@article {pmid42159446,
year = {2026},
author = {Lee, WJ and Cho, K and Kim, GW},
title = {Integrated amyloid, neurodegeneration, and vascular biomarkers estimate the risk of dementia progression in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261445623},
doi = {10.1177/13872877261445623},
pmid = {42159446},
issn = {1875-8908},
abstract = {BackgroundProgression from mild cognitive impairment (MCI) to dementia arises from heterogeneous mechanisms involving Alzheimer's disease (AD) pathology and vascular factors.ObjectiveThis study aimed to develop a multimodal biomarker model to estimate the risk of dementia progression and to examine whether carotid atherosclerosis provides independent prognostic value, particularly in amyloid-β (Aβ)-negative MCI.MethodsWe retrospectively analyzed 300 individuals with MCI who underwent baseline [[18]F]florbetapir PET, structural MRI, carotid Doppler ultrasound, cognitive assessments, and APOE genotyping (2018-2021). Participants were followed for a total of 37 months to dementia based on longitudinal cognitive and functional decline, independent of follow-up amyloid PET findings. Aβ positivity was defined using Brain Amyloid Plaque Load criteria. Multivariable logistic regression and receiver operating characteristic analyses were performed.ResultsAmong 189 Aβ-positive individuals, 30.7% (n = 58) progressed to Aβ-positive AD dementia, while 9.0% (n = 10) of 111 Aβ-negative individuals developed non-AD dementia. Independent factors estimating Aβ-positive AD dementia included higher Aβ burden (OR 2.34, p < 0.001), smaller hippocampal volume (OR 0.71, p < 0.001), greater carotid plaque count (OR 1.45, p = 0.001), lower Mini-Mental State Examination (OR 1.11, p = 0.002), and APOE ε4 carriage (OR 1.82, p = 0.021). The integrated model showed excellent performance (AUC 0.903; 95% CI: 0.814-0.968). In Aβ-negative MCI, carotid plaque burden was the primary estimator of non-AD dementia progression.ConclusionsThe prominent prognostic role of carotid plaques in Aβ-negative MCI underscores the vascular contributions to non-amyloid cognitive decline and highlights the importance of evaluating both AD-related and vascular mechanisms in prodromal dementia.},
}

@article {pmid42159448,
year = {2026},
author = {Arnhardt, S and Singh, S and Steinebach, K and Fuchs, R and Diener, T and Gasser, D and Kornhuber, J and Freiherr, J},
title = {Color-modulated olfactory testing using RAPPIT: An innovative tool for early detection of cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449410},
doi = {10.1177/13872877261449410},
pmid = {42159448},
issn = {1875-8908},
abstract = {BackgroundOlfactory and visual processing are sensitive biomarkers for cognitive impairment; however, unimodal assessments may fail to capture early deficits in higher order cognitive integration. When sensory cues are mismatched, multisensory processing induces crossmodal conflict that requires inhibitory control, which is particularly vulnerable in early neurodegeneration.ObjectiveWe developed RAPPIT (Rapid, massively APPlicable Identification Test), a color-modulated olfactory test to assess multisensory interference as an early marker of cognitive decline.MethodsRAPPIT includes 16 physically presented odors, with a digital application for task control and response recording. Answer options are displayed on color backgrounds derived from the MONEX-40 color profile, either congruent or incongruent with the presented odors. A total of 163 participants from the German population completed the assessment. Odor identification accuracy, effects of color congruence (ΔE00), associations with cognitive performance (Montreal Cognitive Assessment, MoCA), hedonic ratings, and depressive symptoms were analyzed.ResultsOdor identification declined with age. Participants aged ≥ 60 years, a group at increased risk for neurodegenerative disorders including Alzheimer's disease, showed reduced performance under incongruent conditions. Performance exhibited a non-linear relationship with color difference (ΔE00), declining at mid-range values. Accuracy was significantly associated with MoCA scores. Hedonic ratings varied with color cues, while no associations were found with depressive symptoms.ConclusionsThese findings demonstrate that differences between congruent and incongruent odor-color conditions capture cognitively relevant interference effects beyond unimodal olfactory or visual performance, supporting the utility of this approach for early detection of cognitive impairment in older adults, in clinical and home settings.},
}

@article {pmid42159654,
year = {2026},
author = {Fernández-Lebrero, A and Jiménez-Balado, J and García-Escobar, G and Contador, J and Estraguès-Gázquez, I and Peraferrer-Montesinos, L and Suárez-Pérez, A and Manero-Borràs, RM and Beltrán, B and Gramegna, L and Campello, AR and Palacio-Gili, A and Grau, O and Suárez-Calvet, M and Ois, A and Puig-Pijoan, A and Navalpotro-Gómez, I},
title = {CSF Biomarker Profile of Cerebral Amyloid Angiopathy: Diagnostic Performance and Imaging Correlates in a Hospital-Based Neurology Cohort.},
journal = {European journal of neurology},
volume = {33},
number = {5},
pages = {e70613},
doi = {10.1111/ene.70613},
pmid = {42159654},
issn = {1468-1331},
support = {//Instituto de Salud Carlos III/ ; ERA-CVD_JTC2020-015//European Research Area Network on Cardiovascular Diseases/ ; },
mesh = {Humans ; Male ; Female ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/diagnosis/complications ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/complications/diagnosis ; tau Proteins/cerebrospinal fluid ; *Peptide Fragments/cerebrospinal fluid ; Cohort Studies ; Middle Aged ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer's disease (AD), complicating diagnosis in patients with cognitive impairment. The CSF biomarker profile of CAA remains poorly understood, particularly with AD co-pathology. We aimed to characterize CSF biomarkers in CAA, assess diagnostic accuracy, and examine associations with neuroimaging markers.

METHODS: We included 261 participants from a hospital-based cohort, recruited from memory clinic outpatients and neurology inpatients. Groups comprised healthy controls (HC, n = 35), CAA without AD co-pathology (CAA-nonAD, n = 27), CAA with AD co-pathology (CAA-AD, n = 30), and AD (n = 169). CSF Aβ40, Aβ42, p-tau181, and t-tau were quantified using automated immunoassays. Group differences were tested using ANCOVA adjusted for age and sex. ROC analyses with 10-fold cross-validation and bootstrapping assessed diagnostic performance. Associations between CSF biomarkers and CAA-related MRI markers were examined using ANCOVA.

RESULTS: Aβ40 concentrations were lower in CAA-nonAD and CAA-AD compared to AD and HC (p-valuebf < 0.05). Aβ42 was reduced in CAA-AD and AD versus HC, with no difference between CAA-nonAD and AD. p-tau181 and t-tau were elevated in AD and CAA-AD compared with CAA-nonAD and HC (p-valuebf < 0.05). Aβ40 showed the highest diagnostic accuracy for CAA (AUC = 0.73; 95% CI: 0.66-0.80), followed by Aβ42 (AUC = 0.71; 95% CI: 0.64-0.78). In AD patients, Aβ42 best discriminated coexisting CAA (AUC = 0.77). Higher CAA-SVD burden scores were associated with lower Aβ40 (p-valuebf < 0.05).

CONCLUSIONS: CSF Aβ40 and Aβ42 provide complementary diagnostic value for identifying CAA, both in isolation and with AD co-pathology. Reduced Aβ40 is associated with greater CAA-related vascular burden, supporting its role as a marker of vascular amyloid pathology.},
}

Humans
Male
Female
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/diagnosis/complications
*Amyloid beta-Peptides/cerebrospinal fluid
Aged
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/complications/diagnosis
tau Proteins/cerebrospinal fluid
*Peptide Fragments/cerebrospinal fluid
Cohort Studies
Middle Aged
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid42159858,
year = {2026},
author = {Rong, W and Xu, J and Li, B and Li, Y and Xu, Y},
title = {Single-cell atlas reveals the key role of pro-inflammatory IREB2[+] microglia subsets in the microenvironment of Alzheimer's disease.},
journal = {Clinical and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10238-026-02188-2},
pmid = {42159858},
issn = {1591-9528},
support = {U1904207//National Natural Science Foundation of China/ ; 2017YFA0105003//National Key Research and Development Program of China/ ; },
abstract = {Chronic neuroinflammation driven by activated microglia is a critical hallmark of Alzheimer's disease (AD) progression. Metabolic dysregulation, particularly iron metabolism, has been implicated in neurodegeneration, yet the role of iron-responsive element-binding protein 2 (IREB2) in AD-associated neuroinflammation remains poorly understood. We performed integrative analysis of single-cell RNA sequencing (scRNA-seq) data from AD brain tissues, using non-negative matrix factorization (NMF) and intercellular communication algorithms to map cellular landscapes. We identified microglial subpopulations and their inflammatory signaling. To experimentally validate the functional role of IREB2 in inflammatory responses, we conducted siRNA-mediated knockdown in the human neuroblastoma cell line SH-SY5Y, which serves as a neuronal model for assessing IREB2's effect on cytokine expression. Single-cell analysis revealed a distinct microglial subpopulation (IREB2[+] MC C1) that is significantly expanded in AD. This subpopulation exhibits a hyper-inflammatory state, with enrichment of Toll-like receptor and IL-17 signaling pathways, and functions as a primary source of outgoing inflammatory signals (CCL3, CCL4). Furthermore, IREB2 knockdown in SH-SY5Y cells significantly suppressed the expression of key pro-inflammatory cytokines (IL6, IL-1β, and TNF-α), confirming that IREB2 positively regulates inflammation in neurons as well. IREB2 drives both microglial activation and neuronal inflammatory responses in AD, potentially via the NF-κB pathway. The IREB2[+] microglial subpopulation represents a specific pathogenic entity that orchestrates the inflammatory microenvironment. Targeting IREB2 may therefore offer a dual-pronged therapeutic strategy to mitigate neuroinflammation and slow AD progression.},
}

@article {pmid42159968,
year = {2026},
author = {Ollen-Bittle, N and Boesgaard, I and Roseborough, A and Frank, M and Zhang, Q and Pasternak, SH and Hammond, R and Whitehead, SN},
title = {Wasteosomes accumulate in periventricular white matter hyperintensities and exhibit complex relationships with mixed pathology, sclerotic index, and perivascular space.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70110},
doi = {10.1111/bpa.70110},
pmid = {42159968},
issn = {1750-3639},
support = {202104PJT-461038/CAPMC/CIHR/Canada ; RGPIN-2019-04742//Natural Sciences and Engineering Research Council of Canada/ ; //Kappa Kappa Gamma (KKG) Foundation of Canada/ ; },
abstract = {Corpora amylacea or "wasteosomes" are discontinuous lipid labyrinth structures that are polyglucosan rich, retain cellular waste and are thought to be of astrocytic origin. Wasteosomes localize around periventricular (PV) regions, perivascular spaces (PVS), and sub-pial regions; and their accumulation has been found to correlate with aging, vascular disorders, neurodegenerative diseases, and conditions that impair sleep. White matter hyperintensities (WMHs) are diffuse hyperintense areas seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans that represent damage to white matter. PV WMHs are known predictors of mild cognitive impairment, stroke, dementia and death. The relationship between wasteosome accumulation, PV WMHs, vascular pathology and PVS is currently unknown. For the first time, in a mixed diagnostic cohort of pathologically diagnosed: Alzheimer's disease (AD), cerebrovascular disease (CVD), mixed AD/CVD, and control tissue with no pathological diagnosis, we connected the histopathological wasteosome profile in periventricular brain sections in relation to 7T FLAIR-MRI confirmed PV WMHs, vascular sclerosis and PVS. Our results reveal wasteosomes accumulate in PV WMHs, are increased in proximity to large PV venules, and exhibit complex relationships with WMH severity, mixed pathology, sclerotic index and PVS. These findings provide novel insights into the pathophysiology underlying white matter injury.},
}

@article {pmid42160069,
year = {2026},
author = {Angus, DC and O'Connor, MB},
title = {A New Era in Dementia-Advances in Diagnostic Blood Tests, Novel Drugs, and the Power of Lifestyle Changes: A Healthy Dialogue With Gil Rabinovici.},
journal = {JAMA},
volume = {},
number = {},
pages = {e267539},
doi = {10.1001/jama.2026.7539},
pmid = {42160069},
issn = {1538-3598},
}

@article {pmid42160117,
year = {2026},
author = {Chen, H and Wang, T and Xia, K and Li, X and Yao, X and Huang, W},
title = {Emerging Nanoreactors for Precision Disease Treatment: From Principles to Biomedical Applications.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e73859},
doi = {10.1002/smll.73859},
pmid = {42160117},
issn = {1613-6829},
support = {BK20251864//Basic Research Program of Jiangsu/ ; 62288102//Natural Science Foundation of China/ ; //Disciplinary Fund of the School of Pharmaceutical Sciences/ ; 20250285//Nanjing Tech University Teaching Reform Project/ ; },
abstract = {Inspired by natural cellular compartments, nanoreactors are spatially confined nanostructures that precisely regulate chemical and biological reactions and act as high-performance catalytic nanocontainers. Multifunctional integration of these systems surmounts the inherent limitations of conventional therapeutic modalities. This review focuses on recent breakthroughs in organic and organic-inorganic hybrid nanoreactors, highlighting three core effects: (1) the spatial confinement effect, which elevates the reactant concentration, accelerates mass transfer, lowers activation energy, modulates electronic states, and boosts reaction rates by orders of magnitude; (2) the synergistic effect of active sites, which enables efficient cascade reactions via spatially segregated or hierarchical catalytic architectures; (3) the stimuli-responsive effect, which dynamically controls catalysis and cargo release under endogenous (pH, enzymes, ROS) or exogenous (light, temperature) cues. Typical nanoreactors (liposomes, polymeric micelles/vesicles, mesoporous silica, protein cages, and organic-inorganic hybrids) are systematically discussed regarding structural merits and biomedical applications in treating diabetes, rheumatoid arthritis (RA), chronic wound healing, cancer, and Alzheimer's disease (AD). Current challenges and future perspectives are also addressed. Intelligent nanoreactors are expected to offer immense potential for disease diagnosis and therapy.},
}

@article {pmid42160281,
year = {2026},
author = {, },
title = {Editorial Note: Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer's Disease with Plaques and Tangles.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349725},
doi = {10.1371/journal.pone.0349725},
pmid = {42160281},
issn = {1932-6203},
}

@article {pmid42160315,
year = {2026},
author = {Siegel, K and Cabán, M and Tran, E and Meng, A and Wetmore, JB and Ottman, R},
title = {Memory and thinking problems that aging Latinos in New York City would bring to a doctor's attention.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349635},
doi = {10.1371/journal.pone.0349635},
pmid = {42160315},
issn = {1932-6203},
mesh = {Humans ; *Hispanic or Latino/psychology ; New York City ; Middle Aged ; Female ; Male ; Adult ; *Memory Disorders/psychology/diagnosis ; *Aging/psychology ; *Thinking ; *Alzheimer Disease/diagnosis/psychology ; *Memory ; *Patient Acceptance of Health Care ; White ; },
abstract = {The number of individuals with Alzheimer's disease will grow dramatically in the coming decades. Early diagnosis benefits patients, caregivers and society, but depends heavily on afflicted individuals or their family members recognizing early symptoms as possible indications of a medical problem and seeking medical care. To examine the kinds of memory or thinking problems, Latinos ages 40-64 would seek medical care for, we analyzed data from 161 participants in a community-based study in northern Manhattan of the impact of receiving information about one's risk of developing late-onset Alzheimer's disease. Participants were asked whether experiencing each of 5 different memory or thinking problems multiple times over 2-3 months would make them seek medical care. Participants often offer a benign or normalizing attributions for symptoms. Disorientation was the most frequently endorsed problem. Considerations found to be associated with an inclination or disinclination to want to see a doctor about a symptom were identified. A better understanding of what Latinos would consider in deciding whether or not to bring different memory problems to a doctor's attention can help guide the development of educational interventions to encourage help-seeking and facilitate earlier diagnosis.},
}

Humans
*Hispanic or Latino/psychology
New York City
Middle Aged
Female
Male
Adult
*Memory Disorders/psychology/diagnosis
*Aging/psychology
*Thinking
*Alzheimer Disease/diagnosis/psychology
*Memory
*Patient Acceptance of Health Care
White

@article {pmid42160451,
year = {2026},
author = {Schwartz, M and Croese, T},
title = {Treating the immune system to repair the brain.},
journal = {Science translational medicine},
volume = {18},
number = {850},
pages = {eaeb1677},
doi = {10.1126/scitranslmed.aeb1677},
pmid = {42160451},
issn = {1946-6242},
mesh = {Humans ; *Brain/immunology/pathology ; *Immune System ; Alzheimer Disease/immunology/therapy ; Animals ; Neurodegenerative Diseases/therapy/immunology ; },
abstract = {Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.},
}

Humans
*Brain/immunology/pathology
*Immune System
Alzheimer Disease/immunology/therapy
Animals
Neurodegenerative Diseases/therapy/immunology

@article {pmid42160739,
year = {2026},
author = {Das, S and Rao Padubidri, S and K V, S and Shetty, KS and Jena, R and K R, H and Dehury, B and Pandurangan, AP},
title = {From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {3},
pages = {},
doi = {10.1093/bib/bbag231},
pmid = {42160739},
issn = {1477-4054},
mesh = {*Amyloid Precursor Protein Secretases/chemistry/metabolism/antagonists & inhibitors ; Humans ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Artificial Intelligence ; Drug Discovery ; *Computational Biology/methods ; *Drug Design ; },
abstract = {Advancements in computational biology are transforming the study of complex membrane proteins and their therapeutic targeting. The γ-secretase complex, a quintessential intramembrane protease implicated in Alzheimer's disease (AD) and more than 150 other substrates, provides a powerful exemplar to illustrate this transformative shift. Traditional γ-secretase inhibitors have been constrained by off-target toxicity, particularly through disruption of Notch signaling, underscoring the need for deeper mechanistic insights, now increasingly enabled by modern computational methodologies. We evaluate the computational strategies driving next-generation drug discovery of γ-secretase. Integrative modeling frameworks, informed by cryo-electron microscopy (cryo-EM) and biophysical data, have facilitated atomic-resolution reconstructions of γ-secretase dynamics and substrate recognition. All-atom molecular dynamics (MD) simulations, supported by enhanced sampling techniques such as umbrella sampling, steered MD, replica exchange, and Gaussian accelerated MD, have mapped conformational landscapes and elucidated molecular determinants of substrate selectivity. Structure-function mapping of familial AD mutations further demonstrates how computational modeling translates genetic variation into mechanistic understanding. Beyond structural modeling, the integration of artificial intelligence (AI) including deep generative models, machine learning-based activity prediction, and high-throughput virtual screening has created accelerated pipelines for discovering modulators predicted to reduce pathogenic amyloid beta (Aβ) production while preserving essential signaling pathways. These approaches demonstrate how computational methods increasingly serve as predictive and design-oriented engines in drug development. Using γ-secretase, this review highlights how state-of-the-art computational techniques, from integrative structural biology to AI-driven drug design, are reshaping the discovery of safer, more selective modulators with broader relevance across diseases requiring precise modulation of protein function.},
}

*Amyloid Precursor Protein Secretases/chemistry/metabolism/antagonists & inhibitors
Humans
Molecular Dynamics Simulation
*Alzheimer Disease/drug therapy/metabolism/genetics
*Artificial Intelligence
Drug Discovery
*Computational Biology/methods
*Drug Design

@article {pmid42160848,
year = {2026},
author = {Zheng, M and Yang, M and Su, W and Tian, L and Gao, W},
title = {Targeting microglia: A new strategy for the treatment of Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {418},
number = {},
pages = {578966},
doi = {10.1016/j.jneuroim.2026.578966},
pmid = {42160848},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.},
}

@article {pmid42160907,
year = {2026},
author = {Naomi, R and Al-Amin, M and Smykla, J and Rizman-Idid, M and Chong, TT and Murthy, JK and Zubairi, SI and David, P and Satriawan, H and Bakar, NA and Alias, SA},
title = {Network pharmacology and molecular docking of arctic Pseudogymnoascus australis compounds targeting ionotropic glutamate receptors for neuroprotection.},
journal = {Computational biology and chemistry},
volume = {124},
number = {Pt 1},
pages = {109126},
doi = {10.1016/j.compbiolchem.2026.109126},
pmid = {42160907},
issn = {1476-928X},
abstract = {Neurodegenerative diseases constitute a major public health burden, with neurotoxicity representing a critical pathogenic mechanism underlying Alzheimer's disease and Parkinson's disease. Current therapeutic approaches are primarily symptomatic and fail to prevent disease progression, highlighting the urgent need for neuroprotective agents that can modulate pathological pathways at their source. Natural fungal metabolites have emerged as promising sources of bioactive compounds with potential neuroprotective properties. This study investigates the neuroprotective potential of bioactive compounds derived from the Arctic fungus Pseudogymnoascus australis (P. australis) using an integrated in silico method. From 120 identified compounds, nine were selected based on favorable blood-brain barrier (BBB) permeability and pharmacokinetic profiles using ADMET 3.0 predictions. These included 2-aminohexadecanoic acid (AHA), 11-aminoundecanoic acid (AUA), and seven others, all exhibiting optimal drug-likeness (>0.83) and suitable CNS-targeting properties. Network pharmacology analysis identified 226 overlapping targets between the fungal compounds and neurotoxicity-associated genes. Nine hub genes (Gria1, Gria2, Gria4, Grik1, Grik2, Grin1, Grin2a, Grin2b, and Grin2c) were identified as critical nodes. Enrichment analyses revealed significant involvement in the neuroactive ligand-receptor interaction pathway, suggesting these compounds modulate ionotropic glutamate receptors. Molecular docking analysis showed strong binding affinities, with 78% of ligand-receptor complexes displaying RMSD values below 2.0 Å. AHA and Grik1 emerged as the most promising pair, with a docking score of -7.90 kcal/mol and excellent pharmacokinetic properties (drug-likeness: 0.462, BBB penetration: 0.985). Molecular dynamics simulations over 100 nanoseconds confirmed complex stability, with a mean RMSD of 2.45 Å and binding energies averaging -169.02 kcal/mol, demonstrating sustained ligand-protein interactions. These computational findings provide evidence that P. australis contains bioactive compounds capable of attenuating neurotoxicity through sustained modulation of glutamate receptors, with molecular dynamics validation supporting the thermodynamic stability and potential therapeutic relevance of these interactions.},
}

@article {pmid42160956,
year = {2026},
author = {Yan, Y and Hu, D and Kong, L and Li, K and Su, J and Wu, Y and Zhan, H and Zhang, H and Sun, Y and Dou, X and Huang, P and Zhou, J},
title = {Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100600},
doi = {10.1016/j.tjpad.2026.100600},
pmid = {42160956},
issn = {2426-0266},
abstract = {BACKGROUND: Anti-amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.

METHOD: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.

RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.

CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.},
}

@article {pmid42160959,
year = {2026},
author = {Wang, H and Long, Y and Tang, Y and Duan, L and Wang, Z and Zhang, S and Yin, Y and Zhou, J and Wu, W and Zhong, C},
title = {Identification of a CD44-dependent control of astrocytic autophagic activity in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100601},
doi = {10.1016/j.tjpad.2026.100601},
pmid = {42160959},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Despite extensive research, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. This study sought to identify robust molecular targets and cellular basis underlying AD progression.

METHODS: We performed a systematic analysis of cross-regional transcriptomic datasets from AD patients, integrating differential expression analysis across 14 Gene Expression Omnibus (GEO) datasets with cross-regional intersection mapping. Single-nucleus RNA sequencing (snRNA-seq) was employed to resolve cell-type-specific expression patterns. Furthermore, cellular communication analysis and functional enrichment of astrocyte-specific genes were conducted. The biological role of the identified candidate was validated in vitro using Aβ42 oligomer-treated primary astrocytes via siRNA-mediated knockdown and plasmid-driven overexpression, with autophagic activity assessed through LC3-II and p62 expression.

RESULTS: The transmembrane glycoprotein receptor CD44 was identified as consistently upregulated across AD-vulnerable brain regions, including the temporal cortex, frontal cortex, entorhinal cortex, and hippocampus. snRNA-seq analysis identified this upregulation primarily to astrocytes. Intercellular signaling analysis indicated that the CD44-SPP1 axis enhanced astrocyte-glial crosstalk. Functional enrichment analysis linked astrocytic CD44 to the modulation of autophagy pathways. In vitro experiments demonstrated that CD44 knockdown promoted autophagic activation (increased LC3-II and decreased p62), whereas CD44 overexpression suppressed autophagic activity.

CONCLUSION: Our findings establish CD44 as a pivotal regulator of astrocytic autophagy in AD, highlighting its potential as a novel therapeutic target.},
}

@article {pmid42161162,
year = {2026},
author = {, and Caligiore, D},
title = {Response to the Letter Regarding "Explainable machine learning on clinical features to predict and differentiate Alzheimer's progression by sex: Toward a clinician-tailored web interface".},
journal = {Journal of the neurological sciences},
volume = {487},
number = {},
pages = {126005},
doi = {10.1016/j.jns.2026.126005},
pmid = {42161162},
issn = {1878-5883},
}

@article {pmid42161225,
year = {2026},
author = {McNamara, O and Delany, T and Kwakowsky, A},
title = {Bumetanide as a potential treatment for neurodegenerative and neurodevelopmental disorders: A systematic review.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119533},
doi = {10.1016/j.biopha.2026.119533},
pmid = {42161225},
issn = {1950-6007},
abstract = {Neurological disorders represent a major global health burden, affecting an estimated 3.4 billion individuals worldwide. Bumetanide, a clinically approved loop-diuretic and antagonist of the Na[+] -K[+]-Cl[-] cotransporter NKCC1, has recently emerged as a candidate for repurposing in the treatment of neurological disorders. Disrupted excitation-inhibition balance, driven in part by depolarizing GABAA receptor signaling resulting from altered chloride homeostasis, has been implicated across multiple neurodegenerative and neurodevelopmental conditions. This systematic literature review evaluated preclinical and clinical evidence for the efficacy of bumetanide across a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, autism spectrum disorder, schizophrenia, tuberous sclerosis, fragile X syndrome, Down syndrome, and Angelman syndrome. Across in vivo and ex vivo models, bumetanide frequently restored hyperpolarizing GABAergic activity and attenuated behavioral and cognitive abnormalities, although translational relevance is constrained by limited central nervous system penetration following systemic administration. Clinical evidence mainly comes from autism spectrum disorder, where some studies have reported modest improvements in behavioral outcomes and measurable neurophysiological changes, although findings remain inconsistent. Collectively, these findings suggest that NKCC1 inhibition represents a mechanistically relevant but clinically unproven therapeutic strategy. Further research is required to clarify the cellular mechanisms underlying bumetanide responsiveness, optimize delivery to the central nervous system, and identify biomarkers to stratify patients most likely to respond to treatment.},
}

@article {pmid42161327,
year = {2026},
author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A},
title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag178},
pmid = {42161327},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.},
}

@article {pmid42161537,
year = {2026},
author = {Fernández-Romero, L and Díez-Cirarda, M and Delgado-Alonso, C and Cabrera-Martin, MN and González-Rosa, JJ and Sanz-Nieto, C and Pérez-Macías, N and Balugo, P and Gómez-Ruiz, N and Matias-Guiu, J and Portolés-Pérez, A and Matias-Guiu, JA},
title = {Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS).},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e112999},
doi = {10.1136/bmjopen-2025-112999},
pmid = {42161537},
issn = {2044-6055},
mesh = {Humans ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; *Aphasia, Primary Progressive/therapy ; Female ; Aged ; *Language Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Middle Aged ; },
abstract = {INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer's disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

METHODS AND ANALYSIS: The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke's Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

ETHICS AND DISSEMINATION: The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

TRIAL REGISTRATION NUMBER: NCT07158216.},
}

Humans
Double-Blind Method
*Transcranial Direct Current Stimulation/methods
*Transcranial Magnetic Stimulation/methods
*Aphasia, Primary Progressive/therapy
Female
Aged
*Language Therapy/methods
Male
Randomized Controlled Trials as Topic
Treatment Outcome
Middle Aged

@article {pmid42161560,
year = {2026},
author = {Wang, Y and Shi, J and Zhao, L and Kan, B},
title = {LncRNA OIP5-AS1 Is Involved in Alzheimer's Disease by Targeting miR-7-5p to Regulate Microglial Inflammation, Polarization, and Oxidative Stress.},
journal = {The Tohoku journal of experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1620/tjem.2025.J173},
pmid = {42161560},
issn = {1349-3329},
}

@article {pmid42161712,
year = {2026},
author = {Burke, E and Gunstad, J and Bond, D and Carroll, I and Crosby, R and Mitchell, JE and Heinberg, LJ and Steffen, K},
title = {Early changes in cognitive function following bariatric surgery: evidence for rapid improvement or practice effects?.},
journal = {Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.soard.2026.04.013},
pmid = {42161712},
issn = {1878-7533},
abstract = {BACKGROUND: Metabolic bariatric surgery (MBS) is associated with postoperative improvement in neuropsychological test performance and recent work raises the possibility that these gains may emerge within weeks of surgery. However, repeat testing across brief postoperative intervals introduces the possibility of measurement error that artificially increases test scores and distorts understanding of postoperative changes.

OBJECTIVE: Examine cognitive function prior to and 1-month following bariatric surgery.

SETTING: University Hospital.

METHODS: A total of 111 MBS participants completed the NIH Toolbox for the Assessment of Neurological and Behavioral Function test battery before and 1-month after MBS as part of a larger project.

RESULTS: Repeated measures analysis of covariance revealed improved cognitive test scores following both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), though reliability change metrics could not rule out contribution from practice effects. Receiver operating characteristic analyses revealed that lower preoperative body mass index (BMI) was associated with greater likelihood of true cognitive improvement post-MBS on the Pattern Comparison subtest of the NIH Toolbox (area under the curve = .65, 95% confidence interval .53-.76).

CONCLUSIONS: Though both RYGB and SG patients exhibited improved cognitive function 1-month postoperatively, the current results suggest these early gains should be interpreted cautiously as they may reflect more than just neurobiological factors. Preoperative BMI may predict cognitive trajectory post-MBS, though future research is needed to refine cognitive testing procedures with the goals of clarifying the timeline of neurological changes postoperatively and whether MBS may reduce risk of Alzheimer disease and other risk factors for cognitive decline.},
}

@article {pmid42161904,
year = {2026},
author = {Yang, Y and Jia, L and Xu, J and Wu, J and Huang, H and Yang, H and Qi, Z and Wang, Y and Yu, H and Wang, S},
title = {FBXW7α regulates amyloid pathology by mediating ubiquitination and degradation of BACE1 in Alzheimer's disease.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03159-y},
pmid = {42161904},
issn = {2058-7716},
support = {82201347//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {The dysregulation of proteostasis is a hallmark of Alzheimer's disease (AD), characterized by the accumulation of misfolded and aggregated proteins. Dysfunction of the ubiquitin-proteasome pathway is a major contributing factor to proteostasis imbalance. The E3 ubiquitin ligase, F-box and WD repeat domain-containing 7 (FBXW7), a key hub factor in AD, is significantly downregulated in AD patients. FBXW7 mediates the proteasomal degradation of tau and regulates the development of tau pathology. However, the effect of FBXW7 on β-amyloid pathology and the underlying mechanisms remain unclear. This study demonstrated that FBXW7α, the dominant FBXW7 isoform, was localized in both the cytoplasm and nucleus of neurons. Aging led to a decline in FBXW7α protein levels in the brain tissues of both wild-type and 5×FAD mice. Notably, the level of FBXW7 in the brain tissue of 5×FAD mice is significantly lower than that in wild-type mice after 6 months of age. FBXW7α interacted with BACE1 via the conserved phosphodegron motif and targeted BACE1 for degradation. FBXW7 knockdown diminished the ubiquitination of BACE1, impaired its proteasome-mediated degradation, and increased the accumulation of BACE1 in Golgi fractions. Additionally, restoration of FBXW7α in the hippocampus improved cognitive function and ameliorated amyloid pathology in 5×FAD mice. Our findings suggest that FBXW7α acts as a key regulator of amyloid pathology, and highlight FBXW7α as a promising potential therapeutic target for AD intervention.},
}

@article {pmid42161924,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Stage-dependent reorganization of amyloid PET region-symptom bipartite networks in drug-naïve, amyloid-positive Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04064-9},
pmid = {42161924},
issn = {2158-3188},
abstract = {Management of neuropsychiatric symptoms (NPS) is pivotal to care in Alzheimer's disease (AD), yet their alignment with amyloid topology may vary by stage. We examined whether the community (modular) structure of a brain-region-symptom co-occurrence network differs by clinical stage, testing the hypothesis that modular organization is more pronounced in earlier AD and becomes less segregated with increasing severity. In a cross-sectional retrospective cohort from a tertiary dementia clinic, we included 301 consecutive, drug-naïve patients with probable AD and amyloid-positive PET ([18]F-FC119S). Patients were stratified by Clinical Dementia Rating (CDR 0.5, n = 38; CDR 1.0, n = 107; CDR 2.0, n = 156). We built bipartite networks linking six cortical regions (bilateral frontal, temporal, parietal; PET positivity from automated SUVRs) to 12 Korean Neuropsychiatric Inventory (K-NPI) domains (presence = frequency × severity ≥ 1). Network density, community structure (Louvain modularity with 2000 within-symptom permutations), node strength/centralities, and stage-matched backbones were assessed. The pooled network was dense and non-modular. Stage-stratified analyses revealed significant modularity at CDR 0.5 only, with increasing density from CDR 0.5 to 2.0 and loss of community structure thereafter. Left temporal and left frontal cortices emerged as consistent regional hubs, while parietal contributions were minimal. On the symptom side, aggression and delusion carried the largest co-occurrence burdens, followed by disinhibition and anxiety; findings were robust across backbone and sensitivity analyses. These results support a stage-dependent reorganization from modest, symptom-specific modularity in early stage AD to diffuse, hub-centric coupling in later stages. Recognizing this transition may reconcile prior inconsistencies and inform clinical strategy: targeted, domain-focused interventions when modularity persists versus global stabilization as networks densify, with implications for enrichment and endpoint selection in NPS-focused trials.},
}

@article {pmid42161925,
year = {2026},
author = {Kim, DY and Kim, SM and Lee, C and Han, IO},
title = {O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08862-3},
pmid = {42161925},
issn = {2041-4889},
support = {RS-2024-00346770//National Research Foundation of Korea (NRF)/ ; },
abstract = {Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.},
}

@article {pmid42161970,
year = {2026},
author = {Seo, H and Terstege, DJ and Ren, Y and Liu, S and Goring, KR and Ahn, BY and Epp, JR},
title = {Dual platform spatial transcriptomics reveals parvalbumin interneuron subtype vulnerability in mouse models of Alzheimer's disease.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-73474-6},
pmid = {42161970},
issn = {2041-1723},
support = {190215//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Among the earliest regions affected is the retrosplenial cortex (RSC), where parvalbumin-expressing (PV +) interneurons are particularly susceptible to AD-related pathology. To understand the molecular alterations within these vulnerable neurons we employed a dual-platform spatial transcriptomics approach, integrating GeoMx Digital Spatial Profiler (DSP) and Xenium In Situ. We analyzed the transcriptomic profiles of PV+ and NeuN+ neurons in the RSC of female 5xFAD mice. We leveraged the individual strengths of each platform to generate a robust and comprehensive dataset. Using non-negative matrix factorization and k-means clustering, we identified disease-associated metagenes and examined their spatial distribution. Our analysis revealed distinct transcriptional subpopulations within PV+ interneurons, with specific metagenes differentially expressed in RSC. Dner, Gad1, and Pvalb exhibited significant down-regulation in TG mice, suggesting impairments in PV+ interneuron function and GABAergic signalling. Cross-validation between GeoMx DSP and Xenium In Situ as well as RNAscope and immunohistochemistry confirmed the reproducibility and robustness of these findings. This study provides insights into the heterogeneity and molecular vulnerabilities of PV+ interneurons in AD and demonstrates the power of integrating spatial transcriptomic platforms to uncover disease-associated neuronal subtypes and molecular markers.},
}

@article {pmid42162073,
year = {2026},
author = {Zamani, NISM and Hamezah, HS and Mediani, A and Ghazali, M and Sadikan, MZ and Jam, FA},
title = {Selective elimination of amyloid-β-induced senescent neuroblastoma cells by Moringa oleifera leaf extract.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-53311-y},
pmid = {42162073},
issn = {2045-2322},
support = {Fundamental Research Grant Scheme (FRGS/1/2024/SKK10/MUCM/02/1)//Ministry of Higher Education, Malaysia/ ; (MUCM-MRB/001/2024)//MUCM-MRB joint seed grant/ ; },
abstract = {Accumulation of senescent cells (SnCs) in the ageing brain contributes to Alzheimer's disease (AD) progression by secreting a senescence-associated secretory phenotype (SASP) that exacerbates neuroinflammation and neurodegeneration. Senolytic agents that selectively eliminate SnCs have emerged as a potential therapeutic strategy; however, safer natural alternatives remain underexplored. In this study, we aimed to investigate the senolytic potential of Moringa oleifera leaf extract (MOL) in an in vitro AD-senescence model using SH-SY5Y cells exposed to amyloid-β (Aβ1-42) oligomers. SH-SY5Y cells exposed to 20 µM Aβ oligomers exhibited a senescent phenotype, characterised by increased senescence-associated β-galactosidase (SA-β-gal) positivity and upregulated nuclear expression of p21, p16, and γH2AX. Treatment with 300 µg/mL MOL significantly reduced the number of cells expressing senescence-associated molecular markers and induced apoptosis in SnCs, while attenuating the secretion of pro-inflammatory SASP cytokines, including IL-8 and TNF-α. Overall findings suggest that MOL extract preferentially targets SnCs and mitigates SASP-associated inflammation. These results support the potential of MOL as a natural compound with senolytic activity and provide a foundation for further development into its therapeutic relevance in AD.},
}

@article {pmid42162258,
year = {2026},
author = {Otero, M and Carriel-Rubilar, FI and Hernandez, H and Cuadros, J and Condado, JG and Sainz-Ballesteros, A and Santamaria-Garcia, H and Legaz, A and Birba, A and Fittipaldi, S and Lopera, F and Ochoa-Gómez, J and Aguillon, D and González-Hernández, A and Bonilla-Santos, J and Gonzalez-Montealegre, RA and Yener, GG and Güntekin, B and Kıyı, İ and Aktürk, T and Yıldırım, E and Hanoğlu, L and Anghinah, R and Valdes-Sosa, PA and Garcia-Reyes, R and Escudero, J and Lopez, S and Whelan, R and Fernández, A and García, AM and Huepe, D and Soto-Añari, M and Herrera, E and Abasolo, D and Rubido, N and Clark, RA and El-Deredy, W and Cortes, JM and Parra, MA and Babiloni, C and Ibanez, A and Prado, P},
title = {Source-space EEG alpha activity reveals brain age gaps due to neurodegeneration and disparity.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10205-z},
pmid = {42162258},
issn = {2399-3642},
abstract = {Brain clocks are promising tools for evaluating brain health. However, most current methods rely on structural neuroimaging. Functionally based approaches remain scarce, especially for assessing age-related neurodegenerative diseases. This study examines whether the brain age gap (BAG), the difference between chronological and predicted brain age, reflects neurodegeneration when estimated from electroencephalographic resting-state (rsEEG) α-oscillations, a well-established marker of brain functional aging. It also explores whether α-based brain clocks reflect sociodemographic diversity and structural inequality. The BAG was computed using spectral descriptors of α-activity in the rsEEG source space of 1228 healthy participants, individuals with mild cognitive impairment (MCI), and patients with Alzheimer's disease or behavioral variant frontotemporal dementia, residing in 10 countries with varying levels of structural inequality. BAGs are increased in MCI and dementia groups, particularly in posterior cortical regions. Structural inequality emerges as the strongest predictor of BAG, surpassing cognition, education, and sex. The findings indicate that an α-oscillation-based brain clock provides a sensitive functional marker of brain aging, capable of capturing neurodegenerative processes as well as the impact of social disparities. This scalable, accessible approach to brain health shows promise for translational use and population-wide screening in underserved, resource-limited settings.},
}

@article {pmid42162264,
year = {2026},
author = {Renugadevi, K and Jayasankar, T},
title = {Retraction Note: Fusion of transfer learning models for detection of alzheimer's disease using bidirectional long short-term memory with equilibrium optimization algorithm.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41598-026-53577-2},
pmid = {42162264},
issn = {2045-2322},
}

@article {pmid42162276,
year = {2026},
author = {Liu, W and Wu, SA and Zhang, BX and Guo, SH and Li, L and Sun, W and Xiong, X and Nan, J and Wu, J and Zeng, L and Li, P and Cai, ZY and Ye, HF and Zhang, S and Nie, S and Li, B and Wu, D and Cheng, P and Qi, X and Fang, D and Chen, W and Zhang, Y and Chen, Q and Yang, ZH and Han, J and Mo, W},
title = {Tau aggregates cause reactivation of transposable DNA elements, leading to Z-RNA-ZBP1-mediated neuronal death.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42162276},
issn = {1546-1726},
abstract = {Once tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimer's disease being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting the neurotoxicity of tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in tau-related neurodegeneration (PS19 mouse model). Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from heterochromatin protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in individuals with Alzheimer's disease was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged (24-month-old) tau-transgenic mice, highlighting the therapeutic potential of ZBP1 inhibition to combat neurodegeneration in tauopathies.},
}

@article {pmid42162350,
year = {2026},
author = {Jansson, D and O'Boyle, R and Pedersen, TJ and Gino, E and Sevao, M and Vered, R and Suchland, KL and Zhou, B and Fame, R and Keil, SA and Braun, M and Iliff, J},
title = {Diurnal choroid plexus function in mice depends on sex, age, and amyloid-β status.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10335-4},
pmid = {42162350},
issn = {2399-3642},
support = {P30 AG066509/AG/NIA NIH HHS/United States ; },
abstract = {The adult choroid plexus (ChP) produces the majority of cerebrospinal fluid (CSF), yet little is known about the biological and physiological factors that regulate the ChP under healthy conditions. CSF physiology is regulated by sleep and/or time of day and alters with age and in Alzheimer's disease (AD), where sleep and circadian disruption often co-occur. We compare the transcriptome from mouse ChP in three conditions (young, aged, aged with amyloid β (Aβ) pathology) collected at day and night. In young mice, diurnal ChP gene expression changes are reflected in ontology pathways for protein stability and cell metabolism. In aged mice, these pathways shift to membrane transport and ion homeostasis, with diurnal regulation lost with Aβ pathology. ChP protein expression of ion co-transporter NKCC1 varies across diurnal timepoints with both age and sex and accompanies changes in CSF [K[+]]. Together, our work suggests an interplay between diurnal regulation of membrane transport in the ChP and CSF ion composition may shed light on the role of CSF dynamics in brain function and age-related pathological processes.},
}

@article {pmid42162446,
year = {2026},
author = {Megens, VR and Strandhagen, PW and Berntsen, EM and Müller, EG and Van Laere, K and Eikenes, L and Haberg, AK and , },
title = {The clinical Alzheimer's disease spectrum classified in the A/T/N framework with [18]F-Flutemetamol-Centiloid, [18]F-MK-6240-CenTauR, and [18]F-FDG-AD metaROI: a multicenter memory clinic observational study.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42162446},
issn = {1619-7089},
abstract = {PURPOSE: This study pioneers the ability of semi-quantitative A/T/N classification using combined [18]F-Flutemetamol (A), [18]F-MK-6240 (T) and [18]F-FDG (N) positron emission tomography (PET) tracers with binary classifications and standardised scales for Centiloid (A), CenTauR (T), and AD metaROI (N), to clinically describe subjects with Mild Cognitive Impairment (MCI) or Mild Dementia (MD) in Alzheimer's disease (AD).

METHODS: MCI (n = 45, mean age 71.0 ± 8.8, 40% female, MMSE 26.2) and MD (n = 44, mean age 70.1 ± 7.6, 48% female, MMSE 24.1) participants underwent PET with [18]F-Flutemetamol for amyloid-β, [18]F-MK-6240 tau and/or [18]F-FDG for neurodegeneration. Images were semi-quantified using Centiloid, CenTauR, and AD metaROI. Predefined cut-offs classified scans as positive (+) or negative (-), and standard uptake value ratio (SUVR) values semi-quantified A-burden, T-burden, and N-burden.

RESULTS: T+ was more frequent in MD (68%) than in MCI (44%). Among T+ , MD participants were more often A+ (39%) than MCI (27%). T-burden differed significantly between MCI and MD (W = 642, p = 0.004). Increasing A-burden, T-burden, and hypometabolism, reflected by lower N-burden were associated with worse performance in Norwegian validated revised mini-mental state-examination (MMSE-NR3) (p = 0.048, < 0.001, and 0.006, respectively), A-burden and N-burden with CERAD Word List Memory Test for immediate and delayed recall (CERAD) (p = 0.041), T-burden with CERAD Word List Memory Test for recognition (CERAD R) (p < 0.001), and N-burden with Clock-drawing test (CDT) (p = 0.023) and Controlled Oral Word Association Test (COWAT) (p = 0.025).

CONCLUSION: The A/T/N classification was most informative for A (+/-) and T (+/-) PET, with T-PET appearing to distinguish MCI from MD, while N-PET correlated most with cognitive impairment.},
}

@article {pmid42162487,
year = {2026},
author = {Singh, A and Denkinger, MN and Leuzy, A and Dieckhoff, K and Liu, J and Marques, TM and Monuki, E and Stark, C and Grill, JD and Hom, C and Sultzer, D and Doran, E and Lott, I and Wood, K and Gawronski, B and Gonzalez, L and Choudhury, P and Atri, A and Beach, TG and Serrano, GE and Sajjadi, SA and Van Keuren-Jensen, K and Reiman, EM and Head, E and Ashton, NJ},
title = {A plasma protein signature for cerebral amyloid angiopathy.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42162487},
issn = {1432-0533},
support = {U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; contract 211002//Arizona Department of Health Services/ ; contracts 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/blood/pathology/diagnosis ; Female ; Male ; Aged ; Biomarkers/blood ; Aged, 80 and over ; Middle Aged ; Alzheimer Disease ; Cohort Studies ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90% of individuals with Alzheimer's disease (AD) exhibit some level of CAA. Notably, in the new era of disease-modifying treatments for AD, CAA is a significant risk factor for amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-amyloid treatments. Therefore, there is great need for accessible, reliable and accurate in vivo biomarkers (e.g., blood-based) to improve antemortem identification of CAA that would improve risk stratification and reduce symptomatic ARIA. In this study, we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for exploratory biomarker quantification in antemortem plasma of participants with neuropathological assessments for CAA from the Banner Sun Health Research Institute Brain and Body Donation Program (N = 251) and independently validated in the University of California Irvine Alzheimer Disease Research Center cohort (N = 110). We evaluated the differential protein expression in antemortem plasma sample taken < 5 years (mean 1.76 ± 1.3) from death using a logistic regression model. We further compared multi-biomarker models and found that a combination of CRP, IL4, CCL11, NPY and PDLIM5, plus demographic covariates showed an area under the curve (AUC) of 0.90 (95% CI 0.86-0.94) to identify neuropathologically confirmed CAA in the discovery cohort. In our independent replication, the antemortem plasma signature performed better than the basic demographics model showing a potential to predict CAA. The exploration and validation in antemortem plasma indicate that a multi-analyte panel, when combined with in vivo blood biomarkers for AD pathology, may be capable of identifying the presence of CAA and could have an meaningful impact on the clinical evaluation of patients under the investigation for cognitive decline. Further developments in biomarkers for this condition are crucial so that CAA identification could inform treatment decisions by highlighting ARIA risk.},
}

Humans
*Cerebral Amyloid Angiopathy/blood/pathology/diagnosis
Female
Male
Aged
Biomarkers/blood
Aged, 80 and over
Middle Aged
Alzheimer Disease
Cohort Studies

@article {pmid42162490,
year = {2026},
author = {Romero-Flores, IS and Cuervo-Zanatta, D and Chavira, R and Sánchez-Valle, V and García-Mena, J and Perez-Cruz, C},
title = {Soluble Fiber Intake Restores the Estrous Cycle and Sex Hormone Alterations in APP/PS1 Female Mice.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01745-3},
pmid = {42162490},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is the most common form of dementia, with a higher prevalence in women than in men. It has been suggested that the decline in estrogen production after menopause may increase the risk of developing dementia. We have previously shown that transgenic female APP/PS1 mice, overexpressing APP and PS1 proteins, develop spontaneous gut dysbiosis with a consequent dysfunctional estrobolome leading to higher estradiol excretion rate compared to age-matched wildtype (WT) females. It has been demonstrated that soluble fiber intake restores gut microbiota dysbiosis, reduces anxiety and improves cognitive function in APP/PS1 male mice. Therefore, the aim of this study was to evaluate if the intake of soluble fiber can modify the gut microbiota composition, alleviating the estrobolome dysfunction, and restoring sex-hormone alterations in female APP/PS1 mice. We confirm that six-month-old APP/PS1 female mice develop a spontaneous gut dysbiosis, an estrobolome dysfunction, and lower oestrous cycle frequencies than their WT littermates. Soluble fiber intake modulates the gut microbiota composition and increases beta-glucuronidase activity in faecal samples associated with a restoration of estradiol and DHEA plasma levels. Additionally, consuming soluble fiber affects various bacterial metabolic pathways and enhances the production of butyrate and acetate. Improved memory and cognitive performance were also observed in female APP/PS1 mice that were fed fructans. Therefore, soluble fiber intake may represent a preventive strategy to mitigate the alterations associated with the onset of reproductive senescence and dementia in females.},
}

@article {pmid42162801,
year = {2026},
author = {Vilademunt, M and Çabas, I and Grieco, F and Carron, C and Sprenger, T and Larrieu, T and Cardinaux, JR and Toni, N},
title = {Astrocytes reduce microglial activation and enhance adult hippocampal neurogenesis in acute inflammation.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106814},
doi = {10.1016/j.bbi.2026.106814},
pmid = {42162801},
issn = {1090-2139},
abstract = {Adult hippocampal neurogenesis is a major process of neuronal plasticity involved in mood regulation and memory and is tightly regulated by the neurogenic niche that relays signaling from the periphery. Neuroinflammation is principally mediated by microglia and strongly impairs adult neurogenesis, but the contribution of astrocytes to this effect is unclear. In this study, we used in vitro and in vivo approaches to investigate the role of astrocytes in the microglial inflammatory response and its impact on adult hippocampal neurogenesis. In vitro, we found that astrocytes attenuated the response of microglia to Lipopolysaccharide (LPS) inflammatory stimulation, through both secreted factors and direct membrane-bound interactions, with secreted factors displaying the strongest effect. Furthermore, astrocytes rescued the inhibition of adult hippocampal stem cell proliferation by LPS-stimulated microglia. In vivo, the administration of astrocyte-conditioned solution (ACS), containing the astrocyte secretome, attenuated LPS-induced sickness and depressive-like behavior, microglial and astrocytic reactivity in the dentate gyrus and restored the number of neural intermediate progenitors. Together, these findings indicate that astrocytes modulate microglia response to inflammatory cues and highlight the astrocytic secretome as a potent anti-inflammatory and pro-neurogenic agent, with potential implications for neuroinflammation-associated conditions such as Alzheimer's disease and mood disorders.},
}

@article {pmid42162804,
year = {2026},
author = {Yu, R and Suraev, A and Shi, L and Martins, RN and Drummond, E and Kong, S and Bassett, K and Naismith, SL and Michaelian, JC},
title = {Stage-dependent dynamics of neuroinflammation across the Alzheimer's continuum.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106823},
doi = {10.1016/j.bbi.2026.106823},
pmid = {42162804},
issn = {1090-2139},
abstract = {Neuroinflammation is a core feature of Alzheimer's Disease (AD), but glial responses may evolve with disease progression. YKL-40 and GFAP reflect distinct astrocytic processes and may show differential relationships with pathology and cognition across the AD continuum. A total of 420 older adults underwent blood-based biomarker profiling (YKL-40, GFAP, pTau217, Aβ42/40, NfL) and neuropsychological assessment. Composite scores were derived for global cognition, memory, executive function, and processing speed. Linear regression interaction models investigated whether associations of glia markers with AD pathology or cognition differed with advancing disease, defined by plasma pTau217 status (negative < 0.4; positive > 0.6349 pg/mL) and clinical diagnosis (healthy controls [HC], subjective cognitive decline [SCD], mild cognitive impairment [MCI], AD). We observed stage-dependent relationships between YKL-40 and AD pathology. Higher YKL-40 was associated with greater pathology in cognitively unimpaired individuals (HC/SCD), but these associations progressively weakened in MCI and further in AD (pTau217: βinteraction = -0.230, p = 0.020; Aβ42/40: βinteraction = 0.003, p = 0.044). Similarly, the relationship between YKL-40 and pTau217 was dependent on AD likelihood (βinteraction = -0.218, p < 0.001); YKL-40 positively correlated with pTau217 in pTau-negative individuals (r = 0.208, p < 0.001), but negatively in pTau-positive individuals (r = -0.251, p = 0.025). In contrast, GFAP showed stable, monotonic positive relationships with all biomarkers across disease stages, with strengthening associations with poorer cognition, particularly memory and processing speed, at later stages. The findings suggest that astrocytic markers GFAP and YKL-40 exhibit distinct, stage-dependent relationships with AD pathology and cognition, underscoring key implications for biomarker interpretation and disease staging.},
}

@article {pmid42162832,
year = {2026},
author = {Xu, X and Wang, Q and Wang, L and Cheng, W and Li, F and Liu, H and Guo, Y},
title = {Indoleamine 2,3-dioxygenase 1 (IDO1) promoted the activation of inflammatory response in the brain tissue of Alzheimer's disease mice by regulating NF-κB pathway.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138635},
doi = {10.1016/j.neulet.2026.138635},
pmid = {42162832},
issn = {1872-7972},
abstract = {OBJECTIVE: To investigate the regulatory mechanism of IDO1 on brain tissue damage in Alzheimer's disease (AD) mice.

METHODS: APP/PS1 mice (AD model mice) and C57BL/6J mice were treated with IDO1 inhibitor 1-MT. Behavioral changes were assessed using the open field test, and histopathological changes were analyzed using HE staining, Nissl staining, and transmission electron microscopy. TUNEL staining and immunofluorescence were used to detect cell apoptosis and the expression of IDO1 and GFAP, respectively. Metabolomics was analyzed using liquid chromatography-mass spectrometry. An in vitro AD cell model was established, and inflammatory factor levels were measured using ELISA/qPCR, while NF-κB pathway activation was assessed using WB.

RESULTS: In vivo experiments showed that compared with the model group mice, 1-MT intervention improved behavioral abnormalities in AD mice, reduced hippocampal tissue damage, decreased neuronal apoptosis, and downregulated the expression of IDO1 and GFAP. In vitro experiments demonstrated that interfering with IDO1 could decrease the levels of IL-1β, TNF-α, and IL-6, reduce GFAP expression, and inhibit p65 phosphorylation.

CONCLUSION: Interfering with IDO1 can inhibit the NF-κB pathway, reduce the release of inflammatory factors, and improve brain tissue damage in AD mice.},
}

@article {pmid42162905,
year = {2026},
author = {Alamri, MA and Afzal, M and Pandey, SN and Afzal, O and Akela, MA and Rekha, A},
title = {Exosomal miRNA in cerebrospinal fluid as biomarkers for neurodegenerative disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121094},
doi = {10.1016/j.cca.2026.121094},
pmid = {42162905},
issn = {1873-3492},
abstract = {Cerebrospinal fluid protein biomarkers, such as the Aβ42/Aβ40 ratio, phosphorylated tau, and neurofilament light chain, have significantly advanced the diagnostic process for Alzheimer's disease. Nonetheless, these biomarkers face challenges in effectively distinguishing Alzheimer's disease from frontotemporal dementia or Parkinson's disease from dementia with Lewy bodies. This limitation arises from overlapping protein profiles and the variability inherent in immunoassay techniques. A complementary class of analytes is exosomal microRNAs in cerebrospinal fluid, where these non-coding RNAs are secreted by neurons, astrocytes, and microglia, are resistant to RNase degradation, and have a disease-specific expression pattern. This review critically evaluates the existing evidence of cerebrospinal fluid exosomal miRNAs as diagnostic biomarkers in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Exosome isolation techniques and detection platform characteristics were compared using RT-qPCR, droplet digital PCR, and small RNA sequencing. Pre-analytical factors, such as collection protocols, hemolysis contamination, freeze-thaw cycling, and circadian sampling variation, were assessed. miRNA profiling data based on disease stratification, receiver operating characteristic performance of the combinatorial panel, and strategies combining exosomal miRNAs with core cerebrospinal fluid proteins were synthesized. This article brings together disease-specific miRNA signatures, pre-analytical standardization needs, and diagnostic accuracy analyses in a translational model to fill the literature gap and form the basis for developing exosomal miRNA panels for rigorously validated clinical laboratory practice.},
}

@article {pmid42162939,
year = {2026},
author = {Barbosa-Carvajal, JP and García-García, M and Gómez Navarro, LF and Zubiri, V and Gelvez, N and López, G and Reyes, P and García-Cifuentes, E and Aguillón, D and Acosta-Uribe, J and Matallana, DL},
title = {Phenotypic diversity of frontotemporal lobar degeneration in two novel GRN variants from Colombia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71475},
doi = {10.1002/alz.71475},
pmid = {42162939},
issn = {1552-5279},
support = {//the National Institutes of Health/ ; //Intramural Research Program of the NIH/ ; R01 AG057234/AG/NIA NIH HHS/United States ; D43TW012455/TW/FIC NIH HHS/United States ; SG-20-725707/ALZ/Alzheimer's Association/United States ; //Rainwater Charitable foundation-Tau Consortium/ ; //the Bluefield Project to Cure Frontotemporal Dementia/ ; },
mesh = {Humans ; *Frontotemporal Lobar Degeneration/genetics/diagnosis/pathology ; *Progranulins/genetics ; Colombia ; Middle Aged ; Adult ; Male ; Phenotype ; Female ; Magnetic Resonance Imaging ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Pathogenic progranulin (GRN) variants are among the main genetic causes of frontotemporal lobar degeneration (FTLD). These variants have been predominantly reported in European cohorts, but their characterization in Latin America remains scarce. We describe two Colombian cases with novel GRN variants with amnestic and semantic syndromes leading to an initial diagnosis of Alzheimer's disease (AD).

METHODS: We conducted clinical, neuropsychological, neuroimaging, and genetic analysis. Biomarkers were included for one case.

RESULTS: At 42 years old, Case 1 presented a predominant amnestic profile and carried the GRN c.21G > A (p.Trp7*) variant. Case 2 debuted with a semantic impairment at 62 years old and was a carrier of GRN c.1098T > A (p.Cys366*) variant. Brain imaging revealed asymmetric temporal atrophy, and biomarkers supported diagnosis of FTLD.

DISCUSSION: GRN variants can mimic early-onset AD. An integrative approach including serial clinical, genetic, brain imaging, and biomarker analysis are essential for diagnosing Amnestic variants of FTLD in admixed genetic populations.},
}

Humans
*Frontotemporal Lobar Degeneration/genetics/diagnosis/pathology
*Progranulins/genetics
Colombia
Middle Aged
Adult
Male
Phenotype
Female
Magnetic Resonance Imaging
Brain/pathology/diagnostic imaging
Neuropsychological Tests

@article {pmid42162953,
year = {2026},
author = {Karthivashan, G and Wang, S and Wu, Q and Dahal, A and Li, X and Galleguillos, D and Sipione, S and Thinakaran, G and Kar, S},
title = {Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71348},
doi = {10.1002/alz.71348},
pmid = {42162953},
issn = {1552-5279},
support = {MOP-84480//CIHR/Canada ; PJT-175090//CIHR/Canada ; //Alzheimer Society of Alberta and Northwest Territories/ ; RF1AG077610//National Institute on Aging, National Institutes of Health/ ; RF1AG079141//National Institute on Aging, National Institutes of Health/ ; //Ballermann Translational Research Fellowship/ ; //SynAD postdoctoral fellowships/ ; },
mesh = {*Alzheimer Disease/pathology/drug therapy/metabolism ; Animals ; *Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology ; *Nanoparticles/administration & dosage ; Mice ; *Amyloid beta-Peptides/metabolism/drug effects ; Disease Models, Animal ; Male ; Mice, Transgenic ; Brain/pathology/metabolism/drug effects ; },
abstract = {INTRODUCTION: Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.

METHODS: We evaluated the effects of native PLGA in 8-month-old male 5xFAD mice via chronic intracerebroventricular (ICV) infusion using mini osmotic pumps. Cognitive function, amyloid level/burden, synaptic integrity, and neurodegenerative events were assessed along with transcript levels in brain tissues using bulk RNA sequencing (RNA-seq).

RESULTS: PLGA treatment reversed cognitive deficits, reduced Aβ levels/deposits, and attenuated neurodegenerative events. These effects were associated with modulation of Aβ production, oxidative stress, and lysosomal Aβ clearance. RNA-seq revealed transcriptional changes related to vesicle trafficking, immune activity, and redox regulation.

DISCUSSION: Native PLGA, by targeting different facets of the Aβ axis, offer unique therapeutic potential in treating AD-related pathology.},
}

*Alzheimer Disease/pathology/drug therapy/metabolism
Animals
*Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology
*Nanoparticles/administration & dosage
Mice
*Amyloid beta-Peptides/metabolism/drug effects
Disease Models, Animal
Male
Mice, Transgenic
Brain/pathology/metabolism/drug effects

@article {pmid42162956,
year = {2026},
author = {Li, ZJ and Yang, Z and Zhao, D and Qiu, YH and Wan, WY and Huang, ZK and Tian, L and Qi, RQ and Liu, HG and Chen, YH and Min, DY and Xu, XQ and Zhao, WD},
title = {Circulatory pro-CTSD binds brain endothelial LRP1 to trigger its lysosomal degradation leading to amyloid beta clearance deficit in Alzheimer's disease mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71494},
doi = {10.1002/alz.71494},
pmid = {42162956},
issn = {1552-5279},
support = {2023-BSBA-295//Joint Fund Project Doctoral Research Initiation Program of Liaoning Province/ ; 2023JH2/20200163//Science and Technology Funding Project for Supporting the High-Quality Development of China Medical University/ ; 32271203//National Natural Science Foundation of China/ ; 82174114//National Natural Science Foundation of China/ ; U23A20427//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Lysosomes/metabolism ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; *Brain/metabolism/pathology ; Disease Models, Animal ; *Endothelial Cells/metabolism ; Mice ; Humans ; Endocytosis ; },
abstract = {INTRODUCTION: Clearance of cerebral Aβ was primarily mediated by the brain endothelial transporters including LRP1. The regulatory mechanism of LRP1 expression remained unclear.

METHODS: LRP1 in brain endothelial cells treated with pro-CTSD were analyzed by western blot. Transgenic mice with high circulatory pro-CTSD (hCTSD[hi]) were generated to assess LRP1 levels and brain Aβ deposition by immunostaining and live-imaging. Internalization of pro-CTSD and its co-localization with LRP1 was analyzed using confocal and TIRF microscopy.

RESULTS: Circulatory pro-CTSD is increased in the AD models. hCTSD[hi] mice exhibited reduced endothelial LRP1 and impaired Aβ clearance. Soluble pro-CTSD bound the Cluster II domain of LRP1, triggering LRP1 endocytosis and lysosomal degradation. Crossing hCTSD[hi] mice with AD models increased brain Aβ deposition and exaggerated cognitive deficit.

DISCUSSION: Circulatory pro-CTSD triggered degradation of brain endothelial LRP1 to inhibit brain-to-blood Aβ clearance.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Lysosomes/metabolism
*Low Density Lipoprotein Receptor-Related Protein-1/metabolism
*Brain/metabolism/pathology
Disease Models, Animal
*Endothelial Cells/metabolism
Mice
Humans
Endocytosis

@article {pmid42162968,
year = {2026},
author = {Reyna, NC and Hamilton, DA},
title = {Effects of Corticotropin-Releasing Factor 1 Receptor Antagonism on In Vivo Dentate Gyrus Long-Term Potentiation in the TgF344-AD Rat Model of Alzheimer's Disease.},
journal = {Hippocampus},
volume = {36},
number = {3},
pages = {e70103},
doi = {10.1002/hipo.70103},
pmid = {42162968},
issn = {1098-1063},
support = {P20AG068077/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Long-Term Potentiation/drug effects/physiology ; *Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism ; *Dentate Gyrus/drug effects/physiopathology ; *Alzheimer Disease/physiopathology/drug therapy/pathology/genetics ; *Pyrroles/pharmacology ; *Pyrimidines/pharmacology ; Disease Models, Animal ; CRF Receptor, Type 1 ; Rats, Transgenic ; Male ; Rats ; Rats, Inbred F344 ; Excitatory Postsynaptic Potentials/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) is characterized by irreversible neurobiological deterioration and cognitive impairment. AD patients exhibit stress system abnormalities including upregulation of the corticotropin releasing factor type 1 receptor (CRF1) and elevated cortisol. Psychological distress increases the likelihood of AD diagnosis and hastens neurocognitive decline. Administration of the CRF1 antagonist, Antalarmin, reduces AD pathogenesis and anxiety-like behavior in models of AD. Motivated by these observations, the current study examined the potential contributions of CRF1 to altered synaptic plasticity in AD neuropathology and stress in the TgF344-AD rat model. In vivo electrophysiological recordings to assess long-term potentiation (LTP) in the perforant pathway to dentate gyrus synapses were performed in aged transgenic rats and wild-type (WT) controls (2-2.5 years). TgF344-AD rats had abnormal LTP measures of field excitatory post-synaptic potentials (fEPSP) and population spikes (PS). Treatment with Antalarmin did not alter LTP measures in TgF344-AD or WT rats. These observations indicate that LTP in TgF344-AD rats is reduced compared to WT rats and that acute treatment with a CRF1 antagonist did not rescue LTP deficits. Future research should further examine the mechanism of CRF1 in AD and implications of agonism or direct infusions of Antalarmin in vivo.},
}

Animals
*Long-Term Potentiation/drug effects/physiology
*Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism
*Dentate Gyrus/drug effects/physiopathology
*Alzheimer Disease/physiopathology/drug therapy/pathology/genetics
*Pyrroles/pharmacology
*Pyrimidines/pharmacology
Disease Models, Animal
CRF Receptor, Type 1
Rats, Transgenic
Male
Rats
Rats, Inbred F344
Excitatory Postsynaptic Potentials/drug effects/physiology

@article {pmid42163007,
year = {2026},
author = {Chatterjee, A and Alvarez, B and Sharma, RU and Jonson, C and Wilkins, HM and Pa, J and Swerdlow, RH and Goate, A and Yaffe, K and Andrews, SJ and , },
title = {Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's disease and Parkinson's disease using polygenic risk scores and Mendelian randomization.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71469},
doi = {10.1002/alz.71469},
pmid = {42163007},
issn = {1552-5279},
support = {P30AG072973//NIH-NIA/ ; R01AG078186//NIH-NIA/ ; ZO1 AG000534/NH/NIH HHS/United States ; R35AG071916/NH/NIH HHS/United States ; AARF-20-675804/ALZ/Alzheimer's Association/United States ; 23AARG-1023294/ALZ/Alzheimer's Association/United States ; R35AG071916/ALZ/Alzheimer's Association/United States ; //National Institute of Neurological Disorders and Stroke (NINDS)/ ; //Margaret "Peg" McLaughlin and Lydia A. Walker Opportunity Fund/ ; //University of Kansas Alzheimer's Disease Center/ ; AARF-20-675804/ALZ/Alzheimer's Association/United States ; 23AARG-1023294/ALZ/Alzheimer's Association/United States ; AG072973/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Parkinson Disease/genetics ; *Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; *DNA, Mitochondrial/genetics ; *Multifactorial Inheritance/genetics ; Genetic Predisposition to Disease ; DNA Copy Number Variations/genetics ; Risk Factors ; *Mitochondria/genetics ; Genetic Risk Score ; },
abstract = {INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with Alzheimer's disease (AD) and Parkinson's disease (PD). We integrated genetic correlation, polygenic risk scores (PRSs), and Mendelian randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWASs) distort these causal estimates.

METHODS: Using GWASs of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the Alzheimer's Disease Genetics Consortium (N = 27,383), and applied MR methods including latent heritable confounder-MR (LHC-MR).

RESULTS: Across the four mtDNAcn GWASs, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRSs showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk.

DISCUSSION: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.},
}

Humans
*Parkinson Disease/genetics
*Mendelian Randomization Analysis
*Alzheimer Disease/genetics
Genome-Wide Association Study
*DNA, Mitochondrial/genetics
*Multifactorial Inheritance/genetics
Genetic Predisposition to Disease
DNA Copy Number Variations/genetics
Risk Factors
*Mitochondria/genetics
Genetic Risk Score

@article {pmid42163019,
year = {2026},
author = {Qiang, Y and Luo, Q and Zhang, J and Ming, C and Chong, X and Huang, F and Gui, A and Wang, J and Yin, H and Ahmad, MZ and He, HF},
title = {Theanine: a phytochemical candidate for neural protection.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70740},
pmid = {42163019},
issn = {1097-0010},
support = {32102443//National Natural Science Foundation of China/ ; Jining Medical University: cx2024286//College Students' Innovative Entrepreneurial Training Plan Program/ ; cx2024286//Jining Medical University/ ; },
abstract = {Theanine, which accumulates in Camellia sinensis (L.) O. Kuntze, has demonstrated strong neuroprotective effects and other health benefits that have attracted attention. This paper reviews relevant literature published during the past 5 years, analyzing and summarizing studies focusing on the neuroprotective functions of theanine. By alleviating neuroinflammation, theanine exerts therapeutic effects on mental disorders caused by cumulative stress, ranging from mild sleep disturbances to depression induced by sleep deprivation. It has also demonstrated beneficial effects in delaying disease progression and promoting repair in age-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. This paper also reviews studies investigating the protective effects of theanine against organ dysfunction caused by nerve injury, as well as its synergistic effects with other phytochemical components in promoting neurological health. The potential mechanisms underlying the neuroprotective effects of theanine are considered from three perspectives: ferroptosis induced by oxidative stress in neuronal cells, the differentiation and development of neural stem cells (NSCs), and neural signal transduction pathways. Further investigations are needed to achieve a more rigorous and comprehensive understanding of theanine. © 2026 Society of Chemical Industry.},
}

@article {pmid42163170,
year = {2026},
author = {Moore, L and Lund, AE and Russell, C},
title = {Unawareness of deficits in mild cognitive impairment: a systematic review of its role in progression to Alzheimer's disease.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04884-8},
pmid = {42163170},
issn = {1471-2377},
abstract = {BACKGROUND: Reduced awareness or poor insight into cognitive abilities is a well-documented feature of Alzheimer's disease, yet its role in the earlier stages of cognitive decline-particularly in individuals with mild cognitive impairment (MCI)-remains less clear. Understanding whether diminished awareness in MCI is a predictor of progression to dementia is crucial, as it may help identify individuals who are at greater risk and who could benefit from timely support and intervention. This systematic review evaluates the evidence linking reduced awareness in MCI with an increased likelihood of conversion to dementia.

METHOD: Four electronic databases (CINAHL, Medline, Embase and PsychInfo) were systematically searched for all studies assessing awareness in individuals with MCI, which tracked their cognitive status over time. The protocol was registered with PROSPERO and PRISMA guidelines were followed. Inclusion criteria-studies must: Include participants with confirmed MCI diagnosis; Assess the relationship between awareness of cognitive and/or functional abilities and the development of dementia; Have longitudinal design; Be peer-reviewed. Exclusion criteria-studies must not: Be published in a different language to English; Include participants with comorbid neurological conditions; Include participants from the same cohort as another study; Use a case series design. Eleven studies were identified as fulfilling all criteria. Study quality was evaluated using the Critical Appraisal Skills Programme (CASP) checklist for cohort studies.

RESULTS: Six studies reported a statistically significant association between reduced awareness and conversion to dementia. Four studies found a trend toward significance, suggesting a possible link, but either did not test for significance or failed to reach it. Only one study found no association. Study quality was rated as high in five studies, moderate in two, and low in four. Notably, higher-quality studies were more likely to report significant associations. Due to substantial methodological variability across studies, a meta-analysis was not feasible.

CONCLUSIONS: Reduced awareness of memory impairment appears predictive of increased risk of progression from MCI to dementia. Assessing awareness-through informant reports and/or comparisons between subjective and objective cognitive measures-could help identify individuals at elevated risk. These individuals may benefit from closer monitoring to facilitate timely diagnosis and intervention.},
}

@article {pmid42163277,
year = {2026},
author = {Lee, HJ and Seok, J and Kang, S and Oh, S and Hwang, JW and Kim, YJ and Seo, J and Hoe, HS},
title = {The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03855-7},
pmid = {42163277},
issn = {1742-2094},
support = {RS-2024-00357857//NRF/ ; RS-2024-00343370//KDRC/ ; H0501-25-1001//NIPA/ ; 20190058//Whanin Pharm Co., Ltd/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2026-25492172//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.

METHODS: We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays.

RESULTS: BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807 administration downregulated IGF-1R phosphorylation, microgliosis/astrogliosis-related dynamics, and AKT/P38/STAT3 pathway. Notably, BMS-754807 treatment also diminished LPS-induced proinflammatory cytokine levels and STAT3/NF-κB signaling in human microglial models. Furthermore, BMS-754807 treatment decreased Aβ40/Aβ42 levels in hiPSC-derived AD neurons, and increased short-term spatial memory and reduced Aβ plaque accumulation by decreasing β-secretase (BACE1) activity in 5xFAD mice. Finally, in hiPSC-derived AD neurons and PS19 mice, BMS-754807 treatment significantly attenuated tau hyperphosphorylation, CaMKIIα phosphorylation, and tau-mediated astroglial activation.

CONCLUSIONS: Taken together, our results suggest that BMS-754807 exerts anti-inflammatory and potential disease-modifying effects by attenuating LPS/Aβ/tau-evoked glial activation and reducing Aβ and tau pathologies in both human cellular and mouse models of neuroinflammation and AD. Furthermore, BMS-754807 administration improved specific domains of cognitive function in vivo. These findings support pharmacological inhibition of IGF-1R as a potential therapeutic approach for neuroinflammation-associated diseases including AD.},
}

@article {pmid42163294,
year = {2026},
author = {Bao, R and Shi, W and Bao, H and Zhang, T and Li, X and Ding, W and , },
title = {Plasma p-tau217, p-tau181, and Aβ42 predict amyloid PET positivity in cognitively unimpaired adults.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02080-x},
pmid = {42163294},
issn = {1758-9193},
support = {GRK202510//Research Start-up Fund for High-level Talent at the Second Affiliated Hospital of Wannan Medical College/ ; GRK202511//Research Start-up Fund for High-level Talent at the Second Affiliated Hospital of Wannan Medical College/ ; 82501744//National Natural Science Foundation of China/ ; 2024-BSLH-047//Liaoning Provincial Natural Science Foundation Joint Funds Project/ ; LJ212510161032//Department of Education of Liaoning Province/ ; 2024AH040242//Major Scientific Research Project of the Anhui Province Department of Education/ ; EYR202306//High-level Talent Recruitment Program of Wannan Medical College/ ; },
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD) pathology in cognitively unimpaired individuals is critical for preclinical intervention. Plasma biomarkers, especially phosphorylated tau217 (p-tau217), are promising predictors of amyloid-β (Aβ) accumulation.

METHODS: In this cohort study, we analyzed data from cognitively unimpaired older adults in the A4 and LEARN studies (n = 1,407), comprising 452 participants with Aβ positron emission tomography (PET)-negative status and 955 participants with Aβ PET-positive status. We evaluated the accuracy of plasma biomarkers (p-tau217, p-tau181, Aβ42/40 ratio, and others) in predicting Aβ PET positivity using receiver operating characteristic analysis, comparing covariate-adjusted individual biomarker and biomarker-ratio models with a multivariable combined model integrating plasma biomarkers and covariates. (age, sex, apolipoprotein E [APOE] ε4 genotype).

RESULTS: Plasma p-tau217 showed the strongest individual association with Aβ PET status (area under the curve [AUC], 0.85). A combined model integrating p-tau217, p-tau181, Aβ42, age, sex, and APOE ε4 achieved the highest overall discrimination (AUC, 0.87), although the improvement over the covariate-adjusted p-tau217 model was modest.

CONCLUSIONS: Plasma p-tau217 showed the strongest individual performance for predicting Aβ PET positivity in cognitively unimpaired older adults. Adding other plasma biomarkers and clinical covariates provided a modest incremental improvement in classification performance. These findings support blood-based prescreening as a potential enrichment approach, while indicating that confirmatory amyloid assessment remains necessary when definitive Aβ status is required.},
}

@article {pmid42163351,
year = {2026},
author = {Soni, ND and Swain, A and Khokhar, SK and Wilson, NE and Nanga, RPR and Kumar, D and Bouche, E and Cao, Q and Haris, M and Wolk, DA and Lee, VM and Detre, JA and Reddy, R},
title = {An imaging biomarker to detect non-glucogenic shift in brain energy metabolism in Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08073-6},
pmid = {42163351},
issn = {1479-5876},
support = {P41EB029460/EB/NIBIB NIH HHS/United States ; RF1AG087306-01, R01AG071725, R01AG063869/AG/NIA NIH HHS/United States ; R01AG091760/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Cerebral glucose hypometabolism in Alzheimer's disease (AD) leads to enhanced metabolism of fatty acids (FAs) and branched-chain amino acids (BCAAs) as a compensatory mechanism. While there have been some [13]C labeled studies investigating the metabolism of FAs and BCCAs, their clinical translation is challenging. In this study, we investigated the potential of measuring neurometabolic perturbations through macromolecular signal at 0.9 ppm (MM09) in proton magnetic resonance ([1]H MR) spectrum. This signal represents a composite macromolecular signal with contributions from lipids and BCAA associated methyl resonances and may be sensitive to metabolic alterations occurring during glucose hypometabolism in AD.

METHODS: MM09 levels were measured from localized [1]H MR spectra in the hippocampus and thalamus/hypothalamus of male and female APP[NL-F/NL-F] (AD) mice. In addition, the levels of glutamate in these regions were also recorded as it is known to be reduced under glucose hypometabolism in AD. We further studied the metabolic association of MM09 with glutamate in Pearson correlation plots. To find the statistical significance of difference two-way ANOVA analysis with post-hoc Tukey HSD tests were used.

RESULTS: Male AD mice exhibited significantly reduced MM09 (15.42 ± 1.32 vs. 16.93 ± 1.15 mM; p = 0.008) and glutamate levels (15.27 ± 1.65 vs. 17.24 ± 1.21 mM; p = 0.004) in the hippocampus. Female AD mice did not show any changes in glutamate or MM09 levels. MM09 also showed a strong positive correlation with glutamate (R = 0.74; p < 0.0001).

CONCLUSION: The observed reductions in MM09 and glutamate in male AD mice are consistent with neurometabolic alterations associated with impaired glucose metabolism, whereas the absence of such changes in female AD mice may reflect sex-specific metabolic resilience. The strong association between MM09 and glutamate suggests that MM09 may capture neurochemical changes linked to metabolic adaptations in AD. Because the MM09 resonance occurs in a relatively uncrowded region of the [1]H MR spectrum, it may represent a promising spectroscopic marker for investigating metabolic shifts in AD and warrants further evaluation in clinical studies.},
}

@article {pmid42163381,
year = {2026},
author = {Xia, X and Clark, A and Brogaard, NJ and Mourer, A and Areovimata, A and Eriksdotter, M and Zetterberg, H and Kern, S and Skillbäck, T and Jönsson, L},
title = {Correction: Comorbidities predict institutionalization and mortality in biomarker-confirmed alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42163381},
issn = {1758-9193},
}

@article {pmid42163384,
year = {2026},
author = {Hsu, JL and Huang, SY and Wu, HC and Lin, KJ and Huang, KL and Huang, CC and Kim, S and Hsiao, IT},
title = {A clinically feasible framework to estimate tau pathology and clinical-biological discordance in the Alzheimer's disease spectrum.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02083-8},
pmid = {42163384},
issn = {1758-9193},
support = {MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; },
abstract = {BACKGROUND: Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer's disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer's Association (AA-2024) diagnostic framework, and to characterize clinical-biological discordance across the AD continuum.

METHODS: We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [[18]F]florbetapir amyloid PET, [[18]F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL > 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.

RESULTS: Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21-60 (6.1%) but increased in CL 61-100 (22.6%) and > 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical-biological discordance.

CONCLUSION: Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical-biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.},
}

@article {pmid42163385,
year = {2026},
author = {Deng, L and Yin, C and Zhou, X and Feng, C and Wu, J and An, X and Mi, J and Huang, L and Qin, D and Yu, L and Chen, T and Wu, A},
title = {Targeted degradation of aberrant Tau for the discovery of Pulsatilla chinensis in Alzheimer's disease.},
journal = {Chinese medicine},
volume = {21},
number = {1},
pages = {},
pmid = {42163385},
issn = {1749-8546},
support = {2024LZXNYDJ026//Joint Project of Luzhou Municipal People's Government and Southwest Medical University/ ; 81903829//Natural Science Foundation of Henan Province/ ; 2024YFHZ0361//Department of Science and Technology of Sichuan Province/ ; SKLKY2024B0006//State Key Laboratory of Traditional Chinese Medicine Syndrome/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by Tau aggregation, mitochondrial dysfunction, and oxidative stress, yet effective interventions targeting these pathological cascades remain limited. Therapeutic strategies that enhance autophagic and mitophagic clearance, attenuate Tau toxicity, and restore mitochondrial homeostasis are crucial for AD management.

METHODS: This study investigated the neuroprotective effects of Pulsatilla chinensis extract (PCE) in SH-SY5Y neuronal cells and Caenorhabditis elegans (C. elegans) models of Tauopathy. Autophagic flux was evaluated by GFP-LC3 puncta formation, LC3-II conversion, and p62 degradation. Mitochondrial function was assessed through reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and ultrastructural analysis. The roles of autophagy and mitophagy were examined using 3-methyladenine (3-MA) and the Parkin inhibitor AC220. In C. elegans, locomotion, Tau aggregation, oxidative stress, and mitophagosome formation were assessed, and pink-1 knockdown was used to confirm mitophagy dependence.

RESULTS: PCE significantly enhanced autophagic flux, decreased total and phosphorylated Tau (p-Tau Ser404) levels, and improved neuronal viability. It significantly reduced ROS accumulation, maintained MMP, and preserved mitochondrial morphology under both Tau overexpression and H2O2-induced oxidative stress. Inhibition of autophagy or Parkin-mediated mitophagy negated these protective effects. In C. elegans, PCE ameliorated neuromuscular dysfunction, suppressed Tau inclusions, and reduced oxidative injury, while the loss of pink-1 abolished its benefits, underscoring the critical role of mitophagy.

CONCLUSION: PCE exerts potent neuroprotective effects by promoting mitophagy, reducing Tau phosphorylation and aggregation, and restoring mitochondrial integrity. These findings reveal a novel mechanism linking mitochondrial quality control with Tau proteostasis and highlight PCE as a promising natural therapeutic candidate for AD.},
}

@article {pmid42163499,
year = {2026},
author = {Liu, M and Li, X and Fang, H and Miao, D},
title = {Development and validation of a novel single molecular immunology assay for detection of p-Tau181.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453031},
doi = {10.1177/13872877261453031},
pmid = {42163499},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) presents a major public health challenge. Current diagnostic methods for these disorders are often costly, invasive, and not widely accessible. The recently revised NIA-AA criteria highlight the potential of blood-based biomarkers as a promising non-invasive and cost-effective alternative for diagnosis.ObjectiveTo develop a novel single-molecule immunology assay specifically for the detection of phosphorylated tau at threonine 181 (p-Tau181) protein in blood samples.MethodsA novel single-molecule immunoassay targeting p-Tau181 was developed employing the Lychix Homebrew Kit. This new p-Tau181 assay underwent validation through the analysis of plasma samples from 98 clinically confirmed AD patients and 98 age-matched normal controls (NC), with the aim of assessing its effectiveness in differentiating between these two populations.ResultsInitially, the p-Tau181 immunoassay exhibited high nonspecificity and low discrimination between AD and NC plasma samples, with an AUC of 0.76. Further investigation revealed that false positive signals were caused by enzyme attachment to bead surfaces. By adjusting enzyme concentrations, reaction temperatures, and optimizing the sample diluent, it was ultimately discovered that salt concentration was the key factor in effectively minimizing false signals. With the optimized salt ion concentration, the refined p-Tau181 assay significantly improved its ability to distinguish AD from NC, achieving an AUC of 0.9313. The assay demonstrated improved sensitivity of 84.69% (76.27%-90.50%, 95% CI) and specificity of 87.76% (79.81%-92.85%, 95% CI).ConclusionsThe optimized single-molecule immunoassay p-Tau181 demonstrated significantly improved discrimination between AD and NC populations, underscoring its potential as a valuable diagnostic tool for AD.},
}

@article {pmid42163597,
year = {2026},
author = {Karim, A and Alturise, F and Alkhalifah, T and Khan, YD},
title = {predALZ: An Ensemble Learning Framework for Identifying Genetic Biomarkers in Familial Alzheimer's Disease.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501408301251214192633},
pmid = {42163597},
issn = {1873-5592},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a substantial genetic contribution, especially in the early-onset form. Mutations in genes like APP, PSEN1, and PSEN2 serve as crucial biomarkers, indicating a heightened risk of developing AD. Leveraging these genetic markers, we introduce predALZ, a prediction model designed to enhance early detection of familial AD through genomic sequence analysis.

METHODS: The model integrates data derived from genome-wide association studies (GWAS) and employs advanced feature encoding techniques to generate a robust representation of genomic patterns. A diverse ensemble of classifiers, namely XGBoost, Random Forest, LightGBM, and ExtraTrees, is employed to train the predALZ model, utilizing the generated feature vector for training.

RESULTS: The predALZ framework achieved 94% accuracy on an independent test set and approximately 96% accuracy in cross-validation for Alzheimer-related driver gene prediction. The ensemble model also yielded consistently high sensitivity, specificity, and Matthews correlation coefficient values, indicating stable and reliable classification performance.

DISCUSSION: The model's effectiveness was further rigorously validated through a comprehensive evaluation, using metrics such as accuracy, sensitivity, specificity, and Matthew's correlation coefficient. The study underscores the predictor's remarkable performance, consistently achieving 94% accuracy in an independent Test and ~96% in cross-validation.

CONCLUSION: These findings highlight predALZ's potential for application in predictive diagnostics and targeted therapeutic development for Alzheimer's disease.},
}

@article {pmid42163600,
year = {2026},
author = {Qasim, R and Tariq, Z and Ahmed, S and Raza, M and Khan, I and Zahra, R and Noor, A and Mehdi, BJ},
title = {Trends in Cerebrovascular Disease Mortality Among Alzheimer Patients in Older Adults Across the USA: A CDC Wonder Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050429545260402050204},
pmid = {42163600},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is the most common form of dementia, affecting more than 55 million individuals worldwide. Cerebrovascular Disease (CeVD) has been shown to co-exist with AD. This study aimed to shed light on this mortality trend to make a positive difference in improving patient care.

METHODS: Data were extracted from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database using CeVD as the underlying cause of death, and AD as a multiple cause of death, from 1999 to 2020 for older adults (≥ 65 years). The Age- Adjusted Mortality Rates (AAMRs) were calculated per 100,000 individuals, and trends were assessed using Joinpoint as the Average Annual Percentage Changes (AAPCs).

RESULTS: In total, 64,749 deaths were reported. The overall AAMR declined from 10.21 (1999) to 5.28 (2020). Females had higher AAMRs than males (7.75 vs. 5.59). Non-Hispanic White individuals had the highest AAMR (7.26), while the West region (8.57) and non-metropolitan areas (9.14) showed elevated rates. Vermont (11.81) and Washington (11.56) exhibited the highest death rates, in contrast to Nevada (3.08) and New York (3.25). Most deaths occurred in nursing homes, followed by medical facilities.

DISCUSSION: Mortality declined overall, attributed to advancements in healthcare and prevention, but significant disparities persist among women, non-Hispanic White populations, western, and rural regions. Limitations include potential death certificate misclassification. Future studies should further evaluate targeted interventions, such as community-tailored interventions, to enhance equity.

CONCLUSION: These trends showed significant spatiotemporal and demographic variation. Targeted interventions are required to mitigate fatalities, particularly in high-risk populations.},
}

@article {pmid42163660,
year = {2026},
author = {Yang, M and Dai, S and Li, S and Xu, Z and Chen, T},
title = {Involvement and Mechanisms of Aβ and Tau in the Neuroinflammatory Response of Alzheimer's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438314260228195840},
pmid = {42163660},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a common chronic neurodegenerative disorder, serving as the most prevalent cause of dementia among the elderly. The primary histopathological hallmarks of AD encompass senile plaques, induced by excessive deposition of extracellular β-amyloid (Aβ), and neurofibrillary tangles (NFT), resulting from excessive phosphorylation of intracellular Tau protein, leading to neuronal damage and loss. Numerous studies on AD patients and animal models have revealed the widespread presence of neuroinflammatory responses within the AD brain, emphasizing the pivotal role of neuroinflammation in the pathogenesis of AD, which is now widely recognized as one of the primary triggers of AD. Microglia, the resident macrophages in the brain and the first line of defense of the central nervous system, play a central role in neuroinflammation. In the pathogenesis of AD, microglia are considered a double-edged sword, exerting beneficial effects by clearing Aβ deposition while causing detrimental effects through the production of cytotoxic substances, leading to neuronal dysfunction. Although the precise role of neuroinflammation in the pathogenesis of AD remains incompletely elucidated, an increasing number of studies have revealed that pathological Aβ and Tau proteins are extensively involved in the neuroinflammatory process mediated by microglia activation in AD, exhibiting a complex interplay. Therefore, this article will provide a comprehensive review of the research progress on the relationship between Aβ or Tau proteins and neuroinflammation induced by microglia in AD, as well as its associated mechanisms.},
}

@article {pmid42163663,
year = {2026},
author = {Xu, H and Zhang, J and Wang, Y and Ma, G and Zhao, YJ},
title = {The Efficacy of Glucagon-like Peptide-1 Receptor Agonists on Different Cognitive Domains: A Meta-analysis of Randomized Controlled Trials.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X439787260312090015},
pmid = {42163663},
issn = {1875-6190},
abstract = {INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely studied for cognitive enhancement. However, their clinical efficacy remains inconclusive in patients with Alzheimer's disease (AD), Parkinson's disease (PD), and type 2 diabetes mellitus (T2DM). We therefore conducted a domain-specific meta-analysis to evaluate their cognitive effects.

METHODS: The PubMed, Web of Science, and Cochrane Library were searched for studies published up to January 2026. Eligible randomized controlled trials comparing GLP‑1 RAs to control groups, with baseline and post‑intervention cognitive scores, were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using a random‑effects model across six cognitive domains.

RESULTS: Eleven trials met the inclusion criteria. GLP-1 RAs demonstrated no significant benefit across all cognitive domains: pooled SMD for overall cognition was 0.03 (95% CI, -0.11 to 0.18; P =  0.64); memory, 0.21 (95% CI, -0.19 to 0.60; P = 0.30); attention, 0.23 (95% CI, -0.19 to 0.65; P =  0.28); executive function, 0.14 (95% CI, -0.28 to 0.56; P =  0.51); visuospatial ability, 0.04 (95% CI, -0.43 to 0.50; P =  0.88); and motor function, 0.20 (95% CI, -0.19 to 0.59; P = 0.31). Subgroup analyses by disease type and drug class also revealed no statistically significant differences.

DISCUSSION: Our findings suggest that the cognitive benefits of GLP‑1 RAs may be limited in patients with established disease. This may be attributable to irreversible neuropathological alterations in AD, PD, and T2DM patients, which hinder the translation of GLP‑1 RA-mediated neuroprotective actions into measurable symptomatic improvements. A key limitation of the present study is the relatively small sample size for several specific cognitive domains, which may affect the robustness of the results.

CONCLUSIONS: The available evidence from this meta-analysis does not support significant benefits across six cognitive domains with GLP‑1 RAs in patients with AD, PD, and T2DM. Future largescale trials with domain-specific assessments are needed to evaluate their potential in earlier disease stages or specific subgroups.},
}

@article {pmid42163677,
year = {2026},
author = {Tiwari, D and Mukherjee, A and Singh, S},
title = {Interplay of NMDAR and AMPAR in the Pathophysiology of Alzheimer's, Parkinson, ALS, Huntington's, and Epilepsy: An Update in Therapeutic Perspective.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X466249260418090832},
pmid = {42163677},
issn = {1875-6190},
abstract = {Glutamate-mediated excitotoxicity is a central driver of neurodegeneration and represents a shared pathogenic mechanism across neurodegenerative diseases and epilepsy, with N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-tors (AMPARs) occupying central roles in synaptic plasticity, Ca[2+] signalling, and neuronal survival. Dysregulation of these receptors disrupts the balance between pro-survival and pro-death pathways, accelerating neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lat-eral sclerosis (ALS), Huntington's disease (HD), and epilepsy. Disease-specific triggers converge on common patterns of receptor dysregulation, including a shift toward extrasynaptic NMDAR signal-ling and the pathological emergence of Ca[2+]-permeable AMPARs (CP-AMPAR), ultimately driving synaptic failure and neuronal loss. Although numerous NMDAR and AMPAR-directed modulators have demonstrated neuroprotective efficacy in preclinical models, clinical translation has been lim-ited by inadequate spatial, kinetic, and subunit selectivity, as well as adverse effects arising from the disruption of physiological glutamatergic transmission. In this review, we synthesize the literature published between June 1990 and March 2025 to develop an integrative framework that links recep-tor localization, downstream Ca[2+]-dependent signalling, astrocytic regulation, mitochondrial dys-function, and disease progression across these disorders. By critically evaluating both successful and failed therapeutic strategies, we provide insight into evident research gaps in the field and the neces-sity of addressing them to develop precise multi-target approaches at both the genetic and cellular levels as next-generation therapeutics. Such an approach would be essential to move beyond indis-criminate receptor blockade strategies, which have repeatedly proven ineffective over the decades, and towards a future of durable neuroprotection.},
}

@article {pmid42163678,
year = {2026},
author = {Jin, S and Liu, D and Ouyang, J},
title = {An Investigation of the Neurotoxic Mechanisms of Benzo[a]pyrene in Alzheimer's Disease Using an Integrated Approach of Network Toxicology and Machine Learning.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X447239260407111712},
pmid = {42163678},
issn = {1875-6190},
abstract = {INTRODUCTION: Benzo[a]pyrene (BaP) exposure is increasingly associated with the progression of Alzheimer's Disease (AD), yet the specific molecular links remain poorly understood. This study utilizes an integrated computational framework, combining network toxicology, machine learning, and molecular dynamics simulations, to identify core biomarkers and elucidate the potential pathological interplay between BaP and AD.

METHODS: We began our analysis by identifying the intersection of targets and then created a Protein-Protein Interaction (PPI) Network to identify hub genes. To ensure accuracy, we selected final core molecular targets from the intersection of three distinct types of machine learning algorithms. To validate diagnostic value, immune cell infiltration data analysis was performed using the GSE138260 dataset. Finally, we used molecular docking and 100 ns dynamics to assess how BaP interacts with the core molecular target.

RESULTS: We identified four proteins associated with BaP and AD: CASP3 (Caspase 3), HTT (Huntingtin), TH (Tyrosine Hydroxylase), and PARK7 (DJ-1). These proteins signal neuronal apoptosis and neuro-immune dysregulation due to their involvement in pathways associated with these processes. The Receiver Operating Characteristic (ROC) analysis demonstrated strong diagnostic properties for these targets. Molecular docking data also showed BaP as the main target, with TH binding with a value of -10.02 kcal/mol. The stability of this BaP-TH complex was further confirmed by 100 ns molecular dynamics simulations.

DISCUSSION: The research reveals TH's critical effect on BaP-induced neurotoxicity. We also identify the potential molecular mechanisms contributing to Alzheimer's disease pathology via environmental exposure.

CONCLUSION: This research identifies several significant molecular interactions between BaP and AD. One major molecular target for BaP interaction with AD is tyrosine hydroxylase (TH). Our findings here create an opportunity for the development of therapeutics for the treatment of AD cases caused by exposure to environmental toxins.},
}

@article {pmid42163688,
year = {2026},
author = {Malik, P and Singh, S},
title = {2DSDNN: A Novel Approach for Alzheimer's Disease Classification.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056368237251028221129},
pmid = {42163688},
issn = {1573-4056},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is one of the most prevalent types of dementia, which primarily impacts the elderly. Distinguishing AD stages has emerged as a significant challenge. The recent progress in neurological imaging techniques in conjunction with machine learning approaches has proved effective in identifying patterns in medical imaging. This can assist specialists in the early identification of AD.

METHODS: This paper proposes a skull-stripping algorithm to achieve precise image classification on MRI modalities. To achieve this, thresholding and morphological manipulations are executed beforehand on the T1 and T2 weighted MRI slides to eliminate extraneous tissues. Building on these segmentation results, a 2D Sequential Deep Learning Neural Network (2DSDNN) model is proposed that can effectively aid in improving the early detection of AD by utilizing 1,044 MRI scans from the ADNI dataset. 2DSDNN effectively distinguishes between types of Alzheimer's Disease for binary and multiclass classification tasks, providing superior performance over existing models.

RESULTS: Our technique achieves AD vs. CN classification accuracy, sensitivity, specificity, precision, recall, F1-score, and AUC of 98.03%, 99.04%, 97.03%, 98.00%, 99.20%, 98%, and 98.20%, respectively. The accuracy rate for AD vs. MCI classification is 95.03%, with a sensitivity rate, specificity rate, precision, recall, F1-score, and AUC of 97.07%, 94.91%, 96.0%, 97.01%, 96.0%, and 95.97%, respectively. The accuracy rate for CN vs. MCI classification is 94.05%, with sensitivity, specificity, precision rate, recall, F1-score, and AUC score of 94.21%, 94.21%, 95%, 97.01%, 96%, and 94.16%, respectively. The AD vs. MCI vs. CN classification achieved an accuracy of 97.20%, a sensitivity of 97.28%, a specificity of 95%, a precision of 97.32%, a recall of 96.13%, an F1-score of 96% and an AUC rate of 96.62%.

DISCUSSION: Compared with existing methodologies, our proposed 2DSDNN model, applied to T1- and T2-w MRI data, demonstrates a substantial enhancement in performance in the binary and multiclass classification of AD. The proposed skull-stripping algorithm, combined with Gaussian filtering and morphological manipulations, improves image segmentation, leading to more accurate classification of AD, MCI, and CN stages. Moreover, the use of T1 and T2 MRI modalities in a sequential deep learning framework allows superior performance in binary and multiclass classification tasks compared to traditional CNN and DNN models.

CONCLUSION: Our proposed model performed significantly better in binary and multiclass classification than existing contemporary techniques and could identify AD efficiently at an early stage.},
}

@article {pmid42163709,
year = {2026},
author = {Gao, C and Iles, MM and Bunce, D and Wu, B and Luo, H and Pavitt, S and Wu, J and Bishop, DT and Kang, J},
title = {Periodontal diseases and all-cause dementia risk: Genetic instrument analyses in half a million UK Biobank participants.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450558},
doi = {10.1177/13872877261450558},
pmid = {42163709},
issn = {1875-8908},
abstract = {BackgroundNumerous studies suggest that periodontal diseases might be associated with the development of dementia, but the causality is inconclusive.ObjectiveThis study aims to explore the casual effect of periodontal diseases on all-cause dementia.MethodsThe UK Biobank (UKB) data (n = ∼500,000) has been implemented, where participants were divided into two independent groups (2/3train and 1/3test). The exposure is the self-reported periodontal diseases, and the outcome is all-cause dementia measured by both clinical diagnoses based on ICD10 and ICD9 codes, and self-reported dementia. Four sets of genetic instruments were developed based on four different thresholds (main approach: p < 5 × 10[-8]; alternative approach I: p < 5 × 10[-6]; alternative approach II: p < 10[-4]; and alternative approach III: the best-fit p-value threshold calculated by polygenic risk score). The causal association between periodontal diseases and dementia was assessed by inverse-variance weighted (IVW), MR-Egger regression, weighted median, and mode-based estimate models.ResultsThe number of genetic instruments included in these four approaches varied from 3 to 1020, after passing the MR assumption checks. Most MR results suggested no causal association between periodontal diseases and dementia except the IVW model from main approach (coefficient beta: -0.816, 95% confidence interval, CI (-1.617, -0.015)) and the weighted median model from alternative approach II (beta: 0.077 95%CI (0.006, 0.149)) suggested potential causal relationship between periodontal diseases and dementia.ConclusionsThe results showed inconsistent evidence of causal link between periodontal diseases and dementia using UKB. Future studies are needed with clinically defined periodontal diseases to better understand the causal link.},
}

@article {pmid42163711,
year = {2026},
author = {Gabrielli, AP and Weidling, I and Lysaker, CR and Novikova, L and Ranjan, A and Wang, X and Wilkins, HM and Swerdlow, RH},
title = {An aging hallmark, Alzheimer's disease, and APOE nexus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452598},
doi = {10.1177/13872877261452598},
pmid = {42163711},
issn = {1875-8908},
abstract = {BackgroundThe commonality of Alzheimer's disease (AD) in the elderly suggests connections between aging and AD biology. APOE biology is also tied to AD.ObjectiveWe sought to link three aging hallmarks (loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing) to APOE biology.MethodsWe altered SH-SY5Y cell proteostasis directly via heat shock, integrated stress response inhibition (ISRIB), or autophagy inhibition (chloroquine), and indirectly by perturbing mitochondria (mtDNA depletion; oligomycin). We also exposed induced pluripotent stem cell-derived neurons to ISRIB and chloroquine. Conversely, we mitigated protein stress with rapamycin. We assessed intervention impact on APOE expression.ResultsIncreasing protein stress elevated and decreasing protein stress lowered APOE expression. In SH-SY5Y cells rapamycin blocked oligomycin-induced mTOR 2448 phosphorylation, Akt 473 phosphorylation, and APOE expression. In chloroquine-treated neurons rapamycin reduced mTOR phosphorylation and APOE expression.DiscussionProtein stress initiates APOE expression and facilitates mitochondrial dysfunction's impact on APOE by engaging the mTOR pathway. Our findings link aging and AD biology.},
}

@article {pmid42163712,
year = {2026},
author = {Clute-Reinig, N and Helfman, S and Lakis, J and Epstein, L and Niotis, K and Isaacson, R},
title = {Attitudes toward preventive neurology care: A cross-sectional survey study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452599},
doi = {10.1177/13872877261452599},
pmid = {42163712},
issn = {1875-8908},
abstract = {BackgroundUp to 45% of dementia cases due to Alzheimer's disease may be preventable, but implementation of risk-reduction programs have lagged in the United States.ObjectiveThe objective of this study was to understand whether belief in effectiveness, or interest in implementing risk-reducing interventions among healthcare consumers and providers are driving this lag.MethodsA survey was administered online using both directed and free-response questions. Directed questions were translated from Likert scales to numeric, while free-response questions were multi-operator coded and analyzed for themes.ResultsA total of 2054 full or partial responses were recorded; a majority of consumer respondents identified as White, Female, and between the ages of 51 and 79. Consumers were more interested in lifestyle than pharmaceutical interventions (Likert mean 4.5 versus 3.5, p < 0.0001), and were most interested in personalized risk reduction plans (mean 4.82, p < 0.001). Healthcare providers had higher belief in lifestyle interventions than pharmaceutical interventions (means 3.86 and 2.81, p < 0.0001), and they showed interest in medical education, referral networks, and blood biomarker testing (mean 4.15; 69%/58% of responses). Free response coding suggested that healthcare providers want to provide preventive neurology services but want guidance and education.ConclusionsBoth healthcare consumers and providers show interest in preventive neurology offerings. Our data suggest there is substantial demand for this type of care and that measures should be taken to increase clinical preventive neurology capacity.},
}

@article {pmid42163745,
year = {2026},
author = {Abdalla, EA and Fayed, AM and Hussein, MA and Abdel-Aziz, A and Mohamed, ZN},
title = {Multi-Target Neuroprotection of Salvia officinalis Aqueous Extract in a Scopolamine-Induced Model of Alzheimer's Disease: Comparative Efficacy Versus Donepezil.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128429239260312074215},
pmid = {42163745},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex, age-related, neurodegenerative disorder that involves cognitive deterioration, oxidative stress, and neuroinflammation. Symptomatic relief is limited with conventional treatments such as donepezil, sparking a significant interest in multi-target botanicals. We examined the neuroprotective effects of Salvia officinalis aqueous extract (SAGE) on a scopolamine-induced animal model of AD and the related molecular mechanisms regarding GABRA5α, GSK-3β, and pERK pathways.

METHODS: SAGE was characterized using phytochemical profiling and antioxidant assays. IC50 values were determined in vitro for inhibitor activity against GABRA5α and GSK-3β. In vivo experiments included assessment of behavior (Morris water maze), assays for oxidative stress and inflammation, gene expression studies by qPCR, and histopathology of hippocampal tissue. Efficacy versus donepezil was compared. Statistical significance was based on one-way ANOVA followed by Tukey's post-hoc test (p < 0.05) for robust comparisons between all treatment groups.

RESULTS: The SAGE had strong antioxidant abilities and was able to inhibit GABRA5α and GSK-3β in a target-specific way. SAGE treatment greatly enhanced spatial learning and memory, retained the redox equilibrium, decreased neuroinflammatory markers, and normalized AChE activity. Gene expression was found to modulate favourably for GABRA5α, GSK-3β and pERK. Histological findings confirmed neuronal preservation. In all parameters, SAGE was more effective than donepezil. The present findings demonstrated the therapeutic potential of SAGE's phenolics to mitigate oxidative cascades, including those suggested as contributing factors to AD pathology.

DISCUSSION: The superior multi-modal efficacy of SAGE over donepezil due to its phenolic-rich phytochemical profile and capacity to modulate oxidative, inflammatory, and neuronal pathways is demonstrated. This is encouraging, and additional studies should be conducted to investigate pharmacokinetics, mechanistic and clinical significance.

CONCLUSION: S. officinalis AE strongly protects the brain against scopolamine-induced AD-like neuropathology in a superior way over standard treatment via altered multi-targets. Its characteristics promote its further development as a natural therapeutic candidate for AD treatment. There are however constraints, such as nodescription of the pharmacokinetic profiling and no tau/Aβ quantification. Prospective studies with these endpoints and chronic dosing schedules should now address the issue of long-term effectiveness and safety.},
}

@article {pmid42164082,
year = {2026},
author = {Zhu, Y and Tu, Y and Ren, C and Ke, Y and Guo, Q},
title = {Correction: Elevated gonadotropins and risk of dementia in Chinese adults aged over 80: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1859014},
doi = {10.3389/fnagi.2026.1859014},
pmid = {42164082},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2025.1651723.].},
}

@article {pmid42164083,
year = {2026},
author = {Costa, CL and Araujo-Menendez, CEE and Lawrence, A and Mendoza, A and Tarraf, W and Stickel, AM},
title = {No associations between blood pressure and brain volumes in a convenience sample of Hispanic/Latino middle-aged and older adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729134},
pmid = {42164083},
issn = {1663-4365},
abstract = {BACKGROUND: High blood pressure (BP) is a known risk factor for dementia, but the relationships between BP and gross brain volumes are mixed and are understudied in groups who are at particularly high risk for dementia, such as Hispanic/Latino adults. Therefore, we aimed to investigate the relationships between BP and brain volumes, among Hispanic/Latino older adults.

METHODS: Participants included 122 cognitively healthy Hispanic/Latino late middle-aged and older adults ages (mean age = 73.48 years, SD = 7.32) from the National Alzheimer's Coordinating Center. Data were collected from 2005 to 2024 from 20 Alzheimer's Disease Research Centers. BP measures included systolic (SBP), diastolic (DBP), and pulse pressure (PP). Brain outcomes included total, hippocampal, gray matter, and white matter hyperintensity volumes. Covariates included age, sex, Hispanic/Latino heritage, hypertension, diabetes, hypercholesterolemia, body mass index, hypotensive status, and smoking status.

RESULTS: No BP measure was significantly associated with brain outcomes (all p > 0.05).

DISCUSSION: Overall, we found no relationships between BP measures and brain volumes in this sample of late middle-aged and older Hispanic/Latino adults. Our findings warrant longitudinal studies to better characterize the relationships between BP and other cardiovascular disease risk factors with brain health in this population.},
}

@article {pmid42164127,
year = {2026},
author = {Qi, J and Li, L and Duan, H and Sun, Y and Zhang, J},
title = {Integrating neuroimaging and plasma biomarkers to predict preclinical Alzheimer's disease progression.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1801239},
pmid = {42164127},
issn = {1664-2295},
abstract = {OBJECTIVE: To develop and validate a multimodal model integrating neuroimaging and plasma biomarkers for predicting the risk of cognitive progression in preclinical Alzheimer's disease (AD).

METHODS: This retrospective study enrolled 320 patients with Aβ-positive preclinical AD or AD-related mild cognitive impairment. Participants were randomly allocated into training and validation sets at a 7:3 ratio. In the training set, univariable analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariable Logistic regression were employed to identify core predictive variables. Subsequently, four machine learning models were constructed based on these variables. Model performance was evaluated using the area under the receiver operating characteristic Curve (AUC), calibration curves, and decision curve analysis. Interpretability was assessed using SHapley Additive exPlanations (SHAP) values.

RESULTS: The baseline characteristics were balanced between the training and validation sets. LASSO regression identified five core variables: Mini-Mental State Examination total score, Rey Auditory Verbal Learning Test delayed recall, normalized hippocampal volume, plasma phosphorylated tau181, and apolipoprotein E ε4 allele status. Multivariable analysis confirmed these as independent predictors (p < 0.01). The logistic regression model demonstrated robust predictive performance, achieving the highest area under the curve (AUC) in the independent validation set (0.818, 95% confidence interval: 0.703-0.933). Calibration and decision curve analyses conducted on the validation set indicated that the model was accurate and possessed clinical utility. SHAP analysis applied to the optimal model showed that normalized hippocampal volume was the most influential contributor to the predictions.

CONCLUSION: The developed multimodal model exhibits robust predictive performance and clinical utility. It may serve as a quantitative tool for individualized risk management in preclinical AD.},
}

@article {pmid42164258,
year = {2026},
author = {Podder, A and Liew, YJ and Cary, GA and Carter, GW and Uyar, A},
title = {Single-subject proteomic signatures in Alzheimer's disease reflect clinical phenotypes and distinguish asymptomatic from symptomatic cases.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70264},
pmid = {42164258},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) exhibits considerable inter-individual variability in clinical presentation, neuropathological burden, and underlying molecular processes. Conventional cohort-based analyses of omics molecular data often mask individual-level heterogeneity, limiting insights into precision therapeutic strategies. To address this challenge, we developed INdividual-level DIfferential GenOmics (INDIGO), a computational framework that quantifies molecular deviations for each individual relative to healthy controls, enabling subject-specific profiling of disease-associated alterations in proteomic data, with a framework that is readily applicable to other omics modalities.

METHODS: We applied INDIGO to dorsolateral prefrontal cortex (DLPFC) proteomic data from the Religious Orders Study and Memory and Aging Project cohort (N = 610). Protein-level deviations were aggregated into gene set activity scores for Kyoto Encyclopedia of Genes and Genomes pathways and curated AD Biodomain annotations. Functional alterations across AD and asymptomatic AD (AsymAD) individuals were evaluated and correlated with clinical metrics including apolipoprotein E (APOE) genotype, Braak stage, Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and Mini-Mental State Examination scores. Graph-based clustering was used to identify molecularly distinct subgroups based on shared patterns of functional dysregulation.

RESULTS: Limited overlap was observed between cohort-level differential expression analysis and INDIGO single-subject analyses. Individual deviations in various processes, including metabolic, immune, and epigenetic pathways, exhibited sex- and disease stage-specific patterns. Amyloid clearance and immune activation were strongly associated with APOE ε4 dosage, higher amyloid and tau burden, and cognitive decline, whereas upregulation of mitochondrial and synaptic modules correlated positively with preserved cognitive function. By linking individuals through concordant directional proteomic changes, we identified molecularly coherent subgroups that transcended conventional diagnostic boundaries and included both AD and AsymAD subjects. Each subgroup displayed distinct functional signatures defined by a unique set of key regulatory proteins.

DISCUSSION: These results demonstrate that single-subject omics profiling can resolve individual molecular signatures aligned with clinical and neuropathological variation in AD. By linking molecular heterogeneity with disease phenotypes, INDIGO provides a scalable framework for precision modeling and novel therapeutic target discovery.},
}

@article {pmid42164259,
year = {2026},
author = {Giorelli, M},
title = {Reframing Alzheimer's disease as a complex adaptive system: More than an amyloid beta-tau connection.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70256},
pmid = {42164259},
issn = {2352-8737},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, but simple models focusing on amyloid beta and tau only partially explain its variability and limited success in treatment. Evidence from systems biology, neuroimmunology, connectomics, and computational modeling supports viewing AD as a complex adaptive system, a multiscale network in which genetic, molecular, cellular, vascular, and environmental factors interact in complex, non-linear ways over time. In this perspective, disease paths develop from feedback-driven instabilities that spread across different levels, while resilience and compensatory mechanisms influence individual outcomes. This new understanding has important implications: diagnostic approaches should shift from static lesion biomarkers to longitudinal, multimodal measures of network states; treatments should combine pharmacological, metabolic, vascular, inflammatory, cognitive, and neuromodulatory strategies; and adaptive, model-informed algorithms should customize the timing and dosage to each patient's unique dynamics. Recognizing the complexity enables earlier detection of critical tipping points, targeted reinforcement of resilience, and personalized intervention plans, shifting AD care from late-stage, single-target methods to precision network medicine.},
}

@article {pmid42164431,
year = {2026},
author = {Schuller, AJ and Hager, MR and Briggs, AM and Rocha, SM and Yanouri, OA and Smith, EJ and Hall, SE and Montrose, LB and Tjalkens, RB},
title = {Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1805957},
pmid = {42164431},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder world-wide, characterized by progressive neuroinflammation, aberrant protein accumulation, and neuronal loss associated with cognitive decline. Although our understanding of the molecular mechanisms underlying AD pathogenesis has greatly increased in recent years, there remain limited treatment strategies and no cures for this disorder. Because of this, efforts have shifted toward identifying modifiable lifestyle factors which may decrease risk of onset or slow AD progression. One such approach which has shown promise in modulating the disease course is physical exercise. However, sex-specific effects of implementing such activity strategies in aged individuals after the onset of disease are less well studied. We sought to address this knowledge gap by characterizing hippocampal histopathology and DNA modification profiles of aged TgF344-AD rats following progressive treadmill-training. Reduced-representation bisulfite sequencing indicated 94 genes associated with differentially modified cytosines (DMCs) in exercised females (239 differentially modified regions, 54.6% hypermodified) and 87 DMC-associated genes in exercised males (216 differentially modified regions, 50.4% hypermodified) with unique functional enrichment for overrepresented pathways and protein interactions relevant to glial activation and synaptic plasticity. Using quantitative high-throughput slide scanning fluorescence microscopy we additionally examined this brain region for AD-relevant changes including neuronal and microglial density, microglial morphology, and accumulation of pathologic protein. This analysis revealed female-specific reductions in NeuN[+] and Iba1[+] cells in treadmill-trained animals, as well as sex- and exercise-dependent changes in plaque-associated microglial reactivity state. Together, these findings reveal that age of onset, biologic sex, and duration of physical exertion may be important factors in modulating the pathologic progression of AD.},
}

@article {pmid42164525,
year = {2026},
author = {Theodorou, B and Dadu, A and Avants, B and Nalls, M and Sun, J and Faghri, F},
title = {Realistic PET image synthesis from MRI for automated inference of brain atrophy and Alzheimer's.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115747},
pmid = {42164525},
issn = {2589-0042},
abstract = {Positron emission tomography (PET) is a crucial tool in medical imaging diagnostics but remains costly and less accessible than alternatives like X-ray and MRI. To address this, we propose MRI2PET, a 3D diffusion-based model that generates AV45-PET scans from T1-weighted MRI images. MRI2PET incorporates style-transferred pre-training and a Laplacian pyramid loss to leverage unpaired MRI data and structural correspondences between modalities while simultaneously emphasizing crucial details. Using the ADNI dataset, we demonstrate MRI2PET produces realistic PET images and improves downstream clinical classification. Notably, augmenting PET-only training data with MRI2PET-synthesized scans increases AUROC from 0.688 ± 0.014 to 0.780 ± 0.005 when classifying into one of cognitively normal, mild cognitive impairment, and Alzheimer's disease groups. These results highlight MRI2PET's ability to generate high quality, clinically informative PET scans from widely available MRI, offering an accessible, cost-effective approach to enhance machine learning performance and expand diagnostic imaging workflows.},
}

@article {pmid42164526,
year = {2026},
author = {Uzuner Odongo, D and Stephenson, RA and Cheng, L and Yang, LG and Narayan, PS and Çakır, T and Thambisetty, M},
title = {Genome-scale metabolic modeling uncovers cell-type specific signatures associated with APOE variants.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115638},
pmid = {42164526},
issn = {2589-0042},
abstract = {Metabolic dysregulation is a key feature of Alzheimer's disease (AD) pathogenesis, with the APOE ε4 variant (APOE4) representing the strongest genetic risk factor. In this study, we utilized a metabolite-centric approach to investigate how APOE4 reshapes cellular metabolism across brain cell types. Transcriptomic data from isogenic iPSC-derived neurons, astrocytes, and microglia were integrated into a human genome-scale metabolic model to identify genotype-specific alterations. These findings were validated using metabolomics data from the same cell types. In addition to cholesterol and fatty acid dysregulation, we identified alterations in bile acid biosynthesis, folate metabolism, and thyroid hormone metabolism. Similar metabolic signatures were also detected in human postmortem transcriptomic data. Integrating transcriptomic and metabolomic data enhances the understanding of biological mechanisms underlying APOE4-associated metabolic dysregulation in AD.},
}

@article {pmid42164617,
year = {2026},
author = {Garnier-Crussard, A and Dadar, M and Villain, N and Charidimou, A and Boulouis, G and Cotton, F and Brickman, AM and Chételat, G},
title = {White matter hyperintensities in Alzheimer's disease in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70349},
pmid = {42164617},
issn = {2352-8729},
abstract = {White matter hyperintensities (WMHs) are highly prevalent in Alzheimer's disease (AD) and arise from interacting vascular pathologies (including hypertensive small vessel disease and cerebral amyloid angiopathy) alongside inflammatory and neurodegenerative processes. In the era of anti-amyloid monoclonal antibodies, this heterogeneity is increasingly relevant for both treatment efficacy and safety. WMHs may signal mixed AD-vascular pathology that dilutes the cognitive benefit of amyloid-targeting therapies and may also index vulnerability of the neurovascular unit that predisposes to amyloid-related imaging abnormalities (ARIAs), although direct evidence remains limited. In this perspective, we synthesize current knowledge on the origins of WMHs in AD, review advanced magnetic resonance imaging and biomarker approaches that aim to refine lesion characterization in vivo, and discuss how WMHs should be interpreted in memory clinic practice when considering anti-amyloid therapies. We conclude with a research roadmap to integrate WMH phenotyping into precision risk-benefit assessment and ARIA prediction .},
}

@article {pmid42164618,
year = {2026},
author = {Auriacombe, S and Durand, E and Kret, M and Cartz-Piver, L and Etcharry-Bouyx, F and Sauvée, M and Belliard, S and Julian, A and Le Bail, B and Frison, E and Planche, V},
title = {Design and baseline findings of the NEODEM prospective cohort on early-onset neurodegenerative dementia.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70361},
pmid = {42164618},
issn = {2352-8729},
abstract = {INTRODUCTION: Functional prognosis of early-onset neurodegenerative dementia (EOD) remains poorly understood.

METHODS: The Neurodegenerative Early-Onset Dementia (NEODEM) study is an ongoing prospective multicenter cohort study investigating factors associated with decline in daily activities in EOD. Detailed information on behavioral and psychological symptoms of dementia (BPSD) is collected as prognostic factor.

RESULTS: Between May 2020 and May 2023, 162 patients with EOD, including 111 patients with early-onset Alzheimer's disease (AD) and 40 with frontotemporal dementia (FTD) variants, were enrolled in seven tertiary memory clinics in France. The median time from symptom onset to diagnosis was 3 years. By design, Clinical Dementia Rating (CDR) scale score was 0.5 or 1 at inclusion. Baseline level of autonomy was similar in early-onset AD and FTD, but MMSE scores were lower in AD. Baseline BPSD results are presented in the manuscript.

CONCLUSION: Four-year longitudinal data, available from 2027, will help clarify the impact of baseline factors on future functional status, institutionalization, morbidity, and mortality.},
}

@article {pmid42164619,
year = {2026},
author = {Klafki, HW and Derad, C and Hoberg, M and Asendorf, T and Hermann, E and Hassan, MM and Hansen, N and Celano, CM and Heinemann, S and Kutschka, I and Baraki, H and Sadlonova, M and von Arnim, CA and Wiltfang, J and Wirths, O},
title = {Evaluation of fully automated ApoE4 proteotyping for APOE ε4 genotype estimation in the FINDERI cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70362},
pmid = {42164619},
issn = {2352-8729},
abstract = {INTRODUCTION: Carriers of the ε4 allele of the apolipoprotein E (APOE) gene have an increased risk for Alzheimer's disease (AD) and amyloid-related imaging abnormalities (ARIAs) upon anti-amyloid beta (Αβ) immunotherapy. Measuring apoE4 and pan-apoE proteins in blood plasma for apoE4 proteotyping may offer an alternative to APOE genotyping.

METHODS: We assessed apoE4 proteotyping accuracy in 479 participants of the prospective FINd DElirium RIsk factors (FINDERI) study in patients undergoing cardiac surgery and compared results to quantitative polymerase chain reaction (qPCR) genotyping.

RESULTS: Proteotype-genotype discordance occurred in 8 of 479 participants (1.67%). Five of 17 proteotype homozygotes were genotypically heterozygous. Replacing manufacturer provided cut points with custom data-driven thresholds substantially improved classification performance.

DISCUSSION: We confirm the reported overall high classification performance of apoE4 proteotyping but underscore the need to re-evaluate the generalizability of the cut points provided with the assay kits. Misclassification of heterozygous APOE ε4 carriers as homozygous could erroneously exclude eligible patients from anti-amyloid therapies.},
}

@article {pmid42164658,
year = {2026},
author = {Liu, X and Jia, L and Wu, K and Chen, M and Sun, J and Yang, C and Xu, C and Sun, J and Wang, J and Dai, L},
title = {Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.},
journal = {MedComm},
volume = {7},
number = {},
pages = {e70766},
pmid = {42164658},
issn = {2688-2663},
abstract = {Iron (Fe) and copper (Cu) are vital micronutrients that regulate many critical physiological processes in the human body, with their homeostasis in the central nervous system (CNS) being essential for proper neuronal function. Disruptions in their metabolism and regulatory pathways have been associated with the pathogenesis of various forms of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite growing research on metal homeostasis, the intricate molecular mechanisms that link iron and copper metabolism to the initiation and progression of NDDs remain insufficiently elucidated. In this review, we provide a systematic overview of the metabolic processes of iron and copper in the body and CNS, highlighting their interactions with many metal-binding proteins, including transporters, storage proteins, and important intrinsically disordered proteins (e.g., amyloid β-protein, tau, and alpha-synuclein) involved in NDDs. We further dissect the downstream effects of metal ion dyshomeostasis on cellular redox balance, neuroinflammation, autophagy, organelle interaction network, and cell death. Additionally, we discuss current therapeutic strategies aimed at targeting iron and copper dyshomeostasis, as well as the emerging role of artificial intelligence in this field of research. By integrating metal metabolism, metal-protein interactions, the effect of metal dyshomeostasis on downstream biological processes, and potential intervention strategies, this review serves as a comprehensive reference for understanding the pathogenesis of NDDs and offers new perspectives for developing effective therapeutics. Overall, this review underscores the significance of reinstating metal balance for the treatment of neurodegeneration.},
}

@article {pmid42164918,
year = {2026},
author = {Kara, G and Villapol, S},
title = {Toward nanomedicine-enabled RNA therapeutics for Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {22},
pmid = {42164918},
issn = {3059-4944},
abstract = {Alzheimer's disease (AD), the most common cause of dementia, is driven by intersecting proteopathic and inflammatory processes, including amyloid-β aggregation, tau pathology, neuroinflammation, synaptic dysfunction, and progressive neuronal loss. Current therapies remain insufficient to address its multifactorial nature. RNA-based therapeutics, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), enable precise modulation of disease-relevant pathways. However, their clinical translation in AD is constrained by poor stability, immunogenicity, and limited delivery across the blood-brain barrier (BBB). Nanotechnology has enabled clinically successful RNA delivery in several non-CNS indications, yet nanoparticle (NP)-mediated nucleic acid delivery has not been evaluated in AD clinical trials to date. In this review, we integrate the emerging clinical landscape of CNS-directed RNA therapeutics with the preclinical evidence supporting NP-enabled delivery to AD-relevant targets and cell types, and we highlight design features that enhance stability, BBB transport, endosomal escape, and cellular selectivity. We further delineate the key translational requirements to advance these platforms from proof-of-concept to first-in-human studies, including scalable, reproducible manufacturing; rigorous safety and tolerability assessments; mitigation of innate immune activation; and consistent, quantifiable brain exposure and target engagement. Finally, we discuss next-generation strategies, such as multifunctional, stimulus-responsive nanocarriers and combinatorial RNA payloads, aimed at addressing AD heterogeneity and enabling durable, mechanism-based disease modification.},
}

@article {pmid42164955,
year = {2026},
author = {Uchida, Y and Nishimaki, K and Kan, H and Iyatomi, H and Oishi, K},
title = {Hippocampal subregional texture features associated with Alzheimer's disease severity and cognition.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag164},
pmid = {42164955},
issn = {2632-1297},
abstract = {Alzheimer's disease (AD) exhibits selective vulnerability in hippocampal subfields, where microstructural alterations precede overt atrophy. Conventional morphometric measures, such as volume or thickness, are limited in their ability to capture subtle textural heterogeneity that reflects underlying cytoarchitectural disorganization, particularly perforant path fibres within the subiculum. The objective of this study is to determine whether hippocampal subregional texture-based radiomic features can serve as sensitive markers of disease severity and cognitive impairment along the AD continuum. This retrospective, multicentre, cross-sectional study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants who underwent coronal high-resolution T2-weighted 'HighResHippo' magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarker assessment within 1 month of each other between June 2011 and May 2025 were included. Automatic Segmentation of Hippocampal Subfields was used to delineate cornu ammonis 1-3, dentate gyrus, subiculum, and other medial temporal cortices, followed by quality control to exclude mislabelled or artefact-degraded segmentations. After bias-field correction, intensity normalization, and voxel-resampling, first-order, shape, and texture features-including grey-level run-length matrix (GLRLM) metrics-were extracted. Participants were categorized according to cognitive status and CSF amyloid-β (Aβ) positivity. Associations between radiomic features and Montreal Cognitive Assessment (MoCA) scores as well as CSF tau concentrations were evaluated using multiple linear regression, adjusting for age, sex, education, and APOE ε4 status. Among 1264 screened participants, 241 met all inclusion criteria (mean age 73.4 ± 6.9 years; 54% women). GLRLM-based run entropy within the subiculum demonstrated a stepwise increase across the AD continuum (cognitively unimpaired-Aβ- < cognitively unimpaired-Aβ[+] < mild cognitive impairment-Aβ[+] < AD dementia-Aβ[+]). Orientation-specific analyses revealed that the superior-inferior component-aligned with the dominant fibre orientation of the subicular efferent pathway-showed the strongest associations with clinical and biomarker indices. Higher SI run entropy correlated with lower MoCA performance (standardized β = -0.710 [95% CI -1.416 to -0.038]) and higher CSF tau levels (standardized β = 2.307 [95% CI 0.767 to 3.848]) compared with other directional components. Radiomic texture features derived from in vivo high-resolution T2-weighted MRI of hippocampal subregions-particularly subicular GLRLM run entropy aligned with superior-inferior tract orientation-track disease severity and cognitive impairment along the AD continuum. These findings support texture-based imaging biomarkers as sensitive indicators of early microstructural alterations in AD.},
}

@article {pmid42165009,
year = {2026},
author = {Miltiadous, A and Ntetska, A and Aspiotis, V and Moustakli, E and Tsipouras, MG and Tzallas, AT and Giannakeas, N and Glavas, E and Angelidis, P and Tzimourta, KD},
title = {The AHEPA EEG benchmark: setting the standard for machine learning in dementia diagnosis, a scoping review.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {95},
pmid = {42165009},
issn = {1871-4080},
abstract = {Accurate and reproducible electroencephalography (EEG)-based classification of dementia remains a key challenge in computational neurodiagnostics. The open-access AHEPA dataset has become the most commonly used benchmark for Alzheimer's disease (AD) and Frontotemporal dementia (FTD) classification, yet reported results vary widely due to methodological inconsistencies. This study presents the first systematic and quantitative benchmark review of all published machine learning approaches applied to the AHEPA dataset. Forty-six studies were reviewed and stratified into three validity tiers, with Validity 1 representing the highest methodological rigor and Validity 3 the lowest.According to their evaluation rigor: (1) subject-level validation (e.g., Leave-One-Subject-Out cross-validation, LOSO-CV), (2) subject-level train/test splits, and (3) epoch-level k-fold cross-validation. Performance metrics were normalized across classification problems. The analysis revealed that methodological rigor is inversely correlated with reported accuracy: for AD versus Cognitively Normal controls, mean accuracy decreased from 90.81% overall to 82.11% in Validity-1 studies; for FTD versus controls, accuracy dropped from 86.53% to 75.18%. Linear regression analyses demonstrated that weaker validation protocols were associated with systematic increases of 7-10% points in reported accuracy, explaining more than half of the observed performance variance. Deep and hybrid models reported the highest nominal accuracies, but under proper validation, traditional algorithms performed comparably, indicating that data leakage often drives apparent improvements. The review also highlights the lack of cross-configuration generalization and the urgent need for adaptive, montage-independent methodologies. Overall, this benchmark establishes the first reproducible reference framework for EEG-based dementia classification on the AHEPA dataset, providing quantitative baselines and validity criteria against which all future studies should be evaluated.},
}

@article {pmid42165032,
year = {2026},
author = {Dong, Y and Jin, H and Wang, S and Xu, Y},
title = {Salidroside mitigates cognitive deficits in AlCl3 exposed aging mouse by modulating APP processing and mitochondrial dysfunction.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1802923},
pmid = {42165032},
issn = {1662-5153},
abstract = {BACKGROUND AND OBJECTIVES: Mitochondrial dysfunction and oxidative stress are key contributors to the progression of Alzheimer's disease (AD). Salidroside, a bioactive glycoside derived from Rhodiola rosea, exhibits neuroprotective and antioxidative properties; however, its effects on mitochondrial dysfunction and APP processing in AD remain to be fully elucidated.

METHODS AND STUDY DESIGN: We employed both in vivo and in vitro models to evaluate the neuroprotective potential of salidroside. D-galactose-induced AlCl3 exposed aging mouse model was used for behavioral assessments, biochemical analyses of brain tissue biomarkers, and evaluation of mitochondrial dysfunction-related proteins and functions. In vitro experiments with HT-22 hippocampal neurons assessed the effects of salidroside on oxidative stress, mitochondrial integrity, apoptosis, and amyloid precursor protein (APP) processing.

RESULTS: Salidroside significantly improved cognitive performance and reduced Aβ deposition in the AlCl3 exposed aging mouse by modulating APP processing, characterized by downregulation of β- and γ-secretase activities and enhancement of α-secretase activity. These changes coincided with decreased mitochondrial protein aggregation and restored mitochondrial function and redox balance. In vitro, salidroside attenuated reactive oxygen species (ROS) generation, inhibited neuronal apoptosis, and suppressed Aβ production, demonstrating broad neuroprotective effects relevant to AD pathology.

CONCLUSION: Our results suggest that salidroside may alleviate mitochondrial dysfunction and reduce mitochondrial protein aggregation by modulating APP processing, promoting sAPPα production while decreasing β-CTF and Aβ levels. These findings provide preliminary evidence supporting the neuroprotective potential of salidroside in ameliorating mitochondrial impairment and cognitive deficits associated with Alzheimer's disease, warranting further investigation.},
}

@article {pmid42165286,
year = {2026},
author = {Panjwani, M and Holmes, JM and Liu, SH and Lee, E and Rapcsak, S and Harris, A and Kozak, I},
title = {Artificial intelligence for detection and staging of Alzheimer's disease using retinal images.},
journal = {The Cochrane database of systematic reviews},
volume = {5},
number = {},
pages = {CD016358},
pmid = {42165286},
issn = {1469-493X},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Artificial Intelligence ; Algorithms ; *Retina/diagnostic imaging ; Cognitive Dysfunction ; },
abstract = {This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To determine the diagnostic accuracy of AI algorithm-based retinal image reading for detecting referral-requiring Alzheimer's disease in adults who have behavioral symptoms or cognitive decline in the primary care setting. Secondary objectives Where data are available, we will investigate heterogeneity by incorporating covariates in a metaregression.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging
*Artificial Intelligence
Algorithms
*Retina/diagnostic imaging
Cognitive Dysfunction

@article {pmid42165338,
year = {2026},
author = {Saeed, A and Mckennan, C and Clougherty, JE and Zhou, P and Tripathy, S and Kinnee, EJ and Duan, J and Kip, K and Zeng, X and Villemagne, V and Pascoal, T and Mapstone, M and Whitsel, EA and Lopez, OI and Ballantyne, C and Karikari, TK and Yu, B and Reis, S and Cohen, A},
title = {2-aminobutyrate mediates the impact of air pollution on blood biomarkers of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71388},
doi = {10.1002/alz.71388},
pmid = {42165338},
issn = {1552-5279},
support = {R01 AG083874 U24AG082930 P30 AG066468 RF1 AG077474 R01 AG083156 R37 AG023651 R01 AG025516 R01 AG073267 R01 AG075336 R01 AG072641 P01 AG025204//NIH/NIA/ ; U01 NS131740 U01 NS141777//NIH/NINDS/ ; R01 MH108509/MH/NIMH NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; HT94252320064//DoD/ ; //the Anbridge Charitable Fund/ ; //the Department of Psychiatry, University of Pittsburgh/ ; 23CDA1055489//by American Heart Association/ ; ME-02-384//the Pennsylvania Department of Health/ ; //and National Institutes of Health/ ; },
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood ; Male ; *Air Pollution/adverse effects ; Female ; *tau Proteins/blood ; Aged ; Particulate Matter/adverse effects ; Amyloid beta-Peptides/blood ; Cohort Studies ; Middle Aged ; },
abstract = {INTRODUCTION: We examined the impact of mid-life metabolites on late-life Alzheimer's disease (AD) plasma biomarkers and whether these metabolites mediate air pollution effects.

METHODS: In the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort, we applied high-dimensional regression and meditation models, adjusting for observed and latent confounders, with replication in the Atherosclerosis Risk in Communities (ARIC) study. Exposures included mid-life fine particulate matter (PM2.5), black carbon, metals, and metabolites. Outcomes were: late-life plasma p-tau(181, 217, and 231) and amyloid beta 42/40 (Simoa assays).

RESULTS: In the Heart SCORE study, seven lipid- and amnio acid-pathway metabolites measured in mid-life were significantly inversely associated with late-life p-tau181 levels (false discovery rate ≤ 15%) and showed a nominal inverse association with p-tau217 and 231 (P < 0.05). 2-aminobutyrate was associated with mid-life PM2.5 concentration (µg/m[3]; β = -0.047; P = 4.0 × 10-4) and mediated the effect of PM2.5 on p-tau181 (P = 0.0057). Independent replication in the ARIC study confirmed the inverse association.

DISCUSSION: Mid-life metabolite profiles, particularly 2-aminobutyrate, may predict and mediate air pollution-related AD risk.

HIGHLIGHTS: Seven mid-life metabolites were inversely linked to late-life plasma phosphorylated tau (p-tau)181. 2-aminobutyrate was tied to fine particulate matter (PM2.5), black carbon, and heavy metal exposure in two independent cohorts. 2-aminobutyrate may link pollution to Alzheimer's disease (AD) via oxidative stress pathways. This effect is specific to p-tau181, a marker of early AD changes. This is the evidence of a metabolic mediator between air pollution and AD risk.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood
Male
*Air Pollution/adverse effects
Female
*tau Proteins/blood
Aged
Particulate Matter/adverse effects
Amyloid beta-Peptides/blood
Cohort Studies
Middle Aged

@article {pmid42165626,
year = {2026},
author = {Bregman, N and Zifman, N and Fogel, H and Abulher, E and Maidan, I and Shiner, T},
title = {Prefrontal and Occipital Network Excitability Differences in Dementia with Lewy Bodies and Alzheimer's Disease.},
journal = {Clinical EEG and neuroscience},
volume = {},
number = {},
pages = {15500594261452759},
doi = {10.1177/15500594261452759},
pmid = {42165626},
issn = {2169-5202},
abstract = {BackgroundThere is a great need in distinguishing Dementia with Lewy Body (DLB) from Alzheimer's disease (AD) and elucidating its pathophysiology. Transcranial magnetic stimulation (TMS) evoked potentials (TEPs) offer a non-invasive measure of neurophysiological alterations associated with underlying disease pathology.MethodsA total of 39 participants were included: 12 DLB, 10 AD, and 17 age-matched healthy controls (HC). TEPs were measured in the dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1), and primary visual cortex (V1).ResultsGlobal mean field potential (GMFP) TEP (130-250 ms) showed a significant interaction of group and stimulation site (p = .0101, ηp[2] = 0.175) with a significant group effect (p = .0071, ηp[2] = 0.234), attributed to higher GMFP in DLB compared to AD and HC in response to V1 stimulation (p = .001, p = .001, respectively). TEP amplitude corresponding to P60 displayed a significant group*stimulation site interaction (p = .0037, ηp[2] = 0.202) arising from differences in DLPFC stimulation, between DLB compared to AD (p = .0013) and HC (p = .0032). DLPFC N45 presented a significant stimulation site effect not associated to a specific group in addition to DLPFC N45 amplitude being correlated to the UPDRS-III score (r = 0.9, p = .0002). A relative higher left over right DLPFC P30 amplitude was correlated with poorer MoCA scores in AD (r = -0.84, p = .002), as indicated by others before.ConclusionsDLPFC may be a target for both diagnosis and assessment of severity of motor symptoms in DLB and cognitive impairment in AD. These results propose a promising method to non-invasively distinguish DLB from AD and monitor disease, based on DLPFC and V1 network characteristics.},
}

@article {pmid42165881,
year = {2026},
author = {Di Stadio, A and Brenner, MJ and De Luca, P and D'Ascanio, L and Patel, ZM},
title = {Regenerating smell in neurodegenerative disease -translating theory into therapy.},
journal = {European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery},
volume = {},
number = {},
pages = {},
pmid = {42165881},
issn = {1434-4726},
abstract = {PURPOSE: Quantitative and qualitative olfactory dysfunction are one of the earliest and most prevalent symptoms across neurodegenerative diseases, notably Parkinson's and Alzheimer's disease. These pathologies may spread bidirectionally between the peripheral olfactory system and central brain regions, supporting a model in which the olfactory system represents both an early marker and a conduit for disease propagation. This short communication aims to investigate the potential of Platelet Rich Plasma (PRP) to treat smell alteration in the neurodegenerative diseases.

METHOD: We conducted a review of the literature to extract articles that discussed PRP use in the context of olfactory disorders.

RESULTS: 12 studies were identified; 7 studies on COVID-19, 2 on unspecific smell loss, 1 on traumatic anosmia, 1 on nasal polyposis and 1 illustrated the use of PRP in long-term persistent anosmia (> 25 years).

CONCLUSION: Post COVID-19 olfactory impairment has provided insights into mechanisms of smell loss and therapeutic strategies. While olfactory training remains the best studied intervention, its benefits are modest, inconsistent, and often limited in cases with central nervous system involvement. PRP has emerged as a promising candidate due to its growth factors and immunomodulatory properties. Preclinical studies demonstrate that intranasal PRP can enhance neurogenesis, reduce neuroinflammation, and improve olfactory and cognitive outcomes in animal models of Parkinson's and Alzheimer's disease. Early clinical observations also suggest potential benefit in longstanding anosmia of diverse etiologies. Future research should define optimal delivery routes, dosing, and long-term efficacy, with well-designed clinical trials needed to translate these experimental findings into therapeutic applications.},
}

@article {pmid42165911,
year = {2026},
author = {Chen, H and Chen, H and Xie, L and Jiang, K and Xia, E and Mao, J and Liu, Z and Li, X and Xiao, Y and Qian, X and Jin, Z},
title = {Novel salivary biomarkers of Alzheimer's disease identified by integrated metabolomics and microbiomics analysis.},
journal = {Clinical oral investigations},
volume = {30},
number = {6},
pages = {},
pmid = {42165911},
issn = {1436-3771},
support = {LGF22H100005 and LTGY24H100005//the Natural Science Foundation of Zhejiang Province/ ; 2023YFF0611002//the National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/diagnosis ; *Saliva/microbiology/chemistry/metabolism ; Biomarkers/metabolism/analysis ; Male ; *Metabolomics/methods ; Female ; Aged ; *Cognitive Dysfunction/metabolism/microbiology ; Case-Control Studies ; Microbiota ; Aged, 80 and over ; },
abstract = {OBJECTIVES: Alzheimer's disease (AD) and mild cognitive impairment (MCI) represent significant health challenges, with identification of biomarkers from non-invasive biofluid critical for large-scale screening and effective intervention.

MATERIAL AND METHODS: In this study, we performed a comprehensive analysis integrating non-targeted metabolomics and 16S rDNA sequencing of saliva samples from 3 age and sex-matched groups containing 18 AD patients, 15 MCI individuals and 19 healthy controls (HC).

RESULTS: Salivary metabolites including histamine (biogenic amine), carveol (monoterpene), and 2-phosphoglycerate (glycolytic intermediate) were significantly altered in AD patients. In addition, L-glutamic acid (excitatory neurotransmitter) levels were notably reduced in MCI patients, suggesting its potential as a biomarker for MCI. Microbial analysis revealed a decrease in the abundance of Actinomyces and Stomatobaculum in AD patients. In contrast, MCI patients exhibited a reduction in Atopobium and Actinomyces, along with an increase in Gemella and Peptostreptococcus compared to HC. An integrated analysis of microbiota and metabolites uncovered significant correlations, such as a positive correlation between Lactobacillus crispatus and GABA in AD patients, and an association between Klebsiella pneumoniae and multiple metabolites in AD patients. Additionally, MCI patients exhibited a higher abundance of "potentially pathogenic" microbiota species, highlighting a distinct microbiome profile.

CONCLUSIONS: Our findings revealed distinct metabolic and microbiomic alterations across the groups.

CLINICAL RELEVANCE: These findings suggest that saliva may harbor valuable biomarkers for the early diagnosis of AD and MCI. Moreover, our results underscore the involvement of the "oral-brain axis" in the pathogenesis of neurodegenerative diseases, offering new insights into potential therapeutic targets.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/diagnosis
*Saliva/microbiology/chemistry/metabolism
Biomarkers/metabolism/analysis
Male
*Metabolomics/methods
Female
Aged
*Cognitive Dysfunction/metabolism/microbiology
Case-Control Studies
Microbiota
Aged, 80 and over

@article {pmid42165998,
year = {2026},
author = {Oliveira, Â and Almeida, LM and Oliveira, JMA and Pinho, BR},
title = {Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {42165998},
issn = {1573-4919},
abstract = {Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer's and Parkinson's. However, little is known about MPC as a potential therapeutic target in Huntington's disease (HD), a neurodegenerative disorder with dysregulation of the pro-survival pathway integrated stress response (ISR). Here, we investigate if MPC inhibition modulates the ISR and mitigates mutant huntingtin (mut-Htt) proteotoxicity in a cellular HD model. We treated cells expressing N-terminal fragments of wild-type- (wt-) or mut-Htt with two MPC inhibitors (mitoglitazone and UK5099) or solvent control. Metabolism was assessed analysing resazurin reduction, oxygen consumption, extracellular acidification, and ATP levels. ISR activation and huntingtin proteostasis were assessed using western-blot and filter-trap assays. Mut-Htt-expressing cells showed decreased resazurin reduction and ATP levels, and increased eIF2α phosphorylation, indicating metabolic stress and ISR activation. MPC inhibitors (100 µM) increased resazurin reduction and decreased respiration. The latter was rescued by the membrane-permeant methyl pyruvate, which bypasses MPC inhibition. In wt-Htt-expressing cells, MPC inhibitors increased levels of ATP and ISR markers, suggesting metabolic adaptation and ISR activation. In mut-Htt-expressing cells, MPC inhibitors preserved ATP levels and attenuated mut-Htt-induced eIF2α phosphorylation but without changing soluble or aggregated mut-Htt levels. This work showed that MPC inhibition differentially modulates the ISR: it activates ISR in control cells and attenuates overactive ISR in mut-Htt-expressing cells. However, MPC inhibition did not impact the proteostasis of N-terminal fragment mut-Htt. Further studies are essential to explore MPC inhibition in less severe full-length mut-Htt-expressing models to better understand its therapeutic potential in HD.},
}

@article {pmid42166005,
year = {2026},
author = {Kariminejad-Farsangi, H and Kariminejad-Farsangi, H and Mir, Y and Sheibani, V and Joushi, S},
title = {Mechanistic insights into mesenchymal stem cell therapy for cognitive impairments in Alzheimer's disease models: a systematic review and meta-analysis.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {42166005},
issn = {1573-4919},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options that primarily offer symptomatic relief. Mesenchymal stem cells (MSCs) have shown promise in preclinical studies due to their neuroprotective, immunomodulatory, and regenerative properties. This systematic review and meta-analysis aimed to assess the effects of MSC therapy on cognitive performance and molecular pathology in animal models of AD.A systematic search was conducted in PubMed, Web of Science, Scopus, Embase, ProQuest, and gray literature sources. This study included in vivo interventional animal studies that evaluated the effects of MSCs on cognitive outcomes in Alzheimer's disease models using the Morris Water Maze test. The standardized mean difference (SMD) was used as the effect size, and data were synthesized using a random-effects model. Study quality was assessed using the SYRCLE risk of bias tool. Publication bias was evaluated through funnel plots, Egger's test, and the trim-and-fill method. Sensitivity analysis was performed using the leave-one-out method and further supported by a risk-of-bias-based approach.A total of 51 studies met the inclusion criteria, of which 37 were included in the meta-analysis. The findings indicated that MSC therapy significantly reduced escape latency (SMD = -1.18, 95% CI -1.46 to-0.89, I[2] = 56.81%, P = 0.00) and increased time spent in the target quadrant (SMD = 1.93, 95% CI 1.46 to 2.40, I[2] = 78.63%, P = 0.00). MSC treatment also led to an increase in hippocampal BDNF levels and a reduction in Aβ deposition and pro-inflammatory cytokines such as IL-1β and TNF-α. However, the effect on IL-6 levels was not statistically significant.MSCs Improve cognitive function and modulate pathological features in AD animal models. Further high-quality studies with standardized protocols and broader literature inclusion are needed to support clinical translation.},
}

@article {pmid42166031,
year = {2026},
author = {Xu, X and Ni, Z and Wang, YB and Fan, SS and Du, Y and Wang, X and Meng, XY},
title = {Decoding shared pathogenic networks of oxidative stress in neuropsychiatric disorders to prioritize multi-target therapeutics from natural products.},
journal = {Cell biology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10565-026-10208-w},
pmid = {42166031},
issn = {1573-6822},
support = {2508085QC099//Natural Science Foundation of Anhui Province of China/ ; 2025AHGXZK40182//Natural Science Research Project for Youth of Higher Education Institutions of Anhui Province/ ; },
abstract = {BACKGROUND: Neurodegenerative and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia (SZ), are characterized by progressive neuronal loss and synaptic dysfunction. Despite their severity, effective disease-modifying treatments remain unavailable, largely due to the elusive nature of their underlying molecular mechanisms.

METHODS: To elucidate these mechanisms, we conducted an integrative systems biology analysis incorporating transcriptomic datasets, in silico proteomic networks, and inferred metabolomic profiles. Machine learning (ML) and deep learning (DL) models were employed to identify regulatory networks associated with oxidative stress, immune response, and synaptic signaling. Furthermore, network pharmacology approaches were applied to explore multi-target intervention strategies using bioactive compounds from traditional Chinese medicine (TCM).

RESULTS: Our integrative analysis revealed extensive overlap in dysregulated biological processes across all four disorders, particularly involving oxidative stress and immune activation. We identified TP53, NFE2L2, and PPP3CA as central regulatory hubs driving these pathologies. Notably, computational predictions highlighted that TCM-derived compounds, specifically stigmasterol and dodecanoic acid, exhibit promising multi-target effects for modulating these oxidative and inflammatory responses. Subsequent in vivo experimental validation was performed exclusively to corroborate the disease-associated pathways and core gene dysregulation in an Aβ42-induced AD model. These findings demonstrated molecular and behavioral phenotypes consistent with our multi-dimensional computational predictions, establishing a robust mechanistic rationale that merits future in vivo pharmacological validation for the predicted bioactive compounds.

CONCLUSION: This study highlights the utility of a multi-disease, multi-dimensional framework in uncovering shared pathogenic signatures. By integrating computational analytics with pharmacological modeling and experimental validation, we identified key regulatory genes and natural compounds with therapeutic potential. These findings provide a theoretical foundation for the development of multi-target, personalized treatment strategies against neurodegeneration.},
}

@article {pmid42166097,
year = {2026},
author = {Cao, J and Wang, H and Han, B and Song, J and Tang, Z},
title = {ALKBH5-mediated m6A demethylation of PRMT6 inhibits neuronal apoptosis and ferroptosis in Alzheimer's disease via reducing transcription of ACSL4.},
journal = {Cell biology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10565-026-10197-w},
pmid = {42166097},
issn = {1573-6822},
support = {21042230044//The 2023 General Postdoctoral Funding Project of Heilongjiang Province/ ; GZC20230639//National Postdoctoral Researcher Program B Category/ ; },
abstract = {BACKGROUND: Protein arginine methyltransferase 6 (PRMT6) is confirmed to regulate Alzheimer's disease (AD) process. Acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis is involved in regulating AD progression. However, whether PRMT6 regulates AD progression through ACSL4-mediated ferroptosis is unknown.

METHODS: AD mice were injected with adeno-associated virus to explore the role of PRMT6 and AlkB homologue 5 (ALKBH5) in vivo. Neuronal cells were treated with amyloid-β protein fragment 1-42 (Aβ1-42) to mimic AD cell models. The expression levels of PRMT6, ALKBH5, ACSL4, GPX4, and SLC7A11 were tested by qRT-PCR or western blot. Cell viability and apoptosis were detected by CCK8 assay and TUNEL staining. The levels of ROS, MDA, SOD and Fe[2+] were tested to evaluate ferroptosis. Mouse behavior, neuron injury, Aβ deposition, and neuronal cell apoptosis were examined by morris water maze test, novel object recognition test, histological staining and TUNEL staining. The interactions between PRMT6 and ALKBH5 or ACSL4 were analyzed.

RESULTS: PRMT6 expression was upregulated in AD mice. Silencing of PRMT6 repressed Aβ1-42-induced neuronal cell apoptosis and ferroptosis, as well as alleviated cognitive deficits in AD mice. ALKBH5 reduced PRMT6 expression by inhibiting its m6A modification. ALKBH5 overexpression suppressed Aβ1-42 induced apoptosis and ferroptosis in neuronal cells, and this effect was reversed by PRMT6 upregulation. Besides, PRMT6 promoted ACSL4 expression via increasing H3R2me2a on the ACSL4 promoter, and ACSL4 overexpression also abolished the inhibitory effect of PRMT6 knockdown on Aβ1-42-induced cell ferroptosis. Meanwhile, ALKBH5 inhibited neuronal cell ferroptosis to relieve cognitive deficits in AD mice via repressing the PRMT6/ACSL4 axis.

CONCLUSION: ALKBH5 could inhibit neuronal cell ferroptosis to alleviate the progression of AD by decreasing PRMT6-mediated ACSL4 transcription through H3R2me2a.},
}

@article {pmid42166149,
year = {2026},
author = {Bhattacharya, A and Fon, EA and Dagher, A and Iturria-Medina, Y and Stratton, JA and Savignac, C and Stanley, J and Hodgson, L and Hammou, BA and Bennett, DA and Bzdok, D},
title = {Cell type transcriptomic modules reveal shared molecular mechanisms in Alzheimer's and Parkinson's disease.},
journal = {GigaScience},
volume = {},
number = {},
pages = {},
doi = {10.1093/gigascience/giag059},
pmid = {42166149},
issn = {2047-217X},
abstract = {Historically, Alzheimer's disease (AD) and Parkinson's disease (PD) have been investigated as two distinct disorders of the brain. However, a few similarities in neuropathology and clinical symptoms have been documented over the years. Traditional single-gene centric studies, such as differential gene expression analyses, have struggled to unravel the molecular basis for the observed pathological links between AD and PD. To address this, we tailor a latent factor framework to analyze synchronous gene co-expression at sub-cell-type resolution. Utilizing large, single-nucleus transcriptomics datasets in AD (70,634 nuclei) and PD (340,902 nuclei) from postmortem human brains, we systematically extract and juxtapose disease-critical molecular signatures in the brain. Our transcriptomic analysis reveals shared molecular programs between AD and PD that systematically localize to specific glial and neuronal cell types. In neurons, convergent gene groups in AD and PD relate to cytoskeletal dynamics and mitochondrial stress mechanisms. Similarly, overlapping gene groups in microglia modules implicate T cell activation mechanisms and synapse pruning pathways. In parallel, AD- and PD-associated genes in astrocytes are involved in heavy metal processing; oligodendrocytes highlight convergent dysregulation in myelin synthesis. In addition, our analysis reveals APOE, an AD GWAS gene, has disease predictive roles in PD-associated gene modules. Conversely, SNCA, a PD GWAS gene, emerges within AD associated gene modules. Our multi-module sub-cell-type approach offers unique insights into the molecular basis of shared neuropathology in AD and PD.},
}

@article {pmid42166242,
year = {2026},
author = {Kalita, M and Kuo, RC and Straniero, V and Reyes, ST and Pandrala, M and Lanzini, A and Marsango, S and D'Moore, D and Mahn, P and Setiadi, A and Sundar, M and Mak, S and Nagy, S and Alam, IS and Jain, P and Inay, G and Malek, R and Brooks, AF and Beinat, C and Valoti, E and Scott, PJH and Milligan, G and James, ML},
title = {Illuminating proinflammatory myeloid cells with PET tracers targeting GPR84.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {21},
pages = {e2536372123},
doi = {10.1073/pnas.2536372123},
pmid = {42166242},
issn = {1091-6490},
support = {N/A//SU | Wu Tsai Neurosciences Institute, Stanford University (Wu Tsai Neurosciences Institute)/ ; DGE-2146755//NSF | NSF Graduate Research Fellowship Program (GRFP)/ ; APP72799//UKRI | Biotechnology and Biological Sciences Research Council (AFRC)/ ; F31AG094229//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {Animals ; *Positron-Emission Tomography/methods ; *Receptors, G-Protein-Coupled/metabolism/genetics ; Mice ; *Myeloid Cells/metabolism ; Humans ; *Inflammation/diagnostic imaging/metabolism ; Fluorine Radioisotopes ; Microglia/metabolism ; Mice, Inbred C57BL ; Macrophages/metabolism ; Lipopolysaccharides ; Receptors, GABA ; },
abstract = {Innate immunity mediated by myeloid cells defends against infection and injury, but when chronically activated, it drives tissue damage and neurodegeneration. Molecular imaging with positron emission tomography (PET) enables noninvasive, real-time monitoring of such processes in vivo. However, most current neuroinflammation PET tracers lack specificity for activated myeloid cells. G protein-coupled receptor 84 (GPR84) is a promising biomarker that is selectively upregulated on activated microglia and macrophages. Here, we report the development and validation of two fluorine-18-labeled GPR84 tracers, [[18]F]MGX-110S and [[18]F]MGX-111S. Both exhibit specific binding to human GPR84-expressing cells, with [[18]F]MGX-110S demonstrating superior affinity, selectivity, and signal-to-background ratio. [[18]F]MGX-110S enables sensitive detection of systemic- and neuro-inflammation in LPS-treated mice and outperforms PET images obtained using a radiotracer specific for translocator protein 18 kDa in 5xFAD mice-revealing pathology-correlated activation across cortical, hippocampal, and thalamic regions. Taken together, our data indicate that [[18]F]MGX-110S is a highly sensitive and specific tool for visualizing maladaptive myeloid cell activation; its clinical translation could enable more precise detection and staging of inflammation in addition to improved therapeutic monitoring in neurodegenerative disorders and more broadly in inflammatory diseases.},
}

Animals
*Positron-Emission Tomography/methods
*Receptors, G-Protein-Coupled/metabolism/genetics
Mice
*Myeloid Cells/metabolism
Humans
*Inflammation/diagnostic imaging/metabolism
Fluorine Radioisotopes
Microglia/metabolism
Mice, Inbred C57BL
Macrophages/metabolism
Lipopolysaccharides
Receptors, GABA

@article {pmid42166326,
year = {2026},
author = {Cotter, VT and Grudzen, CR and Griffith, J and Cuthel, A and Hoque, A and Arbaje, AI and Gettel, CJ and Durga, A and Emami, A and Goldfeld, K and Chodosh, J and Shah, MN and Brody, AA and , },
title = {Nurse-Led Telephonic Care Following Emergency Department Visits for Persons Living With Dementia and Their Care Partners: A Program Description.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70429},
pmid = {42166326},
issn = {1532-5415},
support = {U19 AG078105-01A1/AG/NIA NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; },
abstract = {Most visits to the emergency department (ED) by persons living with dementia (PLWD) who are then discharged back into the community are preventable. However, care partners and other caregivers of the over 6 million PLWD residing in the United States lack the supports, services and timely access to clinical care to address many common needs in the community. Thus, care partners resort to taking the PLWD to the ED, a sub-optimal environment that can be traumatic to the PLWD, increase iatrogenesis, and ultimately may not resolve the underlying reason for the visit. Longitudinal nurse-led telephonic care (NLTC) provided following an ED visit with community discharge may present an effective and efficient model for health systems to support care partners, decant busy EDs, and provide high-quality, person and family-centered impactful care to support PLWD and their care partners. This paper describes the development of an NLTC program being implemented as part of the Emergency Departments LEading Transformation of Alzheimer's and Dementia Care (ED-LEAD) trial, a factorially designed embedded pragmatic clinical trial in 79 EDs. The NLTC program utilizes components of two previously tested programs, the Aliviado Dementia Care quality improvement program, and the Emergency Medicine Palliative Care Access (EMPallA) nurse-led telephonic palliative and transitional care program to support PLWD and their care partners. Successful implementation of the NLTC program may lead to increased uptake of NLTC programs by health systems, improving quality of care and quality of life for PLWD and their care partners.},
}

@article {pmid42166472,
year = {2026},
author = {Kim, M and Choi, H and Shim, Y and Ryoo, N and Jeong, HT and Yun, G and Lee, H and Kim, S and Youn, YC},
title = {Prediction of cognitive impairment through speech data analysis: A comparative evaluation of deep learning models.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349412},
doi = {10.1371/journal.pone.0349412},
pmid = {42166472},
issn = {1932-6203},
mesh = {Humans ; *Deep Learning ; *Cognitive Dysfunction/diagnosis/physiopathology ; Female ; Aged ; *Speech/physiology ; *Alzheimer Disease/diagnosis/physiopathology ; Aged, 80 and over ; Neural Networks, Computer ; Middle Aged ; },
abstract = {BACKGROUND: The early detection of cognitive impairments, such as mild cognitive impairment (MCI) and Alzheimer's disease (AD), is essential for timely intervention and management. This study evaluates the performance of various deep-learning models in classifying speech recordings from individuals with normal cognition (NC), MCI, and AD, to identify the most effective approach for audio-based cognitive impairment diagnosis.

METHODS: Speech data were obtained from the AI Hub "Cognitive Impairment Diagnosis Voice/Conversation" dataset. The study analyzed voice recordings from 320 female participants (105 with Alzheimer's disease, 92 with mild cognitive impairment, and 123 cognitively normal controls). Three deep-learning architectures were compared: a one-dimensional convolutional neural network (1D CNN), an audio spectrogram transformer (AST), and a speech recognition model (Wav2Vec 2.0). The models were trained using features such as spectrograms, mel-spectrograms, and mel-frequency cepstral coefficients (MFCCs). Model performance was assessed using accuracy, recall, precision, and F1-score, with a five-fold cross-validation strategy to ensure robust and unbiased evaluation. Statistical significance was assessed using pairwise proportion z-tests with Holm-Bonferroni correction, and Wilson score 95% confidence intervals were computed for each model's accuracy.

RESULTS: Wav2Vec 2.0 outperformed the other models, achieving the highest accuracy and F1-scores for NC vs. MCI (accuracy: 0.74, F1: 0.72) and NC vs. AD (accuracy: 0.83, F1: 0.83). Pairwise proportion z-tests with Holm-Bonferroni correction confirmed that Wav2Vec 2.0 significantly outperformed 7 of 10 competing models (corrected p < 0.05) in both classification tasks. Performance varied by model and classification task, with Wav2Vec 2.0 consistently demonstrating superior accuracy across labels.

CONCLUSION: This study emphasizes the importance of selecting appropriate models and features for task-specific optimization and provides a foundation for developing non-invasive, speech-based diagnostic tools for cognitive disorders.},
}

Humans
*Deep Learning
*Cognitive Dysfunction/diagnosis/physiopathology
Female
Aged
*Speech/physiology
*Alzheimer Disease/diagnosis/physiopathology
Aged, 80 and over
Neural Networks, Computer
Middle Aged

@article {pmid42166529,
year = {2026},
author = {d'Orsi, G and Calò, E and Di Claudio, MT and Ferro, CP and Costantino, U and Perrone, E and Latino, RR},
title = {Progressive myoclonus epilepsy in Down syndrome with Alzheimer's disease: An 11-year longitudinal study and proposed diagnostic red flags.},
journal = {Epilepsia open},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi4.70277},
pmid = {42166529},
issn = {2470-9239},
abstract = {OBJECTIVE: Individuals with Down syndrome (DS) face an ultra-high risk of Alzheimer's disease (AD). Within this continuum, Progressive Myoclonus Epilepsy (PME) has emerged as a marker of advanced neurodegeneration. Building on our 2014 characterization of this syndrome, we aimed to define its long-term natural history and pathological substrate.

METHODS: We conducted an 11-year longitudinal study of the original cohort of 12 DS patients with PME. Clinical progression was monitored via a three-stage model. Two additional illustrative cases (aged 50 and 58 years) underwent 18F-Flutemetamol PET to document in vivo amyloid load.

RESULTS: The study reached a 100% mortality rate. Median survival from myoclonus onset was 4.2 years (95% CI: 3.8-4.6). All patients progressed to the terminal phase within 2.5 ± 1.1 years. Both Amyloid-PET-scanned patients revealed a massive cortical burden (Global Z-scores up to 11.55). Iatrogenic clinical worsening due to sodium channel blockers or phenobarbital was observed in 38% of cases. The high uniformity of these findings allowed for the proposal of diagnostic criteria based on a mandatory DS-AD association, a core clinical triad (myoclonus, ataxia, seizures), and supportive biomarkers. PME-DS appears to be driven by an amyloid-related excitatory-inhibitory imbalance. Massive amyloid-beta deposition in motor cortices impairs GABAergic interneurons, triggering cortical hyperexcitability. Thus, the onset of myoclonus serves as a functional marker of peak amyloid burden and terminal neurodegeneration.

SIGNIFICANCE: PME-DS with AD represents a severe electroclinical phenotype within the AD-DS continuum, likely overlapping with the widely recognized LOMEDS (Late-Onset Myoclonic Epilepsy in Down Syndrome). Myoclonus onset serves as a definitive "red flag" of a severe amyloid-driven excitatory-inhibitory imbalance and peak cortical burden, predicting rapid progression to terminal stage (median survival 4.2 years). Standardizing the proposed diagnostic criteria is essential for accurate prognostic counseling and, crucially, to avoid iatrogenic pitfalls in pharmacological management, particularly regarding the use of sodium channel blockers.

PLAIN LANGUAGE SUMMARY: This study followed 12 adults with Down syndrome who developed a severe form of epilepsy linked to Alzheimer's disease. We found that when people with Down syndrome develop jerking movements (myoclonus), it signals advanced brain changes and predicts a rapid decline, with most patients surviving only about 4 years. Brain scans showed a massive buildup of abnormal proteins in the brain. Importantly, certain common seizure medications (like phenytoin and carbamazepine) made symptoms worse in over one-third of patients. Recognizing this pattern early helps doctors provide better care, avoid harmful medications, and prepare families for what to expect.},
}

@article {pmid42166642,
year = {2026},
author = {Veerareddy, V and Wang, Z and Kashyap, PC and Kandimalla, KK},
title = {Butyrate Regulates the Blood-Brain Barrier Transport and Intraendothelial Accumulation of Alzheimer's Disease Amyloid-Beta Peptides.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c01594},
pmid = {42166642},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid β (Aβ) peptides as amyloid plaques and by cerebrovascular dysfunction, both of which drive AD progression. Butyrate, a gut microbial metabolite, is reduced in AD patients, and its supplementation has been shown to improve cognition and reduce the amyloid burden in animal models. However, the underlying mechanisms are unclear. Our previous studies demonstrated that insulin signaling regulates Aβ transport kinetics at the blood-brain barrier (BBB). In this study, we investigated whether butyrate reduces intraendothelial Aβ accumulation and improves BBB integrity through modulation of insulin signaling pathways. The effect of butyrate on Aβ42 accumulation was assessed by flow cytometry in polarized BBB endothelial cell culture models. Activation of insulin signaling and expression of key BBB constituents involved in Aβ transport and accumulation [p-glycoprotein (P-gp), the receptor for advanced glycation end products (RAGE)], as well as BBB integrity (tight junction protein, claudin-5), were evaluated by using Western blotting and confocal microscopy. The roles of insulin signaling nodes, including AKT, ERK, mTOR, and p38 phosphorylation, were investigated by using specific inhibitors MK2206, Trametinib, Rapamycin, and VX-745, respectively. In addition, the effect of butyrate on BBB receptors and transporters involved in Aβ trafficking was examined in vivo in mouse brains colonized with butyrate-producing bacteria via immunohistochemistry. Butyrate significantly decreased endothelial Aβ42 accumulation, an effect associated with the activation of insulin signaling, particularly AKT and ERK phosphorylation. Inhibitor studies established the critical role of these pathways, as co-incubation with MK2206 (AKT inhibitor) or Trametinib (ERK inhibitor) reversed the protective effect of butyrate and increased Aβ42 accumulation, whereas inhibition of mTOR or p38 had no significant effect. Moreover, butyrate restored Aβ-induced reductions in the P-gp efflux transporter expression and claudin-5 tight junction protein levels. These findings were supported by in vivo studies demonstrating upregulation of the tissue inhibitor of metalloproteinases-2 (TIMP-2), a protein associated with AKT activation and extracellular matrix stabilization in mice colonized with butyrate-producing bacteria. In conclusion, our data demonstrate that butyrate reduces Aβ42 uptake at the BBB endothelium by activating the AKT and ERK arms of the insulin signaling pathway. These changes may also enhance BBB integrity by increasing claudin-5 expression, stabilizing the extracellular matrix, and upregulating TIMP-2. Collectively, this study highlights butyrate as a potential therapeutic modulator of AD-associated BBB dysfunction.},
}

@article {pmid42166819,
year = {2026},
author = {Bazine, I and Maadadi, R and Derbal, S and Litim, B and Aissaoui, M and Bensouici, C and Saher, L and Harakat, D},
title = {Perillaldehyde-derived chromeno-dipyrimidines as multi-target-directed ligands: in vitro anticholinesterase and in vivo anti-inflammatory activities supported by molecular modeling.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118958},
doi = {10.1016/j.ejmech.2026.118958},
pmid = {42166819},
issn = {1768-3254},
abstract = {In this work, eight novel chromeno-dipyrimidine derivatives were designed and synthesized through a green, catalyst-free one-pot hemisynthetic approach starting from the natural perillaldehyde, barbituric acid and substituted anilines. All prepared polycyclic heterocycles were isolated in high yields (74-94%), and were fully characterized by IR, [1]H, [13]C, 2D NMR spectroscopy and elemental analysis. Interestingly, the synthesized compounds underwent an unexpected intramolecular cyclization, leading exclusively to the formation of novel heterocyclic products, highlighting the structural versatility and reactivity of this system. The synthesized derivatives exhibited overall promising biological activity; notably, compounds BI-1, BI-2, and BI-3 emerged as the most active, displaying potent acetylcholinesterase inhibition (IC50 = 15.08-17.45 μM) together with moderate butyrylcholinesterase inhibition, while in vivo evaluation BI-3, BI-5, and BI-6 showed most significant anti-inflammatory effects (≤ 4.62%). Furthermore, docking studies performed on the chromeno-dipyrimidine derivatives suggest that the studied molecules exhibit inhibitory activity toward AchE and BchE, supported by their calculated docking scores. The findings from the docking analysis were further confirmed by 100 ns molecular dynamics simulations. The best-scoring complexes showed favorable dynamic behavior and stability when bound to both AChE and BChE during MD simulations.},
}

@article {pmid42166820,
year = {2026},
author = {Czarnota-Łydka, K and Kucwaj-Brysz, K and Cios, A and Mordyl, B and Głuch-Lutwin, M and Jastrzębska-Więsek, M and Partyka, A and Honkisz-Orzechowska, E and Karcz, T and Pakulska, J and Satała, G and Żesławska, E and Dąbrowska, M and Starek, M and Więcek, M and Kurowska, K and Pyka, P and Brunetti, L and Leuci, R and Piemontese, L and Nitek, W and Wesołowska, A and Carrieri, A and Handzlik, J},
title = {New chalcogen-optimized 1,3,5-triazines as dual 5-HT6R/FAAH modulators: A versatile approach to neurodegenerative disorders.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118966},
doi = {10.1016/j.ejmech.2026.118966},
pmid = {42166820},
issn = {1768-3254},
abstract = {The clinical failure of selective serotonin 5-HT6 receptor (5-HT6R) antagonists in Alzheimer's disease (AD) highlights the need for multitarget therapeutic strategies addressing the multifactorial nature of neurodegeneration. Building upon our pioneering discovery of the first-in-class dual 5-HT6R/FAAH (fatty acid amide hydrolase) modulators among O-ether triazine compounds, we here report a comprehensive lead-optimization campaign centered on the triazine-based compound MR3b, identified as a promising lead in the search for AD treatment. Structural modifications based on scaffold contraction and chalcogen bioisosterism generated a focused library of 1,3,5-triazine derivatives with diversified GPCR and FAAH profiles. Several compounds displayed nanomolar affinities for 5-HT6R, 5-HT2AR, and D2R, alongside improved FAAH inhibition and antioxidant properties. Sulfur and selenium substitutions markedly enhanced receptor affinity and reduced cytotoxicity compared to the oxygen-containing lead. Selected compounds demonstrated significant neuroprotective effects in cellular models of AD-related pathology, including mitochondrial dysfunction, amyloid-β, and glutamate-induced toxicity. Furthermore, the thio-analogue 4c effectively reversed memory deficits in vivo, showing superior CNS penetration (Kp,brain = 0.78), an expanded therapeutic window (NOR test), and improved safety relative to MR3b. This study identified compound 4c as a second-generation lead and underscores the potential of multitarget triazine-based ligands combining serotonergic modulation and FAAH inhibition as potential disease-modifying candidates for AD and related neurodegenerative disorders.},
}

@article {pmid42166829,
year = {2026},
author = {Tibon, R and Madan, CR and Vaghari, D and Reyes-Aldasoro, CC},
title = {Structural complexity of brain regions in mild cognitive impairment and Alzheimer's disease.},
journal = {Brain and cognition},
volume = {196},
number = {},
pages = {106443},
doi = {10.1016/j.bandc.2026.106443},
pmid = {42166829},
issn = {1090-2147},
abstract = {Early detection of Alzheimer's disease (AD) is a major focus of current research efforts to guide early interventions. Subtle neural changes might be observed even before symptoms surface. We interrogated brain images obtained with Magnetic Resonance Imaging (MRI) from two large-scale dementia datasets (ADNI and BioFIND) to establish the utility of fractal dimensionality (FD)-an understudied measure that estimates the complexity of 3D structures (in this case, brain regions)-for AD detection. We show that FD measures are consistent across the two datasets, and can be used to detect group differences between patients and controls, as well as for individual-based classification. We further show that the contribution of specific brain regions to individual-based classification adheres to previous literature on the properties of the brain's memory network and how it relates to cognition. Taken together, the study offers novel and interpretable evidence for the utility of FD for the detection of AD.},
}

@article {pmid42166869,
year = {2026},
author = {Banjare, P and Patel, R},
title = {From DNA repair to neurodegeneration: PARP1 mechanisms and inhibitor strategies in Alzheimer's disease.},
journal = {DNA repair},
volume = {163},
number = {},
pages = {103940},
doi = {10.1016/j.dnarep.2026.103940},
pmid = {42166869},
issn = {1568-7856},
abstract = {PARP1 is a key regulator of DNA damage responses. Reports from cell and animal models suggest that when excessively active, PARP1 exacerbates oxidative stress, mitochondrial dysfunction, and neuroinflammation, which are indicative of Alzheimer's disease (AD) pathogenesis. Recently, there have been great advances in the biology of PARP and modulation of PARP for potential repurposing for neuroprotection. This narrative review details the molecular and interrelationship of PARP1 activity and Alzheimer's progression while trying to implement strategies to mitigate PARP1 activity. This includes molecular pathways, gene associations, and increasing interest in nicotinamide therapies and next-generation PARP-inhibitory drugs. It has been shown that uncontrolled regulation of PARP1 activity will lead to cell death via parthanatos. Increased destruction of cellular NAD+ and ATP, loss of mitochondrial energy, and the unbalanced, unregulated NF-κB neuroinflammation will focus on cell death. Preclinical studies have shown that nicotinamide and NAD+ , cell-permeable PARP1-active agents, enhance mitochondrial function and cognitive resilience. Moreover, brain-penetrant inhibitors such as veliparib and AZD9574 offer enhanced selectivity and access to the central nervous system (CNS). The future calls for CNS-optimized, selective inhibitors that combine safety with bioavailability. This review highlights the exciting possibilities of PARP1 modulation not only for symptomatic relief but also as a marked improvement for the future of treating AD.},
}

@article {pmid42166905,
year = {2026},
author = {Munafó, JP and Makowski, M and Fabiani, C and Maniscalchi, A and Salvador, GA and López Montero, I and Peñalva, DA and Antollini, SS},
title = {Cholesterol-dependent modulation of β-amyloid 1-40 peptide aggregation by membrane organization.},
journal = {Journal of colloid and interface science},
volume = {721},
number = {},
pages = {140739},
doi = {10.1016/j.jcis.2026.140739},
pmid = {42166905},
issn = {1095-7103},
abstract = {HYPOTHESIS: Cholesterol (chol) is a key lipid for nervous system development and function. While aging is associated with reduced brain chol, Alzheimer's disease (AD) is characterized by altered chol metabolism and asymmetric membrane distribution, particularly between neuronal body and synaptic compartments. The impact of these changes on β-amyloid (Aβ) aggregation, a central event in AD pathogenesis, remains unclear-especially under physiologically low Aβ concentrations. We hypothesize that Aβ nucleation in colloidal systems requires chol as an initial anchoring site, but that progression toward fibril formation is modulated by the system's interfacial properties.

EXPERIMENTS: To test this hypothesis, we employed biomimetic colloidal systems in the form of large and giant unilamellar vesicles (LUVs and GUVs) composed of POPC, brain sphingomyelin (bSM), and varying chol levels. By selectively modifying membrane composition to modulate membrane order and interfacial organization, we created distinct physicochemical environments. A combination of fluorescence spectroscopy, fluorescence microscopy, transmission electron microscopy, and dot blot assays was used to monitor Aβ1-40 aggregation dynamics and structural states, complemented by molecular dynamics simulations.

FINDINGS: We found that chol is essential to initiate Aβ 1-40 oligomerization. However, when chol levels were held constant but lipid composition was altered -by removing POPC or bSM, or replacing bSM with SM 24:1-Aβ aggregation outcomes varied significantly. These results demonstrate that while chol is necessary to initiate Aβ aggregation, the interfacial properties of the colloidal system govern its progression to fibril formation, revealing a novel interfacial mechanism linking membrane organization and peptide aggregation.},
}

@article {pmid42166920,
year = {2026},
author = {Li, X and Qi, J and Pan, F and Zhang, Y and Wang, L and Yi, Z and Liu, H and Zheng, J and Pan, Y and Liu, F and Jiang, L and Chen, S},
title = {AI-assisted integrative framework combining microarray data analysis and cerebrospinal fluid pharmacology for revealing molecular mechanism in Alzheimer's disease: A case study of Psoraleae Fructus.},
journal = {Journal of pharmaceutical and biomedical analysis},
volume = {279},
number = {},
pages = {117570},
doi = {10.1016/j.jpba.2026.117570},
pmid = {42166920},
issn = {1873-264X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, with a complex pathogenesis involving multiple targets and signaling pathways, and current therapeutic strategies remain insufficient to achieve satisfactory outcomes. Psoraleae Fructus (PF) has been reported to exhibit potential therapeutic effects against AD. However, its multi-target mechanisms of action have not yet been systematically elucidated. In this study, an AI-assisted integrative computational and experimental framework was established to comprehensively investigate the molecular basis of PF intervention in AD. Targeted constituents of PF were first identified using UPLC-Q Exactive Orbitrap high-resolution mass spectrometry, followed by the integration of Artificial intelligence modeling, microarray data, and network pharmacology to screen hub targets. Cerebrospinal fluid-based pharmacological assays, together with molecular docking, molecular dynamics simulations, microarray validation, and western blot, were subsequently employed to validate. The results demonstrated that PF markedly modulated the expression of GSK3β and PPARγ, thereby regulating core AD-related pathological markers, including p-tau, Aβ42, β-secretase, and inflammatory mediators. Collectively, this study delineated a multi-target regulatory network underlying the anti-AD effects of PF and provided a robust theoretical foundation for its further translational investigation.},
}

@article {pmid42166963,
year = {2026},
author = {He, ZX and Lin, ZQ and Liu, YX and Wang, SH and Lin, L and Guan, LP},
title = {Studies of design, synthesis and biological properties, ADMET profiling, molecular docking, network pharmacology and molecular dynamics simulation of novel chalcone derivatives containing benzoyl-piperazin.},
journal = {Bioorganic chemistry},
volume = {179},
number = {},
pages = {109991},
doi = {10.1016/j.bioorg.2026.109991},
pmid = {42166963},
issn = {1090-2120},
abstract = {A close causal relationship exists between Alzheimer's disease (AD) and inflammation, where chronic inflammation serves as a critical driver in AD pathogenesis. To address this, a series of novel chalcone derivatives containing benzoyl-piperazin (2a-2v) were synthesized based on the multi-target drug synthesis strategy. All compounds were tested for their cholinesterase inhibitory activity and antioxidant activity, some compounds were further evaluated for their Aβ1-42 aggregation inhibitory ability, cytotoxicity, metal ion chelating ability, anti-inflammatory activity and in vivo mouse organ toxicity. On this basis, ADMET, molecular docking, network pharmacology analyses and molecular dynamics (MD) simulations were performed on the compounds with better activity. Among these, compound 2q emerged as the most promising candidate, exhibiting the strongest inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and anti- inflammatory effects. The IC50 values were 73.65 ± 3.50 μM, 88.20 ± 9.56 μM and 31.42 ± 1.91 μM, respectively. Notably, compound 2q achieved a 35.30 ± 2.40% inhibition rate against Aβ1-42 aggregation. Importantly, 2q demonstrated no significant cytotoxicity within the 200 μM concentration range, with no adverse effects on hepatic or renal function, though it exhibited certain metal-ion chelating capabilities. Network pharmacology analysis further identified its interaction with inflammation and AD associated gene targets, including HSP90AA1 and GSK-3β. Furthermore, the stability of the binding of 2q to AChE and BChE was verified by MD simulations. Collectively, these findings suggest that compound 2q, as a multi-targeting agent, warrants further investigation for its therapeutic potential in AD.},
}