel of imidazo[1,2-a]pyridines bearing catechol or resorcinol motifs previously designed as SIRT1-activating agents. Their antioxidant profile was evaluated using in vitro DPPH and ABTS assays, which revealed promising radical scavenging activities, and TBARS assays on rat brain homogenates showing inhibition of lipid peroxidation, strictly dependent on the phenolic pattern. UV-Vis studies revealed metal-binding properties, particularly Cu[2+] and Fe[2+] interactions. In Aβ1-42 aggregation assays, the most active derivatives appeared to promote fibril maturation and the growth of large, ThT-low aggregates with distinct morphological features observed by TEM. Notably, Aβ1-42 aggregates generated in the presence of these compounds exhibited reduced cytotoxicity, preserved cell viability, and induced lower ROS levels in RA-differentiated SH-SY5Y cells compared to aggregates formed in their absence. Imaging and FRET analyses further indicated reduced formation of membrane-binding toxic species. Overall, our data suggest that polyphenolic imidazo[1,2-a]pyridines can remodel Aβ1-42 aggregation, redirecting it toward structurally distinct and less toxic assemblies, while also counteracting oxidative and metal-associated damage. These findings highlight their potential as multifunctional agents capable of addressing several pathological hallmarks of AD.},
}

@article {pmid42510665,
year = {2026},
author = {Mitroshina, EV and Strelkova, PL and Korokozova, MV and Vedunova, MV},
title = {HIF1 Stabilization by Roxadustat Improves Cognition and Prevents Neuron Loss in Alzheimer's Diseases In Vivo.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141118},
pmid = {42510665},
issn = {2079-7737},
support = {22-15-00178-p//Russian Science Foundation/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide and is characterized by progressive memory impairment, cognitive decline, and behavioral dysfunction. The brain's high energy demand makes it vulnerable to hypoxia, which can trigger AD pathology. Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular and tissue adaptation to low oxygen levels. HIF-1 plays a dual role in AD: on the one hand, it is considered a potential neuroprotective target; on the other hand, its activation may exacerbate disease pathogenesis by promoting amyloid plaque formation. Given this ambiguity, further studies are needed. This study investigated the HIF prolyl hydroxylase inhibitor Roxadustat in 6-month-old male 5xFAD mice. Stabilization of the HIF-1 complex exerted a positive effect on learning ability and the retention of long-term spatial memory in 6-month-old male 5xFAD mice. Four-week treatment with Roxadustat significantly reduced pathological morphological alterations in cells of the prefrontal cortex. In addition, animals treated with Roxadustat exhibited significantly increased expression of the brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Our findings suggest that stabilization of the HIF-1 complex through inhibition of HIF prolyl hydroxylase may represent a promising strategy for neuroprotection in AD.},
}

@article {pmid42510722,
year = {2026},
author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C},
title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141176},
pmid = {42510722},
issn = {2079-7737},
abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.},
}

@article {pmid42510815,
year = {2026},
author = {Deng, K and Deng, X and Li, S and Fang, S and Wei, F},
title = {The Genetic and Transcriptomic Nexus of Age-Related Hearing Loss and Alzheimer's Disease.},
journal = {Genes},
volume = {17},
number = {7},
pages = {},
pmid = {42510815},
issn = {2073-4425},
support = {2023A1515012713//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {Introduction: Despite the recognized association between age-related hearing loss (ARHL) and Alzheimer's disease (AD), the genetic relationship and shared transcriptional mechanisms between them remain largely unexplored. Methods: We systematically investigated the ARHL-AD axis using a multi-layered genomic strategy, incorporating causal inference, cis-eQTL mediation, Bayesian colocalization, and independent replication cohort validation. Results: Genetically predicted ARHL was associated with a reduced risk of overall AD and its early/late-onset subtypes, with no evidence of reverse causality in reverse MR analyses. Among 36 identified mediating genes, CSK showed the most consistent mediation signals across discovery and replication cohorts, although the replication was statistically partial (Sobel p = 0.078). Pathway analyses revealed that these genetic links predominantly involve Wnt signaling and endoplasmic reticulum protein processing. Discussion: Our integrative multi-omics findings suggest a potential genetic association between ARHL liability and AD risk. More importantly, we identified a prioritized CSK-driven transcriptional network, providing novel mechanistic insights and highlighting a candidate gene for future functional investigation in neurodegeneration.},
}

@article {pmid42510931,
year = {2026},
author = {Schuck, PF and da Costa Ferreira, G and Freitas, HR},
title = {Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter SLC13A5 and Citrate Metabolism Genes Across Alzheimer's Disease Pseudoprogression: A Single-Nucleus RNA Sequencing Analysis of the Human Middle Temporal Gyrus.},
journal = {Current issues in molecular biology},
volume = {48},
number = {7},
pages = {},
doi = {10.3390/cimb48070691},
pmid = {42510931},
issn = {1467-3045},
support = {307377/2023-7//National Council for Scientific and Technological Development/ ; 445305/2024-0//National Council for Scientific and Technological Development/ ; 312744/2025-0//National Council for Scientific and Technological Development/ ; E-26/200.256/2026//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; E-26/210.624/2025//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; U24NS133077//Allen Institute/ ; 2024/2025 Scholarship for Young Professors and Researchers from Latin American Universities//Coimbra Group/ ; Early-Career Investigator Research Grant (2022/2023)//Tess Research Foundation/ ; },
abstract = {The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT's role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer's disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (~20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = -0.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: -0.307 to -0.349, FDR < 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 transcript in the SEA-AD MTG dataset was detected almost exclusively in astrocyte nuclei, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expanded with advancing AD pathology. Because these are nuclear transcript measurements, they delimit where SLC13A5 mRNA is detectable rather than establishing the cellular site of NaCT protein or activity, which requires in situ validation.},
}

@article {pmid42510934,
year = {2026},
author = {Wang, TS and Tzeng, IS and Chen, YC and Chen, ML},
title = {Herbal Bioactives Targeting Rho GTPases: A Multi-Targeted Strategy for Mitigating Neuroinflammation in Alzheimer's and Parkinson's Diseases.},
journal = {Current issues in molecular biology},
volume = {48},
number = {7},
pages = {},
doi = {10.3390/cimb48070694},
pmid = {42510934},
issn = {1467-3045},
support = {TCRD-TPE-111-28 (1/3) -(3/3)//Taipei Tzu Chi Hospital/ ; },
abstract = {Neuroinflammation plays an essential role in the pathogenesis of several associated brain diseases, including neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS)), and traumatic brain injury (TBI). In these diseases, persistent microglial and astrocyte aggregates, elevated proinflammatory cytokines, and oxidative stress drive neuronal injury and cognitive disability. Rho GTPases, in particular the Rho family members Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division control protein 42 homolog (CDC42), regulate neuroinflammation, cytoskeletal dynamics, immune responses, and the maintenance of BBB integrity. These proteins are involved in many neuropathological diseases due to dysregulation, making them interesting therapeutic targets. Bioactives used in herbal care have attracted interest for their ability to influence neuroinflammation and even their anti-neurodegenerative activity. Studies show that flavonoids, alkaloids, polyphenols, and other botanical compounds alter Rho GTPase activity, which, in turn, leads to decreased inflammation. This review critically summarizes current evidence regarding phytochemical regulation of Rho GTPase signaling in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), with particular emphasis on the underlying molecular mechanisms, context-dependent signaling responses, and current translational challenges. Furthermore, existing knowledge gaps and future research priorities are discussed to facilitate the development of mechanism-based therapeutic strategies targeting Rho GTPases.},
}

@article {pmid42511444,
year = {2026},
author = {Suwansukho, B and Poempul, K and Samee, W and Tadtong, S},
title = {The Synergistic Neuroprotective Effect of Honokiol and Magnolol Against Amyloid-β and MPP[+]-Induced Neurotoxicity in SH-SY5Y Cells: An Antioxidant, Molecular Orbital, and ADMET Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511444},
issn = {1422-0067},
support = {Grant No. 634/2568//Srinakharinwirot University/ ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two main neurodegenerative diseases and cause disability and death in patients worldwide. Neurodegeneration is characterized by a progressive loss of neuronal function and structure, causing enormous impairment in cognitive-motor function. Magnolol and honokiol are isomeric biphenyl neolignans and have exhibited neuroprotective activity in previous studies. Hence, we assessed and compared honokiol, magnolol, and mixtures of honokiol and magnolol in honokiol/magnolol molar ratios of 1:3, 1:1, and 3:1 in terms of their neurotoxicity, using the cell counting kit-8 (CCK-8) assay, and of their neuroprotective effect on intracellular reactive oxygen species (iROS) against amyloid-beta (Aβ)- and 1-methyl-4-phenylpyridinium ion (MPP[+])-induced neurotoxicity in SH-SY5Y cells, using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) assay. The results showed that honokiol (H) and magnolol (M) at 0.1 μM and the mixtures of honokiol and magnolol in H/M ratios of 1:3, 1:1, and 3:1 at 0.0001 μM exhibited a significant neuroprotective effect of reducing iROS in SH-SY5Y cells where neurotoxicity was induced by Aβ- and MPP[+] (p-value with respect to Aβ-treated cells < 0.005 and p-value with respect to MPP[+]-treated cells < 0.0001). Moreover, magnolol and honokiol possess antioxidant properties according to computational molecular analysis with Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) prediction, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and Ferric Reducing Antioxidant Power (FRAP) assays. The mixtures of honokiol and magnolol exerted synergistic neuroprotective ability at all ratios while showing better antioxidation ability than that of pure magnolol alone but comparable to that of pure honokiol alone. Drug-likeness, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction, and toxicity profiles showed that both compounds are promising neuroprotective agents and that one of the possible targeting mechanisms is the ROS-mediated oxidative stress pathway. Additional neuronal cell lines and in vivo models are required to determine similar effects or other protective mechanisms involving the neuroprotective ability of honokiol and magnolol.},
}

@article {pmid42511465,
year = {2026},
author = {Alshamari, AK and Magdy, N and Basiony, EA and Hassan, NA and Alshammari, OAO and Abdel-Rahman, AA and Alsaif, NOS and Alshammari, MZ and Elrashedy, AA and Hassan, AA},
title = {Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511465},
issn = {1422-0067},
support = {RG-23 108//University of Ha'il/ ; },
abstract = {Thienopyrimidine derivatives are emerging as potent scaffolds for cholinesterase inhibition in Alzheimer's disease therapy. In this work, a novel series of substituted thieno[2,3-d]pyrimidines was synthesized via Gewald's reaction, followed by cyclization and functionalization through nucleophilic substitution and hydrazone formation. Structural confirmation was achieved using spectroscopic techniques, and biological evaluation was performed against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with donepezil and rivastigmine as reference drugs. Compound 4 emerged as the most potent and selective AChE inhibitor (IC50 = 0.58 µM), while compound 7 also showed strong AChE inhibition (IC50 = 0.63 µM). Notably, compound 9 exhibited superior BChE inhibition (IC50 = 3.05 µM) compared to donepezil (IC50 = 8.41 µM). Dual inhibitory activity was observed for compounds 5, 6, and 11, highlighting their multitarget potential. Molecular dynamics simulations (200 ns) and MM/GBSA binding free energy calculations provided mechanistic insights. Compound 4 showed the most favorable binding energy (ΔGbind = -59.16 kcal/mol), driven by hydrogen bonds with Tyr121 and Glu199 and π-π stacking with Trp83. Residue-level decomposition identified Tyr121, Trp83, Glu199, and Tyr338 as critical contributors to binding stability. Structure-activity relationship analysis confirmed that nitrogen-containing substituents and cyclic amino moieties enhance potency, whereas bulky aromatic groups reduce activity. These findings establish thieno[2,3-d]pyrimidine derivatives as promising candidates for the development of next-generation anti-Alzheimer agents.},
}

@article {pmid42511496,
year = {2026},
author = {Cha, S and Kim, J and Kim, J and Kim, D and Song, H and Lim, KS and Chae, S},
title = {Spatial Transcriptomics for Dissecting Cellular and Molecular Heterogeneity in the Aging and Diseased Brain.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511496},
issn = {1422-0067},
support = {RS-2024-00441289//National Research Foundation of Korea/ ; RS-2025-00512586//National Research Foundation of Korea/ ; RS-2023-00301850//Ministry of Education/ ; },
abstract = {The brain is a spatially organized tissue where the molecular characteristics of each cell are closely linked to its anatomical location. However, conventional bulk and single-cell RNA sequencing lose this spatial context during the tissue separation process. Spatial transcriptomics (ST) overcomes these limitations by measuring gene expression while preserving the positional information of cells within intact tissues, making it a powerful approach for elucidating the cellular and molecular heterogeneity that defines brain structure and disease. This review summarizes the two main types of ST technology: next-generation sequencing (NGS)-based platforms (Visium, Stereo-Seq, Slide-Seq) and in situ platforms (MERFISH, seqFISH+, Xenium). NGS-based platforms provide unbiased whole-transcriptome profiling across extensive tissue regions, while in situ platforms offer subcellular resolution within individual cells. We aim to assist in platform selection by comparing the principles, advantages, and limitations of each platform. Next, we focus on how spatial sequencing (ST) has been utilized to analyze the spatial heterogeneity of aging and diseased brains, and examine region- and cell-type changes observed in brain aging, the lesion-related microenvironments of Alzheimer's and Parkinson's diseases, and the spatially isolated tumor cell states and immunosuppressive environments of glioblastoma. We also introduce the key brain ST data resources that underpin these studies. Collectively, ST is emerging as an essential tool for understanding the spatial logic of brain function and pathology, demonstrating increasingly greater potential in the field of precision medicine.},
}

@article {pmid42511504,
year = {2026},
author = {Post, WM and Widomska, J and Oosterwijk, E and De Witte, W and Tiemessen, DM and Klemann, CJHM and Ruisch, IH and Coenen, MJH and Janssen, DAW and Martens, F and Carnes, MU and Marks, JA and Page, GP and Richter, HE and Cartwright, R and Minassian, VA and Thomas, LF and Skogholt, AH and Stafne, SN and Hveem, K and Kluivers, KB and Poelmans, G},
title = {Amyloid Precursor Protein Processing Links Female Urgency Urinary Incontinence with Alzheimer's Disease: Implications for Treatment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511504},
issn = {1422-0067},
support = {PROJ00787 (DIABIP)//European Fund for Regional Development (EFRD)/ ; },
abstract = {Urgency urinary incontinence (UUI) and Alzheimer's disease (AD) are highly comorbid conditions in women, but the underlying molecular mechanisms are largely unknown. Therefore, we used network enrichment analyses and an elaborate literature search to integrate the most significant genes from four genome-wide association studies (GWASs) and other genetic, expression and functional evidence into a molecular landscape of female UUI. This molecular landscape centers around local, i.e., bladder-based, processing of the AD-associated amyloid precursor protein (APP). To further elucidate how APP processing is implicated in the comorbidity between UUI and AD, we conducted polygenic risk score (PRS)-based analyses, which showed that genetic risk factors associated with AD and a decreased amyloid beta 42/40 blood level ratio (also) contribute to UUI susceptibility. In conclusion, APP processing constitutes a putative molecular link between UUI and AD, adding further weight to their clinical comorbidity and having implications for the treatment (and prevention) of both traits.},
}