@article {pmid42090936,
year = {2026},
author = {Kose, MR and Ahirwal, MK and Atulkar, M},
title = {Causal ordinal connections based characterization of weighted effective brain network for schizophrenia detection.},
journal = {Psychiatry research. Neuroimaging},
volume = {361},
number = {},
pages = {112225},
doi = {10.1016/j.pscychresns.2026.112225},
pmid = {42090936},
issn = {1872-7506},
abstract = {The human brain is responsible for a wide range of a person's behavioral and cognitive capabilities. The functionality of the brain is affected by various disorders like schizophrenia, epilepsy, and Alzheimer. This study presents a novel framework for the automated detection of schizophrenia using EEG-based Weighted Effective Brain Connectivity Networks (WEBCNs). The proposed method introduces a new network descriptor called Weighted Directed Ordinal Connection (WDOC) that integrates causal directionality, connection strength, and ordinal relation between edges to capture complex brain dynamics. EEG signals from schizophrenia patients and healthy controls are preprocessed and transformed into WEBCNs using four causal connectivity estimators: Directed Transfer Function (DTF), Granger Causality (GC), Partial Directed Coherence (PDC), and Transfer Entropy (TE). WDOC-based features are extracted and classified using multiple machine learning algorithms, including KNN, SVM (linear, polynomial, RBF), and Random Forest. Among all models, the SVM with RBF kernel achieved the best performance, yielding 94.44% accuracy, 95% precision, 94% recall, and 89% kappa score for PDC-based networks. Structural and statistical analyses confirm distinct topological alterations in the causal flow between frontal and parietal regions in schizophrenia. The results demonstrate that WDOC-based characterization enhances discriminative power and interpretability in effective brain network analysis.},
}

@article {pmid42090937,
year = {2026},
author = {Rudraraju, A and Lakshmi, SV},
title = {Alzheimer's disease with progression analysis using a novel dilated convolutional attention based long short term memory model.},
journal = {Psychiatry research. Neuroimaging},
volume = {361},
number = {},
pages = {112232},
doi = {10.1016/j.pscychresns.2026.112232},
pmid = {42090937},
issn = {1872-7506},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative syndrome that affects memory, cognitive abilities and behaviour. Detecting AD in the early stage is crucial to improve the quality of life. However, traditional diagnostic approaches and manual analysis of neuroimaging data are slow, subjective and lead to human mistakes. Existing machine learning techniques often have difficulty in identifying complex patterns in high-dimensional biomedical data. These drawbacks emphasize the necessity for a more efficient and automated diagnostic system. This study introduced a new deep learning based hybrid framework for classifying and predict progression of AD. The method comprises three main steps: data acquisition, feature extraction and classification. Initially, EEG signals are collected from the CAU-EEG dataset. Then, features such as time domain features, frequency domain features and time frequency domain features are extracted. Finally, classification is performed by dilated convolutions attention based long short term memory (DC-ALSTM). Investigational results show that the proposed model outperforms existing baseline methods. DC-ALSTM achieved a classification 99.26% accuracy, 99.21% precision, recall at 99.23% and 99.22% F1-score, which indicates outstanding diagnostic capability.},
}

@article {pmid42091035,
year = {2026},
author = {Chandio, BQ and Olivetti, E and Romero-Bascones, D and Thomopoulos, SI and Villalon-Reina, JE and Nir, TM and Harezlak, J and Thompson, PM and Garyfallidis, E},
title = {BundleWarp: Enhancing white matter tractometry and morphometry with precise neuronal mapping using streamline-based nonlinear registration.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104114},
doi = {10.1016/j.media.2026.104114},
pmid = {42091035},
issn = {1361-8423},
abstract = {Tractometry analysis represents a significant advancement in neuroimaging, offering a detailed examination of the brain's white matter at a micro level. Unlike traditional ROI or voxel-based methods, tractometry precisely reconstructs and characterizes white matter tracts. Using advanced diffusion MRI and tractography algorithms, it maps the trajectory, shape, and connectivity patterns of individual white matter bundles. Accurate alignment of these tracts across different groups is crucial for reliable and reproducible results. Nonlinear registration techniques are essential for achieving this alignment, harmonizing bundle shapes, and improving sensitivity to disease-related changes. However, nonlinear registration is complex, especially with tractography data, which digitally represents the brain's white matter anatomy. Potential structural changes in the bundle's shape during registration can lead to artifacts that obscure critical anatomical details needed for disease identification. We introduce BundleWarp, a streamline-based nonlinear deformable registration method designed specifically for white matter tracts. BundleWarp employs a sophisticated approach to align two white matter bundles while preserving their topological and anatomical features. It is formulated as a probability density estimation problem with motion coherence penalties, ensuring coherent movement of points along streamlines and maintaining the anatomical integrity of tracts through displacement field regularization. Additionally, we introduce a tract morphometry framework utilizing the displacement field generated by BundleWarp to analyze white matter tract shape differences. Our results show that BundleWarp effectively quantifies bundle shape differences and enhances structural harmonization in tractometry analysis for diverse subjects, including those with Alzheimer's and Parkinson's disease. Test-retest experiments further demonstrate that BundleWarp substantially improves subject fingerprinting by increasing within-subject reproducibility of both bundle shape and microstructural profiles (FA, MD, RD, AD). It precisely maps the brain's neuronal pathways, offering a robust tractometry framework with enhanced sensitivity for detecting disease-related structural and microstructural changes in white matter tracts associated with Mild Cognitive Impairment (MCI), dementia, and early-stage Alzheimer's biomarkers, including amyloid-beta plaques and tau neurofibrillary tangles.},
}

@article {pmid42091041,
year = {2026},
author = {Plaza-Florido, A and Carrera-Bastos, P and Lucia, A},
title = {Exerkine GPLD1 bridges liver and brain.},
journal = {Cell metabolism},
volume = {38},
number = {5},
pages = {841-843},
doi = {10.1016/j.cmet.2026.04.002},
pmid = {42091041},
issn = {1932-7420},
mesh = {Humans ; *Brain/metabolism ; *Liver/metabolism ; *Phospholipase D/metabolism ; Animals ; *Exercise/physiology ; },
abstract = {A recent study by Bieri et al. shows that exercise elevates hepatic glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), which cleaves endothelial tissue-nonspecific alkaline phosphatase (TNAP) to rejuvenate cerebrovascular signaling, enhance cognition in aging, and attenuate Alzheimer's-related pathology. This liver-to-brain enzymatic axis positions hepatokines as potent mediators of exercise-induced neuroprotection, which redefines systemic metabolism as a driver of brain resilience.},
}

Humans
*Brain/metabolism
*Liver/metabolism
*Phospholipase D/metabolism
Animals
*Exercise/physiology

@article {pmid42091384,
year = {2026},
author = {Guan, L and Mao, Z and Yang, S and Wu, G and Chen, Y and Yin, L and Qi, Y and Han, L and Xu, L},
title = {Corrigendum to "Dioscin alleviates Alzheimer's disease through regulating RAGE/NOX4 mediated oxidative stress and inflammation" [Biomed. Pharmacother. 152 (2022) 113248].},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119454},
doi = {10.1016/j.biopha.2026.119454},
pmid = {42091384},
issn = {1950-6007},
}

@article {pmid42091757,
year = {2026},
author = {Puthusseri, SP and Ravivarma, S and Johny, M and Vengellur, A},
title = {Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.},
journal = {Journal of physiology and biochemistry},
volume = {82},
number = {1},
pages = {},
pmid = {42091757},
issn = {1877-8755},
mesh = {*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; Humans ; *Oxidative Stress ; Energy Metabolism ; Animals ; *Neurons/metabolism/pathology ; *Mitochondrial Dynamics ; *Mitochondria/metabolism/pathology ; Homeostasis ; *Nerve Degeneration/metabolism/pathology ; },
abstract = {Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor with an inherently paradoxical biology: under mild-to-moderate hypoxic stress, it functions as a pro-survival regulator, yet under severe or prolonged hypoxia, the same signalling axis promotes apoptotic and autophagic cell death. This duality carries particular significance in neurons, where HIF-1α serves as a critical nexus among neuronal survival, metabolic adaptation, and mitochondrial integrity, and where the consequences of its dysregulation are most profound given their exceptional metabolic demands and limited regenerative capacity. This review examines the molecular determinants governing this protective-to-detrimental switch, integrating key interconnected dimensions: the context-dependent regulation of oxidative stress, the control of mitochondrial bioenergetics, dynamics, mitophagy, and axonal transport; the dual role of HIF-1α in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia; and the therapeutic implications of precision-targeted HIF-1α modulation. Across all these contexts, a consistent pattern emerges: early or acute HIF-1α activation is broadly neuroprotective, while chronic or severe hypoxic stress converts the same pathway into a driver of neurodegeneration. Understanding the determinants of this switch, including hypoxia duration, severity, and cell-type specificity, provides a framework for designing temporally precise therapeutic interventions for hypoxia-related neurological disorders.},
}

*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics
Humans
*Oxidative Stress
Energy Metabolism
Animals
*Neurons/metabolism/pathology
*Mitochondrial Dynamics
*Mitochondria/metabolism/pathology
Homeostasis
*Nerve Degeneration/metabolism/pathology

@article {pmid42091766,
year = {2026},
author = {Kumar, V and Kakoty, V and Wadhwa, P},
title = {Advancements in Gene Delivery using Nucleic Acid Loaded Nanoparticles for Region Specific Delivery in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42091766},
issn = {1559-1182},
mesh = {*Alzheimer Disease/therapy/genetics ; *Nanoparticles/chemistry/administration & dosage ; Humans ; *Gene Transfer Techniques ; Animals ; *Nucleic Acids/administration & dosage ; *Genetic Therapy/methods ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive and the most common neurodegenerative condition, having a deleterious effect on memory, eventually leading to death. In the recent past, gene therapy has emerged as a promising and revolutionary treatment for AD. This study demonstrated that nucleic acid-loaded nanoparticles which deliver small interfering RNA through lipid nanoparticles successfully reduced Alzheimer's disease-related symptoms in preclinical models by decreasing amyloid-β levels and enhancing cognitive abilities. However, every rose has its thorn, as the output of gene therapy is considerably hampered by the physiological barriers of the brain, which include the blood-brain barrier and the brain's extracellular matrix (ECM). For this reason, many researchers have modified the gene delivery technique by developing 'brain penetrating' NPs coated with components that can prevent sticking to the ECM. Moreover, to overcome the challenge of low transgene expression and reduced accumulation in the brain, even when delivered at high doses, scientists have proposed that injection/delivery of gene vectors directly into a specific area in the brain can achieve maximum therapeutic efficacy. Hence, this review focuses on the advancements and advantages of region-specific delivery of nucleic acid-loaded NPs for the effective therapeutic management of AD.},
}

*Alzheimer Disease/therapy/genetics
*Nanoparticles/chemistry/administration & dosage
Humans
*Gene Transfer Techniques
Animals
*Nucleic Acids/administration & dosage
*Genetic Therapy/methods
Brain/metabolism

@article {pmid42091792,
year = {2026},
author = {Otaegui, L and Lehoux, J and Begu, S and Moujellil-Legagneur, T and Zussy, C and Vitalis, M and Mathias, M and Beau, A and Durand, T and Givalois, L and Bernoud-Hubac, N and Crauste, C and Desrumaux, C},
title = {Intranasal lipid nanocapsule administration of the new lipophenol quercetin-3-O-DHA-7-O-iPr reduces carbonyl stress and improves behavior in a mouse model of Alzheimer's disease.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42091792},
issn = {2190-3948},
support = {CBS2 PhD grant//Université Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université Montpellier/ ; PhD grant//Association France Alzheimer/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; ANR-18-CE18-0017//Agence Nationale de la Recherche/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; },
abstract = {Oxidative and carbonyl stresses (COS), which damage brain cells through the accumulation of toxic reactive carbonyl species (RCS), are key players in the etiology of Alzheimer's disease (AD). Our group developed lipophenols, i.e. COS-targeting hybrid molecules combining polyunsaturated fatty acids (PUFAs) and alkyl-(poly)phenols. Among them, quercetin-3-O-docosahexaenoate-7-O-isopropyl (Quercetin-3-O-DHA-7-O-iPr or "Q-iP-DHA") afforded neuroprotection against acrolein-induced toxicity, reduced carbonyl stress, and lowered amyloid-beta secretion in neuroblastoma cells. To evaluate Q-iP-DHA in vivo, it was formulated into lipid nanocapsules (to allow solubilization) then administered intranasally to J20 transgenic mice, a model of AD. This approach was chosen to optimize blood-brain barrier (BBB) penetration. This delivery led to improvements in well-being, organizational skills and spatial memory. In addition, Q-iP-DHA treatment reduced hippocampal amyloid plaque numbers, normalized expression of the Receptor for Advanced Glycation End-products (RAGE), and decreased microglial activation, indicating anti-inflammatory effects. Overall, our preclinical findings suggest that intranasal administration of nanoformulated Q-iP-DHA may represent a promising multitarget therapeutic approach against AD.},
}

@article {pmid42091863,
year = {2026},
author = {Corbett, A and Sander-Long, M and Ashton, NJ and Huber, H and Vavra, J and Braun-Wohlfahrt, LS and Zetterberg, H and Montoliu-Gaya, L and Cummings, J and Bateman, F and Davis, C and Ballard, C},
title = {Alzheimer's Disease blood biomarkers measured through remote capillary sampling correlate with cognition in older adults.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42091863},
issn = {2041-1723},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Aged ; Male ; Female ; tau Proteins/blood ; *Cognition/physiology ; *Cognitive Dysfunction/blood/diagnosis ; Aged, 80 and over ; *Blood Specimen Collection/methods ; Middle Aged ; Capillaries ; },
abstract = {Blood biomarkers are rapidly becoming established for Alzheimer's Disease (AD) diagnosis. However, there is a need for more scalable tools to reach the 99% of individuals with early cognitive impairment who are not seen in specialist healthcare services. A recent study validated a capillary blood sampling technique to detect the p-tau217 and GFAP biomarkers. Here we used our PROTECT research study to show that these biomarkers, when collected using self-administered fingerprick tests, correlate well with venous blood biomarkers and with cognition and function in 174 people who were cognitively normal or who had mild cognitive impairment or AD. They can be used in combination with computerised cognitive testing to identify people with the highest risk of AD. The GFAP biomarker appears to be associated with vascular risk, unlike p-tau217. Patient feedback indicates high acceptability and usability of the capillary test method, giving confidence in the feasibility of this technology. The work suggests that capillary blood biomarkers could be used to enable triage of people with varying levels of risk of AD in clinical practice and for clinical trials, and could be used outside of clinical settings.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Aged
Male
Female
tau Proteins/blood
*Cognition/physiology
*Cognitive Dysfunction/blood/diagnosis
Aged, 80 and over
*Blood Specimen Collection/methods
Middle Aged
Capillaries

@article {pmid42092056,
year = {2026},
author = {Teunissen, CE and van Harten, AC},
title = {Plasma biomarkers for Alzheimer disease: the road from laboratory results to clinical practice.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42092056},
issn = {1759-4766},
}

@article {pmid42092241,
year = {2026},
author = {Jiao, J and Wu, T and Li, F and Yang, S and Yu, C and Lv, S and Tian, S and Zhang, Z and Ge, Z and Jiang, J and Bi, Y},
title = {Associations of Visceral Obesity Indices and Risk of Mild Cognitive Impairment in Patients With Diabetes: A Retrospective Cohort Study.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70832},
pmid = {42092241},
issn = {1463-1326},
support = {14380546//The Fundamental Research Funds for the Central Universities/ ; 2024ZD0523200//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; BK20240116//The Natural Science Foundation of Jiangsu Province of China/ ; BK20241721//The Natural Science Foundation of Jiangsu Province of China/ ; 82470866//National Natural Science Foundation of China Grant Awards/ ; 2024-92//National Chinese-Western Medicine Clinical Collaboration Project for Major Difficult Diseases/ ; BE2022666//The Key Research and Development Program of Jiangsu Province of China/ ; BE2023774//The Key Research and Development Program of Jiangsu Province of China/ ; 2022-LCYJ-ZD-03 and 2022-LCYJ-PY-02//Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University/ ; },
abstract = {AIMS: This study aimed to investigate the associations between visceral obesity indices and the risk of mild cognitive impairment (MCI) in patients with diabetes and to identify the most valuable visceral obesity index to develop a risk assessment nomogram.

MATERIALS AND METHODS: We explored the relationship between visceral obesity indices and MCI risk in patients with diabetes and developed a nomogram utilising a cohort of 1080 patients from Nanjing Drum Tower Hospital. MCI was diagnosed according to the criteria recommended by the National Institute on Aging-Alzheimer's Association Workgroup. Logistic regression models were used to identify factors independently associated with MCI in the cohort. Furthermore, the nomogram was externally validated by a multicenter retrospective cohort (Cohort 2) and a prospective cohort with a follow-up period of up to 10 years (Cohort 3).

RESULTS: We identified a positive but non-linear dose-response relationship between visceral obesity indices and the risk of MCI in patients with diabetes. Compared with a body shape index (ABSI), visceral adiposity index (VAI), lipid accumulation product (LAP) and Chinese visceral adiposity index (CVAI), body roundness index (BRI) exhibited superior discriminative ability (AUC: 0.734, 95% CI: 0.703-0.764). The nomogram constructed from BRI, age, education and haemoglobin A1c (HbA1c) achieved an optimal AUC of 0.804 (95% CI: 0.777-0.830) in the internal validation cohort. The model exhibited consistent performance across external validations, yielding a discriminative AUC of 0.756 (95% CI: 0.722-0.790) in Cohort 2 and a 10-year predictive AUC of 0.762 (95% CI: 0.727-0.797) in Cohort 3.

CONCLUSIONS: Higher visceral obesity indices were associated with an increased risk of MCI in patients with diabetes. Assessment of visceral obesity may help identify patients with diabetes who are at a high risk of MCI.},
}

@article {pmid42092335,
year = {2026},
author = {Shrestha, S and Zhu, X and Windham, BG and Sullivan, KJ and Palta, P and Gottesman, RF and Tracy, RP and Jack, CR and Cogswell, PM and Vemuri, P and Seshadri, S and Mosley, TH and Griswold, ME and Fornage, M},
title = {Associations of blood biomarkers of glial cell dysfunction and neuronal injury with future cognitive decline and incident dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71422},
doi = {10.1002/alz.71422},
pmid = {42092335},
issn = {1552-5279},
support = {75N92022D00001/HL/NHLBI NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; U01HL096812/NH/NIH HHS/United States ; U01HL096814/NH/NIH HHS/United States ; U01HL096899/NH/NIH HHS/United States ; U01HL096902/NH/NIH HHS/United States ; U01HL096917/NH/NIH HHS/United States ; U19NS120384/NH/NIH HHS/United States ; UH3NS100605/NH/NIH HHS/United States ; andUF1NS125513/NH/NIH HHS/United States ; R00AG052830/AG/NIA NIH HHS/United States ; Intramural Research Program/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; *Dementia/blood/epidemiology ; *Cognitive Dysfunction/blood ; Aged ; Chitinase-3-Like Protein 1/blood ; Glial Fibrillary Acidic Protein/blood ; *Neuroglia/pathology/metabolism ; tau Proteins/blood ; Middle Aged ; Prospective Studies ; Neurofilament Proteins/blood ; Ubiquitin Thiolesterase/blood ; *Neurons/pathology ; Incidence ; },
abstract = {INTRODUCTION: Prospective studies of blood-based biomarkers reflecting pathogenic processes, other than Alzheimer-specific pathologies, that contribute to dementia in diverse cohorts are lacking.

METHODS: We jointly fitted linear mixed-effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble cluster of differentiation-14 (sCD14), neurofilament light chain (NfL), total tau (t-tau), and ubiquitin C-terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community-based Atherosclerosis Risk in Communities Study. sCD14 and YKL-40 were measured in 3082 participants and the other four biomarkers in 1766 participants.

RESULTS: Higher serum GFAP, YKL-40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log-base2 YKL-40 was associated with -0.11SD faster 25-year cognitive decline (95% confidence interval [CI]: -0.15,-0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t-tau and UCHL1 were also associated with faster cognitive decline.

DISCUSSION: Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.},
}

Humans
*Biomarkers/blood
Female
Male
*Dementia/blood/epidemiology
*Cognitive Dysfunction/blood
Aged
Chitinase-3-Like Protein 1/blood
Glial Fibrillary Acidic Protein/blood
*Neuroglia/pathology/metabolism
tau Proteins/blood
Middle Aged
Prospective Studies
Neurofilament Proteins/blood
Ubiquitin Thiolesterase/blood
*Neurons/pathology
Incidence

@article {pmid42092343,
year = {2026},
author = {Burkett, BJ and Wiste, HJ and Johnson, DR and Boeve, BF and Kantarci, K and Petersen, RC and Knopman, DS and Vemuri, P and Graff-Radford, J and Lowe, V and Cogswell, PM and Pillai, J and Schwarz, CG and Nguyen, AT and Murray, ME and Dickson, DW and Jack, CR},
title = {Abnormal amyloid PET usually represents intermediate/high Alzheimer's disease neuropathologic change.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71449},
doi = {10.1002/alz.71449},
pmid = {42092343},
issn = {1552-5279},
support = {//Alexander Family Professorship of Alzheimer's Disease Research/ ; //GHR Foundation/ ; P30 AG062677//Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *Positron-Emission Tomography ; Male ; Female ; Autopsy ; Aged ; *Brain/pathology/diagnostic imaging/metabolism ; Aged, 80 and over ; *Amyloid/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET.

METHODS: Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years).

RESULTS: Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death (n = 39) not/low ADNC occurred in 3/39 (8%).

DISCUSSION: Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*Positron-Emission Tomography
Male
Female
Autopsy
Aged
*Brain/pathology/diagnostic imaging/metabolism
Aged, 80 and over
*Amyloid/metabolism

@article {pmid42092345,
year = {2026},
author = {Butler, CA and Gee, MS and O'Gara, K and Milinkeviciute, G and Da Cunha, C and Kawauchi, S and Lu, YH and Kwang, N and Tsourmas, KI and Prekopa, C and Shi, Z and Liang, HY and Collins, SD and Pashkutz, ZA and Sanchez, JA and Shi, KX and Walker, AD and Wang, S and Wong, MLA and Genaro, K and Neumann, J and Gomez-Arboledas, A and Duong, DM and Seyfried, NT and Tenner, AJ and LaFerla, FM and Mortazavi, A and Swarup, V and MacGregor, GR and Green, KN},
title = {Abi3[S212F] Alzheimer's disease variant alters plaque structure and disrupts microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71452},
doi = {10.1002/alz.71452},
pmid = {42092345},
issn = {1552-5279},
support = {U54 AG054349/AG/NIA NIH HHS/United States ; P30CA62203//Chao Family Comprehensive Cancer Center/ ; },
mesh = {*Microglia/pathology/metabolism ; *Alzheimer Disease/genetics/pathology ; Animals ; *Plaque, Amyloid/pathology/genetics ; Mice ; Humans ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Cytoskeletal Proteins/genetics ; Brain/pathology ; },
abstract = {BACKGROUND: Genetic variants affecting microglial function can influence Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. The AD-associated ABI3[S209F] (Abi3[S212F] in mouse) variant regulates cytoskeletal dynamics, but its in vivo impact on pathology is unknown.

METHODS: An Abi3[S212F] mouse was developed and crossed with two humanized amyloid beta (Aβ) models. Amyloid pathology, microglial survival, and remodeling were analyzed using confocal imaging, biochemical assays, spatial transcriptomics, and single-cell analyses across the lifespan.

RESULTS: Abi3[S212F] produced a dysfunctional microglial state that reduced dense-core plaque compaction, selectively lowering dense-core burden without affecting diffuse or total Aβ. The variant also caused microglial loss via apoptosis and pyroptosis, requiring aging and human Aβ but occurring even without plaques, indicating plaque-independent vulnerability. Spatial transcriptomics revealed an age-dependent shift toward an Abi3-high state that predisposes microglia to degeneration.

DISCUSSION: Abi3[S212F] produces microglial dysfunction and vulnerability, highlighting cytoskeletal and cell death pathways as therapeutic targets.},
}

*Microglia/pathology/metabolism
*Alzheimer Disease/genetics/pathology
Animals
*Plaque, Amyloid/pathology/genetics
Mice
Humans
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Cytoskeletal Proteins/genetics
Brain/pathology

@article {pmid42092516,
year = {2026},
author = {Jaiswal, A and Sinnarkar, V and Sharma, DB},
title = {Comment on "Effect of extra virgin olive oil on mild cognitive impairment and dementia in older adults: a systematic review and meta-analysis of clinical trials".},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {103313},
doi = {10.1016/j.clnesp.2026.103313},
pmid = {42092516},
issn = {2405-4577},
}

@article {pmid42092578,
year = {2026},
author = {Mohammady, RW and Samir, RK and Sayed, RM and Malak, MH and Magdy, MK and Mohamed, RG and Tawfiq, AH and Kamel, RA and Kamel, NM},
title = {Targeting eukaryotic elongation factor 2 (eEF2)/eEF2 kinase in neurological and neuropsychiatric Disorders: Mechanisms, therapeutic Implications, and translational challenges.},
journal = {Brain research},
volume = {1886},
number = {},
pages = {150368},
doi = {10.1016/j.brainres.2026.150368},
pmid = {42092578},
issn = {1872-6240},
abstract = {Eukaryotic elongation factor 2 kinase (eEF2K) phosphorylates eukaryotic elongation factor 2 (eEF2) and slows translation elongation. In the nervous system, this pathway links neuronal activity, calcium signaling, energy status, and stress responses to selective protein synthesis programs that shape synaptic plasticity, circuit excitability, and cell survival. Dysregulated eEF2K/eEF2 signaling has been implicated in epilepsy, Alzheimer's disease, Parkinson's disease, major depressive disorder, Down syndrome, and other brain conditions. However, the literature remains fragmented, largely preclinical, and often interpreted in an overly therapeutic manner. This review synthesizes the field using a mechanistic framework. Across disorders, altered eEF2 phosphorylation converges on five major axes: synaptic plasticity and excitatory/inhibitory balance, oxidative and mitochondrial stress responses, neuroinflammation/neuroimmune regulation, and aging-related neurogenesis and cognitive resilience. In chronic neurodegenerative and neurodevelopmental settings, excessive eEF2K activity is frequently associated with impaired de novo protein synthesis, synaptic dysfunction, and cognitive decline, whereas genetic or pharmacological suppression can improve selected behavioral and electrophysiological outcomes. By contrast, in acute metabolic stress or certain immune-cell contexts, eEF2K activity may serve adaptive and anti-inflammatory functions. These findings indicate that eEF2K has context-dependent, rather than uniformly pathogenic, roles. We also highlight major translational barriers, including dependence on rodent models, limited causal human data, incomplete cell-type resolution, and the off-target liabilities of commonly used inhibitors such as NH125 and A-484954. Overall, the eEF2K/eEF2 axis represents a biologically important but therapeutically complex target that will require selective, cell-aware, and stage-specific modulation. Future progress depends on better biomarkers, human models, and more selective brain-penetrant inhibitors.},
}

@article {pmid42092705,
year = {2026},
author = {Sun, M and Zhao, X and Gao, K and Ding, G and Yu, J},
title = {Hypothalamic microstructure and function are associated with mild cognitive impairment in aging.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111921},
doi = {10.1016/j.brainresbull.2026.111921},
pmid = {42092705},
issn = {1873-2747},
abstract = {BACKGROUND: The hypothalamus serves as a critical neuroendocrine center, yet its specific topographical and microarchitectural vulnerabilities during the preclinical stages of Alzheimer's disease remain poorly elucidated. This study aimed to comprehensively investigate the macroscopic volumetric and microstructural alterations within hypothalamic subregions in patients with mild cognitive impairment (MCI) and their associations with cognitive and functional decline.

METHODS: In this cross-sectional study, a total of 92 participants, comprising 47 MCI patients and 45 healthy controls (HC), underwent 3T multimodal magnetic resonance imaging. The hypothalamus was automatically segmented into five bilateral subregions. Macroscopic volumetry (adjusted for estimated total intracranial volume) and diffusion tensor imaging (DTI) metrics-including fractional anisotropy (FA) and mean diffusivity (MD)-were extracted. Multiple regression models and sex-stratified correlation analyses were utilized to map structural trajectories against age, education, and clinical assessments.

RESULTS: Hypothalamic alterations in MCI showed marked spatial heterogeneity and sexual dimorphism. Age-related volume loss was observed in HCs, whereas MCI patients exhibited sex-specific atrophic trajectories. MCI patients showed significantly reduced FA in the left anterior-inferior subregion compared with HCs. Microstructural disruption in the left tubular-superior subregion was significantly associated with lower MMSE scores and higher ADL scores. Higher educational attainment was independently associated with preserved microstructure in the posterior hypothalamus, supporting the cognitive reserve hypothesis.

CONCLUSION: Hypothalamic degeneration in MCI is a spatially heterogeneous and sex-specific process. Localized microstructural disruption, especially in the left tubular-superior subregion, represents a sensitive imaging biomarker for early cognitive and functional impairment.},
}

@article {pmid42092970,
year = {2026},
author = {Liu, H and Hu, C and Liu, H and Gong, Z and Jiang, S and Xie, J and Li, Y and Liu, C and Wang, Y and Zou, C and Yang, G},
title = {Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03815-1},
pmid = {42092970},
issn = {1742-2094},
support = {2023JJ40952//the Natural Science Foundation of Hunan Province/ ; 2024JJ6618//the Natural Science Foundation of Hunan Province/ ; 82204733//Foundation for Innovative Research Groups of the National Natural Science Foundation of China/ ; 20254677//Health Research Project of Hunan Provincial Health/ ; 82474009//the National Natural Science Foundation of China/ ; },
abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.},
}

@article {pmid42093338,
year = {2026},
author = {Silva, MG and Vasconcelos, MB and Silva, RG and Feitosa, MÁL},
title = {Oral Health in Alzheimer's Disease: A Life-Course Perspective on Clinical Management and Caregiver Support.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {3},
pages = {e70179},
doi = {10.1111/scd.70179},
pmid = {42093338},
issn = {1754-4505},
support = {Finance Code 001//the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Humans ; *Alzheimer Disease/complications ; *Caregivers/psychology ; *Oral Health ; },
abstract = {AIM: To synthesize current evidence on oral health conditions in individuals with AD and to discuss stage-specific dental management strategies, including caregiver involvement, from a life-course perspective.

METHODS: A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, Scielo, and Web of Science using MeSH and free-text terms related to Alzheimer's disease, oral health, and caregivers, with no language or time restrictions.

RESULTS: Individuals with AD commonly present with periodontal disease, root caries, xerostomia, traumatic mucosal lesions, and prosthesis-related complications. The available evidence does not strongly support a bidirectional causal relationship; instead, poor oral health and AD appear to be cumulative conditions influenced by shared antecedent factors, such as biological aging and chronic inflammation. Functional dependence and behavioral symptoms further contribute to oral deterioration over time. Effective dental care therefore requires stage-adapted approaches, ranging from preventive and restorative interventions in early stages to palliative strategies focused on infection control and comfort in advanced disease.

CONCLUSION: Oral health care for individuals with AD should be grounded in a life-course and biopsychosocial framework, prioritizing realistic, stage-specific clinical management and structured caregiver support within interdisciplinary geriatric care.},
}

Humans
*Alzheimer Disease/complications
*Caregivers/psychology
*Oral Health

@article {pmid42093362,
year = {2026},
author = {Liu, Q and Wang, Y and Wang, B and Wang, J and Zhang, M and Liu, Y and Min, X},
title = {Ziziphus jujuba Mill. Suspension Ameliorates Scopolamine-Induced Cognitive Impairment via PTGS2-Centered Neuroinflammatory Signaling.},
journal = {Mediators of inflammation},
volume = {2026},
number = {1},
pages = {e8871660},
doi = {10.1155/mi/8871660},
pmid = {42093362},
issn = {1466-1861},
support = {2022-JYJ-153//Luzhou Science and Technology Bureau/ ; 2022QN114//Natural Science Foundation of Southwest Medical University/ ; },
mesh = {Animals ; *Ziziphus/chemistry ; Mice ; *Scopolamine/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; *Cyclooxygenase 2/metabolism ; Male ; Signal Transduction/drug effects ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Mice, Inbred C57BL ; Inflammation/metabolism/drug therapy ; },
abstract = {BACKGROUND: Cognitive impairment is a common feature of neurodegenerative diseases, in which sustained neuroinflammation critically contributes to neuronal dysfunction and memory decline. As a representative condition, Alzheimer's disease (AD) provides key insights into inflammation-associated cognitive impairment. However, current anti-inflammatory interventions exhibit limited efficacy and potential adverse effects, highlighting the need for safer strategies targeting neuroinflammation-related cognitive dysfunction.

OBJECTIVE: Guided by the concept of food-medicine homology, this study aimed to elucidate the molecular mechanisms by which Ziziphus jujuba alleviates cognitive impairment associated with neuroinflammation.

METHODS: AD-relevant targets associated with cognitive dysfunction were obtained from Gene Expression Omnibus (GEO) and GeneCards, and active compounds of Z. jujuba were retrieved from traditional Chinese medicine systems pharmacology (TCMSP). Shared targets were prioritized using least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM) algorithms. The diagnostic value of the core target was evaluated by receiver operating characteristic (ROC) analysis and a nomogram model with calibration and decision curve analysis (DCA). Functional enrichment, localization analyses, and molecular docking were performed. Experimental validation was conducted in a scopolamine-induced cognitive impairment mouse model using the Morris water maze (MWM), histopathology, and western blotting.

RESULTS: PTGS2 was identified as a key inflammatory target associated with neuroinflammation-related cognitive impairment and was enriched in the NOD-like receptor (NLR) signaling pathway. ROC and nomogram analyses indicated good diagnostic and predictive performance (area under the curve [AUC] > 0.7). PTGS2 was localized on chromosome 1 and showed relatively high expression in the cerebral cortex. Z. jujuba compounds exhibited strong binding to PTGS2 (ΔG ≤ -8.0 kcal/mol). In vivo, Z. jujuba improved cognitive performance, alleviated hippocampal injury, and downregulated PTGS2 and related inflammatory signaling pathways, including NLRP3/NF-κB/MAPK and interleukin (IL)-1β.

CONCLUSION: This study demonstrates that Z. jujuba ameliorates neuroinflammation-related cognitive dysfunction primarily by suppressing PTGS2-centered inflammatory signaling. Integrating computational analyses and in vivo validation in scopolamine-induced mice, our findings support Z. jujuba as a safe multitarget intervention for inflammation-associated cognitive impairment and highlight the potential of food-medicine homology in neuroinflammatory cognitive disorders.},
}

Animals
*Ziziphus/chemistry
Mice
*Scopolamine/toxicity
*Cognitive Dysfunction/drug therapy/chemically induced/metabolism
*Cyclooxygenase 2/metabolism
Male
Signal Transduction/drug effects
Molecular Docking Simulation
*Neuroinflammatory Diseases/drug therapy/metabolism
Mice, Inbred C57BL
Inflammation/metabolism/drug therapy

@article {pmid42093397,
year = {2026},
author = {Patir, S and Baruah, A},
title = {Computational investigation of BMS-984923 against Alzheimer's amyloid-beta (Aβ) structures: insights into their molecular interactions and inhibition of aggregation.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5cp04916d},
pmid = {42093397},
issn = {1463-9084},
abstract = {Normal brain function involves soluble Aβ peptides that support synaptic activity. However, Aβ peptides are prone to aggregation under abnormal or pathogenic conditions, forming clumps known as oligomers and protofibrils, which subsequently lead to the formation of mature, stable β-sheet rich fibrils. The accumulation of such misfolded amyloid aggregates in the brain is the hallmark of Alzheimer's disease (AD). Recent experimental studies suggested that BMS-984923 successfully blocks the action of Aβ induced toxicity while preserving glutamate signaling via the metabotropic glutamate receptor 5 (mGluR5), which is a key excitatory neurotransmitter in the brain. However, the molecular mechanism by which BMS-984923 interacts with Aβ peptide remains unclear. In this work, we investigated the inhibitory mechanism of BMS-984923 against the Aβ monomeric structures with the help of molecular docking and molecular dynamics (MD) simulations. To elucidate the atomic level interactions, we employed DSSP for performing secondary structure analysis, MM-PBSA, per-residue decomposition and free energy landscape (FEL) analyses. The two representative structures from the apo simulation are further subjected to MD simulation, followed by similar analyses. MD simulation analyses revealed the distinct modes of ligand interaction across the different monomeric forms, accompanied by extensive contacts with residues in the binding region. Therefore, our study, which provides insights for evaluating the efficacy of BMS-984923 to facilitate subsequent binding with the target protein, will offer a framework for the rational design of potential inhibitors against the pathogenic Aβ peptide.},
}

@article {pmid42093461,
year = {2026},
author = {Andreão, FF and da Silva, RO and Negreli, MFLA and Aguiar-Barros, ABP and Santos, DH},
title = {Baseline epidemiological differences between donanemab and lecanemab users in real-world settings: a retrospective cohort study.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/17582024.2026.2667432},
pmid = {42093461},
issn = {1758-2032},
abstract = {AIMS: Donanemab and Lecanemab are anti-amyloid monoclonal antibodies recently approved for the treatment of Alzheimer's disease. Although their efficacy and safety have been investigated in randomized trials, real-world epidemiological data on treated populations remain limited. This study aimed to compare baseline clinical and laboratory characteristics of patients treated with donanemab versus lecanemab in routine practice.

PATIENTS AND METHODS: We conducted a retrospective analysis using the TriNetX US Collaborative Network, including patients with Alzheimer's disease treated with donanemab or lecanemab between January 2024 and September 2025. Demographics, laboratory values, comorbidities, and concomitant medications were compared using standardized mean differences (SMD) and p-values. Variables with SMD ≥0.1 or p < 0.05 were considered meaningfully different.

RESULTS: A total of 1,799 patients were included (donanemab n = 360; lecanemab n = 1,439). Demographic characteristics were well balanced (mean age 73.1 vs 72.5 years; SMD 0.028). Lecanemab users were more likely to be prescribed antidepressants (52% vs 41%; p < 0.0001; SMD = 0.23) and donepezil (61% vs 52%; p = 0.0145; SMD = 0.14). Donanemab users had higher prothrombin time (12.2 ± 2.17 vs 11.8 ± 1.66 s; p = 0.0158; SMD = 0.20) and INR (1.06 ± 0.19 vs 1.03 ± 0.13; p = 0.0369; SMD = 0.17), and a higher prevalence of vascular dementia (81% vs 76%; p = 0.0272; SMD = 0.12).

CONCLUSION: While demographic variables were similar. These findings likely reflect real-world clinical selection patterns and should be accounted for in comparative effectiveness and safety analyses of anti-amyloid therapies.},
}

@article {pmid42093645,
year = {2026},
author = {Dolai, S and Alam, A},
title = {Lipid transport mechanisms in human ABCA family transporters: a structural perspective.},
journal = {Biochemical Society transactions},
volume = {54},
number = {5},
pages = {477-488},
doi = {10.1042/BST20250138},
pmid = {42093645},
issn = {1470-8752},
support = {5R01GM146906//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R21AG069180//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *ATP-Binding Cassette Transporters/metabolism/chemistry ; Biological Transport ; *Lipid Metabolism ; Lipid Bilayers/metabolism/chemistry ; Protein Conformation ; Models, Molecular ; },
abstract = {ATP-binding cassette (ABC) transporters are essential membrane proteins that couple ATP hydrolysis to move diverse substrates across lipid bilayers through large-scale conformational changes. In humans, 48 ABC transporters span seven subfamilies (A-G); within these, the ABCA subfamily mediates cellular lipid handling in contexts ranging from neural function to pulmonary surfactant production, and its dysfunction contributes to human disease from cardiovascular disorders to Alzheimer's. These diverse physiological roles all depend on precise lipid translocation within or across membrane systems, a shared principle that is often underemphasized in broad "lipid-transporter" classifications. This review summarizes the structural landscape of the ABCA family and re-examines the mechanistic insights that have emerged. We compare and contrast transport models derived from detergent-solubilized and lipid-embedded structures, with particular emphasis on lipid-embedded ABCA7, which supports a membrane-integrated mechanism in which the bilayer itself contributes to the transport pathway. We highlight shared rigid-body transitions, outline open questions surrounding transport directionality and protein-lipid coupling, and suggest that future models should treat the membrane not merely as a passive scaffold but as an integral component of the transport mechanism, while recognizing that membrane-integrated behavior is currently established structurally only for ABCA7 and remains a working hypothesis for other family members.},
}

Humans
*ATP-Binding Cassette Transporters/metabolism/chemistry
Biological Transport
*Lipid Metabolism
Lipid Bilayers/metabolism/chemistry
Protein Conformation
Models, Molecular

@article {pmid42093680,
year = {2026},
author = {Wu, J and Li, X and Liu, W and Ma, Y and Zhao, Q and Xiao, M and Wang, J},
title = {The Feasibility and Preliminary Effects of a Stress Process Model-Based Program in Dementia Caregiving (DeCare-SPM) for Family Caregivers: A Mixed-Methods Pilot Study.},
journal = {Journal of multidisciplinary healthcare},
volume = {19},
number = {},
pages = {585820},
pmid = {42093680},
issn = {1178-2390},
abstract = {BACKGROUND: Dementia caregiving causes significant stress, making psychosocial interventions crucial. However, its success depends on effective implementation. This study aimed to evaluate the feasibility, acceptability, and preliminary effects of DeCare-SPM, a theory-driven program designed to enhance positive aspects of caregiving and reduce burden.

METHODS: A single-group pre-post study without a control group, using an embedded mixed-methods design, was conducted from June to July 2023. The 1-month intervention included three face-to-face sessions and four weekly telephone-based consultations. The feasibility was evaluated through recruitment rate, adherence, and satisfaction. Focus group interviews with implementers and caregivers provided qualitative insights. Preliminary effects on positive aspects of caregiving (PAC), caregiver burden, sense of competence, social network, anxiety and depression, quality of life for caregivers, and neuropsychiatric symptoms and quality of life for individuals with dementia were measured at the end of the 1-month intervention period.

RESULTS: 32 caregivers were recruited; no dropouts. 81.3% (26/32) attended all sessions, and 87.5% (28/32) completed telephonic interventions. Overall satisfaction a showed a median score of 4 (P25-P75: 3.25-5), with the highest ratings for the intervention team (median 4, P25-P75: 4-4). Participation demonstrated a median score of 4 (P25-P75: 3.25-4), with particularly high engagement in reading the provided materials (median 4.5, P25-P75: 4-5). The most frequently applied strategy was seeking support from family and friends (median 4, P25-P75: 4-4). (2) Qualitative findings revealed four themes: Perceived Benefit, Peer Support, Suggestions for Improvement, and Reasons for Low Application. Post-intervention improvements were seen in PAC (t=3.553, P=0.001, d=0.63), sense of competence (t=4.673, P<0.001), social network (t=3.645, P=0.001), and EQ-5D index (t=2.785, P=0.009). Burden (t=-3.083, P=0.004, d=0.55) and anxiety (t=-3.544, P=0.001) decreased significantly.

CONCLUSION: The DeCare-SPM was feasible and acceptable for family caregivers and showed preliminary effects on family caregivers.},
}

@article {pmid42093988,
year = {2026},
author = {Wang, H and Li, F and Wang, H and Tian, Z and Fan, H and Shi, Z},
title = {Resveratrol and the neuroinflammation axis in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1758356},
pmid = {42093988},
issn = {1664-3224},
mesh = {Humans ; *Resveratrol/therapeutic use/pharmacology ; Animals ; *Multiple Sclerosis/drug therapy/metabolism/immunology ; *Alzheimer Disease/drug therapy/metabolism ; *Parkinson Disease/drug therapy/metabolism/immunology ; *Brain Ischemia/drug therapy/metabolism/immunology ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {Resveratrol (RES), a naturally occurring polyphenolic compound found in grapes, berries, and peanuts, has attracted considerable interest because of its antioxidant, anti-inflammatory, and neuroprotective properties. This narrative review examines the current evidence regarding the potential effects of RES on memory-related processes and neuroinflammatory biomarkers in major neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia. Relevant literature was identified through searches of major scientific databases, and studies addressing the molecular mechanisms, experimental outcomes, and therapeutic implications of RES in these conditions were evaluated. The available evidence indicates that RES can modulate several biological pathways associated with neurodegeneration, including oxidative stress, inflammatory signaling, mitochondrial dysfunction, and neuronal survival. Experimental studies suggest that RES may influence key molecular mediators such as pro-inflammatory cytokines, nitric oxide (NO) signaling, and matrix metalloproteinases, which are implicated in neuronal damage and blood-brain barrier disruption. In preclinical models of AD and PD, RES has been associated with improvements in cognitive performance, reduction of neuroinflammatory markers, and attenuation of neuronal loss. Similarly, studies in MS and cerebral ischemia models indicate that RES may modulate immune responses, reduce oxidative damage, and limit ischemia-related neuronal injury. However, most of the current evidence derives from in vitro and animal studies, and clinical data remain limited. Moreover, the low bioavailability of RES and variability in dosing regimens represent important challenges for clinical translation. Therefore, although experimental findings support the potential neuroprotective role of RES, further well-designed clinical studies are required to determine its therapeutic relevance and safety in human neurological disorders. This narrative review was developed through a structured search of PubMed, Scopus, and Web of Science for articles published between 2000 and 2024, focusing on mechanistic, preclinical, and clinical investigations of RES in neurological disorders. This review synthesizes current evidence on the molecular and cellular mechanisms underlying the neuroprotective effects of RES, with particular emphasis on its antioxidant, anti-inflammatory, and immunomodulatory activities. By integrating findings from experimental and clinical research, the review highlights the potential of RES to modulate key pathways involved in neurodegeneration and neuroinflammation. Although further well-designed clinical studies are required to clarify its therapeutic efficacy and translational relevance, the available evidence supports continued investigation of RES as a promising candidate for neuroprotective strategies in neurological disorders.},
}

Humans
*Resveratrol/therapeutic use/pharmacology
Animals
*Multiple Sclerosis/drug therapy/metabolism/immunology
*Alzheimer Disease/drug therapy/metabolism
*Parkinson Disease/drug therapy/metabolism/immunology
*Brain Ischemia/drug therapy/metabolism/immunology
*Neuroinflammatory Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid42094052,
year = {2026},
author = {Tug, T and Liang, D and Teschke, S and Tan, Y and Gearing, M and Levey, AI and Lah, JJ and Wingo, AP and Wingo, TS and Lau, M and Ickstadt, K and Hüls, A},
title = {Development and Application of Brain Tissue Based Multi-omics Profile Scores for Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9438710/v1},
pmid = {42094052},
issn = {2693-5015},
abstract = {BACKGROUND Advances in omics technologies, such as epigenomics and metabolomics, provide novel insights into the biological mechanisms underlying Alzheimer's disease (AD). However, little is known how different omics layers interact and jointly relate to AD neuropathology. METHODS We performed a comprehensive single- and multi-omics analysis integrating genome-wide DNA methylation and high-resolution metabolomics data from 157 frontal cortex samples. We developed novel single and multi-omics profile scores (PS) for AD pathology, using a combination of machine learning, regression, and pathway analysis. RESULTS For the ABC score (Amyloid, Braak, CERAD) the PS of DNAm outperformed metabolomics-based PS (median R[2]: 0.11 vs. 0.04). Combining both omics layers with the best-performing multi-omics PS yielded a partial R[2] of 0.15 for the ABC score independent of age, sex, race and socioeconomic factors. DNAm-specific pathways highlighted redox balance, immune activation, synaptic signaling, and lipid biosynthesis, whereas metabolomics-specific pathways emphasized inflammatory, hormonal, lipid, and energy metabolism. Notably, both omics layers converged on lipid metabolism and signal transduction as shared biological systems implicated in AD neuropathology. CONCLUSIONS Despite limited gains in predictive accuracy, integrative pathway and network analyses of DNAm and metabolomics PS converged on lipid metabolism and signal transduction, underscoring shared biological mechanisms and the value of multi-omics approaches for biological insight rather than prediction alone.},
}

@article {pmid42094058,
year = {2026},
author = {Goate, A and Podlesny-Drabiniok, A and Kim, J and Bezemer, L and Patel, T and Cheng, H and Sewell, M and Montecillo, M and Church, N and Walley, A and Garretti, F and Marcora, E},
title = {MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer's disease risk in macrophages.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9164252/v1},
pmid = {42094058},
issn = {2693-5015},
abstract = {Risk alleles for late-onset Alzheimer's disease (AD) are enriched in myeloid cis-regulatory elements, implicating myeloid gene-regulatory networks in disease susceptibility. A conserved lipid-associated transcriptional signature-spanning disease-associated microglia and peripheral lipid-associated macrophages (DLAM)-emerges across neurodegenerative and metabolic diseases characterized by lipid overload, yet the transcriptional regulators of this gene expression program remain incompletely defined. Here, we show that MEF2C-a candidate AD risk gene-is a master DLAM regulator. Using MEF2C knockout and knockdown in human iPSC-derived microglia and macrophages, we found that total or partial MEF2C loss is sufficient to induce DLAM-associated transcriptional, epigenomic, and functional remodeling, including enhanced lysosomal activity and cholesterol efflux. Integration of chromatin accessibility and regulatory epigenetic profiles with functionally informed fine-mapping linked candidate causal variants in AD risk loci to MEF2C-regulated cis-regulatory elements that target candidate AD risk genes at these loci. In a triculture model of AD, microglial MEF2C loss is associated with an increased DLAM population and a reduced Aβ42/40 ratio, supporting context-dependent reprogramming of microglia as a potential biological mechanism to modulate AD-relevant pathology.},
}

@article {pmid42094065,
year = {2026},
author = {Tamer, Y and Noon, A and Yang, Z and Yu, K and Shah, A and Karam, A and Hajjar, I},
title = {The Brain Vulnerability Index: Development and Validation of a Machine Learning-Derived, Community-Informed Geospatial Risk Score for Cognitive Impairment.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9381770/v1},
pmid = {42094065},
issn = {2693-5015},
abstract = {Background Social determinants of health (SDOH) are increasingly recognized as important contributors to cognitive impairment, including Alzheimer's disease and related dementias. Existing indices are heavily weighted toward financial indicators and are not validated against cognitive outcomes. We aimed to develop and validate a novel brain-specific SDOH index that identifies high-risk communities for cognitive impairment. Methods The Brain Vulnerability Index (BVI) integrates patient-level electronic health record data with neighborhood-level SDOH from the Community Vulnerability Compass, a population health analytics framework. In the model development phase, electronic health record data were obtained from patients seen at Parkland Health (Dallas, TX). Cases were defined as individuals with at least one ICD-10 diagnosis suggestive of cognitive impairment from 2015 to 2023 and controls were age-matched with no ICD-10 diagnosis. External validation against serial cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and clinically adjudicated consensus diagnosis of cognitive impairment of any etiology was performed in community-based (Dallas Heart Study) and clinically based (Alzheimer's Disease Research Center) cohorts. Results The model development sample included 39,570 cases and 192,060 controls. Derived BVI at the block group level achieved detection of electronic health documentation suggestive of cognitive impairment at a balanced accuracy of 54.6%. In external validation (n = 1,395), higher BVI values were associated with lower MoCA scores (β = -0.35; p = 0.009) and with faster cognitive decline (- 1.04 vs - 0.42 MoCA points/year in high- vs low-risk groups; p < 0.0001). BVI was also associated with adjudicated cognitive impairment in the community-based cohort only (p = 0.04). Across analyses, BVI correlated with but outperformed existing neighborhood indices. Conclusions BVI, a novel multidimensional brain-specific SDOH index, is clinically anchored and is externally validated. It may assist in earlier identification of at-risk communities with accelerated cognitive decline and aid in resource allocation for targeted prevention strategies.},
}

@article {pmid42094067,
year = {2026},
author = {Fabian-Fine, R and Roman, AG and Winters, MJ and Lathram, KJ and Bennett, CH and Kipingi, LK and Brännare-Gran, SM and Whitley, AE and Paul, CM and Altman, LM and Carrillo, IC and Joyce, FM and Kragh, LA and McKnight, TJ and Reding, CJ and Reiderer, LJD and Rivera, LJ and Steen, HA and Weaver, AL},
title = {Uncovering the invisible giant: Amyloid beta plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9337412/v1},
pmid = {42094067},
issn = {2693-5015},
abstract = {According to the prevalent 'Amyloid Hypothesis,' the underlying cause for neurodegeneration in Alzheimer Disease (AD) is attributed to the accumulation of misfolded Amyloid ß and tau protein in the form of extracellular sticky plaques and neurofibrillary tangles, respectively. These protein accumulations are thought to be caused by impaired waste removal. In an alternative hypothesis, we have proposed the existence of an extensive glial canal system that is likely formed by myelinated aquaporin-4 (AQP4)-expressing tanycytes and removes cellular waste from the hippocampal formation. Here, we demonstrate that tanycyte-derived waste-internalizing receptacles are immunoreactive for Aß and emanate from specialized nucleus-like organelles in the following referred to as 'tanysomes.' Utilizing RNA-scope in situ hybridization, we demonstrate that these receptacle-forming tanysomes express RNA for AQP4 and the Aß-related genes, amyloid precursor protein, and presenilin-1. These findings suggest that Aß is likely synthesized where receptacle formation is observed and that Aß may play an important structural role in receptacle formation. In AD-affected hippocampus, excessive amounts of Aß-immunoreactive waste receptacles emerge from tanysomes and have the appearance of plaques in Aß-immunolabeled hippocampus. Moreover, we demonstrate that the same receptacle-forming organelles exhibit strong immunolabeling for hyperphosphorylated tau protein in AD-affected tissue. We postulate that both proteins may play important structural roles in waste uptake and that hypertrophic swelling of impaired tanycytes in AD-affected brain may be due to obstructions of this extensive interconnected glial canal system.},
}

@article {pmid42094071,
year = {2026},
author = {Area-Gomez, E and Cardona-Gómez, G and Salomon-Cruz, I and Galvis-Garrido, N and Lozano-Trujillo, L and Barbosa-Carvajal, J and Agudelo-Castrillon, S and Yun, T and Montesinos, J and Henao, E and Quiroz, Y and Kosik, K and Schon, E and Larrea, D and Aguillon, D and Villegas-Lanau, A and Aguirre-Acevedo, D and Arias-Londoño, J},
title = {Circulating lipids uncover early membrane disruption as a primary event preceding Alzheimer's disease onset.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9357482/v1},
pmid = {42094071},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is not a single entity but a biologically heterogeneous disorder, with substantial inter-individual variability in clinical presentation, molecular drivers, and disease trajectories. This heterogeneity limits current diagnostic and therapeutic strategies, which largely rely on late-stage protein biomarkers that, while sensitive to prodromal impairment, remain insufficient for primary prevention and patient stratification. Lipids are fundamental to brain structure and function, yet their role in the earliest stages of AD remains poorly defined. Here, we identify a robust, early-life lipid signature in serum from asymptomatic carriers of the PSEN1-E280A mutation, detectable from childhood. Using latent profile analysis, we resolve distinct lipid states associated with risk and resilience to dementia, modulated by genetic status, sex, and APOE genotype, and supported by concordant changes in circulating protein biomarkers. Mechanistically, these lipid alterations point to early and sustained disruptions in cholesterol and sphingolipid metabolism, suggesting that impaired lipid turnover is a primary event in AD pathogenesis rather than a downstream consequence. Our findings position circulating lipids as dynamic reporters of disease-relevant cellular pathways and reveal a previously unrecognized metabolic dimension of the presymptomatic phase of AD. Together, this work reframes AD as a disorder of early metabolic dysregulation and highlights lipidomic profiling as a powerful approach for early detection, risk stratification, and mechanistic insight.},
}

@article {pmid42094127,
year = {2026},
author = {Zambrano-Astorga, MF and Moreno-Ulloa, A and , },
title = {Reproducibility-driven discovery and systematic benchmarking reveal a robust cerebrospinal fluid proteomic signature in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.26.26351766},
pmid = {42094127},
abstract = {UNLABELLED: Numerous cerebrospinal fluid (CSF) proteomic signatures for Alzheimer's disease (AD) diagnosis and prognosis have been proposed. However, cross-cohort reproducibility and head-to-head comparison among signatures remain uncertain. We implemented a reproducibility-driven framework integrating systematic review, multi-cohort validation, and systematic benchmarking to prioritized robust biomarkers. Across eight discovery studies (n=759) we identified eleven consistently dysregulated proteins (termed PPAV11). In three independent validation cohorts (n=1,198), PPAV11 demonstrated high diagnostic accuracy (AUC>0.94) and significant prognostic capacity (CU to A[+]T[+] MCI HR>4.96, p =0.004; A[+]T[+] MCI to A[+]T[+] dementia HR>3.23, p =3.13×10[-7]). Comparative benchmarking against thirteen published signatures revealed superior cross-context stability across diagnostic definitions, disease stages, and proteomic platforms. Biologically, PPAV11 captures synaptic, metabolic, immune, and vascular processes and correlates with cognitive decline and neurodegeneration. Together, these findings establish reproducibility as an important criterion for proteomic biomarker prioritization and define a stable molecular signature for integrated AD diagnosis and prognosis.

HIGHLIGHTS: A reproducibility framework identifies stable CSF proteomic signature for AD.PPAV11 shows strong diagnostic accuracy across cohorts, platforms, and stratifications.PPAV11 levels correlate with cognitive decline and predict AD progression.PPAV11 unites synaptic, metabolic, immune, and vascular pathways in AD dynamics.},
}

@article {pmid42094129,
year = {2026},
author = {Guen, YL and Park, J and Peña-Tauber, A and Greicius, MD},
title = {Proteomic Signatures of Protected APOE -ε4 Carriers Reveal Causal Pathways Associated with Delayed Alzheimer's Disease Onset.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.26352191},
pmid = {42094129},
abstract = {INTRODUCTION: APOE -ε4 is the strongest common genetic risk factor for Alzheimer's disease (AD), yet many carriers remain cognitively unimpaired into late life. We tested whether a protected-ε4-first proteomic approach could identify plasma proteins associated with delayed clinical onset among ε4 carriers.

METHODS: We analyzed harmonized plasma proteomics from the Global Neurodegeneration Proteomics Consortium. Protected ε4 carriers (ε3/ε4 aged ≥75 years; ε4/ε4 aged ≥65 years; CDR=0; n=456) were compared with ε4 carriers with AD (n=1,096). Protein-wise linear models adjusted for age, sex, ε4 dosage, and plasma proteomic principal components. Top signals were integrated with high-confidence loss-of-function burden testing and plasma/CSF Mendelian randomization.

RESULTS: ε4 protected was associated with 721 protein levels. Integrated analyses prioritized proteins linked to ε4-modified disease biology, including LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10, and proteins aligned with broader AD-related change, including OMG, SELENOW, VAT1, and TPPP3. TREM2 and ACE were also identified, providing internal biological validation of the approach.

DISCUSSION: A protected-ε4-first plasma proteomic strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset and helps prioritize candidate ε4-specific modifiers for prevention-focused therapeutics.},
}

@article {pmid42094138,
year = {2026},
author = {Arrotta, K and Williams, M and Thompson, NR and Bangen, KJ and Reyes, A and Zawar, I and Punia, V and Wang, I and Shih, JJ and Bekris, LM and Ferguson, L and Almane, DN and Jones, JE and Hermann, BP and Busch, RM and McDonald, CR},
title = {AT(N) Framework in Older Adults with Epilepsy: Plasma Biomarkers and Associations with Demographic, Clinical, and Cognitive Features.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.24.26351489},
pmid = {42094138},
abstract = {BACKGROUND AND OBJECTIVES: Older adults with epilepsy have a 2- to 4-fold increased risk of dementia, including Alzheimer's disease (AD), yet underlying mechanisms remain poorly defined. The NIA-AA classifies AD using amyloid (A), tau (T), and neurodegeneration [(N)] biomarkers. We applied this framework to characterize AT(N) profiles and clinical correlates in epilepsy.

METHODS: Eighty-four older adults with focal epilepsy (mean age=66.3 years) from the Brain Aging and Cognition in Epilepsy (BrACE) study were classified as A+, T+, and/or (N)+ using plasma β-amyloid (Aβ) 42/40 ratio, phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) levels, and grouped into normal, AD-continuum, and non-AD pathologic change. Demographic, clinical, and cognitive characteristics were compared. Cognition was assessed using the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) and the Montreal Cognitive Assessment (MoCA). Memory was examined using IC-CoDE memory domain classification, with word-list delayed recall analyzed separately. Associations with cognition were modeled using logistic and linear regression. Secondary analyses examined biomarkers continuously, including p-tau217, and substituted hippocampal volume for NfL.

RESULTS: Only 32% of participants had normal biomarkers, while 37% were on the AD-continuum and 31% showed non-AD pathologic change. Participants with normal biomarkers were younger with shorter epilepsy duration, whereas APOE -ε4 carriers were enriched in the AD-continuum group. Early-onset compared to late-onset epilepsy (cutoff:≥55 years) showed higher odds of biomarker abnormality (aOR=8.84, 95% CI [2.35, 41.89], P =0.003), driven by elevated p-tau217, NfL, and greater amyloid burden. While categorical AT(N) profiles were not associated with cognition, higher p-tau181 levels were independently associated with lower word-list delayed recall (95% CI [-10.31, -0.86], P =0.021). Substituting hippocampal volume for NfL shifted more participants to normal profiles (48% vs. 32%) and fewer to non-AD pathologic change (15% vs. 31%).

DISCUSSION: AT(N) biomarker profiles showed substantial heterogeneity, with higher abnormality rates than in aging populations, particularly among those with early-onset epilepsy. Continuous p-tau181 was associated with memory performance while categorical AT(N) profiles were not, and NfL and hippocampal volume showed discordant classifications, highlighting divergence across neurodegeneration markers. These findings underscore the complexity of applying AD-centric frameworks to epilepsy and support multimodal, epilepsy-adapted biomarker approaches to characterize neurodegenerative risk.},
}

@article {pmid42094273,
year = {2026},
author = {Wen, Z and Biros, G},
title = {LNODE: latent dynamics reveal the shared spatiotemporal structure of amyloid-$β$ progression.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42094273},
issn = {2331-8422},
abstract = {We introduce LNODE, a mechanism-based phenomenological model for amyloid beta (A$β$) dynamics, calibrated using positron emission tomography (PET) imaging. A$β$ is a key biomarker of Alzheimer's disease. LNODE is designed to support the fusion, harmonization, quantitative analysis, and interpretation of Abeta PET scans. We evaluate LNODE on 1461 subjects in the ADNI cohort and 1070 subjects in the A4 Study, using MUSE and DKT anatomical atlases. LNODE is formulated as a regional neural ordinary differential equation (ODE) model that is jointly calibrated on all available scans within a cohort. The model captures the spatial propagation, proliferation, and clearance of A$β$ and incorporates a latent-state representation that modulates A$β$ dynamics. The temporal evolution of these latent states is governed by cohort-shared parameters, enabling LNODE to represent both population-level trajectories and subject-specific deviations. The proposed model demonstrates strong parameter identifiability and stability properties, supported by synthetic experiments and analytical analysis of the Hessian condition number. To mitigate overfitting and reduce spurious correlations, LNODE is intentionally underparameterized, employing approximately five to ten parameters per subject. Despite this parsimonious parameterization, LNODE achieves $R^2 > 0.99$ in both the ADNI and A4 datasets. LNODE exhibits strong predictive performance: in the A4 cohort, it accurately forecasts the A$β$ PET signal in previously unseen follow-up scans, including cases with inter-scan intervals exceeding four years. Clustering in the learned latent-state space reveals distinct subgroups, consistent with the existence of different subtypes of Alzheimer's disease progression.},
}

@article {pmid42094347,
year = {2026},
author = {Zhao, Z and Locascio, JJ and Li, H and Gowravaram, N and Green, RJ and Kastanenka, K and Bacskai, B and Hyman, BT and Gomperts, SN},
title = {Amyloid plaques drive state-dependent long-range circuit reorganization in the hippocampus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.22.720180},
pmid = {42094347},
issn = {2692-8205},
abstract = {Amyloid plaques are a pathological hallmark of Alzheimer's disease, but how they drive widespread neuronal dysfunction remains unclear. While studies in anesthetized animals show that plaques drive local hyperactivity [1,2] , it is unknown how this pathology shapes functional hippocampal maps in freely behaving animals. We combined chronic 1-photon calcium imaging, local field potential recordings, and post hoc 2-photon plaque imaging in freely behaving APP/PS1 mice across behavior and sleep to correlate real-time hippocampal activity and place coding with precise plaque topography. Here we show that plaques exert nonlocal, long-range effects on hippocampal activity that depend on plaque size, laminar position, and the animal's behavioral state. Place cells, which encode spatial position and are normally uniformly distributed, are preferentially enriched near plaques, revealing an aberrant reorganization of plaque-adjacent neurons into the hippocampal map of space. In longitudinal experiments, pre-existing place cell locations do not predict future plaque sites, whereas hyperactivity during slow-wave sleep weakly predicts future amyloid deposition. These findings identify a mechanism by which amyloid pathology reorganizes brain circuits, degrading the functional architecture of the hippocampus and contributing to widespread dysfunction and cognitive impairment in Alzheimer's disease.},
}

@article {pmid42094385,
year = {2026},
author = {Sanders, B and Korthauer, M and Singh Parihar, K and Ifergan, I},
title = {Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles attenuate neuroinflammation and Alzheimer's disease-related pathology in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.720934},
pmid = {42094385},
issn = {2692-8205},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, amyloid-β deposition, neuroinflammation, and neurodegeneration, yet effective and well-tolerated therapies remain limited. Because dysregulated myeloid responses are increasingly recognized as important drivers of disease progression, we investigated the therapeutic potential of poly(lactic-co-glycolic acid) immunomodulatory nanoparticles in the 5xFAD mouse model of amyloid-driven neurodegeneration. Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles and fluorescently labeled particles displayed the expected size range and negative surface charge. After intraperitoneal administration, fluorescent particles were preferentially associated with myeloid cells in the blood, spleen, and brain, with greater uptake by brain myeloid populations in 5xFAD mice than in wild-type controls. Therapeutic treatment of 6.5-month-old 5xFAD mice, a stage at which behavioral abnormalities are already established, resulted in significant improvement in elevated plus maze behavior and a more modest improvement in Barnes maze performance. Flow cytometric analysis performed 9 weeks after the final treatment demonstrated persistent changes in brain immune composition, with the most prominent effects observed in P2RY12 [+] microglial populations, particularly the CD11c [+] subset, and comparatively limited sustained effects in CD11b [+] P2RY12 [-] myeloid cells. These changes were accompanied by reduced expression of activation- and disease-associated markers and lower pro-inflammatory cytokine production within microglial populations. Histological analysis further showed reduced cortical amyloid plaque burden, decreased CD68 immunoreactivity, and reduced neurodegeneration in treated 5xFAD mice. Together, these findings show that systemically administered poly(lactic-co-glycolic acid) immunomodulatory nanoparticles produce durable behavioral, immunological, and pathological benefits in 5xFAD mice and support further investigation of this biodegradable myeloid-targeted platform as a therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42094407,
year = {2026},
author = {Flax, R and Lacigová, A and Howell, S and Li, H and Bashore, FM and Čajánek, L and Axtman, AD},
title = {Development of Potent and Cell Active 5-Azaindole-Based Tau Tubulin Kinase Inhibitors.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.721186},
pmid = {42094407},
issn = {2692-8205},
abstract = {We have developed and characterized a potent and cell active tau tubulin kinase 1 and 2 (TTBK1 and TTBK2) inhibitor, 13 . Compound 13 demonstrates in-cell, kinome-wide selectivity, and potently inhibits both TTBK1 and TTBK2. As part of our medicinal chemistry campaign, we also identified a structurally similar negative control, compound 5 , which lacks in-cell affinity for TTBK1 and TTBK2. Based on their substrates, which include TDP-43, tau, and tubulin, TTBK1 and TTBK2 inhibition has been pursued as a therapeutic approach for Alzheimer's disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. TTBK2 is also an effector of ciliogenesis, acting in concert with CEP164, CP110, and CEP83 to initiate the biogenesis of primary cilia. The development of selective chemical tools for these kinases facilitates investigation into TTBK1/2-mediated pathways and potential disease-altering ramifications linked to their pharmacological perturbation.},
}

@article {pmid42094412,
year = {2026},
author = {Tilahun, K and Parameswaran, J and Dudley, M and Pun, D and Ma, F and Zhang, J and Bold, T and Jiang, J},
title = {TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.23.719939},
pmid = {42094412},
issn = {2692-8205},
abstract = {TMEM106B is a lysosomal membrane protein and major genetic modifier of multiple neurodegenerative diseases, including frontotemporal lobar degeneration, Alzheimer's disease, and amyotrophic lateral sclerosis. Proteolytically generated C-terminal fragments of TMEM106B assemble into amyloid fibrils that accumulate in the brains of individuals with neurodegenerative disease and in cognitively normal aged adults, yet how these fibrils produce neuronal dysfunction has remained unclear. Here, we show that cytosolic and lysosome-directed TMEM106B C-terminal fragments (CTF and gCTF) form detergent-insoluble amyloid aggregates, drive redistribution of endogenous TDP-43 from the nucleus to the cytoplasm, and accelerate neuronal death. Unbiased proximity proteomics identified the inner nuclear membrane LAP1-TorsinA axis as a fragment-specific interactome, and co-immunoprecipitation confirmed a direct physical interaction between gCTF and LAP1 that was not observed with full-length TMEM106B. Fragment expression disrupted Lamin B1 organization, mislocalized the nuclear import machinery KPNB1 and RanGAP1, and impaired importin-dependent nuclear transport in primary cortical neurons. Critically, neurons harboring endogenous TMEM106B fibrillar pathology in aged human frontal cortex exhibited the same phenotypes, namely disrupted Lamin B1 and LAP1 localization and cytoplasmic redistribution of TDP-43, whereas fibril-negative neurons from the same cases and younger control tissue retained intact nuclear envelope organization. These findings define TMEM106B proteinopathy as an upstream driver of nuclear envelope disruption and nucleocytoplasmic transport failure, linking a widespread feature of brain aging to a central mechanism of neurodegeneration.},
}

@article {pmid42094448,
year = {2026},
author = {Foiani, MS and Bourdenx, M and Kraller, L and Nirujogi, RS and Yiu, A and Davies, H and Patel, S and Damoc, LS and Mitchener, L and Jaunmuktane, Z and Coscia, F and Duff, KE},
title = {Spatial Single-Cell Proteomics Reveals Molecular Trajectories Of Tangle-Bearing Neurons In Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.26.720932},
pmid = {42094448},
issn = {2692-8205},
abstract = {Neurofibrillary tangles composed of hyperphosphorylated tau are a defining pathological hallmark of Alzheimer's disease (AD); however, the pathways and mechanisms associated with the transition from physiological tau to tangle pathology remain unclear. Here, we integrate laser microdissection of post-mortem, fixed human AD brain tissue labelled with an antibody recognizing tangle-associated phospho-tau (AT8) with mass spectrometry-based proteomics, applied to individual neurons and to small neuronal pools. This approach identified ∼2,000 and ∼5,000 proteins, respectively, and enabled direct detection of disease-associated tau phosphorylation sites without prior enrichment. A layered analysis of the proteome of tangle-positive and tangle-negative neurons revealed heterogeneous disease-associated states. Pseudotime analysis, combined with an AI-driven analytical framework, indicates that neurons do not segregate into discrete classes but instead organize along a continuum of proteomic changes that correlate with tau abundance. This organization enabled the construction of a trajectory of pathological neuronal responses that can be resolved within an individual brain. Early stages of this trajectory are characterized by coordinated remodeling of proteostasis networks, including reduced proteasome component abundance and increased lysosomal acidification machinery, followed by disruption of synaptic pathways. Notably, despite extensive proteomic remodeling, neurons bearing tangles show little evidence of activated cell-death programs, suggesting prolonged molecular adaptation rather than acute degeneration. Together, these findings establish a framework for single-cell-resolved proteome analysis of human brain disease in situ and define a continuum of neuronal states underlying tau pathogenesis, revealing early vulnerabilities and adaptive responses during AD progression.},
}

@article {pmid42094463,
year = {2026},
author = {Ahmed, W and Nogueras-Ortiz, C and Sagar, R and Dong, D and Boyd, RJ and Yao, PJ and Iliuk, A and Lyketsos, CG and Witwer, KW and Kapogiannis, D and Mahairaki, V},
title = {Proteomic identification and validation of novel neuronal EV-based markers for Alzheimer's disease biomarker discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.26.720870},
pmid = {42094463},
issn = {2692-8205},
abstract = {Extracellular vesicles (EVs) circulate in biofluids and carry tissue-specific molecular cargo, offering significant potential for the discovery of minimally invasive biomarkers. However, translation in neurodegenerative diseases has been hindered by the lack of validated neuronal EV surface markers that enable selective isolation from plasma. We hypothesized that proteomic profiling of EVs released from human induced pluripotent stem cell (hiPSC)-derived neurons would identify 1. robust Alzheimer's disease (AD)-associated signatures that reflect disease pathogenesis, and 2. surface-accessible neuronal markers capable of enriching disease-relevant cargo. Neurons differentiated from AD patients and age-matched cognitively normal (CN) individuals were used to isolate EVs, which were characterized and analyzed by LC-MS proteomics in both total and membrane-enriched fractions. Proteomic profiling identified numerous dysregulated proteins, with a subset validated across independent AD datasets. We identified CNTNAP2 and STX1B as neuronal, brain-enriched EV surface proteins accessible for selective capture and confirmed their presence in EVs from post-mortem human brain, supporting them as bona fide brain-derived EV markers. Immuno-isolation of plasma EVs showed that CNTNAP2-positive EVs had a robust AD-associated increase in phosphorylated tau, identifying CNTNAP2 as a highly discriminative brain-derived EV marker and supporting its potential for blood-based AD diagnostics.},
}

@article {pmid42094473,
year = {2026},
author = {Gutierrez, JC and Chen, Y and Babaian, A and Dhindsa, RS and Lareau, CA},
title = {Resolving human neuronal herpesvirus reactivation via petabase-scale association studies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721769},
pmid = {42094473},
issn = {2692-8205},
abstract = {Mounting evidence implicates herpesvirus reactivation in the etiology of Alzheimer's disease, yet we lack a refined molecular characterization of pathogenesis in neurodegeneration. Here, we mine over 10 petabytes of human sequencing data for viral transcripts, identifying recurrent herpes simplex virus 1 (HSV-1) reactivation in healthy but not pathological post-mortem human brain tissue. Integrative single-nucleus analyses resolve direct evidence of HSV-1 expression in RORB+ glutamatergic neurons, implicating viral reactivation in a neuronal population progressively lost during dementia.},
}

@article {pmid42094502,
year = {2026},
author = {DeWit, JM and Tebyanian, T and Unapanta, A and Vaughn, MN and Powell, SB and Risbrough, VB and Zhou, X},
title = {Pro-Cognitive Effects of IgM Isotype Anti-NMDAR1 Autoantibodies in Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.24.720689},
pmid = {42094502},
issn = {2692-8205},
abstract = {Natural anti-NMDAR1 autoantibodies are present at varying levels in the general human population, but their effects on cognitive function remain unclear. Recent human studies reported significant associations between higher blood levels of natural anti-NMDAR1 autoantibodies and potential neuroprotective outcomes in Alzheimer's disease, traumatic brain injury-associated depression and PTSD symptoms, and schizophrenia. However, whether these natural autoantibodies play a causal role in emotional and cognitive function has not been investigated. Since natural autoantibodies in human blood are predominantly of the IgM isotype, we immunized Aicda mutant mice to produce only IgM isotype anti-NMDAR1 autoantibodies without IgG and IgA isotypes. Mice were tested for sensorimotor gating and conditioned fear and extinction, cross species measures of information processing and emotional memory, respectively. Mice with higher levels of IgM anti-NMDAR1 autoantibodies exhibited significantly increased sensorimotor gating and improved fear extinction recall compared with mice with baseline levels of these autoantibodies. These findings indicate that IgM anti-NMDAR1 autoantibodies are pro-cognitive, unlike previous reports of poor cognition associated with IgG anti-NMDAR1 autoantibodies. Together, these studies suggest that IgM may hold therapeutic potential for a range of neurodegenerative, neurological, and psychiatric disorders.},
}

@article {pmid42094534,
year = {2026},
author = {Moore, SJ and Murphy, GG},
title = {Acarbose improves cognitive function in a mouse model of normal aging but not Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.28.721469},
pmid = {42094534},
issn = {2692-8205},
abstract = {INTRODUCTION: Declines in function occur in both normal aging (in the absence of disease) and age-related pathological contexts, like Alzheimers disease (AD). Whether anti-aging interventions (that extend lifespan) also promote cognitive function in aging and AD remains unexplored.

METHODS: We assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice.

RESULTS: In mid-aged and aged Ntg-HET3 mice, acarbose treatment resulted in performance equivalent to young adults. Conversely, acarbose failed to ameliorate age-related deficits in 5xFAD-HET3 mice.

DISCUSSION: This work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it reinforces that AD is not simply accelerated aging and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.},
}

@article {pmid42094538,
year = {2026},
author = {Woodham, TA and Kelsey, MMG and Sedivy, JM},
title = {Characterization of Cellular Senescence in Primary Human Astrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721581},
pmid = {42094538},
issn = {2692-8205},
abstract = {Senescent astrocytes have been identified in the brains of patients with neurodegenerative disorders, including Alzheimer's disease, yet the molecular characteristics of replicative senescence in human astrocytes remain largely unexplored. Prior work has been hampered by the low proliferative capacity and limited telomere shortening of primary human astrocytes in culture. Here, we describe a culture system in which primary human astrocytes propagated under physiological (3%) oxygen reach canonical telomeric replicative senescence after extensive expansion (up to ~76 population doublings). Senescence was confirmed through multiple biomarkers, including reduced EdU incorporation, elevated senescence-associated beta-galactosidase (SA-β-gal) activity, persistent DNA damage foci (γH2AX and 53BP1) predominantly localized to telomeres, and nuclear accumulation of p53. RNA sequencing across a 12-week time course revealed early upregulation of young LINE-1 (L1HS) retrotransposon transcripts, type-I interferon (IFN-I) and senescence-associated secretory phenotype (SASP) pathway genes, alongside downregulation of cell-cycle and DNA repair programs. To resolve L1HS expression at individual locus resolution, we performed Nanopore DNA sequencing to generate a custom reference genome incorporating non-reference LINE-1 insertions. Applying our TE-Seq pipeline, we identified two full-length intergenic L1HS elements consistently upregulated across the replicative senescence time course, one of which, L1HS_9q22.32_2, retained intact ORF1 and ORF2 open reading frames, indicating potential retrotransposition competence. To contextualize the astrocyte replicative senescence program, we compared it to three additional conditions. First, parallel astrocyte cultures maintained under normoxic (20%) oxygen entered senescence earlier and showed stronger SASP upregulation. Second, DNA damage-induced senescence (DDIS) triggered by etoposide treatment produced a stronger pro-inflammatory transcriptional signature than replicative senescence, including elevated IL6, IL1A, and IL1B expression. DDIS also upregulated L1HS_9q22.32_2 as well as a second intact element, L1HS_14q23.2_3, which we have previously identified among the small number of intact L1HS loci activated during replicative senescence in fibroblasts. The convergent activation of these intact elements across cell types and senescence modalities reinforces L1HS-driven IFN-I signaling as a conserved feature of the senescent program. Third, comparison with replicatively senescent fibroblasts revealed cell-type-specific SASP regulation: the pro-inflammatory cytokines IL6 and CCL2 were downregulated in senescent astrocytes relative to proliferating cells, opposite to their behavior in fibroblasts. Together, these data establish the first comprehensive transcriptomic profile of replicative senescence in human astrocytes, offering a resource for understanding brain aging and senescence-associated neurodegeneration.},
}

@article {pmid42094552,
year = {2026},
author = {Grudny, MM and Rodriguez, N and Murdy, TJ and Simon, ZD and Vo, Q and Li, W and Burns, MR and Lamb, DG and Kaczorowski, CC and Chakrabarty, P and Febo, M},
title = {Dissociable species-specific impact of Aβ on static and dynamic functional connectomes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.26.720907},
pmid = {42094552},
issn = {2692-8205},
abstract = {Temporal dynamics in functional connectomes provide a physiologically grounded signature of 'hidden' pathologies during preclinical stages of Alzheimer's disease (AD). We evaluated the effect of beta-amyloid (Aβ) on dynamic functional connectomes in transgenic mice and human subjects. Functional magnetic resonance images (fMRI) were collected in two strains of Aβ mice. fMRI-derived connectomes were segmented into discrete states using a hidden Markov model, and network strength, efficiency, and transitivity were analyzed per state. Human fMRI-derived connectome measures were analyzed across 3 states. Static network measures were significantly different between Aβ mice and controls, the former having high values for strength, efficiency and clustering coefficient in anterior cingulate, hippocampus, and retrosplenium. Dynamic network measures were stable within-states in Aβ mice. Similarly, human subjects with high Aβ had high node strength in precuneus and temporoparietal areas compared to low Aβ. Conversely, high Aβ was associated with high switch rates, high fractional occupancy, and state dwell times. Also, global strength, efficiency, and transitivity were less stable within states in the high Aβ group. Our results indicate that static, but not dynamic, connectome strength, efficiency, and network integration are increased in Aβ mice, while dynamic network states appear less stable in human functional connectomes. This data supports a dissociable, species-specific impact of Aβ, with dynamic network alterations present in humans but not in Aβ mouse models, suggesting additional non-Aβ-driven influences on dynamic functional connectivity in preclinical AD.},
}

@article {pmid42094563,
year = {2026},
author = {Kumar, S and Haber, A and Spruce, C and Duong, D and Seyfried, NT and Bailey, L and Choi, SH and Hachem, S and Mou, Y and Ha, SK and Park, JE and Homanics, GE and Sukoff Rizzo, SJ and Silva, AC and Carter, GW},
title = {PSEN1 mutant marmoset fibroblasts mimic multi-omic signatures of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.24.720222},
pmid = {42094563},
issn = {2692-8205},
abstract = {INTRODUCTION: The slow, age-related development of Alzheimer's disease (AD) and inaccessibility of early-stage brain tissue necessitates model studies to understand its origins and progression. Non-human primate models can provide a platform for linking molecular changes to translatable phenotypes. Here, we assess fibroblast lines derived from marmosets with engineered variants in the PSEN1 gene.

METHODS: Fibroblast cultures were obtained from 10 animals and assayed using a NanoString AD gene expression panel and label-free proteomics. We compared mutant expression changes to human AD signatures in human iPSC-derived neurons and postmortem brains to assess disease relevance.

RESULTS: Gene products involved in amyloid-beta interaction and regulation were differentially expressed, providing evidence for the functional relevance of the engineered fibroblasts. Both gene and protein expression changes in the undifferentiated fibroblasts correlated with human iPSCs from AD donors reprogrammed into neuronal lineages, as well as postmortem brains derived from case-control cohorts. Altered expression profiles were noted based on marmoset donor sex and mutation status, highlighting underlying sex-specific biology relevant to Alzheimer's disease.

DISCUSSION: These findings demonstrate that disease-relevant pathways and processes are altered in fibroblasts from mutant marmosets, emphasize the complementarity of transcriptomic and proteomic profiling in AD, and provide a roadmap for more advanced molecular studies of AD in aging marmosets and marmoset-derived cell models.},
}

@article {pmid42094567,
year = {2026},
author = {Jacobson, A and Murguia, A and Swanson, SD and Nielsen, JF and Fessler, JA and Seraji-Bozorgzad, N},
title = {Phantom- and simulation-based validation of combined diffusion relaxometry in ex vivo ADRD white matter.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.721146},
pmid = {42094567},
issn = {2692-8205},
abstract = {PURPOSE: In principle, combined T 2 -Diffusion (D) MRI has the microstructural and chemical sensitivity to detect axonal and myelin water changes in Alzheimer's disease and related dementias (ADRD), but its practical implementation may be hindered by demanding hardware requirements. This work assesses the feasibility and accuracy of T 2 -D for ex vivo analysis of WM lesions in ADRD tissue.

METHODS: A thawed ex vivo brain sample from the Michigan Brain Bank and a T 2 -D phantom were scanned at 7T using a combined diffusion relaxometry (CDR) sequence. A non-negative least squares (NNLS) conventional data processing pipeline was used to disentangle water pools with unique T 2 -D signatures. Simulations examined the effects of minimum TE and SNR on recovery of myelin water (short T 2 , slow diffusion).

RESULTS: Across tissue types, T 2 -D data consistently resolved three spectral components. Phantom experiments showed detection of short T 2 and slow diffusion features similar to those observed in ADRD ex vivo tissue, and confirmed CDR's ability to accurately resolve multiple components. Simulations indicated reliable T 2 -D recovery for myelin with SNR > 30 dB and minimum TE < 25 ms.

CONCLUSION: Strong T 2 and D weighting could be combined to capture the expected axonal, myelin, and extracellular (EC) regions in T 2 -D space. The observed short-T 2 , restricted-D components are therefore unlikely to be artifacts and instead support interpretations as physically meaningful myelin and axonal water signatures.},
}

@article {pmid42094584,
year = {2026},
author = {Bartels, P and Rougé, S and Scripter, JD and Zeng, Z and Estrada-Tobar, ZM and Price, J and Jacobi, AA and Berumen, RA and Ho, SY and Avedisyan, A and Xiang, YK and Chen, CY and Nieves-Cintron, M and Navedo, MF and Horne, MC and Hruska, M and Hell, JW},
title = {A Unifying Mechanism for Synaptic Amyloid β Toxicity β Adrenergic Potentiation of the Ca [2+] Channel CaV1.2 by Amyloid β.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.25.720803},
pmid = {42094584},
issn = {2692-8205},
abstract = {UNLABELLED: Amyloid β peptides (Aβ) trigger Alzheimer's disease (AD) but how has remained elusive. Aβ stimulates the β 2 adrenergic receptor (β 2 AR), which forms a unique signaling complex with the L-type Ca [2+] channel (LTCC) Ca V 1.2. LTCCs have been implicated in the etiology of dementia and AD. We show that Aβ acutely potentiates Ca V 1.2 via the β 2 AR, which triggers postsynaptic recruitment of Ca [2+] permeable (CP) AMPARs in hippocampal cultures and impairs LTP in hippocampal slices within minutes. The long-term consequence is a loss of postsynaptic structure of glutamatergic synapses and neurotoxicity. Disrupting this signaling cascade with highly specific tools prevented all of these effects, unifying a number of currently divergent findings on Aβ synaptotoxicity including dysregulation of AMPARs and synaptic plasticity.

TEASER: Amyloid β peptide is the primary pathological agent in Alzheimer's disease. It affects the nanoscale structure and function of glutamatergic synapses. The molecular mechanisms are largely unknown except for identification of several binding proteins including the β 2 adrenergic receptor. We show that this binding potently (EC 50 <100 nM) augments Ca [2+] influx through the L-type Ca channel Ca V 1.2. This effect leads to improper recruitment of Ca [2+] -permeable glutamate receptors to postsynaptic sites (EC 50 <100 nM), synaptic dysfunction and ultimately neuronal death. This work identifies an essential mechanism in amyloid β neurotoxicity and explains many of the observed postsynaptic alterations.

HIGHLIGHTS: Immediate effects of Aβ-induced stimulation of β 2 AR on Cav1.2: Aβ induces phosphorylation of Cav1.2 on S1928 by PKA Aβ augments Cav1.2 activity via β 2 AR-induced S1928 phosphorylation within seconds Aβ-induced β 2 AR - Cav1.2 signaling has the following synaptotoxic effects. Aβ induces postsynaptic accumulation of Ca-permeable AMPARs via β 2 AR - Cav1.2 signaling within 20 min Aβ impairs long-term potentiation (LTP) via β 2 AR - Cav1.2 signaling Aβ impairs postsynaptic structure and neuronal viability over 24 h Potency of Aβ in all the above effects is very high (100 nM Aβ is saturating!) All effects are prevented in S1928A KI mice and acute displaces β 2 AR from Cav1.2 with tat-Pep 1923.},
}

@article {pmid42094593,
year = {2026},
author = {Zhang, DY and Wang, J and Dokholyan, NV},
title = {Mechanistic role of APOE lipidation in Alzheimer's disease pathogenesis.},
journal = {Theranostics},
volume = {16},
number = {11},
pages = {5926-5950},
pmid = {42094593},
issn = {1838-7640},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Apolipoproteins E/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; *Lipid Metabolism ; Cholesterol/metabolism ; Apolipoprotein E4/metabolism/genetics ; },
abstract = {The apolipoprotein E (APOE) ε4 allele is the primary genetic driver of late-onset Alzheimer's disease (AD), a complex neurodegenerative disorder characterized by the interplay of amyloid-β (Aβ) accumulation, tau pathology, neuroinflammation, and lipid metabolism dysfunction. Emerging evidence suggests that these pathological hallmarks are fundamentally linked to deficits in neuroplasticity and the continuous turnover of synapses. A growing body of evidence highlights APOE lipidation, a process by which APOE is loaded with lipids via cellular transporters such as ABCA1, as a key determinant of APOE function and toxicity. While lipidated APOE2 and APOE3 facilitate cholesterol transport and Aβ clearance, lipid-poor APOE4 is associated with impaired receptor-mediated clearance of Aβ, disrupted microglial function, increased neuroinflammation, and synaptic deficits. Furthermore, APOE lipidation status differentially influences tau pathology, potentially linking cholesterol dysregulation to tau hyperphosphorylation and aggregation. Here, we systematically examine the mechanistic role of APOE lipidation in AD pathogenesis, focusing on its effects on Aβ and tau pathology. We also discuss how dysregulation of APOE lipidation may serve as a central molecular mechanism connecting APOE4 to multiple pathological hallmarks of AD. This review examines how APOE lipidation is involved in amyloid-related and tau pathology in AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Apolipoproteins E/metabolism/genetics
Amyloid beta-Peptides/metabolism
Animals
tau Proteins/metabolism
*Lipid Metabolism
Cholesterol/metabolism
Apolipoprotein E4/metabolism/genetics

@article {pmid42094831,
year = {2026},
author = {Cheng, M and Ma, J and Yang, Y and Cao, M and Zhang, E and Feng, B and Wang, Q and Du, Z},
title = {Iron dyshomeostasis in neuropsychiatric disorders.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1771423},
pmid = {42094831},
issn = {1664-0640},
abstract = {Iron is an indispensable element for the normal physiological function of the brain. In terms of neuronal metabolism, iron is involved in multiple critical biological processes such as oxygen transport, energy metabolism, DNA synthesis, neurotransmitter synthesis and myelin formation. Maintaining brain iron homeostasis is crucial for neurodevelopment and function. Iron dyshomeostasis has been associated with the onset and progression of various neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, depression, schizophrenia, attention deficit hyperactivity disorder, and autism spectrum disorder. In neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, abnormally elevated iron levels can be detected in specific brain regions, including the basal ganglia and the prefrontal cortex. These changes are often accompanied by pathological processes such as oxidative stress, neuroinflammation, and pathological protein aggregation. Therefore, brain iron metabolism is an important entry point for understanding the pathophysiological process of neuropsychiatric disorders. Mechanistically, iron overload induces oxidative damage through the Fenton reaction, exacerbating mitochondrial dysfunction and abnormal protein aggregation. The effects of iron deficiency vary across different diseases; its impact on myelination and neurotransmitter synthesis may increase the risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD), while its effects on immune activation and energy metabolism may contribute to the development of mental disorders such as depression. This article systematically reviews the current research progress of the role of cerebral iron metabolism in neuropsychiatric diseases. It focuses on the mechanisms underlying iron homeostasis imbalances in neurodegenerative and psychiatric diseases. Building on this foundation, the article analyzes the therapeutic targets and clinical significance of iron metabolism-related interventions and outlines future research directions in this field.},
}

@article {pmid42094855,
year = {2026},
author = {Mei, X and Ni, Z and Zhong, S and Wang, J and Zhu, L and Shi, Z and Chen, Y and Zheng, H and Hu, J and Shen, Y},
title = {Olfactory enrichment mitigates delayed neurocognitive recovery after major orthopaedic surgery in older patients: A randomised controlled trial.},
journal = {General psychiatry},
volume = {39},
number = {},
pages = {e70022},
pmid = {42094855},
issn = {2517-729X},
abstract = {BACKGROUND: Delayed neurocognitive recovery (dNCR) is a prevalent complication in older patients undergoing surgery. It may progress to long-term cognitive impairment and increase the risk of Alzheimer's disease.

AIMS: This study aimed to evaluate the effects of olfactory enrichment on dNCR and to examine the association between olfactory function and dNCR.

METHODS: This sham-controlled, assessor-blind, parallel-group randomised trial enrolled 149 participants aged 65 or older undergoing elective total knee or hip replacement under general anaesthesia. Participants were assigned to either the olfactory enrichment group or the sham group. The intervention group received daily olfactory enrichment from 3 days preoperatively to 7 days postoperatively. Cognitive function was evaluated using a neuropsychological test battery 3 days before and 7 days after surgery. Olfactory identification ability was assessed by five-odour olfactory detection arrays. Propensity score matching analysis was employed to mitigate potential confounding and selection bias.

RESULTS: A total of 131 patients completed the study (62 in the olfactory enrichment group and 69 in the sham group). The overall incidence of dNCR was 26.7% (35 out of 131). In the intention-to-treat analysis, the difference between groups was not statistically significant (19.4% vs. 33.3%; χ [2] = 3.259; p = 0.071). However, in the 1:1 propensity score-matched cohort (n = 82), the incidence of dNCR was significantly lower in the olfactory enrichment group than in the sham group (12.2% vs. 39.0%; χ [2] = 7.476; p = 0.005). Raw postoperative cognitive scores and individual change scores did not differ between the groups. Participants with decreased olfactory identification scores (n = 32) had a significantly higher incidence of dNCR than those with stable or improved scores (40.6% vs. 22.2%; χ [2] = 4.183; p = 0.041).

CONCLUSIONS: In older patients undergoing major orthopaedic surgery, perioperative olfactory dysfunction is associated with an increased risk of dNCR. Olfactory enrichment may represent a potential nonpharmacological strategy for reducing postoperative cognitive decline in this population.},
}

@article {pmid42094987,
year = {2026},
author = {Müller, L and Di Benedetto, S and Müller, V},
title = {Nutrition as a systems regulator of brain aging trajectories.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1825800},
pmid = {42094987},
issn = {1662-5099},
abstract = {Nutrition is increasingly recognized as a central determinant of brain health across the lifespan. Beyond their classical roles as energetic substrates, dietary components and their bioactive metabolites may act as signaling molecules capable of reshaping neuronal and glial phenotypes through integrated metabolic, epigenetic, and immunological mechanisms. Emerging evidence positions nutritional inputs as dynamic regulators of synaptic integrity, cellular bioenergetics, neurotransmission, neuroimmune interactions, and blood-brain barrier function. These effects occur across multiple temporal and spatial scales, from acute modulation of neuronal excitability to long-term reprogramming of gene expression and chromatin landscapes. This mini-review integrates current molecular neuroscience perspectives to propose a systems-level framework in which nutritional signals act across interconnected regulatory layers linking peripheral metabolism with central nervous system homeostasis. We examine nutrient-sensing pathways that preserve proteostasis and synaptic resilience, as well as metabolic and membrane-associated processes that govern neuronal excitability, network stability, and mitochondrial quality control. Furthermore, we discuss how dietary modulation may influence glial activation states, neuroinflammatory cascades, and epigenetic remodeling, and how gut-derived metabolites contribute to these processes. Understanding nutrition as an active signaling network rather than a passive support system may offer novel opportunities for preventive and therapeutic intervention in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as in age-associated cognitive decline. We propose that targeted nutritional modulation represents a tractable strategy to reprogram brain aging trajectories toward enhanced resilience, functional plasticity, and long-term cognitive health.},
}

@article {pmid42095059,
year = {2026},
author = {Rizzi, L and Ribeiro, IC and da Rocha Silva, MC and Aventurato, ÍK and Santos, LE and Dos Santos Silva, AM and Pinheiro, TL and Fernandes, GBP and De Felice, FG and Balthazar, MLF},
title = {Plasma Aβ42/p-Tau217 ratio and p-Tau217 independently predict CSF-defined Alzheimer's disease pathology in a Brazilian admixed cohort.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1773606},
pmid = {42095059},
issn = {1663-4365},
abstract = {INTRODUCTION: Blood-based biomarkers offer a promising, minimally invasive approach to Alzheimer's disease (AD) diagnosis, yet validation in admixed populations remains limited. We investigated whether plasma biomarkers predict CSF-defined AD pathology in a Brazilian cohort.

METHODS: Seventy-eight older adults [including individuals with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and cognitively unimpaired controls] underwent cognitive testing, neuroimaging, and plasma biomarker assessment. CSF data were available for symptomatic participants (MCI and SCD; n = 61), and regression and ROC analyses were performed in the subset with both CSF and APOE genotyping data (n = 53). Plasma Aβ42, p-Tau181, p-Tau217, t-Tau, and derived ratios were quantified. Multivariable logistic regression and ROC analyses evaluated prediction of abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42, adjusting for age, sex, and APOE ε4 status.

RESULTS: Approximately 25% of individuals with MCI exhibited abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42 ratios. Moderate correlations were observed between plasma and CSF biomarkers (r > 0.4), particularly for Aβ42/p-Tau217 and p-Tau217. In adjusted models, plasma p-Tau217 and the Aβ42/p-Tau217 ratio independently predicted abnormal CSF pathology. Each one standard deviation increase in p-Tau217 was associated with 3.53-4.83-fold higher odds of abnormal CSF (p ≤ 0.003). In contrast, higher Aβ42/p-Tau217 ratios were associated with substantially lower odds of pathology, with each one standard deviation increase corresponding to a 91%-93% reduction in risk (p ≤ 0.002). The ratio showed stronger associations than p-Tau217 alone. ROC analyses demonstrated good discrimination. For CSF p-Tau181/Aβ42, Aβ42/p-Tau217 achieved an AUC of 0.88 (83% sensitivity, 85% specificity), compared with 0.83 for p-Tau217. For CSF t-Tau/Aβ42, both biomarkers yielded AUCs of 0.89.

DISCUSSION: Plasma Aβ42/p-Tau217 and p-Tau217 effectively identify CSF-defined AD pathology in an admixed cohort. While higher p-Tau217 levels were associated with increased odds of pathology, higher Aβ42/p-Tau217 ratios were associated with lower pathological burden and demonstrated stronger effect sizes, supporting the added value of combining amyloid and tau biomarkers. These findings provide initial evidence for local validation of blood-based AD biomarkers in Brazil.},
}

@article {pmid42095064,
year = {2026},
author = {Cummings, JL and Zhou, Y and Yang, Y and Zhong, K and Fonseca, J and Osse, AL and Cheng, F},
title = {Alzheimer's disease drug development pipeline: 2026.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70251},
pmid = {42095064},
issn = {2352-8737},
abstract = {INTRODUCTION: Discovery and development of new therapies for Alzheimer's disease (AD) are urgently needed to address the world's growing population of individuals on the AD pathophysiological continuum. Clinicaltrials.gov is a resource for studying drugs in development for treatment of AD.

RESULTS: There are currently 158 drugs in 192 AD trials. Of the agents in trials, 39% are small molecule disease targeting therapies (DTTs); 34% are biologic DTTs; 18% are cognition enhancing symptom targeted therapies (STTs); and 10% are STTs being developed to treat neuropsychiatric symptoms of AD. Currently active trials require 54,728 participants of which 38,417 are in Phase 3. The biopharmaceutical industry sponsors 59% of AD trials including 72% of Phase 3 trials. Repurposed drugs represent 35% of the drugs in trials.

DISCUSSION: The AD drug development pipeline has a growing number of trials and drugs in trials. A diverse array of AD pathophysiological processes is being addressed by drugs in trials.},
}

@article {pmid42095074,
year = {2026},
author = {Reid, MJ and Salazar, ML and Troakes, C and Lynham, S and Srivastava, DP and Perez-Nievas, BG and Noble, W},
title = {Erratum: Alzheimer's disease brain-derived tau extracts show differential processing and transcriptional effects in human astrocytes.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115926},
doi = {10.1016/j.isci.2026.115926},
pmid = {42095074},
issn = {2589-0042},
abstract = {[This corrects the article DOI: 10.1016/j.isci.2025.112793.].},
}

@article {pmid42095076,
year = {2026},
author = {Sajan, MP and Aggarwal, G and Hwang, JJ and Smith, DM and Cooper, DR and Duncan, MA and Hansen, BC and Nguyen, AD and Farese, RV},
title = {Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115720},
pmid = {42095076},
issn = {2589-0042},
abstract = {Molecular mechanisms in frontotemporal dementia (FTD) and Alzheimer's disease (AD) are obscure. FTD can result from loss-of-function progranulin mutations, although pathogenetic consequences are uncertain. Progranulin insufficiency also increases human AD risk, and progranulin treatment improves mouse AD. Furthermore, AD and FTD risks are abetted by obesity/diabetes-induced hyperinsulinemia and hyperactivation of brain insulin signaling, and progranulin deficiency activates insulin signaling in fat and liver. Here, we found progranulin deletion in mouse brain increased activation of IRS-1 and activities of downstream PKC-λ/ι, NF-κB and mTOR, but diminished IRS-2 and Akt. Similarly, in microglial cells, progranulin deletion increased, and progranulin treatment diminished, activation of IRS-1, PKC-λ/ι, NF-κB, and mTOR. These progranulin-related changes in IRS-1 activation were due to JNK-mediated phosphorylation of inhibitory serine-302/307 residues in IRS-1. Progranulin deficiency in brain selectively activates an IRS-1-dependent insulin signaling pathway, and the resultant increases in inflammation and impaired autophagy/lysosomal function may augment progranulin deficiency-related neuropathology.},
}

@article {pmid42095275,
year = {2026},
author = {Burkhard, T and Milne, E and Qian, K and Campagnolo, P and Santamaria, S},
title = {Proteolytic remodelling of the extracellular matrix by pericytes.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70569},
pmid = {42095275},
issn = {1742-4658},
support = {FS/IBSRF/20/25032/BHF_/British Heart Foundation/United Kingdom ; //Humane Research Trust/ ; MR/X009203/1/MRC_/Medical Research Council/United Kingdom ; //University of Surrey/ ; },
abstract = {Pericytes (PCs) are perivascular cells that lie in close association with endothelial cells (ECs), with both cell types embedded within a shared basement membrane (BM), a specialised form of extracellular matrix (ECM). PCs regulate vascular integrity, angiogenesis and capillary blood flow and are capable of differentiating into other cell types including fibroblasts and smooth muscle cells. In recent years, a central role for PCs in regulating the development and maturation of the vasculature, maintaining tissue homeostasis and directing the pleiotropic remodelling of tissues during regeneration has emerged. Here, we review how PCs contribute to the synthesis and remodelling of the ECM in different pathophysiological conditions. Moreover, we provide an atlas of the PC matrisome, the complex of ECM molecules expressed by PCs, based on recent transcriptomics (in particular single-cell RNA sequencing) and proteomics datasets, with the caveat that such an entity does not exist in isolation due to the physical and paracrine interactions between PCs, ECs and other cell types. Understanding the role of PCs in modulating their microenvironment through active synthesis and degradation of specific matrisome components is essential to understand the role these plastic cells play in angiogenesis and in different pathologic conditions, including stroke, Alzheimer's disease and cancer.},
}

@article {pmid42095683,
year = {2026},
author = {Grudzen, CR and Brody, AA and Chodosh, J and Goldfeld, KS and Shah, MN},
title = {Emergency Departments Leading the Transformation of Alzheimer's and Dementia Care.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70506},
pmid = {42095683},
issn = {1532-5415},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U19 AG078105-01A1/AG/NIA NIH HHS/United States ; },
}

@article {pmid42095849,
year = {2026},
author = {Banos, JC and Tan, S and Asp, IE and Snytte, J and Bondi, MW and Smith, CN},
title = {Structural neuroanatomy of semantic retrograde memory in older adults.},
journal = {Behavioral neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1037/bne0000652},
pmid = {42095849},
issn = {1939-0084},
support = {//US Department of Veterans Affairs; Clinical Sciences Research and Development Service/ ; /AG/NIA NIH HHS/United States ; },
abstract = {Studies of brain lesions or volumes indicate that the integrity of medial and lateral temporal lobe structures is important for news event memory accuracy, but the relationship between cortical thickness and news event memory accuracy has not yet been investigated in older adults. In a mixed sample of 70 older adults with variable cognitive abilities but without dementia, we investigated the relationship between cortical volume, hippocampal volume, and cortical thickness with news event recognition memory accuracy across the entire adult lifespan using the Retrograde Memory News Events Test. Partial Least Squares analysis was used to identify brain regions where news event memory accuracy scores significantly correlated with cortical volume, hippocampal volume, and cortical thickness. We found that mean news event memory accuracy significantly correlated with volume/thickness for a network of regions that included the hippocampus, medial/lateral temporal lobe, medial/lateral parietal lobe, and specific areas within the medial/lateral prefrontal cortex. Poorer performance was associated with a thinner cortex (and smaller volumes). Almost all regions in this network exhibited decreasing brain-behavior correlations as the age of memory increased; thus, retrieval of remote memories was less reliant on the network. We also found regions in this network that were not identified by the Retrograde Memory News Events Test posttest (a measure of episodic anterograde memory for the Retrograde Memory News Events Test content) nor traditional neuropsychological tests. The regions identified as uniquely contributing to news event memory overlap with regions known to exhibit increasing Alzheimer's disease pathology and cortical thinning when pathology begins to spread outside of the medial temporal lobe. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42095886,
year = {2026},
author = {Maiese, K},
title = {Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, wnt, and WISP1.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2671269},
pmid = {42095886},
issn = {1751-2441},
abstract = {INTRODUCTION: Increased global lifespan is paralleled by a rise in non-communicable diseases with osteoarthritis and dementia, including Alzheimer's disease, impacting all nations with severe disability, death, and financial burden.

AREAS COVERED: Given that osteoarthritis and dementia are worsened with advancing age, progressive in nature, and presently remain only with symptomatic treatments, development of advanced comprehensive therapies is critical for these disorders. New innovative work offers insight into the underlying clinical bond between degenerative joint disease and cognitive loss. Data sources using systematic literature search employed PubMed, Scopus, Web of Science, and ScienceDirect from January 2021 through February 2026.

EXPERT OPINION: Although affecting diverse organ systems, degenerative joint disease and dementia are intimately connected by shared cellular pathways responsible for disease onset and progression. Pioneering avenues of investigation of oxidative stress, autophagy, the mechanistic target of rapamycin (mTOR), cellular metabolism mechanisms with glucagon-like peptide-1 (GLP-1) receptors and AMP activated protein kinase (AMPK), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) offer exciting treatment opportunities for osteoarthritis and Alzheimer's disease. Ultimately, these complex pathways will necessitate focus upon their intricate dependence that may benefit from several targeted approaches including artificial intelligence applications for fruitful clinical translation.},
}

@article {pmid42095905,
year = {2026},
author = {Dortez, S and Chávez, M and Montero-Calle, A and Barderas, R and Pacheco, M and Escarpa, A},
title = {Label-free paper-based electrochemical aptasensor with tunable selectivity for assessing neurotransmitter imbalance in Alzheimer's disease.},
journal = {Mikrochimica acta},
volume = {193},
number = {6},
pages = {},
pmid = {42095905},
issn = {1436-5073},
mesh = {*Alzheimer Disease/metabolism/diagnosis ; Humans ; *Aptamers, Nucleotide/chemistry ; *Electrochemical Techniques/methods/instrumentation ; *Biosensing Techniques/methods ; Gold/chemistry ; Metal Nanoparticles/chemistry ; *Dopamine/analysis/metabolism ; *Paper ; *Neurotransmitter Agents/analysis/metabolism ; *Serotonin/analysis/metabolism ; Electrodes ; Limit of Detection ; },
abstract = {A paper-based electrochemical aptasensor (PEA) is reported for the simultaneous detection of extracellular dopamine (DA) and serotonin (SE) in human brain samples, enabling the assessment of neurotransmitter imbalances associated with Alzheimer's disease (AD). The PEA integrates a dual-selectivity strategy that combines aptamer-mediated molecular recognition with potential-resolved electrochemical neurotransmitters discrimination, allowing reliable differentiation between healthy and AD-diagnosed left prefrontal cortex tissues based on altered dopaminergic and serotonergic levels. Thiolated aptamers immobilized onto gold nanoparticles (AuNPs) at the paper electrode interface provide selective neurotransmitter biorecognition, while the distinct oxidation potentials of DA (+ 0.10 V) and SE (+ 0.25 V vs. Ag/AgCl) enable their label-free, simultaneous quantification on a single disposable electrode. The PEA read biologically meaningful concentration shifts across a clinically relevant dynamic range, spanning levels characteristic of healthy tissue to those observed in advanced pathological stages. The PEA approach highlights its potential for liquid biopsy-oriented neurochemical monitoring and supports its application in multiplexed biosensing within organ-on-a-chip systems, enabling early diagnostic strategies for neurodegenerative diseases.},
}

*Alzheimer Disease/metabolism/diagnosis
Humans
*Aptamers, Nucleotide/chemistry
*Electrochemical Techniques/methods/instrumentation
*Biosensing Techniques/methods
Gold/chemistry
Metal Nanoparticles/chemistry
*Dopamine/analysis/metabolism
*Paper
*Neurotransmitter Agents/analysis/metabolism
*Serotonin/analysis/metabolism
Electrodes
Limit of Detection

@article {pmid42096068,
year = {2026},
author = {Spallazzi, M and Zilioli, A and Capellari, S},
title = {Pooling Alzheimer's disease: when methodological rigor risks obscuring biological complexity.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {6},
pages = {},
pmid = {42096068},
issn = {1590-3478},
}

@article {pmid42096138,
year = {2026},
author = {Zhang, Q and Li, Y and Li, Y and Han, L and Yan, J and Zhan, M and Liu, T and Ke, P and Wang, Q and Huang, X},
title = {Anti-CRISPR Protein Regulates CRISPR/Cas12a Fusogenic-Nanovesicle-Based Platform for Extracellular Vesicle-Encapsulated Non-Nucleic Acid Target In-Vesicle Detection.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e6795217},
doi = {10.1002/anie.6795217},
pmid = {42096138},
issn = {1521-3773},
support = {2024ZD0533400//National Key Research and Development Program of China/ ; 2024ZD0533401//National Key Research and Development Program of China/ ; 0720240230//Guangdong Special Support Program Health and health talents List Project of Provincial Health Commission/ ; 2024A1515030043//Natural Science Foundation of Guangdong Province/ ; 2026A1515010500//Natural Science Foundation of Guangdong Province/ ; SZ2022QN09//"Young Talents Program" of Guangdong Academy of Traditional Chinese Medicine/ ; SKLKY2024B0011//State Key Laboratory of Traditional Chinese Medicine Syndrome Projects/ ; 2023A03J0755//Guangzhou Science and Technology Plan Projects/ ; 2023B110008//Guangdong Provincial Clinical Research Guangdong Provincial Clinical Research Center for Laboratory Medicine/ ; 2025JY-A1004//Guangdong Provincial Clinical Research Guangdong Provincial Clinical Research Center for Laboratory Medicine/ ; //Science and Technology Innovation Center of Guangzhou University of Chinese Medicine/ ; },
abstract = {The detection of non-nucleic acid targets encapsulated in extracellular vesicles (EVs) faces two major challenges: (1) difficulties in efficient isolation and the risk of content degradation, and (2) the low abundance of target molecules encapsulated in EVs always leads to failed signal transduction and inadequate output signal intensity. To overcome these limitations, we propose a high-efficiency in-vesicle analysis strategy that integrates targeting probe delivery and regulation by protein signal amplification. By applying aptamer-mediated membrane fusion and "locked-activated" CRISPR-Cas12a-AcrVA1 (LACA) for protein signal regulation, we fabricated a yly12-aptamer-functionalized self-assembled nanovesicle which encapsulate LACA-system (yly12-lipo@Cas12a nanovesicle) as an in-vesicle bioanalytical platform. Leveraging the high specificity of the aptamer and the regulatory function of AcrVA1 in selectively modulating Cas12a activity, the platform enables highly specifiec and sensitive detection, offering advantages of simple operation and versatility across platforms within only 2.5 h. Clinical analysis demonstrated effective differentiation between patients and healthy controls, yielding high diagnostic performance with an AUC of 0.965. The proposed platform shows great potential for EV-carrying protein biomarker analysis and has broad prospects for the disease's diagnosis in clinical settings.},
}

@article {pmid42096531,
year = {2026},
author = {Uchida, H and Gobbi, G and Zohar, J and Young, AH and Rujescu, D and Huang, MC and Sundram, S and Atwoli, L and Vukovic, J and Ikeda, K},
title = {Global Perspectives on CNS Drug Innovation: Achievements, Barriers, and Priorities for the Next Decade.},
journal = {The international journal of neuropsychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/ijnp/pyag023},
pmid = {42096531},
issn = {1469-5111},
abstract = {BACKGROUND: Over the past decade, neuropsychopharmacology has shifted from stagnation to momentum, with first-in-class mechanisms and biomarker-enabled trials spanning psychiatry and neurology.

METHODS: We narratively synthesized advances from 2013 to 2026 across central nervous system (CNS) discovery and development, including pivotal trials, regulatory actions, digital/real-world evidence, genetics, artificial intelligence (AI), and implementation/global-access themes that are endorsed by international societies.

RESULTS: Therapeutic gains include rapid-acting drugs for treatment-resistant depression (intranasal esketamine); psychedelic-assisted therapy for posttraumatic stress disorder and depression; neuroactive steroid γ-aminobutyric acid-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression; non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia; orexin receptor antagonists for insomnia; and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease. Persistent barriers include high mid-/late-stage attrition that is driven by placebo effects, subjective endpoints, and preclinical-to-clinical gaps; regulatory and economic headwinds; and limited generalizability from tightly run trials. Emerging enablers include adaptive/platform designs, digital health technologies, patient-reported outcomes, and clinical outcome assessments, real-world evidence (RWE), AI/machine learning (ML), genetics for target de-risking and biomarker-guided stratification, and publicly accessible large CNS relevant biological datasets.

CONCLUSIONS: To convert momentum into durable progress, we recommend: (i) deeper academia-industry/stakeholder collaboration and sustained funding for high-risk/high-reward science from industry, governments and non-for profit foundations; (ii) modernized regulation (flexible evidentiary paths, novel endpoints, and clear guidance on adaptive/platform trials); (iii) data-driven development integrating RWE, AI/ML, and precision medicine; (iv) the adoption of Neuroscience-based Nomenclature (NbN); and (v) a global-access mandate with essential-medicine inclusion, equitable pricing/licensing, capacity building, tele-enabled mental health, and geographically diverse research. Aligning scientific innovation with implementation and equity can accelerate translation and ensure new treatments benefit patients worldwide.},
}

@article {pmid42096618,
year = {2026},
author = {Schihada, H and Shahraki, A and Turku-Metsänen, A and Rath, M and Wirth, L and Nemec, K and Tselepli, H and Heitzer, L and Vallaster, B and Fadel, M and Schulte, G and Hilger, D and Pockes, S and Lohse, MJ and Kolb, P},
title = {GPR3 Ligands Discovered through Combined Virtual and Conformational Biosensor-Based Screening.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.6c06780},
pmid = {42096618},
issn = {1520-5126},
abstract = {GPR3 belongs to the protein superfamily of G protein-coupled receptors (GPCRs) and plays a central role in both benign and malignant physiological processes, such as energy expenditure in adipocytes and Alzheimer's disease pathology, respectively. Despite the therapeutic potential of both receptor agonists and inverse agonists, GPR3 so far has lacked drug-like ligands and innovative screening technologies, hindering effective drug discovery efforts targeting this receptor. To overcome the limitations of conventional ligand screening techniques based on cAMP accumulation or β-arrestin recruitment, we developed a conformational GPR3 biosensor to monitor receptor activity in living cells with high-throughput screening (HTS)-compatible sensitivity and robustness. Combined with virtual compound screening against homology models of GPR3 and classical medicinal chemistry, this biosensor enabled us to identify new ligands, one of which (compound 33) modulates GPR3-dependent Gs activity with an average potency in the nanomolar range. Our study not only presents novel GPR3 ligands for future optimization efforts and paves the way for even further expansion of the GPR3 ligand repertoire, but our sensor approach also provides a blueprint for targeting other therapeutically attractive yet challenging orphan GPCRs.},
}

@article {pmid42096632,
year = {2026},
author = {Odongo, R and Çakır, T},
title = {Metabolite-centric identification of antimetabolite drug targets across cancer and neurodegenerative diseases.},
journal = {Molecular omics},
volume = {},
number = {},
pages = {},
doi = {10.1093/molecular-omics/aaiag018},
pmid = {42096632},
issn = {2515-4184},
abstract = {Antimetabolites, primarily studied in cancer, are novel drugs targeting metabolic networks by mimicking and inhibiting disease-causing metabolites, enabling poly-pharmacologic effects essential for complex diseases. Moreover, predicting patients likely to positively respond to antimetabolite drugs is necessary to simplify clinical applications. However, existing computational approaches for antimetabolite target discovery lack incorporation of disease-induced metabolic state perturbations, and their applicability beyond cancer remains unexplored. We introduce MATADOR (Metabolite-centric Analysis of TARgets for Drug ORientation), a computational workflow that integrates patient-derived omic data with metabolic networks to identify, evaluate and prioritize antimetabolite targets based on metabolic state transformation. Applying MATADOR to RNA-seq data from breast, colon, lung, and liver cancers, we achieved a 66±6% sensitivity in recapturing known antimetabolite targets, strongly supported thioredoxin as a pan-cancer target, and linked top-ranked targets to poor 5-year survival in breast and liver cancers. Extending beyond cancer, MATADOR nominated metabolites with proinflammatory effects as potential antimetabolite targets in Alzheimer's and Parkinson's diseases, aligning well with their known pathological mechanisms. Finally, applying MATADOR on personalized metabolic networks, machine learning models trained on metabolic gene expression demonstrated the ability to leverage gene expression to personalize antimetabolite targets. The proposed approach may expedite prioritization and personalization of antimetabolite targets during pre-clinical studies across diseases with systemic metabolic alterations.},
}

@article {pmid42096658,
year = {2026},
author = {Fang, Y and Leng, Y},
title = {Can Targeting Circadian Rhythms Help Prevent Alzheimer Disease?: Lessons From Down Syndrome.},
journal = {Neurology},
volume = {106},
number = {10},
pages = {e218086},
doi = {10.1212/WNL.0000000000218086},
pmid = {42096658},
issn = {1526-632X},
}

@article {pmid42096659,
year = {2026},
author = {Chung, PA and Fleming, VL and Reid, KJ and Plante, DT and Hom, CL and Ances, BM and Handen, BL and Christian, BT and Head, E and Mapstone, M and Hartley, SL and Zee, PC and , },
title = {Circadian Rest-Activity Rhythms, Cognition, and Alzheimer Disease Dementia in Adults With Down Syndrome.},
journal = {Neurology},
volume = {106},
number = {10},
pages = {e214938},
doi = {10.1212/WNL.0000000000214938},
pmid = {42096659},
issn = {1526-632X},
mesh = {Humans ; *Down Syndrome/complications/physiopathology/psychology ; Male ; Female ; Middle Aged ; *Alzheimer Disease/physiopathology/complications/psychology ; Adult ; Cross-Sectional Studies ; *Circadian Rhythm/physiology ; *Cognition/physiology ; Actigraphy ; *Cognitive Dysfunction/physiopathology ; *Rest/physiology ; Neuropsychological Tests ; },
abstract = {BACKGROUND AND OBJECTIVES: There is a paucity of research on the role of circadian rhythm disruption in Alzheimer disease (AD)-related cognitive impairments in adults with Down syndrome (DS). The aim of this study was to examine the association of the 24-hour rest-activity rhythm with cognition, dementia symptoms, and clinical AD status in adults with DS.

METHODS: In this cross-sectional study, adults with DS aged 25-61 years in the Alzheimer's Biomarkers Consortium-Down Syndrome underwent wrist-worn actigraphy (≥4 days) and cognitive assessment. Primary variables included interdaily stability, intradaily variability, relative amplitude, most active 10-hour period (M10), and least active 5-hour period (L5). Secondary measures included coefficient of variation of total sleep time, sleep midpoint, sleep efficiency, and the sleep regularity index. Cognitive outcomes included modified Cued Recall Test (mCRT), Wechsler Block Design with Haxby Extension (Block Design), Purdue Pegboard, Cat and Dog Modified Stroop Task, DS Mental Status Examination (DSMSE), National Task Group-Early Detection Screen for Dementia (NTG-EDSD), Dementia Questionnaire for People with Learning Disabilities (DLD), and clinical AD status based on a case consensus process (stable vs mild cognitive impairment [MCI]/dementia). Linear and logistic regression models were adjusted for age, sex, intellectual disability level, site, and obstructive sleep apnea severity, with false discovery rate (FDR) correction.

RESULTS: Of 115 participants (mean age 40.0 ± 9.2 years; 43.5% female), higher interdaily stability was associated with higher DSMSE scores B = 20.6 (95% CI 5.0-36.2). Higher intradaily variability was associated with worse cognitive performance and increased dementia symptoms: mCRT B = -9.2 (95% CI -15.2 to -3.1), Block Design B = -11.0 (95% CI -19.0 to -3.0), DSMSE B = -12.0 (95% CI -20.1 to -3.9), and DLD-cognitive B = 6.3 (95% CI 3.0-10.5). Lower M10 was associated with increased dementia symptoms: NTG-EDSD B = -0.004 (95% CI -0.008 to -0.001); DLD-cognitive B = -0.004 (95% CI -0.006 to -0.001), and DLD-social B = -0.003 (95% CI -0.005 to -0.0008). All associations remained significant after FDR correction (p < 0.05). Fifteen participants had MCI/dementia. Higher intradaily variability was associated with increased odds of MCI/dementia (OR: 1.45; 95% CI 1.04-2.29) although this was not significant after FDR correction.

DISCUSSION: Fragmentation and low amplitude of the 24-hour rest-activity rhythm are associated with AD-related cognitive impairment, dementia symptoms, and increased odds of MCI/dementia in adults with DS. Circadian rhythm disruption may contribute to AD-related outcomes in adults with DS and potentially serve as a modifiable risk factor.},
}

Humans
*Down Syndrome/complications/physiopathology/psychology
Male
Female
Middle Aged
*Alzheimer Disease/physiopathology/complications/psychology
Adult
Cross-Sectional Studies
*Circadian Rhythm/physiology
*Cognition/physiology
Actigraphy
*Cognitive Dysfunction/physiopathology
*Rest/physiology
Neuropsychological Tests

@article {pmid42096792,
year = {2026},
author = {Banu, ASG and Hazra, S and Banu, MRA},
title = {Comment on "A systematic review: Brain age gap as a promising early diagnostic biomarker for Alzheimer's disease".},
journal = {Journal of the neurological sciences},
volume = {487},
number = {},
pages = {125954},
doi = {10.1016/j.jns.2026.125954},
pmid = {42096792},
issn = {1878-5883},
}

@article {pmid42096938,
year = {2026},
author = {Hazan, J and Liu, KY and Howard, R},
title = {Clarity AD open-label extension data do not robustly confirm disease course modification by lecanemab in ApoE4 heterozygotes and non-carriers.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100587},
doi = {10.1016/j.tjpad.2026.100587},
pmid = {42096938},
issn = {2426-0266},
}

@article {pmid42096939,
year = {2026},
author = {Lui, KK and Wang, X and Dratva, MA and Lifset, ET and Stiver, J and Heyworth, NC and Shen, Q and Thomas, M and DeYoung, PN and Malhotra, A and Sundermann, EE and Banks, SJ},
title = {Sleep complaints and genetic risk of Alzheimer's disease in older women: associations with memory and tau deposition.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100581},
doi = {10.1016/j.tjpad.2026.100581},
pmid = {42096939},
issn = {2426-0266},
abstract = {BACKGROUND: Emerging evidence point to a bidirectional relationship between sleep disturbances and Alzheimer's disease (AD). Poor sleep may be an overlooked risk factor for older women, who are disproportionately affected by AD and report worse subjective sleep quality than men. High genetic AD risk-characterized by the polygenic hazard score (PHS), including apolipoprotein (APOE) ε4 carriership-may further compound the effects of disrupted sleep on AD, particularly for older women.

OBJECTIVE: This study examined the moderating effect of genetic AD risk on subjective sleep as it related to memory and tau burden in a sample of older women.

PARTICIPANTS: The sample consisted of older women (≥65 years old) from the Women Inflammation Tau Study.

MEASUREMENT: Participants completed the Pittsburgh Sleep Quality Index (PSQI), Rey Auditory Learning Test, and Brief Visuospatial Memory Test-Revised. They also underwent [18]F-MK6240 positron emission tomography. Tau burden was calculated in composite regions across Braak stages. Genetic risk groups were characterized by PHS stratified at the 75th percentile. PSQI global score × PHS group interactions on memory composite scores (N = 69) and tau burden (N = 63) were examined.

RESULTS: PSQI global score × PHS group interactions were observed on visual memory and pathological tau in Braak regions III/IV (ps<0.10). Poorer subjective sleep was associated with worse visual memory and greater limbic tau deposition only among higher genetic risk women (ps<0.04). No significant associations were observed for verbal memory or tau in Braak regions I/II or V/VI.

CONCLUSION: Older women with elevated genetic AD risk and subjective sleep difficulties may be at greater risk for visual memory deficits and tau burden in regions affected in early AD. This suggests that sleep complaints may represent a promising AD risk factor. Improving sleep may be a potential intervention target for AD mitigation and prevention, particularly for older women.},
}

@article {pmid42096995,
year = {2026},
author = {Huang, X and Sun, H and Zhong, J and Niu, T and Geng, X and Zeng, Y},
title = {Therapeutic efficacy of computerized cognitive remediation therapy on cognitive function, inflammatory biomarkers, and brain structure in patients with amnestic mild cognitive impairment and Alzheimer's disease: A randomized controlled trial.},
journal = {Journal of psychiatric research},
volume = {199},
number = {},
pages = {252-258},
doi = {10.1016/j.jpsychires.2026.04.040},
pmid = {42096995},
issn = {1879-1379},
abstract = {Cognitive and behavioral impairments in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) represent significant neuropsychiatric challenges. This randomized controlled trial evaluated a 6-month computerized cognitive remediation therapy (CCRT) as a non-pharmacological intervention. Fifty-seven participants (32 aMCI, 25 mild AD) were assigned to CCRT or standard care. Outcomes included cognitive function (MMSE, MoCA), daily living activities (ADL), anxiety/depression (HAMA, HAMD-17), serum high-sensitivity C-reactive protein (Hs-CRP), and longitudinal brain MRI analyzed via voxel-based morphometry (VBM). Compared to controls, the CCRT group showed significant improvements in global cognition (ΔMMSE: +2.12 vs. -1.93, p < 0.001), daily functioning, and anxiety scores. A notable reduction in systemic inflammation (ΔHs-CRP, p < 0.01) was also observed. VBM revealed progressive gray matter atrophy in temporal and parahippocampal regions across both groups, yet cognitive gains in the CCRT cohort occurred independently of structural decline. CCRT effectively enhances cognitive-behavioral outcomes and modulates inflammatory activity in AD-spectrum patients, despite ongoing neurodegeneration. These findings support its integration as a neuropsychiatric intervention aimed at preserving function and promoting neural compensation in dementia care.},
}

@article {pmid42097044,
year = {2026},
author = {Shu, Y and Ding, ZH and Chen, XQ and Liu, F},
title = {40 Hz light flicker stimulation for neurodegenerative diseases: Mechanisms and clinical perspectives.},
journal = {Biochemical and biophysical research communications},
volume = {821},
number = {},
pages = {153858},
doi = {10.1016/j.bbrc.2026.153858},
pmid = {42097044},
issn = {1090-2104},
abstract = {Neurodegenerative diseases are a class of disorders characterized by the progressive degeneration and dysfunction of neurons, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Due to their high incidence rate, irreversible pathological processes and huge social and economic burdens, these diseases have become a major challenge in global public health. Light Flicker Stimulation (LFS), as a non-invasive form of physical therapy, shows significant neuroprotective potential by modulating electrical brain oscillations and particular signaling pathways. We critically examine the role of stimulation parameters (frequency, wavelength, multisensory combination) and discuss the state of clinical translation, including completed and ongoing trials, safety considerations, and technological innovations such as alternating bilateral stimulation and organic light-emitting diode (OLED) devices. By integrating mechanistic insights with clinical perspectives, this review aims to identify key gaps and future directions for harnessing 40 Hz LFS as a viable treatment for neurodegenerative diseases.},
}

@article {pmid42097136,
year = {2026},
author = {Tang, JY and Tan, Q and Yu, ZY and Yuan, ZY and Zeng, R and Liu, XY and Zhu, XY and Zhao, Y and Li, JH and Bai, YD and Zeng, GH and Wang, C and Wang, YJ},
title = {Hepatic expression of APOE3 Christchurch mitigates APOE4-related Alzheimer's disease pathologies in mice.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.04.027},
pmid = {42097136},
issn = {1097-4199},
abstract = {The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We successfully delivered APOE3Ch or APOE3 into the liver by adeno-associated virus in APP/PS1 mice expressing human APOE4. We observed that hepatic APOE3Ch delivery reduced amyloid-β (Aβ) burden in the brain. Hepatic APOE3Ch expression attenuated neuroinflammation, neurodegeneration, and cognitive impairments. Mechanistically, APOE3Ch expression increased the capacity of Aβ clearance by monocytes and hepatocytes. Our findings demonstrate that hepatic APOE3Ch expression attenuates AD-type pathologies in APOE4-expressing APP/PS1 mice, highlighting liver-directed APOE3Ch gene transfer as a promising therapeutic strategy for APOE4-associated AD.},
}

@article {pmid42097270,
year = {2026},
author = {Cho, E and Lee, S and Lee, H and Kim, J and Kwon, YW and Hoe, HS and Kim, D and Yoon, JH},
title = {An integrative proteomic approach to reveal altered signaling modules during Alzheimer's disease progression in PS19 tauopathy mice.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101580},
doi = {10.1016/j.mcpro.2026.101580},
pmid = {42097270},
issn = {1535-9484},
abstract = {Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that is characterized by cognitive, functional, and behavioral impairments. These changes occur owing to the progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is associated with the dysfunction of several essential neurotransmitter systems, such as dopamine, and impaired neurotransmission. Despite the association of neurotransmitter changes within the brain and AD pathology, in-depth profiling studies on neurotransmitters and their related proteomic changes are limited. This study was conducted to profile and integrate the proteomes and neurotransmitters in seven brain regions of PS19 (Tau P301S) mice according to AD progression between 4 and 7 months. Proteomic analysis revealed significantly altered canonical pathways in various brain regions, including metabolic abnormalities. In the neurotransmitter profile, we found significant alterations in the levels of six neurotransmitters-dopamine, serotonin, homovanillic acid, norepinephrine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid-during AD progression. Using an integrative approach between proteome and neurotransmitter profiles, we found that AD progression-dependent dopamine- and serotonin-related signaling modules are closely related to neurotransmitter changes, especially in the hippocampus and cerebellum. This integrative approach could provide new signaling modules to help understand AD progression and thereby enable improved treatment and clinical outcomes.},
}

@article {pmid42097313,
year = {2026},
author = {Chen, R and Qiu, Z and Luo, Y and Fu, Y and Cui, X and Jiang, M},
title = {The Role of Neurogenesis in Neurodegenerative Diseases: Mechanisms and Interventions.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103160},
doi = {10.1016/j.arr.2026.103160},
pmid = {42097313},
issn = {1872-9649},
abstract = {Neurogenesis is the process by which new neurons are generated from neural stem cells (NSCs) and neural progenitor cells (NPCs). Impairment in this process can lead to cognitive and memory deficits, among other issues. Research indicates that defective neurogenesis is closely associated with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). These conditions not only affect a significant global population but also exert profound societal and economic impacts. However, the precise mechanisms underlying neurodegenerative diseases remain incompletely understood, and the relationship between neurogenesis and these disorders requires further exploration. This review examines the role of neurogenesis in major neurodegenerative diseases, emphasizing the importance of early diagnosis and precision therapy. The findings aim to provide a foundation for developing novel treatments, thereby alleviating the burden on patients and their families.},
}

@article {pmid42097394,
year = {2026},
author = {Choudhury, RR and Kushwaha, S and Karunakaran, S},
title = {Prolonged β-adrenergic stimulation reduces β2-adrenergic receptor levels and limits astrocytic responsiveness during early amyloid pathology.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138618},
doi = {10.1016/j.neulet.2026.138618},
pmid = {42097394},
issn = {1872-7972},
abstract = {Early Alzheimer's disease (AD) is associated with declining noradrenergic tone and early alterations in astrocytic regulation. β-adrenergic signaling links norepinephrine activity to extracellular signal-regulated kinase (ERK) activation and astrocytic responses, but the effects of sustained adrenergic stimulation during early amyloid exposure remain unclear. In this study, wild-type (WT) and pre-plaque APPSwe/PSEN1dE9 (APP/PS1) mice received chronic oral isoproterenol (ISO) from postnatal day 26-47. Hippocampal adrenergic signaling and astrocytic responses were examined at 3 months of age. ISO exposure was associated with reduced β2-adrenergic receptor (β2AR) protein levels and increased β-arrestin-1 expression, consistent with receptor desensitization-associated signaling changes, while ERK phosphorylation remained detectable in both genotypes. WT mice showed increased glial fibrillary acidic protein (GFAP) expression, whereas APP/PS1 mice displayed attenuated molecular responses despite comparable ERK activation. Morphometric analysis revealed no clear evidence of robust astrocytic structural changes at the animal level. These findings indicate that sustained β-adrenergic stimulation is associated with reduced β2AR levels while downstream ERK signaling persists, suggesting that astrocytic responsiveness to adrenergic signaling may be constrained during early amyloid pathology.},
}

@article {pmid42097395,
year = {2026},
author = {Shahsavari, F and Rajizadeh, MA and Pirmoradi, Z and Sabzalizadeh, M and Kohlmeier, KA and Soti, M and Shabani, M},
title = {Abscisic acid ameliorates cognitive deficits in an amyloid-β-induced mouse model of Alzheimer's disease associated with alterations in markers of neuroplasticity and neuroinflammation.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138619},
doi = {10.1016/j.neulet.2026.138619},
pmid = {42097395},
issn = {1872-7972},
abstract = {Abscisic acid (ABA, C15H20O4), a mammalian hormone, exhibits neuroprotective and anti-inflammatory properties. This study aimed to investigate the effects of ABA on the hippocampal-dependent processes: anxiety-, depression-like behaviors and cognitive impairments as well as levels of factors involved in neuroplasticity and neuroinflammation in an amyloid-β (Aβ)-induced mouse model of Alzheimer's disease (AD). One week following intracerebroventricular (i.c.v.) injection of Aβ1-42 in male mice, ABA was administered i.c.v. at doses of 10 or 15 µg/µl for 7 consecutive days. Behavioral assessments were conducted using the novel object recognition, open field, elevated plus maze, tail suspension, Morris water maze, and passive avoidance tests. Hippocampal gene expression levels of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor (NMDAR), and nuclear factor-κB (NF-κB) were evaluated using real-time PCR. ABA treatment significantly attenuated anxiety-like behaviors and improved spatial, avoidance and recognition memory deficits induced by Aβ1-42 administration with more behavioral domains affected at the 15 µg/µl dose. ABA induced significant upregulation in the hippocampus of NMDAR and BDNF expression and marked suppression of NF-κB in the ABA (15 µg/µl)-treated Aβ group, which could have played a mechanistic role in improvements in behaviors controlled by this structure. Histological analysis demonstrated attenuation of neuronal degeneration and pyknosis in the hippocampal CA1 region following ABA intervention. Collectively, these findings suggest that ABA ameliorates anxiety-related behaviors and cognitive impairments in an experimental mouse model of AD, potentially through modulation of neuroinflammatory and neuroplasticity-related pathways.},
}

@article {pmid42097406,
year = {2026},
author = {Serpa, RO and Tufano, E and Connor, JR},
title = {Reimagining the contribution of iron in Parkinson's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107434},
doi = {10.1016/j.nbd.2026.107434},
pmid = {42097406},
issn = {1095-953X},
abstract = {Parkinson's Disease (PD) is the fastest-growing neurodegenerative disease globally, with prevalence increasing more rapidly than Alzheimer's disease. PD pathogenesis has traditionally been framed around iron accumulation in the substantia nigra (SN), resulting in oxidative injury to vulnerable dopaminergic neurons. However, excess iron alone does not readily explain the temporal emergence of dopaminergic susceptibility across the lifespan. Epidemiological and clinical studies consistently show that iron deficiency often precedes PD diagnosis by more than a decade, suggesting that early iron dysregulation establishes a prodromal metabolic state that destabilizes the nigrostriatal system. Here we propose a dynamic two-phase framework in which iron deficiency establishes a latent vulnerability state characterized by impaired iron-dependent enzymatic activity, diminished ferritin buffering, weakened mitochondrial function, and reduced antioxidant defenses. In this primed context, subsequent increases in dopaminergic flux during L-DOPA therapy may amplify oxidative stress by elevating cytosolic dopamine, perturbing iron handling, and promoting dopamine iron redox chemistry that generates quinones and reactive oxygen species (ROS). Transitions in iron availability including iron supplementation, may further aggravate this process but are not required for its initiation. By reframing PD as a disorder shaped by dynamic changes in iron availability interacting with dopaminergic demand, this review integrates evidence across iron biology, dopaminergic signaling, oxidative stress, and neuroinflammation to propose a mechanistically novel model of PD pathogenesis. This conceptual shift highlights new opportunities for risk stratification, biomarker development, and refinement of dopaminergic therapy within iron dysregulated states.},
}

@article {pmid42097410,
year = {2026},
author = {Zhu, PF and Lyu, Z and Wang, Q and Li, S and Wang, X and Luo, A},
title = {ISRIB as a Prototype eIF2B Activator: Pharmacology, Mechanisms, and Translational Potential in Aging-Related Cognitive Disorders.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108228},
doi = {10.1016/j.phrs.2026.108228},
pmid = {42097410},
issn = {1096-1186},
abstract = {Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for "tuning" ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer's disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders.},
}

@article {pmid42097478,
year = {2026},
author = {Matošević, A and Maraković, N and Barić, D and Igert, A and Brazzolotto, X and Kovarik, Z and Bosak, A},
title = {Integrative Structural and Kinetic Analysis of the Molecular Basis for Reduced Carbamate Inhibition in Atypical Butyrylcholinesterase.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112134},
doi = {10.1016/j.cbi.2026.112134},
pmid = {42097478},
issn = {1872-7786},
abstract = {Butyrylcholinesterase (BChE) plays a key role in cholinergic transmission and the metabolism of various drugs, making its regulation a promising therapeutic strategy for several diseases, including Alzheimer's disease. Selective inhibition of BChE helps regulate brain acetylcholine levels. However, genetic polymorphisms in the BCHE gene, particularly the Asp70Gly mutation in atypical BChE, can impact treatment outcomes. This study compares the inhibitory potency of 13 carbamates against atypical and usual BChE. Using molecular docking, quantum chemical cluster calculations, and crystallization of wild-type BChE with the most potent carbamate, we identified key differences in carbamylation mechanisms. Atypical BChE shows a less favorable enzyme-inhibitor complex orientation, lacking the hydrogen bond stabilization of the reactive carbonyl oxygen. Additionally, Asp70 in usual BChE contributes to stabilizing the non-reactive carbamate group, whereas Gly70 in atypical BChE is too distant to form such interactions.},
}

@article {pmid42097486,
year = {2026},
author = {Deloncle, R},
title = {Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115812},
doi = {10.1016/j.expneurol.2026.115812},
pmid = {42097486},
issn = {1090-2430},
abstract = {Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.},
}

@article {pmid40844393,
year = {2025},
author = {Grøntvedt, GR},
title = {[Blood-based biomarkers in Alzheimer’s disease].},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {145},
number = {},
pages = {},
doi = {10.4045/tidsskr.25.0118},
pmid = {40844393},
issn = {0807-7096},
}

@article {pmid42039580,
year = {2026},
author = {Balaan, C and Patwardhan, GY and Sachs, RK and Kumasaka, H and Sadagopan, S and Aou, S and Lee, AJ and Nelson, LT and Hew, BE and Owens, JB and Polgar, N and Ortega, MA and Nichols, RA and Fogelgren, B},
title = {The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {42039580},
issn = {2692-8205},
abstract = {Intracellular trafficking of amyloid precursor protein (APP) critically influences amyloidogenic processing, yet the mechanisms regulating this pathway remain incompletely defined. The exocyst is a highly conserved, insulin-responsive, eight-protein Rab effector complex that directs intracellular transport vesicle targeting and docking. We identified APP in a proteomics screen of neuronal cell surface proteins altered after chemical inhibition of exocyst activity. In SH-SY5Y cells expressing a mutant APP that enhances amyloidogenic processing, RNAi-mediated silencing of exocyst subunits significantly decreased sAPP and Aβ secretion, leading to significant intracellular APP accumulation. We found high-resolution co-localization of APP with exocyst subunits in soma and neurites of differentiated human SH-SY5Y neurons and mouse primary hippocampal neurons, and live-cell TIRF microscopy identified highly coordinated movement between fluorescently-tagged exocyst and APP proteins. These interactions were confirmed in these cells and in mouse brain histological sections by proximity ligation assays (PLAs) demonstrating close (<40nm) APP-EXOC5 association. To examine if exocyst activity in neurons is regulated by insulin, as it is in adipocytes and muscle, we generated a SH-SY5Y cell line with pHluorin-tagged GLUT4. Inhibition of the exocyst prevented exocytosis of GLUT4 to the plasma membrane in response to insulin. Additionally, using PLAs in mouse primary hippocampal neurons and SH-SY5Y neurons, we found that GLUT4-EXOC5 associations were increased by insulin signaling, but APP-EXOC5 associations were markedly reduced, indicating insulin-dependent retargeting of the exocyst complex away from APP+ vesicles towards GLUT+ vesicles. All together, these data identify the exocyst as a novel insulin-regulated mediator of neuronal APP trafficking and Aβ secretion.},
}

@article {pmid42085916,
year = {2026},
author = {Abbas, A and Tsai, HC and Hsu, YL and Kenneth, MJ and Hussain, B and Lai, LM and Hsu, BM},
title = {Multimodal deep learning neuroimaging approach to enhance CT-based diagnosis of Alzheimer's disease.},
journal = {Psychiatry research. Neuroimaging},
volume = {361},
number = {},
pages = {112234},
doi = {10.1016/j.pscychresns.2026.112234},
pmid = {42085916},
issn = {1872-7506},
abstract = {Neuroimaging plays a critical role in the diagnosis of Alzheimer's disease (AD), with Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) providing detailed structural and functional information for deep learning (DL) based classification. However, their high cost and limited availability restrict widespread clinical use. Computed Tomography (CT), while affordable and widely accessible, is diagnostically insufficient for detecting subtle neurodegenerative changes associated with early AD. To address this limitation, this study proposes a multimodal DL framework that enhances CT-based AD diagnosis by leveraging complementary feature representations learned from MRI. A custom convolutional neural network (CNN) was trained and evaluated using paired CT and MRI data from the Open Access Series of Imaging Studies (OASIS-3). A total of 772 participants with available MRI and CT scans were selected based on Clinical Dementia Rating (CDR) scores and corresponding clinical diagnoses. Participants were categorized as Normal Control (NC) (CDR = 0, n = 300), mild cognitive impairment (MCI) (CDR = 0.5, n = 250), or AD (CDR ≥ 1, n = 222). The overall sex distribution comprised 352 males and 420 females. The CT-only model achieved an accuracy of 84%, with 92% sensitivity and 83% specificity for AD classification. The proposed multimodal model demonstrated superior performance, achieving 92% accuracy, 95% sensitivity, and 91% specificity. Importantly, during CT-only inference, the multimodal framework retained high diagnostic accuracy in identifying disease status, indicating effective transfer of MRI-derived features to CT. These results demonstrate a scalable solution for improving AD detection using CT imaging in resource-limited healthcare.},
}

@article {pmid42085921,
year = {2026},
author = {Wang, C and Piao, S and Chen, Z and Chen, T and Li, Z and Zhang, T and Li, Y and Zhao, XM and Shan, H and , and , },
title = {E[2]AD: Enhanced and explainable Alzheimer's disease detection framework via anatomy- and relation-aware cross-modal knowledge distillation.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104099},
doi = {10.1016/j.media.2026.104099},
pmid = {42085921},
issn = {1361-8423},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which MRI and PET provide complementary structural and molecular information. Yet PET remains costly and often unavailable, motivating MRI-only diagnostic systems that still benefit from multimodal supervision. Existing methods either synthesize PET from MRI or limit cross-modal learning to low-dimensional spaces, underutilizing MRI-PET complementarity and leading to limited robustness and generalizability. To address these challenges, we introduce E[2]AD, an Enhanced and Explainable AD detection framework that leverages anatomy- and relation-aware cross-modal knowledge distillation (KD). Using paired MRI-PET data during training but only MRI at inference, E[2]AD augments traditional logit-based KD through two synergistic components: (1) anatomy-aware distillation that transfers within-subject anatomical dependencies through an anatomical Mixture-of-Mappers, yielding spatially meaningful and clinically traceable cues; and (2) relation-aware distillation that promotes stable between-subject structural relations through generalizable pairwise alignment, yielding a representation space with better cross-cohort generalization. To enhance clinical utility, we further introduce a tailored multi-agent workflow that translates E[2]AD's anatomical attention into structured, clinician-oriented MRI reports. Extensive experimental results on the internal ADNI cohort and two external cohorts (AIBL and NACC) demonstrate that E[2]AD outperforms state-of-the-art baselines, offering faster convergence, improved data efficiency, stronger cross-cohort generalization, and enhanced explainability. Source code is available at https://github.com/thibault-wch/E2AD-for-Alzheimer-disease.},
}

@article {pmid42086074,
year = {2026},
author = {Si, P and He, N and Liu, J and Wang, Q and Lin, J and Dai, C},
title = {Investigation of the Therapeutic Effects of Transcorneal Electrical Stimulation on Alzheimer's Disease Using Optical Coherence Tomography.},
journal = {Journal of biophotonics},
volume = {19},
number = {5},
pages = {e70274},
doi = {10.1002/jbio.70274},
pmid = {42086074},
issn = {1864-0648},
support = {62175156//National Natural Science Foundation of China/ ; 22S31903000//Science and Technology Commission of Shanghai Municipality/ ; },
mesh = {*Tomography, Optical Coherence ; *Alzheimer Disease/therapy/diagnostic imaging/pathology ; Animals ; Mice ; *Cornea/diagnostic imaging ; Retina/diagnostic imaging ; *Electric Stimulation Therapy ; Male ; *Electric Stimulation ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking reliable noninvasive indicators for early diagnosis. Transcorneal electrical stimulation (TES) has emerged as a noninvasive neuromodulation approach, yet its effects on AD-related pathology and eye-brain interactions remain unclear. In this study, TES was applied to wild-type (WT) and AD mice, followed by longitudinal optical coherence tomography (OCT) and OCT angiography (OCTA) imaging of the retina and cerebral cortex over a 30-day period. Quantitative imaging metrics, together with histologically assessed amyloid-β (Aβ) plaque deposition, were used to assess TES-associated structural and neurovascular changes. In addition to retinal thickness, retinal vascular density (VD) was evaluated as an objective, noninvasive imaging metric associated with AD-related neurovascular alterations. These findings demonstrate the utility of longitudinal OCT/OCTA imaging for investigating intervention-associated retinal and cerebral neurovascular changes along the eye-brain axis.},
}

*Tomography, Optical Coherence
*Alzheimer Disease/therapy/diagnostic imaging/pathology
Animals
Mice
*Cornea/diagnostic imaging
Retina/diagnostic imaging
*Electric Stimulation Therapy
Male
*Electric Stimulation

@article {pmid42086094,
year = {2026},
author = {Wang, E and Kang, Y and Chen, D and Tian, R and Hu, Y and Wang, H and Jun, L and Zhou, Z and Tian, T and Xu, H and Huang, J},
title = {Alternative splicing fuels the functional diversity of GPCR in neurological and psychiatric disorders: An emerging path toward RNA-targeted neurotherapeutics.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118026},
doi = {10.1016/j.bcp.2026.118026},
pmid = {42086094},
issn = {1873-2968},
abstract = {Dysfunction in intricate neural circuits contributes to numerous neurological and psychiatric disorders, affecting a substantial portion of the global population and significantly contributing to the global disease burden. This highlights the urgent need for more precise therapeutic targets. G protein-coupled receptors (GPCRs) are the predominant targets commonly utilized in the development of novel therapeutics for nervous system disorders. Alternative splicing (AS) generates numerous tissue- and cell type-specific GPCR isoforms that are regulated by cis-acting elements, trans-acting factors, and underlying epigenetic modifications. These isoforms exhibit distinct distributions, leading to signaling bias and conformational diversity. However, their role in GPCR signaling heterogeneity is often overlooked due to limited data on expression and function in various neuropathological conditions. This review examines GPCR splicing variants (SVs) in neurodegenerative diseases such as Alzheimer's and Parkinson's, neuropsychiatric disorders including depression, anxiety, autism spectrum disorder, and schizophrenia, as well as pain and addiction. It emphasizes how alternative splicing shapes tissue-specific GPCR expression and diverse biological functions. Emerging technologies and AI-based structural modeling are underscored as powerful tools for resolving GPCR variant structures and enabling isoform-specific drug development. The review aims to provide new insights into GPCR functional heterogeneity and promote an isoform-focused therapeutic strategy based on GPCR-ligand interactions to guide future treatments.},
}

@article {pmid42086102,
year = {2026},
author = {Chen, M and Huang, X and Li, Y and Hu, L and Lu, R and Li, L},
title = {Microplastics as an emerging environmental pollutant potentially leading to neurodegenerative diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.04.033},
pmid = {42086102},
issn = {1873-7544},
abstract = {Microplastics (MPs), defined as plastic fragments less than 5 mm in diameter, are ubiquitous in the environment. As an emerging environmental pollutant, MPs can infiltrate the human body through multiple pathways, including inhalation, ingestion, dermal contact and bloodborne transmission.Correspondingly, MPs, which can penetrate the blood-brain barrier and enter the central nervous system (CNS), have been linked to the development of neurodegenerative diseases (NDs).In this review, we provide a comprehensive analysis of the environmental distribution of MPs, the pathways of entry into the human body, and the distribution within the CNS. Furthermore, we explore intrinsic factors influencing the neurotoxicity of MPs and elucidate the mechanisms underlying MPs-induced NDs, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Beyond mechanistic insights, we offer a novel perspective by exploring the potential adaptation of emerging environmental MPs detection and removal technologies for CNS applications. Ultimately, elucidating these mechanisms positions the reduction of MPs accumulation as a critical intervention point, highlighting the adaptation of environmental technologies as a promising strategy for the prevention and management of NDs.},
}

@article {pmid42086126,
year = {2026},
author = {Bai, X and Dai, J and Wang, X and Gao, H},
title = {Exploring the differences in efficacy and mechanisms of Schisandra chinensis and its processed products in treating Alzheimer's disease based on UPLC-Q-TOF-MS/MS, network pharmacology, and experimental validation.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107268},
doi = {10.1016/j.fitote.2026.107268},
pmid = {42086126},
issn = {1873-6971},
abstract = {This study aims to elucidate the efficacy differences and underlying mechanisms of Schisandra chinensis (SC) and its processed products against Alzheimer's disease (AD). A total of 39 compounds were identified from SC and its processed products through UPLC-Q-TOF-MS/MS in both positive and negative ion modes. Multivariate statistical analysis revealed significant differences in chemical composition among the various processed products, with schisandrol A, epigomisin O, and angeloylgomisin O identified as key significantly differential components. Based on the identified compounds, potential targets were predicted via Swiss Target Prediction, which were then intersected with AD targets from the GeneCards and OMIM databases to construct a protein-protein interaction (PPI) network of "SC-AD" intersection targets. Enrichment analysis indicated that the core mechanism of its anti-AD effect involves the regulation of the PI3K/AKT signaling pathway. Experimental validation was conducted using the Aβ25-35-induced HT22 cell injury model and a D-galactose combined with scopolamine-induced AD mouse model. The results demonstrated that SC and its processed products significantly improved the behavioral performance of AD mice, alleviated pathological damage in brain tissue, and reduced pro-inflammatory factor levels. Furthermore, they upregulated AKT protein expression and inhibited mTOR protein expression. Notably, the regulatory effects of the processed products on these indicators were significantly superior to those of the raw products. In conclusion, both SC and its processed products can ameliorate AD by activating the PI3K/AKT pathway, with the effect significantly enhanced post-processing. This mechanism may be associated with the regulation of the PI3K/AKT signaling pathway.},
}

@article {pmid42086387,
year = {2026},
author = {Sah, NKP and Saxena, S and Desai, D},
title = {Comment on "Alzheimer's disease diagnosis: An update and review of biomarkers, positron emission tomography, and emerging therapies".},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.04.135},
pmid = {42086387},
issn = {0929-6646},
}

@article {pmid42086543,
year = {2026},
author = {Liu, WZ and Huang, LY and Chi, S and Ma, YH and Tan, CC and Tan, L and , and Xu, W},
title = {Correction: The blood lipidome fatty acid profile predicts the disease risk and clinical phenotypes of Alzheimer's disease: associations from two prospective cohort studies.},
journal = {Translational psychiatry},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41398-026-04062-x},
pmid = {42086543},
issn = {2158-3188},
}

@article {pmid42086977,
year = {2026},
author = {Khan, TTS and Wong, CYJ and Sheikh, Z and Fathi, A and Maleknia, S and Oveissi, F and Abrams, T and Knox, W and van der Hoven, J and Antonito, A and Murray, M and Svolos, M and Suman, J and Tietz, O and Ong, HX and Traini, D},
title = {Repurposing insulin for Alzheimer's disease treatment: intranasal delivery of a thermoresponsive nanocarrier-based insulin formulation to the brain.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42086977},
issn = {2190-3948},
abstract = {The Intranasal route provides an effective pathway for insulin delivery to the brain compared to oral/subcutaneous routes as it provides direct access to the brain, bypassing the restrictive blood-brain barrier (BBB), while minimizing systemic exposure. The present study investigated the potential of a thermoresponsive polymer, PNPHO, as a nanocarrier for brain-targeted insulin delivery through the intranasal route, with the aim of repurposing insulin for Alzheimer's disease treatment. Insulin-loaded nanoparticles (NP) were formulated using an advanced crossflow mixing technology with lower (F1) and higher (F2) PNPHO concentrations and characterised in vitro for size, zeta potential, encapsulation efficiencies, stability, drug deposition, and transport and in vivo for biodistribution. Both F1 and F2 NP demonstrated particle sizes ranging from 35.9 to 49.8 nm with low polydispersity index (< 0.3), negative surface charges, high encapsulation efficiencies (> 99%), and conserved structural integrity post 4 weeks of stability study. NP demonstrated significantly greater in vitro nasal deposition compared to insulin alone. Notably, the PNPHO nanocarrier protected insulin from enzymatic degradation, overcoming a key barrier associated with protein/peptide delivery. In vitro drug transport studies showed an initial delay in NP transport across nasal cells due to PNPHO-mucoadhesive properties, followed by increased transport. Significantly enhanced time-dependent NP transport across the BBB cells compared to insulin alone (p < 0.0001) confirmed NP's ability to cross the BBB. In vivo, NP demonstrated prolonged nasal retention and higher brain: serum ratio in mice, suggesting sustained drug release and improved brain delivery compared to insulin alone. Collectively, the study highlight the potential of PNPHO as a promising nanocarrier for achieving targeted and efficient intranasal delivery of insulin to the brain.},
}

@article {pmid42087072,
year = {2026},
author = {Cho, J and Won, J and Kim, YG and Jeon, CY and Lim, KS and Seo, J and Seong, JB and Yeo, HG and Kim, K and Kim, M and Gwon, LW and Jung, Y and Nguyen, TTH and Min, J and Moon, G and Choi, WS and Park, SH and Lee, HY and Jeong, KJ and Bae, GS and Jeon, E and Cheong, DY and Lee, G and Kim, HC and Baeg, E and Yang, S and Huh, JW and Park, J and Lee, Y},
title = {Repeated Intra-cisterna Magna Injections with Amyloid-beta Oligomers to Induce Alzheimer's Disease in Cynomolgus Monkey (Macaca fascicularis): A Pilot Study.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en25052},
pmid = {42087072},
issn = {1226-2560},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder which results in cognitive decline and memory loss, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Despite numerous efforts to develop animal models of AD across various species to understand its pathological characteristics and underlying mechanisms, the model that accurately mimics the pathological phenotypes of AD remains elusive. In this study, we aimed to induce sporadic AD pathological progression in non-human primates (NHP) through the repeated administration of Aβ oligomers (AβO) via the CBCT-guided intra-cisterna manga (ICM) injection. Cynomolgus monkeys were administered AβO twice a week for four weeks, and then euthanized one week after the final injection. We found that AβO-injected NHP developed AD pathologies, including Aβ deposition, synaptic impairment, and neuroinflammation in the CA1 area of the hippocampus. Additionally, the levels of hyperphosphorylated tau were significantly increased in the cerebrospinal fluid (CSF) of AβO-injected NHP. Our results demonstrate that repeated AβO injection via the ICM route induces several early-stage AD-like neuropathological alterations, including intracellular Aβ accumulation, tau phosphorylation, and synaptic dysfunction. The present study indicates that repeated ICM administration of AβO could be good approach to reproduce a translational NHP model of AD, enabling the study of AD pathogenesis and pre-clinical testing of potential therapeutic candidates for AD.},
}

@article {pmid42087418,
year = {2026},
author = {Yin, X and Peng, H and Li, Y and Song, Y and Chen, L and Yao, N and Li, P and He, Z and Chen, H and Huang, L and Shen, Z and Chen, Q},
title = {The Association Between Physical Activity and Domain-Specific Cognitive Function in the Elderly: A Cross-Sectional Study and Genetic Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71423},
doi = {10.1002/brb3.71423},
pmid = {42087418},
issn = {2162-3279},
support = {82360943//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Cross-Sectional Studies ; Aged ; Male ; *Exercise/physiology ; Female ; *Cognition/physiology ; Middle Aged ; Nutrition Surveys ; Aged, 80 and over ; *Aging/genetics/physiology ; Mendelian Randomization Analysis ; Neuropsychological Tests ; Cognitive Dysfunction/genetics ; },
abstract = {BACKGROUND: Population aging is intensifying worldwide, increasing the prevalence of dementia. More than 50 million people globally are affected by dementia. There is some evidence that physical activity (PA) benefits cognitive function (CF). However, it is unclear which types and amounts of PA are best for specific cognitive domains.

METHODS: This study used a cross-sectional design and genetic analysis to test its hypotheses. Participants were drawn from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, including 2578 adults aged 60 years or older. Cognitive abilities were measured using standardized tests, and PA levels were assessed with the Global Physical Activity Questionnaire (GPAQ). The analysis included multivariable regression, threshold effect testing, and subgroup analysis to explore links between PA patterns, intensities, and specific CF domains. Furthermore, a Mendelian randomization (MR) approach was employed to assess whether PA intensity exerts an effect on CF.

RESULTS: NHANES data analysis showed that the regular activity (RA) pattern was positively associated with the Consortium to Establish a Registry for Alzheimer's Disease Word Learning test (CERAD-WL) scores (β = 0.07; 95% confidence interval [CI]: 0.02, 0.16; p = 0.018), Animal Fluency Test (AFT) scores (β = 0.31; 95% CI: 0.21, 0.41; p = 0.002), Digit Symbol Substitution Test (DSST) scores (β = 0.19; 95% CI: 0.09, 0.30; p = 0.017), and overall CF (β = 0.23; 95% CI: 0.14, 0.32; p < 0.004). Threshold-effect analysis revealed an inverted U-shaped relationship between PA levels and cognitive performance. The inflection points occurred at 650, 535, and 550 min per week for AFT, DSST, and overall CF, respectively. Above these values, further cognitive gains plateaued. The inverse-variance weighted (IVW) method of the MR analyses showed that moderate-intensity physical activity (MPA) increased correct counting (odds ratio [OR] = 0.710; 95% CI: 0.606, 0.832; p < 0.001), fluid intelligence (OR = 0.470; 95% CI: 0.346, 0.638; p < 0.001), and overall cognitive performance (OR = 0.707; 95% CI: 0.653, 0.764; p < 0.001). For vigorous-intensity physical activity (VPA), we observed causal associations with memory outcomes, reaction time, correct matches, fluid intelligence, and cognitive performance.

CONCLUSION: The findings suggest that PA is associated with multiple domains of CF, and the RA pattern is linked to better cognitive performance. Genetically, VPA appears to have a stronger promotive effect. Thus, different patterns and intensities of PA may help delay cognitive decline and maintain brain health in older adults.},
}

Humans
Cross-Sectional Studies
Aged
Male
*Exercise/physiology
Female
*Cognition/physiology
Middle Aged
Nutrition Surveys
Aged, 80 and over
*Aging/genetics/physiology
Mendelian Randomization Analysis
Neuropsychological Tests
Cognitive Dysfunction/genetics

@article {pmid42087556,
year = {2026},
author = {Loncke, J and Callens, M and Bultynck, G and Vervliet, T},
title = {RYR:ATP6V0A1 complexes couple ER-lysosome contact sites to dynamic autophagy control.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2669981},
pmid = {42087556},
issn = {1554-8635},
abstract = {Ryanodine receptors (RYRs) are ER-resident Ca[2] [+] -release channels enriched in excitable cells, including neurons. RYR hyperactivity is implicated in early pathogenesis of disorders such as Alzheimer's disease (AD), which is associated with impaired autophagy. We recently uncovered a mechanism linking RYR activity to lysosome availability for autophagy. RYRs localize to ER - lysosome contact sites via direct binding to ATP6V0A1, a V-ATPase subunit that also suppresses RYR-mediated Ca[2] [+] release. In human iPSC-derived cortical neurons, spontaneous RYR activity promotes lysosomal secretion, depleting the intracellular lysosomal pool and inhibiting autophagic flux. RYR inhibition promotes ER - lysosome contacts, limits lysosomal secretion, and restores lysosome availability for autophagosome fusion and cargo degradation (including APP). Conversely, disrupting the RYR:ATP6V0A1 interaction using a RYR-derived protein fragment serving as a "decoy" for ATP6V0A1 evokes RYR hyperactivity and stimulates lysosomal secretion. In this Punctum, we discuss how this RYR2:ATP6V0A1 "contact-site hub" may be perturbed in disease and highlight open questions on how lysosomes decode RYR-derived Ca[2] [+] signals.},
}

@article {pmid42087592,
year = {2026},
author = {Liu, X and Xu, H and Zhao, Y and Yang, J and Zhang, L and Wang, Z and Lim, K and Zhang, C and Lu, L},
title = {Roles of POU3F2 in Brain Development and Neuropsychiatric Disorders.},
journal = {Developmental neurobiology},
volume = {86},
number = {3},
pages = {e70034},
doi = {10.1002/dneu.70034},
pmid = {42087592},
issn = {1932-846X},
support = {202200331//Cooperative Research Project/ ; //Shanxi Province Higher Education/ ; 82571379//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Humans ; *Brain/growth & development/metabolism ; *Mental Disorders/metabolism/genetics ; *POU Domain Factors/metabolism/genetics ; *Homeodomain Proteins/metabolism ; *Nerve Tissue Proteins/metabolism ; },
abstract = {POU3F2, a member of the Pit-Oct-Unc (POU) domain transcription factor family, is widely expressed in the central nervous system and essential for the development and maturation of brain. POU3F2 deletion results in impaired hypothalamus and neocortex development, and most mice die between postnatal days 0 and 10. Recently, emerging evidences have demonstrated that POU3F2 is involved in neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, and autism spectrum disorder, albeit still with some limitations in current studies. Besides, POU3F2 also plays a vital role in the reprogramming of somatic cells into neuronal lineages, which provides new ideas and directions for the treatment of neuropsychiatric disorders. This review aims to systematically summarize and analyze the diverse roles of POU3F2 in brain development, neuropsychiatric disorders, and neuronal reprogramming. Furthermore, the potential of POU3F2-targeted therapies for neuropsychiatric disorders and proposed key questions for future research are also emphasized. POU3F2 plays a pivotal role in brain development, the pathogenesis of neurological and psychiatric disorders, and the reprogramming of neural cells. A more comprehensive and systematic understanding of its molecular mechanism might provide novel therapeutic approaches for neuropsychiatric disorders.},
}

Animals
Humans
*Brain/growth & development/metabolism
*Mental Disorders/metabolism/genetics
*POU Domain Factors/metabolism/genetics
*Homeodomain Proteins/metabolism
*Nerve Tissue Proteins/metabolism

@article {pmid42087776,
year = {2026},
author = {Rodriguez Colmenares, NA and Alvarez, L and Gilbreath, J and Markaki, A and Schexnayder, J and Puga, F},
title = {Anticipatory grief among caregivers of people living with dementia: A scoping review.},
journal = {Palliative & supportive care},
volume = {24},
number = {},
pages = {e130},
doi = {10.1017/S1478951526102478},
pmid = {42087776},
issn = {1478-9523},
mesh = {Humans ; *Caregivers/psychology ; *Dementia/psychology/complications ; *Grief ; Adaptation, Psychological ; Stress, Psychological/psychology ; },
abstract = {OBJECTIVES: As Alzheimer's disease and related dementias (ADRD) progress, family caregivers may experience grief before the death of the person living with ADRD. This type of grief is commonly referred to as anticipatory grief, which can contribute to increased psychological distress (i.e., depressive and anxiety symptoms) and potentially affect caregivers' long-term mental health. This scoping review aimed to synthesize evidence on risk and resilience factors associated with anticipatory grief, its relationship with caregiver mental health, and psychosocial interventions targeting anticipatory grief among caregivers of people living with ADRD.

METHODS: Guided by the Stress Process Model and the Grief-Stress Model, a literature search was conducted in PubMed, CINAHL, Embase, Scopus, Web of Science, and PsycINFO in May 2025.

RESULTS: Thirty articles met the inclusion criteria. Caregiver characteristics, such as being a spousal caregiver and greater caregiving involvement, were associated with higher levels of anticipatory grief. Caregiving-related stressors and relationship changes across the ADRD trajectory were consistently linked to anticipatory grief across studies, while psychosocial resources, such as adaptive coping and social support, were generally associated with lower levels of anticipatory grief. Anticipatory grief was consistently associated with depressive symptoms. Intervention studies were limited, but those focused on acceptance and preparedness showed potential for reducing anticipatory grief.

SIGNIFICANCE OF RESULTS: Anticipatory grief represents an important dimension of caregiver mental health that reflects ongoing loss. Conceptualizing anticipatory grief within caregiving stress frameworks highlights how vulnerability to distress may emerge from the interplay between caregiving stressors, relationship changes, and psychosocial resources. This conceptual framing may inform future research and palliative care interventions to support the well-being of family caregivers across the dementia trajectory.},
}

Humans
*Caregivers/psychology
*Dementia/psychology/complications
*Grief
Adaptation, Psychological
Stress, Psychological/psychology

@article {pmid42087813,
year = {2026},
author = {Magadi, SS and Jonson, M and Lucena, PB and Caliandro, MF and Almeida, B and Bilalli, L and Budinger, D and Tsoi, A and Ntzouni, M and Maqdissi, JA and Kaczmarczyk, L and Zijlstra, JJ and Faketija, M and Perkins, M and Paul, G and Hallbeck, M and Ingelsson, M and Watts, JC and Reichenbach, N and Petzold, GC and Schieweck, R and Heneka, MT and Jackson, WS},
title = {Neuroinflammation and neurodegeneration trigger a specific splice form of ribosomal protein S24.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag166},
pmid = {42087813},
issn = {1460-2156},
abstract = {Neuroinflammation, particularly that involving reactive microglia, the brain's resident immune cells, is implicated in the pathogenesis of major neurodegenerative diseases (NDs). Multiple studies have reported changes in ribosomal protein (RP) expression during neurodegeneration, but the significance of these changes remains unclear. Ribosomes are evolutionarily conserved protein-synthesizing machines, and although commonly viewed as invariant, accumulating evidence suggests functional ribosome specialization through variation in their protein composition. Among RPs, S24, encoded by RPS24 in humans and Rps24 in mice, is unique as its transcripts undergo alternative splicing to produce protein variants with different C-terminal sequences that are differentially expressed across tissues and cell types. Understanding heterogeneous RP expression patterns across brain regions and cell types could reveal mechanisms underlying selective vulnerability in NDs and provide new biomarkers for neuroinflammatory responses. To identify RP expression patterns across brain regions in neurons, astrocytes, and microglia we analyzed cell type-specific translating mRNAs from mice. To investigate Rps24 isoform-specific expression, we performed cell type-resolved transcript analysis and developed antibodies specific for the S24-PKE protein variant encoded by mRNA isoform Rps24c. We examined Rps24c/S24-PKE expression in brains from mouse models of aging and neurodegeneration, as well as in human postmortem tissue from patients with Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This work revealed distinct RP expression patterns across brain regions and between neurons, astrocytes, and microglia, including neuron-enriched RPs Rpl13a and Rps10. Analysis of RP paralogs revealed complex expression relationships with their canonical counterparts, suggesting regulated mechanisms for generating heterogeneous ribosomes. Across brain regions and cell types, Rplp0 and Rpl13a, commonly used normalization references, showed heterogeneous expression, raising important methodological considerations for gene expression studies. Rps24 isoforms exhibited striking cell type-specific expression patterns. Rps24c was predominantly expressed in microglia and was increased by neuroinflammation caused by aging, neurodegeneration, or inflammatory chemicals. Using S24-PKE-specific antibodies, we verified increased expression of this protein variant in brains with AD, PD, and HD, and in relevant mouse models. These findings establish heterogeneous RP expression as a feature of brain cell types which may enable cell type-specific translation regulation via specialized ribosomes. This work also identifies Rps24c/S24-PKE as a potential novel marker for neuroinflammation and neurodegeneration and provides new tools for monitoring these responses.},
}

@article {pmid42087846,
year = {2026},
author = {Yang, Y and Wu, T and Fan, X and Yao, Y and Chen, C and Kang, K and Tang, X and Huang, T and Xu, Y and He, Y and Chen, Z and Chen, Z and Yang, H},
title = {Dynamic Covalent Peptide-Drug Conjugates Address the Heterogeneity in Alzheimer's Disease Progression.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e16343},
doi = {10.1002/adma.202516343},
pmid = {42087846},
issn = {1521-4095},
support = {22421002//National Natural Science Foundation of China/ ; 22334004//National Natural Science Foundation of China/ ; 22577014//National Natural Science Foundation of China/ ; 22404025//National Natural Science Foundation of China/ ; C2301011//Shenzhen Medical Academy of Research and Translation/ ; KJZD20230923114406014//Shenzhen Science and Technology Major Project/ ; //New Cornerstone Science Foundation/ ; },
abstract = {A growing understanding of the pathophysiological evolution of Alzheimer's disease (AD) underscores the heterogeneity in its progression as a critical factor undermining the success of various candidate interventions and complicating the establishment of effective pharmacotherapeutic regimens. Here, we introduce the development of a hierarchical-responsive therapeutic agent self-assembled from phenylboronate ester-linked Tjernberg's KLVFF peptide-curcumin conjugates (CPKNAs), which is designed to dynamically track the spatiotemporal coordinates of biomarkers associated with AD heterogeneity in progression. The dynamic covalent phenylboronate ester bond undergoes varying degrees of dissociation in response to the temporal evolution patterns of amyloid-β, reactive oxygen species, and glucose, three key indicators for staging AD progression, enabling self-adaptive regulation of drug distribution and dosing tailored to specific phenotypes. Employing seven cellular models and three types of transgenic mice simulating different AD stages, we demonstrate that CPKNAs effectively minimize the risks of under- or overtreatment, achieving consistent therapeutic outcomes in mitigating cellular damage and improving brain dysfunction.},
}