@article {pmid42343639,
year = {2026},
author = {Watzlawik, JO and Bustillos, BA and Rodriguez Martinez, C and Dickson, DW and Wszolek, ZK and Ross, OA and Springer, W and Fiesel, FC},
title = {Robust and sensitive ELISA detection of total and activated PRKN.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/15548627.2026.2694658},
pmid = {42343639},
issn = {1554-8635},
abstract = {Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; IBR: In-between-RING; iPSC: induced pluripotent stem cell; KO: knockout; LoB: limit of blank; LoD: limit of detection; LoQ: limit of quantification; MSD: Meso Scale Discovery; PD: Parkinson disease; p-S65-PRKN: serine 65 phosphorylated PRKN; p-S65-Ub: serine 65 phosphorylated ubiquitin; REP: repressor element of PRKN; RING: really interesting new gene; Ub: ubiquitin; UBL: ubiquitin-like domain; VCL: vinculin; WT: wild-type.},
}

@article {pmid42392247,
year = {2026},
author = {Kumar, R and Sinha, S and Babu, MA},
title = {Interactions-Guided Blueprint of Acetylcholinesterase Binding: A Review on Structural and Molecular Determinants.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112224},
doi = {10.1016/j.cbi.2026.112224},
pmid = {42392247},
issn = {1872-7786},
abstract = {Acetylcholinesterase (AChE) remains one of the most extensively studied enzymatic targets in neuropharmacology due to its central role in cholinergic neurotransmission and its relevance in symptomatic cognitive disorders, toxicology, and neuromodulation. AChE terminates cholinergic neurotransmission by hydrolysing acetylcholine, and its inhibition provides clinically established symptomatic relief in cholinergic dysfunction-associated pathological conditions. For any newly discovered ligand, the precise target binding mode often remains challenging, and unfortunately, the binding patterns of most reported compounds have not been experimentally resolved. However, with recent advances in structural biology, particularly biomolecular crystallographic structures deposited in the Protein Data Bank, have significantly enriched our understanding of the active site of AChE and its interactions with diverse chemical classes of ligands. To this end, this article presents a comprehensive systematic analysis of 202 AChE-ligand complexes (1993-2025) since the first breakthrough, categorizing ligands by their core scaffolds or functional groups, including decamethonium, huprine, galanthamine, quinoline, huperzine, tacrine, pyridinium, sulphonamide, and quaternary amine derivatives. Crucial interactions with core residues of the binding pocket, such as hydrogen bonding, cation-π, carbon-π, π-π stacking, and van der Waals forces, primarily associated with the stabilization of AChE-ligand complexes, are discussed involving organisms like Tetronarce californica, Homo sapiens, and Mus musculus, emphasizing their role in inhibitory potency. All ligands are further evaluated using Lipinski's Rule of Five filters to assess drug-likeness and identify optimization strategies for improved bioavailability and pharmacokinetics. By integrating structural insights with ligand features, this article provides a comprehensive framework for the rational design and optimization of next-generation AChE modulators across neurological and toxicological conditions.},
}

@article {pmid42392306,
year = {2026},
author = {Zhang, Y and Pu, J and Shen, Z and Ye, Z and Liu, J and Zhang, D and Deng, K and Yao, Y},
title = {Global Trends and Evolving Frontiers in Intranasal Delivery for CNS Diseases (2000-2025): A Bibliometric Analysis and Systematic Review.},
journal = {World neurosurgery},
volume = {},
number = {},
pages = {125172},
doi = {10.1016/j.wneu.2026.125172},
pmid = {42392306},
issn = {1878-8769},
abstract = {BACKGROUND: Intranasal administration (nose-to-brain delivery) has emerged as a pivotal non-invasive strategy to bypass the blood-brain barrier (BBB) for treating central nervous system (CNS) disorders. However, the exponential growth of literature in this domain presents challenges in grasping the holistic research trajectory and identifying emerging hotspots.

METHODS: This study conducted a comprehensive bibliometric analysis of 4,009 publications retrieved from the Web of Science Core Collection (WoSCC) spanning from 2000 to 2025. Tools including VOSviewer, CiteSpace, and R-bibliometrix were employed to map spatiotemporal trends, collaborative networks, and keyword evolution.

RESULTS: The analysis reveals a robust upward trend in global research output, predominantly driven by China and the United States. Keyword clustering identified five major research sub-domains: Alzheimer's disease, Oxytocin (behavioral/psychiatric applications), Stroke and Neuroinflammation, Brain Tumors, and Nanoparticles. Burst detection analysis elucidates a distinct paradigm shift in scientific focus: early investigations prioritized mucosal absorption mechanisms and tolerance; the focus subsequently transitioned to specific therapeutic agents (e.g., insulin, oxytocin); and most recently, the field has been dominated by the optimization of delivery vectors, specifically lipid-based nanoparticles and exosomes.

CONCLUSION: While nanotechnology has become the current technological frontier for enhancing brain targeting, a critical gap remains between promising preclinical results and clinical translation. Future research must prioritize the development of biomimetic delivery systems and highly predictive translational models to bridge the divide between bench and bedside. This review provides a strategic roadmap for researchers to navigate current trends and address the barriers hindering clinical application.},
}

@article {pmid42392339,
year = {2026},
author = {Salman, Y and Denning, AE and Schaeverbeke, JM and Tomé, SO and Joudiou, N and Khandelwal, P and Yushkevich, PA and Vandenberghe, R and Gallez, B and Wisse, LE and Hanseeuw, BJ},
title = {Volumetric postmortem MRI of the medial temporal lobe in Alzheimer's disease and related disorders: methodological advances and implications for in vivo biomarker development.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122098},
doi = {10.1016/j.neuroimage.2026.122098},
pmid = {42392339},
issn = {1095-9572},
abstract = {Magnetic resonance imaging (MRI) is central to the study and diagnosis of neurodegenerative diseases. Yet, no MRI biomarker is currently specific to a given neurodegenerative disease. This may result from the limited resolution of conventional MRI, which restricts detailed investigation of medial temporal lobe (MTL) subregions, a crucial hub for many neuropathologies. Moreover, in vivo MRI cannot be directly compared with neuropathological data, the gold standard for disease definition. Even when antemortem MRI and postmortem analyses are combined, the time gap between imaging and neuropathological examination allows pathogenic processes to progress, reducing the accuracy of these correlations. Over the past two decades, postmortem MRI has gained increasing interest because it enables long, motion-free acquisitions and the use of specialized coils and preclinical scanners, providing ultra-high spatial resolution. Additionally, it allows direct correspondence between imaging and neuropathological measures. Consequently, volumetric postmortem MRI, particularly investigations of the MTL, has become an increasingly common approach in Alzheimer's disease and related disorders (ADRD). This narrative review specifically focuses on volumetric postmortem MRI of the MTL and summarizes the main methodologies for anatomical postmortem MTL imaging in ADRD and recent advances in the characterization of neurodegenerative changes, from brain preparation to MRI acquisition. It also highlights the translational potential of volumetric postmortem MRI for developing in vivo biomarkers, optimizing imaging protocols and segmentation methods, and assessing the impact of proteinopathies. Finally, it outlines current limitations, technical challenges, and perspectives for future research.},
}

@article {pmid42392383,
year = {2026},
author = {Dhar, I and Gupta, S and Mishra, R and Dadhich, A},
title = {Gingipains as macromolecular mediators at the periodontal-brain interface: Mechanistic, diagnostic, and therapeutic evidence in Alzheimer's and Parkinson's diseases.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153320},
doi = {10.1016/j.ijbiomac.2026.153320},
pmid = {42392383},
issn = {1879-0003},
abstract = {Chronic periodontitis, driven by Porphyromonas gingivalis, has emerged as a modifiable risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD) the two most prevalent and socioeconomically burdensome neurodegenerative disorders through systemic dissemination of its signature cysteine proteases, gingipains (RgpA, RgpB, Kgp). This narrative critical review is explicitly scoped to AD and PD, the only neurodegenerative conditions for which postmortem detection of gingipains in affected brain regions, mechanistic evidence from cellular and animal models, and clinical epidemiological data currently exist in sufficient depth to support an integrated synthesis. Robust meta-analyses confirm that periodontitis is associated with elevated AD/PD risk (OR/HR 1.2-3.5), while gingipains have been detected in a high proportion (>85-90%) of postmortem AD/PD brains, correlating with tau/α-synuclein pathology, neuroinflammation, and neuronal loss. Mechanistic studies in cellular and animal models demonstrate that gingipains can disrupt blood-brain barrier integrity via tight-junction cleavage, trigger NF-κB/NLRP3-driven glial activation, catalyse amyloid-β/α-synuclein seeding, induce tau truncation/hyperphosphorylation, and precipitate mitochondrial oxidative damage, thereby generating self-amplifying neurotoxic cascades. Salivary gingipain activity offers a non-invasive, high-sensitivity biomarker candidate for early risk stratification that may outperform conventional fluid markers in prodromal cohorts. Therapeutically, small-molecule gingipain inhibitors have shown neuroprotective effects in preclinical models (e.g., atuzaginstat/COR388 failed primary endpoints in the Phase 2/3 GAIN trial but demonstrated subgroup benefits in P. gingivalis-positive participants; the next-generation inhibitor LHP588 is advancing in the Phase 2 SPRING trial). Emerging approaches including nanotechnology, CRISPR-based virulence gene disruption, and targeted delivery platforms aim to improve brain exposure and specificity. This review provides an integrated, isoform-resolved framework linking gingipain structure-function to neurodegeneration. While associative and mechanistic evidence is compelling, definitive causation in humans and disease-modifying efficacy require further validation through biomarker-guided clinical trials. Precision inhibition of gingipains represents a promising upstream strategy for addressing a potentially modifiable microbial contributor at the oral-brain interface.},
}

@article {pmid42392515,
year = {2026},
author = {Pandey, JK and Verma, SK and Kumar, J and Perwej, Y and Jha, DSK and Panchal, BY and Ferdouse, R and V, S and Banerjee, S and Tiwari, M and Badal, R and Mandal, P and Baghel, JS},
title = {Transformative Role of Advanced Neural Computation in Clinical Image Diagnostics: A Review of Key Concepts and Applications.},
journal = {Seminars in ultrasound, CT, and MR},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.sult.2026.06.010},
pmid = {42392515},
issn = {1558-5034},
abstract = {Medical imaging plays a crucial role in modern diagnostic practices, but traditional techniques often face limitations in accuracy, efficiency, and scalability. The emergence of deep learning (DL) has led to significant improvements that are transforming this field. This review discusses how DL algorithms are enhancing diagnostic imaging by improving accuracy, enabling automated analysis, and supporting personalized treatment plans. It focuses on key deep learning (DL) frameworks, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). The review examines their applications in important medical imaging tasks such as image classification, segmentation, reconstruction, and disease prediction. It also considers how DL techniques are integrated with tools like radiomics, data augmentation strategies, and predictive analytics models. DL methods have shown superior performance in detecting and classifying diseases like pneumonia, tuberculosis, and Alzheimer's. They also improve the quality and speed of imaging modalities such as MRI, CT, and ultrasound. Despite these advances, challenges remain in data availability, model interpretability, clinical validation, and ethical issues related to bias and privacy. Addressing these challenges is essential for the successful clinical use of DL in medical imaging. This review ends with suggestions for future directions and best practices for ethically and practically integrating DL technologies into routine healthcare.},
}

@article {pmid42392701,
year = {2026},
author = {Li, JY and Wang, XX and Wan, SF and Feng, TT and Guo, AJ and Liu, JY and Feng, K},
title = {[Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2143-2152},
doi = {10.19540/j.cnki.cjcmm.20260113.701},
pmid = {42392701},
issn = {1001-5302},
mesh = {Humans ; PTEN-Induced Putative Kinase ; *Protein Kinases/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Mitophagy/drug effects ; Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mitochondria/metabolism/drug effects ; },
abstract = {Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.},
}

Humans
PTEN-Induced Putative Kinase
*Protein Kinases/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology
*Ubiquitin-Protein Ligases/metabolism/genetics
*Mitophagy/drug effects
Animals
*Drugs, Chinese Herbal/administration & dosage
Mitochondria/metabolism/drug effects

@article {pmid42392719,
year = {2026},
author = {Yuan, CB and Ju, YT and Liu, YM and Wang, BS and Zhang, L and Yu, CY and Yang, YL and Chen, WY and Leng, YJ and Cheng, MJ and Min, DY},
title = {[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2323-2334},
doi = {10.19540/j.cnki.cjcmm.20251210.801},
pmid = {42392719},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism ; Male ; *Quercetin/administration & dosage ; Signal Transduction/drug effects ; Mice ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; *Cyclic AMP/metabolism/genetics/immunology ; *Cyclic AMP-Dependent Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy/genetics ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/drug effects ; },
abstract = {This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism
Male
*Quercetin/administration & dosage
Signal Transduction/drug effects
Mice
*Cyclic AMP Response Element-Binding Protein/genetics/metabolism
Humans
*Cyclic AMP/metabolism/genetics/immunology
*Cyclic AMP-Dependent Protein Kinases/genetics/metabolism
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy/genetics
Mice, Transgenic
Disease Models, Animal
Hippocampus/drug effects

@article {pmid42392731,
year = {2026},
author = {Lyu, SY and Wang, XZ and Chen, XY and Guo, R},
title = {[Exploring mechanism of "treating different diseases with the same method" for depression and Alzheimer's disease based on "liver-spleen-kidney" axis and advances in traditional Chinese medicine intervention].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2726-2738},
doi = {10.19540/j.cnki.cjcmm.20260108.302},
pmid = {42392731},
issn = {1001-5302},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Drugs, Chinese Herbal/administration & dosage/therapeutic use ; *Spleen/drug effects/physiopathology ; *Kidney/drug effects/physiopathology ; *Liver/drug effects/physiopathology ; Animals ; *Medicine, Chinese Traditional ; *Depression/drug therapy/physiopathology ; },
abstract = {Depression(major depressive disorder, MDD) and Alzheimer's disease(AD) are two highly prevalent neuropsychiatric disorders. With the aging population, their comorbidity rate continues to rise. The pathogenesis of MDD and AD is complex, and modern medicine still lacks strategies that can simultaneously intervene in the core processes of both diseases. The theory of "treating different diseases with the same method" in traditional Chinese medicine(TCM) is an important therapeutic principle, which means that different diseases showing identical syndromes during their development can be treated with the same approach. This provides a TCM perspective for the diagnosis and treatment of their comorbidity. Based on the theory of the "liver-spleen-kidney" axis, this study identified that MDD and AD shared common pathogenesis: liver dysfunction in free coursing, spleen dysfunction in transportation, and kidney essence deficiency. It further connected this pathogenesis with the dysregulation of the neuroendocrine-immune(NEI) network in modern medicine, revealing common pathological mechanisms in neuroinflammation, dysfunction of the "hypothalamic-pituitary-adrenal"(HPA) axis, and gut microbiota dysbiosis. Meanwhile, it also reviewed specific mechanisms of TCM herbs such as Bupleuri Radix(Chaihu), Paeoniae Radix Alba(Baishao), and Astragali Radix(Huangqi), as well as their active components, in treating MDD and AD by regulating the NEI network through multiple targets and pathways. This may provide evidence for the application of the "treating different diseases with the same method" theory and broaden the perspective for the treatment of MDD and AD.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
*Drugs, Chinese Herbal/administration & dosage/therapeutic use
*Spleen/drug effects/physiopathology
*Kidney/drug effects/physiopathology
*Liver/drug effects/physiopathology
Animals
*Medicine, Chinese Traditional
*Depression/drug therapy/physiopathology

@article {pmid42392749,
year = {2026},
author = {Liu, MY and Zhong, XQ and Zhang, H and Huang, MT and Liang, YS and Ren, YK and Huang, LP and Deng, MZ},
title = {[Mechanism of Ding-Zhi-Xiao-Wan on sphingolipid metabolism disorders in Alzheimer's disease based on network pharmacology, molecular docking, and animal experiments].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2906-2917},
doi = {10.19540/j.cnki.cjcmm.20260104.801},
pmid = {42392749},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Mice ; *Sphingolipids/metabolism ; Network Pharmacology ; Molecular Docking Simulation ; Humans ; *Drugs, Chinese Herbal/administration & dosage/chemistry ; Male ; Disease Models, Animal ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; },
abstract = {Exploring the mechanism of Ding-Zhi-Xiao-Wan(DZXW) on disorders of sphingolipid metabolism in Alzheimer's disease(AD) through network pharmacology, molecular docking and animal experiments. The chemical constituents of DZXW were obtained via the TCMSP, with target prediction conducted using the SwissTargetPrediction database; the GeneCards database was consulted to identify targets associated with AD and sphingolipid metabolism disorders. The intersecting targets from these three databases underwent GO and KEGG enrichment analyses. Cytoscape was employed to construct networks and screen core components and targets for molecular docking validation. Animal experiments employed AD model mice, utilising the water maze, ELISA, qPCR, LC-MS, and Western blot to evaluate the effects of DZXW on behavioural, oxidative stress, inflammatory, apoptotic, and sphingolipid metabolism-related indicators. Network pharmacology identified 51 common targets, with enrichment analysis indicating their involvement in multiple pathways including signal transduction, apoptosis, and the phosphatidylinositol 3kinase/protein kinase B(PI3K/Akt) pathway. Molecular docking revealed that multiple components within DZXW(such as cerevisterol and isorhamnetin) interacted with targets including caspase 3(CASP3), mitogen-activated protein kinase 14(MAPK14), estrogen receptor 1(ESR1), and silent information regulator factor 2 related enzyme 1(SIRT1), with SIRT1 being particularly crucial. Animal studies indicate that DZXW enhances learning and memory capacity in AD mice, reduces ceramide levels, and inhibits oxidation factors [4-hydroxynonenal(4-HNE), 8-hydroxy-2'-deoxyguanosine(8-OHdG), nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)] and inflammatory factors [tumour necrosis factor-α(TNF-α), interleukin(IL)-1β], downregulates CASP3, MAPK14, sphingomyelin phosphodiesterase 1-3(SMPD1-3), B cell chronic lymphocytic leukaemia/lymphoma-2(Bcl-2)-associated X protein(Bax), and increases IL-10, ESR1, mammalian target of rapamycin(mTOR), SIRT1, PI3K phosphorylation, Akt phosphorylation, and Bcl-2. In conclusion, DZXW may improve sphingolipid metabolism disorders in AD by inhibiting neuronal apoptosis and mitigating oxidative and inflammatory responses through the SIRT1/PI3K/Akt pathway.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/genetics
Mice
*Sphingolipids/metabolism
Network Pharmacology
Molecular Docking Simulation
Humans
*Drugs, Chinese Herbal/administration & dosage/chemistry
Male
Disease Models, Animal
Signal Transduction/drug effects
Oxidative Stress/drug effects
Apoptosis/drug effects

@article {pmid42392863,
year = {2026},
author = {Jiménez-Huete, A and Rognoni, T and Montoya, G and Borda, MG and Riverol, M and , },
title = {Diagnostic accuracy of a two-cut-off approach using the FAQ/MMSE ratio and FAQ for clinical preselection of patients for anti-amyloid therapy.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-338997},
pmid = {42392863},
issn = {1468-330X},
abstract = {BACKGROUND: Anti-amyloid therapies for Alzheimer's disease (AD) require efficient patient selection. The Clinical Dementia Rating (CDR) scale is the reference standard for staging, but it is time-consuming to administer. Simple tools to distinguish early-stage cognitive impairment (CDR 0.5-1) from more advanced stages (CDR 2-3) would therefore be of substantial clinical value.

METHODS: Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts 1-3 with CDR ≥0.5 were analysed. Three logistic regression models using Mini-Mental State Examination (MMSE), Functional Assessment Questionnaire (FAQ) or the FAQ/MMSE ratio as predictors were developed. Two cut-offs per model were selected to ensure minimum sensitivity and specificity of 0.99, defining rule-out, rule-in and intermediate (uncertain) zones. Performance was assessed using discrimination, calibration and decision curve analysis.

RESULTS: Among 1533 ADNI participants with CDR ≥0.5, two-thirds (n=1022) were assigned to the training set and one-third (n=511) to the test set. FAQ/MMSE and FAQ showed excellent discrimination (area under the curve, AUC 0.97-0.98), outperforming MMSE (AUC 0.94-0.95). FAQ/MMSE demonstrated the best overall performance, although differences compared with FAQ were small and not statistically significant. Dual cut-offs for FAQ/MMSE (0.67 and 1.44) and FAQ (12 and 27) enabled clinically meaningful stratification, with 80% and 70% of participants classified into high-confidence zones, respectively. Results were consistent across the training and test sets.

CONCLUSIONS: The FAQ/MMSE ratio and FAQ score show high accuracy in distinguishing early-stage (CDR 0.5-1) from more advanced cognitive impairment (CDR 2-3). These simple measures may support the clinical preselection of patients for further evaluation in the context of anti-amyloid therapy.},
}

@article {pmid42392958,
year = {2026},
author = {Zhao, H and King, KY and Wong, ST},
title = {Clonal hematopoiesis in Alzheimer's brain: Protective, pathogenic, and context-dependent?.},
journal = {Trends in molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molmed.2026.06.009},
pmid = {42392958},
issn = {1471-499X},
abstract = {Clonal hematopoiesis is emerging as a surprising modifier of Alzheimer's disease. Recent findings suggest that mutant myeloid cells may enter or expand within the brain, adopting either inflammatory or reparative states. We propose that their effects depend on the mutation, timing, clone size, brain niche, and disease stage.},
}

@article {pmid42392996,
year = {2026},
author = {Zhang, Y and Zhu, F and Wu, X and Li, Z and Huang, P and Gao, Y and Zeng, L},
title = {[Epigenetic regulator DOT1L controls neuronal amyloid pre-cursor protein expression via the p38 mediated mitochondrial fission-fusion homeostasis axis].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-13},
doi = {10.3724/zdxbyxb-2025-0706},
pmid = {42392996},
issn = {1008-9292},
abstract = {OBJECTIVES: To investigate the regulatory role of epigenetic regulator disruptor of telomeric silencing 1-like (DOT1L) and its mediated histone H3 lysine 79 (H3K79) methylation in modulating neuronal amyloid precursor protein (APP) expression, and to elucidate the underlying mechanisms involving mitochondrial homeostasis and the upstream p38 kinase.

METHODS: Alzheimer's disease (AD) models were established using APP/presenilin-1 (APP/PS1) double-transgenic mice and N2a cells overexpressing the human Swedish mutant APP (N2a-APPswe). Immunofluorescence staining was employed to assess DOT1L expression and localization in mouse brain tissues. N2a-APPswe cells were treated with the DOT1L-specific inhibitor EPZ5676 and divided into four groups: blank control, solvent control, DOT1L inhibitor, and DOT1L inhibitor plus p38 agonist (Gynostemma pentaphyllum extract). Western blotting was performed to measure the phosphorylation levels of DRP1 at Ser616 and Ser637 (key mitochondrial fission regulators), the levels of autophagy-related proteins p62 and the LC3-Ⅱ/LC3-Ⅰ ratio, the phosphorylation level of p38, as well as the expression of APP and APP-processing proteins BACE1 and PS1. Real-time quantitative polymerase chain reaction was used to detect mRNA levels of APP and genes involved in mitochondrial fission and fusion. Proteomics data were systematically analyzed through Gene Ontology analysis, WikiPathways enrichment analysis, and STRING protein-protein interaction network analysis to identify key signaling pathways. Mitochondrial morphology was evaluated by Mito-Tracker fluore-scence staining to measure average branch length.

RESULTS: DOT1L expression was signifi-cantly reduced in neurons of APP/PS1 mice compared to wild-type controls. DOT1L inhibition led to decreased H3K79me2 levels (P<0.01), accompanied by a marked increase in APP protein expression (P<0.01), although APP mRNA levels were reduced (P<0.01). Proteomics analysis revealed that differentially expressed proteins were highly enriched in the mitochondrial electron transport chain. Compared with the solvent control, the DOT1L inhibitor group showed inhibited mitochondrial fission, as evidenced by decreased p-DRP1 (Ser616), increased p-DRP1 (Ser637), downregulated MIEF1 mRNA, upregulated MFN1 mRNA (all P<0.05), and increased average mitochondrial branch length (P<0.05), along with reduced p-p38 levels (P<0.05). Co-administration of the p38 agonist significantly reversed these mitochondrial dynamics abnormalities (all P<0.05) and attenuated the abnormally elevated protein levels of APP, BACE1, and PS1 (P<0.05) compared to the DOT1L inhibitor group.

CONCLUSIONS: DOT1L maintains normal mito-chondrial fission and functional homeostasis through regulation of the p38 signaling pathway, thereby modulating APP expression.},
}

@article {pmid42393071,
year = {2026},
author = {Feng, LR},
title = {The cancer Alzheimer's disease paradox.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42393071},
issn = {2731-6068},
}

@article {pmid42393277,
year = {2026},
author = {Weinberg, MS and Kodali, MC and Li, Z and Galler, JA and Tidball, AR and Reynolds, WC and Young, C and Devitte-McKee, K and Fatima, HA and Kivisäkk, P and Chatterjee, M and Kulkarni, A and Billingsly, JM and Bartlett, AL and Sui, SH and Kühtreiber, WM and Gerber, J and McManus, AJ and Tanzi, RE and Das, S and Faustman, DL and Arnold, SE},
title = {Bacillus Calmette-Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer's biomarkers: results from two open-label clinical trials.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42393277},
issn = {2730-664X},
support = {T32-MH112485//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; UL3AG067696//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG062421//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; UL1TR002541//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; UM1TR004408//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; AACSF-22-970716/ALZ/Alzheimer's Association/United States ; PTC REG-20-653582/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We assessed whether BCG induces trained immunity-like responses in adults with and without Alzheimer's-related changes.

METHODS: We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart. Protocol-defined objectives included safety, neurocognitive outcomes, and longitudinal immune and Alzheimer's biomarker changes in blood and cerebrospinal fluid. Immune responses were assessed using cytokine assays and single-cell profiling. All enrolled participants were included where data were available; longitudinal changes were analyzed using mixed-effects models.

RESULTS: Here we show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed.

CONCLUSIONS: These findings suggest trained immunity-like responses in the central nervous system that may influence Alzheimer's-relevant pathways. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04507126 (June 23, 2020) and NCT05004688 (August 6, 2021).},
}

@article {pmid42393306,
year = {2026},
author = {Benussi, A and Bozzali, M},
title = {Mixing apples and antibodies: when the Cochrane average obscures the evidence in Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {7},
pages = {},
pmid = {42393306},
issn = {1590-3478},
}

@article {pmid42393367,
year = {2026},
author = {Vostrý, M and Binter, J and Kovářová, K and Posel, Z and Kubová, N and Cmorej, PC and Kroufek, R},
title = {Feasibility and preliminary effects of outdoor versus indoor cognitive-motor therapy in women with Alzheimer's disease: A randomized single-blind pilot study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-60446-5},
pmid = {42393367},
issn = {2045-2322},
support = {CZ.02.01.01/00/23_021/0010653//Programme Johannes Amos Comenius/ ; },
abstract = {Alzheimer's disease is associated with progressive cognitive, functional and social decline. Non-pharmacological interventions that combine cognitive and motor stimulation are increasingly used in long-term care, but less is known about the feasibility and preliminary effects of delivering such programmes in outdoor rather than indoor settings. This exploratory randomized single-blind pilot study compared outdoor and indoor cognitive-motor therapy in institutionalized older women with Alzheimer's disease, focusing on global cognitive performance, selected functional outcomes, attendance and practical implementation. Fifty women aged 66.1-70.2 years with late-onset Alzheimer's disease were randomized to a seven-month outdoor cognitive-motor programme (n = 25) or an indoor cognitive-motor programme (n = 25). Sessions were delivered five times weekly for 45 min. Outcome assessors and data analysts were blinded to group allocation; therapists and participants could not be blinded because of the intervention setting. Global cognition was assessed with the Mini-Mental State Examination (MMSE). Functional outcomes were assessed using modified FIM-based indicators for daily tasks, mobility and social adaptability. Attendance and adverse events were recorded as feasibility outcomes. All randomized participants completed the study. Mean attendance was 91% in the outdoor group and 89% in the indoor group, and no intervention-related adverse events were recorded. Both groups improved on the MMSE, with a median increase of approximately two points. The outdoor group showed statistically significant within-group improvements in all three FIM-based indicators (daily tasks, mobility and social adaptability), whereas the indoor group did not show statistically significant functional change. However, these broader gains were observed in the context of baseline functional imbalance, including lower outdoor-group mobility and social-adaptability scores, and the small female-only sample and partial non-equivalence of intervention content limit between-group causal interpretation. A seven-month cognitive-motor programme was feasible in participating long-term care facilities. The findings suggest that outdoor delivery may be associated with broader functional gains than indoor delivery, but the results should be interpreted as preliminary and in light of the baseline functional imbalance. A fully powered, prospectively registered trial with more equivalent intervention arms, repeated measurement points, standardized functional outcomes and detailed monitoring of comorbidities and medication changes is warranted.},
}

@article {pmid42393497,
year = {2026},
author = {Ramesh, A and Reddy, R and Patel, AB},
title = {Quantitative Assessment of Neurometabolism by Deuterium and Proton NMR Spectroscopy Using [6,6'-[2]H2]Glucose.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00030},
pmid = {42393497},
issn = {1948-7193},
abstract = {Neurometabolic analysis is routinely performed using [13]C NMR/MRS in conjunction with the administration of [13]C-labeled tracers. Despite its widespread use, the low sensitivity of [13]C NMR necessitates long acquisition times. To address this limitation, the present study introduces an indirect approach that uses a single [1]H NMR acquisition to measure deuterium labeling by exploiting labeling at specific sites, thereby providing a novel and more efficient strategy for assessing neurometabolism. In this study, male SD rats were infused with [6,6'-[2]H2]glucose for 10-90 min, and the [2]H labeling of cortical metabolites was measured ex vivo using [2]H NMR spectroscopy. After 90 min of [6,6'-[2]H2]glucose infusion, resonances corresponding to [3-[2]H2]lactate, [4-[2]Hx]glutamate, [4-[2]Hx]glutamine, and [3-[2]H]aspartate (∼2.60 ppm) were detected. In contrast, signals corresponding to [2-[2]H]aspartate (∼3.90 ppm), [2-[2]H]glutamate (∼3.76 ppm), and [3-[2]H]glutamate (∼2.09 ppm) were not detected, even after prolonged infusion, suggesting complete loss of the [2]H label during the second turn of the tricarboxylic acid cycle. The cerebral metabolic rate of glucose oxidation, estimated by fitting an exponentially saturating curve to the pooled labeling of [4-[2]Hx]glutamate, [4-[2]Hx]glutamine, and [3-[2]H]aspartate, was 0.389 ± 0.031 μmol/g/min. The [4-[2]Hx]glutamate levels were also derived by subtracting the [4-[1]H2]glutamate resonance intensity from total [4-[1]H2]glutamate intensity estimated using the [3-[1]H2]glutamate intensity in unedited [1]H NMR spectra. The concentrations of [4-[2]Hx]glutamate determined from [1]H NMR spectra were comparable to those determined from [2]H NMR. Moreover, when applied to 5xFAD mice (2.53 ± 0.43 μmol/g, n = 7), a model of Alzheimer's disease, this indirect approach revealed significantly reduced (p = 0.028) [4-[2]Hx]glutamate levels compared with controls (2.99 ± 0.15 μmol/g, n = 7). This decrease was comparable to that observed with the direct [2]H NMR measurements and was consistent with findings from [13]C tracer-based studies.},
}

@article {pmid42393517,
year = {2026},
author = {Wen, Y and Dong, H},
title = {Generalizable Protein Folding Pathway Exploration with DA2-GRASP: Extending Beyond Miniproteins.},
journal = {Journal of chemical theory and computation},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jctc.6c00480},
pmid = {42393517},
issn = {1549-9626},
abstract = {Elucidating protein dynamics is crucial for deciphering fundamental biological processes, from enzyme catalysis to cellular signaling, as its dysregulation directly causes protein misfolding diseases such as Alzheimer's and Parkinson's. While artificial intelligence has revolutionized static protein structure prediction, capturing the high-dimensional dynamics of protein folding remains a formidable challenge that limits our ability to fully understand these vital biological phenomena. Here we present DA2-GRASP, a computational framework that overcomes this barrier by integrating deep learning with advanced sampling techniques to map protein folding pathways with unprecedented efficiency and accuracy. DA2-GRASP learns low-dimensional latent representations of protein conformations via a variational autoencoder and combines multidirectional generative sampling guided by local potential energy gradients to efficiently steer conformational transitions along energetically favorable paths, enabling accurate and efficient reconstruction of folding pathways. Our method achieves sublinear computational scaling with sequence length, contrasting the quadratical scaling of molecular dynamics-based conventional approaches, enabling tractable simulations. It maintains high precision in quantifying mutation-induced perturbations to folding thermodynamics, crucial for understanding disease mutations. It also enables atomistic characterization of the folding process of medium-sized proteins such as ubiquitin and small ubiquitin-like modifier (SUMO, ∼80 residues) on standard workstations, a task typically requiring specialized supercomputing platforms such as Anton. Analysis of these proteins provides new mechanistic insights into how structurally similar folds with low sequence identity navigate divergent folding pathways. DA2-GRASP thus establishes a versatile and powerful framework for exploring protein-folding dynamics and their functional consequences.},
}

@article {pmid42393750,
year = {2026},
author = {Zhang, J and Yang, N and Zou, P and Zong, X},
title = {Microglial checkpoint collapse in Alzheimer's disease: a tri-axial framework for biomarker-informed neuroimmune therapy.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03924-x},
pmid = {42393750},
issn = {1742-2094},
support = {24CDA1269588//American Heart Association/ ; },
abstract = {BACKGROUND: Anti-amyloid antibodies have validated amyloid-β (Aβ) as a disease-relevant target in Alzheimer's disease (AD), but their modest clinical effect, efficacy largely restricted to early disease, and amyloid-related imaging abnormalities (ARIA) indicate that Aβ removal alone does not resolve the glial, lipid, and inflammatory programmes that sustain neurodegeneration. Microglia sit at the centre of this therapeutic gap. Single-nucleus and spatial profiling has resolved several AD-associated microglial states, yet state labels remain descriptive and do not explain why adaptive engagement becomes maladaptive.

MAIN BODY: We frame AD-relevant microglial dysfunction as checkpoint collapse: progressive failure of regulatory nodes that coordinate lipid sensing, lysosomal competence, neuronal restraint, and inflammatory threshold control. The central nodes are TREM2-mediated lipid and apolipoprotein sensing, progranulin-associated lysosomal regulation, CX3CR1-dependent neuron-microglia restraint, and CD33/Siglec-3 inhibitory tone. When these controls destabilise, downstream pathology can be organised around three coupled effector axes: a lipid axis centred on APOE-biased cholesterol trafficking, ACSL1/DGAT2-driven lipid-droplet accumulation, and impaired lysosomal flux; an iron/ferroptosis axis involving labile iron, phospholipid peroxidation, and insufficient GPX4/FSP1 defences; and an inflammation/complement axis linking NLRP3 activation, type-I interferon signalling, and C1q/C3-dependent synaptic engulfment to tau pathology and synapse loss. White-matter injury, astrocyte-microglia crosstalk, and cGAS-STING-linked senescence are integrated as cross-axis amplifiers.

CONCLUSIONS: This framework is proposed as a hypothesis-generating scaffold for biomarker-informed translational studies, rather than as a validated clinical stratification system. It may help organise stage-aware therapeutic hypotheses, including regulatory-node preservation in early disease, lipid-handling restoration and ferroptosis control at intermediate stages, and complement- or senescence-directed modulation in later disease. Current glial, iron, inflammatory, and imaging biomarkers remain insufficiently specific to assign individual patients reliably to discrete pathological axes in clinical practice.},
}

@article {pmid42393875,
year = {2026},
author = {Behera, A and Chandrasekaran, Y and Dhonthi Shekar, N and Saravanan, S and Manickam Dakshinamoorthi, B and Srinivasan, GP and Dharmalingam Jothinathan, MK},
title = {Genetic Approaches in Zebrafish Neurology: Genetic, Drug and Therapy Insights.},
journal = {Current drug research reviews},
volume = {},
number = {},
pages = {},
doi = {10.2174/0125899775470368260619041554},
pmid = {42393875},
issn = {2589-9783},
abstract = {Zebrafish (Danio rerio) has emerged as a valuable vertebrate model organism widely used in biological and biomedical research due to its rapid embryonic development, optical transparency, high fecundity, and genetic similarity to humans. These characteristics have made zebrafish an important experimental model in developmental biology, toxicology, cancer research, and particularly in the investigation of neurodegenerative diseases. A significant proportion of human genes have functional counterparts in zebrafish, allowing researchers to explore disease mechanisms and genetic pathways relevant to human neurological disorders. Advances in genetic technologies, including CRISPR-Cas9 genome editing, transgenic approaches, and mutagenesis screening, have further strengthened the use of zebrafish in neuroscience research. These tools enable precise manipulation of genes involved in neuronal development, degeneration, and disease progression. Zebrafish models have been successfully employed to study major neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition, the model provides an efficient platform for drug screening, neurotoxicity studies, and therapeutic evaluation. This review highlights the role of zebrafish in genetic approaches to neurological research, emphasizing its contributions to disease modeling, drug discovery, and the development of potential therapeutic strategies for complex neurodegenerative disorders.},
}

@article {pmid42393905,
year = {2026},
author = {Zelek, MC and Walker Ii, JQ and Crocker-Sabbagh, I},
title = {Real-World Cognitive Stabilization via CDSS-Guided Multidomain Interventions in MCI and Older Adults with Cognitive Concerns.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098476197260627055743},
pmid = {42393905},
issn = {1874-6128},
abstract = {INTRODUCTION: Randomized multidomain trials have established that cognitive decline requires coordinated action across modifiable contributors, but routine care lacks delivery infrastructure. We evaluated real-world cognitive trajectories in older adults receiving uMETHOD Health clinical decision support system (CDSS)-guided care plans and assessed whether this multidomain approach could be operationalized in routine care.

METHODS: This retrospective, nonrandomized implementation-and-outcomes study analyzed the complete eligible paired cohort: individuals with CDSS-guided care plans and two valid sameinstrument cognitive assessments ≥6 months apart. No additional selection was made by outcome, adherence, or trajectory. The CDSS integrates EHR-derived diagnoses, medications, biomarkers, vital signs, genomics, and lifestyle factors through expert clinical rules with constrained AI support to generate individualized clinician-, patient-, and caregiver-facing plans.

RESULTS: Favorable cognitive trajectories were observed in 294 of 345 matched assessment pairs (85.2%) over a mean follow-up of 14.1 months. Assessments used seven validated instruments; mean age was 74.6 years, and baseline medication use was 11.7 medications/patient. Favorable trajectories included 83.5% stable, improved, or minor decline without diagnostic progression and 1.7% slower-than-expected decline on benchmarked instruments (MoCA, MMSE, or SAGE).

DISCUSSION: The CDSS served as an implementation layer, translating multidomain evidence into prioritized, patient-specific next-best actions within ordinary clinical workflows. This positions multidomain cognitive management as a scalable, routine-care activity rather than a researchonly protocol.

CONCLUSION: Multidomain cognitive management was made executable in routine practice, with favorable trajectories observed in 85.2% of paired assessments. The practical implication is immediate: evidence-based cognitive management can be operationalized now at the point of care.},
}

@article {pmid42394082,
year = {2026},
author = {Khan, A and Kabir, H},
title = {Evaluating the User Experience and Therapeutic Efficacy of Humanoid Socially Assistive Robots in Alzheimer's Disease and Related Dementias (ADRD) Care.},
journal = {Studies in health technology and informatics},
volume = {338},
number = {},
pages = {626-630},
doi = {10.3233/SHTI260920},
pmid = {42394082},
issn = {1879-8365},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; *Robotics ; Male ; *Self-Help Devices ; Aged ; *Dementia/therapy/psychology ; Aged, 80 and over ; Intelligent Systems ; Treatment Outcome ; },
abstract = {BACKGROUND: Addressing neuropsychiatric symptoms in Alzheimer's Disease and Related Dementias (ADRD) requires scalable, non-pharmacological interventions. This study evaluated the user experience and clinical efficacy of a humanoid Socially Assistive Robot (SAR) in an ADRD care setting.

METHODS: A randomized, 8-week, baseline-controlled intervention was conducted (N=19), utilizing each participant's pre-intervention status as the control. Outcomes included acute mood change, sustained depressive symptoms via the Geriatric Depression Scale (GDS), and user acceptance via the User Experience Questionnaire (UEQ).

RESULTS: The SAR achieved "Excellent" UEQ ratings (x > 2.0) across all dimensions, indicating high accessibility and engagement. Analysis revealed a significant acute positive mood boost (p < 0.001) and a sustained reduction in GDS scores over 8 weeks compared to baseline. A strong correlation existed between robotic stimulation and clinical GDS improvement (p < 0.01).

CONCLUSION: Humanoid SARs are highly accepted and efficacious adjunctive tools for improving emotional health in ADRD populations, supporting their integration into formal dementia care protocols.},
}

Humans
*Alzheimer Disease/therapy/psychology
Female
*Robotics
Male
*Self-Help Devices
Aged
*Dementia/therapy/psychology
Aged, 80 and over
Intelligent Systems
Treatment Outcome

@article {pmid42394100,
year = {2026},
author = {Yoon, S and Patterson, M and Sun, F and Broadwell, P and Crupi, R and Kim, M and Davis, N},
title = {Leveraging the J48 Algorithm to Inform Community-Based AI Solutions for African American Dementia Caregiving.},
journal = {Studies in health technology and informatics},
volume = {338},
number = {},
pages = {713-717},
doi = {10.3233/SHTI260938},
pmid = {42394100},
issn = {1879-8365},
mesh = {Humans ; *Black or African American ; *Caregivers/psychology ; *Artificial Intelligence ; *Dementia/ethnology/nursing ; *Algorithms ; Adult ; Female ; Male ; Middle Aged ; United States ; Adolescent ; Young Adult ; Alzheimer Disease ; },
abstract = {We applied the J48 machine learning algorithm to build models that identify demographic and caregiving factors associated with perceived risks and benefits of community-based AI solutions for African American family caregiving. 572 diverse family members of a person with Alzheimer's disease and related dementias (ADRD) participated in this online survey in the U.S. The J48 algorithm (C4.5) identified race as the primary predictor for AI support, with African Americans favoring AI-enabled hospital-based diagnostic testing and faith-based apps regardless of their demographic or caregiving factors. Conversely, risk perceptions were heightened among highly educated White family members (aged 25-34) for clinical AI and among younger family members (ages 18-34) for community-based meal-related apps. Overall, model's F-measures (0.83) and PRC areas (0.74) confirm that community-based AI preference is driven more by cultural context and specific use cases than by general caregiving circumstances. While African Americans are willing to support the development of AI applications, enthusiasm does not extend uniformly across all community settings. While scientists should prioritize AI in clinical and faith-based settings, they must exercise caution in the nutritional domain where algorithms may perpetuate bias.},
}

Humans
*Black or African American
*Caregivers/psychology
*Artificial Intelligence
*Dementia/ethnology/nursing
*Algorithms
Adult
Female
Male
Middle Aged
United States
Adolescent
Young Adult
Alzheimer Disease

@article {pmid42394275,
year = {2026},
author = {Hernandez-Kapila, YL and Weisenberger, DJ},
title = {Of mice and men-The emerging oral-gut-brain axis of health and disease.},
journal = {Periodontology 2000},
volume = {},
number = {},
pages = {},
doi = {10.1111/prd.70064},
pmid = {42394275},
issn = {1600-0757},
support = {U54AG089335/NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: Oral health's inextricable links to systemic health are highlighted by the emerging oral-gut-brain axis and other well-known axes. There is growing evidence of a complex oral-gut-brain axis linking mouth and gut microbiomes with the central nervous system. Axis disruptions, characterized as oral and gut dysbiosis or microbial imbalances, can trigger oral and systemic inflammation and neuroinflammation, contributing to diseases such as Alzheimer's disease and Parkinson's disease.

MATERIALS AND METHODS: We summarize the oral-gut-brain axis mechanistic pathways, key evidence from human clinical and animal studies, and how the oral microbiome modulates human health and disease.

RESULTS: Periodontal disease (PD) is associated with increased oral pathogen presence in diseased tissues throughout the human body. Preclinical models recapitulate these findings. Experimental periodontal infection induces dysbiosis that is linked to activation of inflammatory pathways that promote diseased phenotypes. Novel therapeutic approaches, including the probiotic fbacteriocin nisin, are increasingly recognized for targeted microbiome therapy at multiple inflection points across the axis. Nisin restores microbial balance, reduces inflammation, inhibits end-organ pathology, prevents periodontal bone loss, and reduces brain amyloid/tau accumulation and cytokine expression.

CONCLUSIONS: These findings highlight the complexity of the oral-gut-brain axis and the ability to modulate the axis using bacteriocin-based approaches.

CLINICAL RELEVANCE: Future probiotic or antimicrobial strategies aimed at ameliorating neuroinflammatory and metabolic diseases via microbiome-targeted therapy hold clinical promise.},
}

@article {pmid42394367,
year = {2026},
author = {Kreiselmaier, S and Keller, M and Nardi, L and Mueller, C and von Wiegen, N and Bickenbach, K and Gröbner, L and Abukhalaf, M and Tholey, A and Mueller, MM and Körschgen, H and Schmeisser, MJ and Becker-Pauly, C and Pietrzik, CU},
title = {The Role of Meprins on the Brain Extracellular Matrix and Perineuronal Nets.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {13},
pages = {e72097},
doi = {10.1096/fj.202601333R},
pmid = {42394367},
issn = {1530-6860},
support = {CRC 1080 A15//Deutsche Forschungsgemeinschaft (DFG)/ ; CRC 1080 Z2//Deutsche Forschungsgemeinschaft (DFG)/ ; },
mesh = {Animals ; *Perineuronal Nets/metabolism ; *Extracellular Matrix/metabolism ; Mice ; Brevican/metabolism ; *Metalloendopeptidases/metabolism/genetics ; *Brain/metabolism ; Mice, Transgenic ; Synapses/metabolism ; Long-Term Potentiation/physiology ; Male ; Neurocan/metabolism ; Alzheimer Disease/metabolism ; Humans ; },
abstract = {Meprin α and meprin β are zinc metalloproteases that are strongly expressed in intestinal and renal tissues and are expressed as homo- and heterodimers. In the kidney and intestine, they are involved in extracellular matrix assembly and modulation of inflammatory responses. However, meprin β has recently attracted attention because it generates Alzheimer's Disease (AD)-specific Aβ peptides and cleaves brevican, a major component of the perineuronal nets (PNNs) in the brain. PNNs stabilize synapses, thereby regulating plasticity and memory formation. Brevican cleavage correlated with impaired spatial memory formation and impaired CA1 long-term potentiation (LTP) in meprin β transgenic mice. Furthermore, numerous studies have shown the dysregulation of PNN components in AD. Still, the physiological and pathological functions of proteolytic PNN remodeling remain elusive. This study identified an essential role of meprin α in brevican cleavage. It enhanced meprin β's catalytic activity on brevican in co-expression. Moreover, an N-terminomics analysis identified novel meprin β substrates, neurocan, and receptor-type tyrosine-protein phosphatase zeta (RPTPζ) in the brain. Both are key components of PNNs. RPTPζ cleavage by meprin α and meprin β was confirmed in vitro. To assess the functional impact of meprin-mediated proteolysis on the brain extracellular matrix, PNNs and synaptic organization were investigated in vivo using immunofluorescence and electron microscopy. Meprin-mediated proteolysis disrupted PNN structure and decreased synapse density in the hippocampal CA1 region of meprin β transgenic mice. This identifies meprin-dependent PNN remodeling as a novel mechanism contributing to synaptic dysfunction.},
}

Animals
*Perineuronal Nets/metabolism
*Extracellular Matrix/metabolism
Mice
Brevican/metabolism
*Metalloendopeptidases/metabolism/genetics
*Brain/metabolism
Mice, Transgenic
Synapses/metabolism
Long-Term Potentiation/physiology
Male
Neurocan/metabolism
Alzheimer Disease/metabolism
Humans

@article {pmid42394391,
year = {2026},
author = {Rabichow, BE and Nixon, L and Tallant, LE and Gibson, KA and Nascari, DG and Barnett, JH and Massa, N and Fryer, JD},
title = {Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71639},
doi = {10.1002/alz.71639},
pmid = {42394391},
issn = {1552-5279},
support = {NS110435//NINDS Lewy Body Dementia Center Without Walls/ ; //Translational Genomics Research Institute (TGen) Foundation/ ; NS084974/GF/NIH HHS/United States ; AG062556/GF/NIH HHS/United States ; AG062110/GF/NIH HHS/United States ; NS094137/GF/NIH HHS/United States ; AG057997/GF/NIH HHS/United States ; AG062077/GF/NIH HHS/United States ; AG047327/GF/NIH HHS/United States ; AG049992/GF/NIH HHS/United States ; NS110435/GF/NIH HHS/United States ; },
mesh = {Animals ; *alpha-Synuclein/metabolism/genetics ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; *Neuroinflammatory Diseases/pathology/metabolism ; *Mixed Dementias/pathology ; *Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; Mice, Transgenic ; Plaque, Amyloid/pathology ; Phosphorylation ; },
abstract = {INTRODUCTION: Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear.

METHODS: We induced brain-wide neuronal asyn/tau pathologies via viral expression of wild-type asyn, mutant asyn[E46K], mutant tau[A152T], or both asyn[E46K]/tau[A152T] in adult amyloidosis knock-in mice and controls, either post-plaque deposition (6 months old) or pre-plaque (3 months old). Open-field behavior was assessed baseline and 3 and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses.

RESULTS: Post-plaque induction in amyloid mice increased asyn/tau total and phosphorylated levels and exacerbated amyloid-related hyperlocomotion/anxiety. Pre-plaque induction produced robust phosphorylated pathologies irrespective of amyloid, while causing similar amyloid-dependent behavioral synergy. Tau pathology drove LGALS3[+] inflammatory glial responses in white-matter fibers.

DISCUSSION: Amyloid context gates vulnerability, with certain synergies manifesting across stages. White-matter gliosis is a novel mechanism of tau[A152T] risk. Together, our data argue for the development of stage-aware, multitarget interventions and biomarkers.},
}

Animals
*alpha-Synuclein/metabolism/genetics
*tau Proteins/metabolism/genetics
Disease Models, Animal
Mice
*Neuroinflammatory Diseases/pathology/metabolism
*Mixed Dementias/pathology
*Amyloid beta-Peptides/metabolism
Brain/pathology/metabolism
Mice, Transgenic
Plaque, Amyloid/pathology
Phosphorylation

@article {pmid42394394,
year = {2026},
author = {Prados, M and Acosta, C and Mattke, S},
title = {Estimated labor market outcomes of people progressing from preclinical to early-stage Alzheimer's disease in the United States.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71628},
doi = {10.1002/alz.71628},
pmid = {42394394},
issn = {1552-5279},
support = {//Research contract from Biogen to USC/ ; },
mesh = {Humans ; *Alzheimer Disease/economics/epidemiology ; United States/epidemiology ; Female ; Male ; *Employment/statistics & numerical data ; Aged ; Middle Aged ; Disease Progression ; *Cognitive Dysfunction/epidemiology/economics ; *Income/statistics & numerical data ; },
abstract = {INTRODUCTION: Secondary prevention treatments for Alzheimer's disease (AD) that are currently in late-stage clinical trials may preserve productivity and workforce participation.

METHODS: Using the nationally representative Health and Retirement Study waves from 1996 to 2020, we estimated changes in labor force participation, annual earnings, and social assistance payments between incident cases of cognitively impaired and statistically matched cognitively normal individuals.

RESULTS: Among 20,717 respondents (aged 50 to 79), 5232 developed mild cognitive impairment or mild dementia. Disease onset was associated with a five-percentage-point (p.p.) reduction in workforce participation, annual earnings losses of US$8233 (23%) and US$5616 (18%) for men and women who remained in the labor force, respectively, and an increase of 3.5. p.p. male and 5.6 p.p. female social assistance beneficiaries.

DISCUSSION: Onset of cognitive impairment was associated with statistically significant and meaningful reduction in workforce participation and earnings and increased participation in social assistance programs.},
}

Humans
*Alzheimer Disease/economics/epidemiology
United States/epidemiology
Female
Male
*Employment/statistics & numerical data
Aged
Middle Aged
Disease Progression
*Cognitive Dysfunction/epidemiology/economics
*Income/statistics & numerical data

@article {pmid42394416,
year = {2026},
author = {Ceron, C and Casquero-Veiga, M and Lamanna-Rama, N and Fernández-Nueda, I and Fernández-Pena, A and Olazagoitia, N and Sobrino, G and Herraiz, A and González, MI and Muñoz-Hernando, M and Ruperti-Repilado, A and Romero-Sanz, E and Morcillo, MÁ and Pérez-Medina, C and Moro, MA and Villaverde, G and Rubio, J and Fernandez-Ferro, J and Desco, M and Herranz, F and Salinas, B and Fuster, V and Cortes-Canteli, M},
title = {Unveiling the procoagulant state in Alzheimer's disease: A novel PET imaging strategy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71652},
doi = {10.1002/alz.71652},
pmid = {42394416},
issn = {1552-5279},
support = {CPII21/00007//Instituto de Salud Carlos III/ ; AC20/00091//Instituto de Salud Carlos III/ ; AC20/00077//Instituto de Salud Carlos III/ ; A2023012F//BrightFocus Foundation/ ; JDC2022-048922-I//Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033)/ ; RED2022-134299-T//Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033)/ ; JDC2022-048922-I//European Union NextGenerationEU/PRTR/ ; ICT2021-006950//European Union NextGenerationEU/PRTR/ ; PID2024-157521OB-I00//European Union NextGenerationEU/PRTR/ ; CNS2023-144316//European Union NextGenerationEU/PRTR/ ; PID2022-140616OB-I00//European Union NextGenerationEU/PRTR/ ; PDC2022-133493-100//European Union NextGenerationEU/PRTR/ ; ref.202180E048//Nanomedicine CSIC Hub/ ; S2022/BMD-7403//Comunidad de Madrid/ ; //PTI-NEUROAGING CSIC/ ; JPND2020-568-025//EU Joint Programme - Neurodegenerative Disease Research/ ; RYC2023-043741-I//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; ICT2021-006950//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PID2024-157521OB-I00//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; CNS2023-144316//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PID2022-140616OB-I00//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PDC2022-133493-100//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; CEX2020-001041-S//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; },
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging ; *Positron-Emission Tomography/methods ; Humans ; Mice ; Mice, Transgenic ; *Brain/diagnostic imaging/pathology/metabolism ; Fibrin/metabolism ; Female ; Male ; Aged, 80 and over ; Gallium Radioisotopes ; Zirconium ; Disease Models, Animal ; Blood Platelets ; },
abstract = {INTRODUCTION: A subset of Alzheimer's disease (AD) patients exhibits a procoagulant state that remains undiagnosed despite available treatments. We developed positron emission tomography (PET) strategies to in vivo detect cerebral microthrombi in TgCRND8 mice.

METHODS: PET was performed with a fibrin-binding probe (FBP) in TgCRND8 and wild-type mice using a zirconium-89-radiolabeled and a click-chemistry pre-targeted gallium-68 radiotracer. Platelet content was assessed in post mortem brain tissue from AD patients and TgCRND8 mice, and evaluated by PET using a CD41 pre-targeted gallium-68 nanoradiotracer.

RESULTS: Cerebral FBP uptake differentiated TgCRND8 from wild-type mice, particularly ex vivo and with advancing age. Cerebral fibrin burden correlated with platelet content in AD patients, and elevated cerebral platelet burden in TgCRND8 mice was confirmed in post mortem tissue and in vivo by PET.

DISCUSSION: Our findings support PET-based detection of AD-associated cerebral microthrombi and the development of imaging biomarkers to stratify AD patients by procoagulant status and inform personalized therapies.},
}

Animals
*Alzheimer Disease/diagnostic imaging
*Positron-Emission Tomography/methods
Humans
Mice
Mice, Transgenic
*Brain/diagnostic imaging/pathology/metabolism
Fibrin/metabolism
Female
Male
Aged, 80 and over
Gallium Radioisotopes
Zirconium
Disease Models, Animal
Blood Platelets

@article {pmid42394922,
year = {2026},
author = {Zhang, D and Zhang, J and Liu, B and Liu, M and Chen, W and Du, G},
title = {HDFT-MViT: a progressive core-enhanced mix framework for Alzheimer's disease classification using MRI images.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860368},
pmid = {42394922},
issn = {1664-2295},
abstract = {BACKGROUND: Early and accurate diagnosis of Alzheimer's disease (AD) is critical. In MRI-based computer-aided diagnosis, convolutional neural networks (CNNs) excel at extracting local features but struggle to model long-range dependencies, while Vision Transformers (ViTs) offer strong global modeling capabilities but suffer from high computational complexity, limiting their deployment in resource-constrained settings.

NEW METHODS: This paper proposes HDFT-MViT, a lightweight hybrid architecture based on MobileViT that integrates a hierarchical dynamic filter with a lightweight Transformer. The model adopts a progressive Core-Enhanced Mix design: Shallow layers employ MobileNetV2 inverted residual blocks for efficient local feature extraction; intermediate and deep layers incorporate a dual-branch module that integrates a dynamic filter for frequency-domain global modulation and a lightweight Transformer for spatial long-range dependency modeling, followed by hierarchical fusion via learnable weights. A channel attention mechanism is further introduced to enhance feature discriminability.

RESULTS: Evaluations on the public ADNI-1 (3-class) and ADNI-2 (4-class) MRI datasets show that HDFT-MViT achieves state-of-the-art classification accuracies of 98.85 ± 0.27% and 98.07 ± 0.54%, respectively, while maintaining a lightweight profile with only 3.46 M parameters, confirming its effectiveness and efficiency.

CONCLUSION: HDFT-MViT achieves an optimal balance between local detail perception and global semantic understanding within a computationally efficient framework, offering a promising tool for clinical AD diagnosis. Code will be released upon acceptance.},
}

@article {pmid42394931,
year = {2026},
author = {Jeon, YH and Kim, JA and Kang, DY and Lee, S and Choi, NK and Park, JY},
title = {Ginkgo biloba extract for dizziness-related symptoms in central neurological disorders: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860538},
pmid = {42394931},
issn = {1664-2295},
abstract = {BACKGROUND AND PURPOSE: Dizziness associated with central neurological disorders-broadly defined as dizziness or vertigo attributable to central nervous system pathology affecting central vestibular processing-is a clinically challenging and heterogeneous condition with limited treatment options. Ginkgo biloba extract-through its microcirculatory, neuroprotective, and anti-inflammatory mechanisms-represents a biologically plausible intervention. However, its efficacy in this setting has not been comprehensively established. We evaluated the efficacy and safety of Ginkgo biloba extract through a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS: Nine international and Korean databases were searched from January 1974 through November 2025. Studies were eligible if they were RCTs enrolling adults aged 18 years or older with cerebrovascular disease, neurodegenerative disease, or central vestibular dysfunction who had dizziness, vertigo, or balance-related symptoms or relevant outcome assessments. Cochrane RoB 2.0 tool and certainty of evidence was rated using the Assessment, Development and Evaluations (GRADE) approach. Prespecified subgroup analyses by underlying etiology and intervention type, together with leave-one-out sensitivity analyses, were performed to explore heterogeneity.

RESULTS: Nine RCTs (N = 2,394) were included; participants were predominantly drawn from dementia populations (71.6%), with smaller contributions from cerebral arteriosclerosis (23.0%) and vertebrobasilar or posterior circulation disorders (5.4%). Ginkgo biloba significantly reduced dizziness/vertigo severity on the 11-point box scale (MD - 0.76, 95% CI - 1.35 to -0.18; p = 0.01) and VAS (SMD - 0.38, 95% CI - 0.58 to -0.19; p = 0.0001). Moderate-certainty evidence suggested improvements in functional outcomes and quality of life, including the Alzheimer's Disease Activities of Daily Living International Scale (MD = -0.17, 95% CI: -0.22 to -0.13) and the Dementia Quality of Life - Proxy (MD = 2.00, 95% CI: 0.85 to 3.15). The intervention was generally well tolerated, with significantly lower risks of angina pectoris (OR 0.51, 95% CI 0.31 to 0.85) and tinnitus (OR 0.37, 95% CI 0.22 to 0.63) and no significant increase in other adverse events.

CONCLUSION: Ginkgo biloba extract may reduce dizziness severity and improve daily functioning in patients with central neurological disorders accompanied by dizziness or vertigo, with a favorable safety profile. However, given the small number of eligible trials, substantial clinical and statistical heterogeneity, and the predominance of dementia-derived data, these findings should be interpreted with caution. Well-designed RCTs in clearly defined central vestibular populations, ideally confirmed by neuroimaging or vestibular testing, are needed to confirm these results.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251229692, PROSPERO: CRD420251229692.},
}

@article {pmid42394935,
year = {2026},
author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS},
title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1824840},
pmid = {42394935},
issn = {1664-2295},
abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.},
}

@article {pmid42395011,
year = {2026},
author = {Lee, MY and Jeon, SJ and Kim, HJ and Kim, M},
title = {Red ginseng-mediated modulation of the NLRP3 Inflammasome in neuroinflammatory-related cognitive impairments.},
journal = {Journal of ginseng research},
volume = {50},
number = {4},
pages = {101022},
pmid = {42395011},
issn = {1226-8453},
abstract = {The NLRP3 inflammasome is a key immune regulator involved in the pathophysiology of neuroinflammation and various neurodegenerative diseases. Recent studies have shown that both activation and inhibition of the NLRP3 inflammasome can influence disease progression and symptoms in models of cognitive impairment, including Alzheimer's disease (AD). Red ginseng (RG), a traditional medicinal plant, possesses anti-inflammatory properties and shows potential for modulating the NLRP3 inflammasome pathway. This review highlights the effects of RG on the NLRP3 inflammasome, with a particular focus on its therapeutic potential in AD and related cognitive impairments. The structure and activation mechanism of the NLRP3 inflammasome are first described, followed by a discussion of its role in neurodegenerative diseases and neuroinflammation. We then explore how RG and its major components regulate the priming and activation phase of the NLRP3 inflammasome, and discuss their therapeutic potential based on findings from the neuroinflammatory-related cognitive impairment model. Furthermore, we identify supporting evidence for the application of the RG-NLRP3 mechanism in other central nervous system disorders (CNS) disorders, such as cerebral ischemia and vascular dementia. Overall, RG emerges as a promising therapeutic candidate for mitigating neuroinflammation and enhancing cognitive function in neuroinflammatory-related cognitive disorders through NLRP3 inflammasome regulation. Future studies using various neurodegenerative disease (NDD) models and clinical trials are necessary to further validate the therapeutic potential of the RG-NLRP3 pathway.},
}

@article {pmid42395049,
year = {2026},
author = {Hofmann, A and Perneczky, R},
title = {Obstacles and solutions for implementing amyloid-targeting treatments in Europe.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70367},
pmid = {42395049},
issn = {2352-8729},
abstract = {Recent approvals of disease-modifying therapies by the European Medicines Agency mark a historic shift in the treatment landscape of Alzheimer's disease (AD) within the European Union that will challenge national health-care systems and require major adaptations and modernization. This Perspective article provides an overview of the major obstacles in Europe concerning successful implementation of amyloid-targeting treatments and offers potential solutions to overcome them. Major hurdles include a lack of recognition regarding the critical importance of an early, biomarker-based AD diagnosis; low acceptance of blood tests and digital cognitive screening tools; insufficient investment in magnetic resonance imaging capacities; and a fragmented infrastructure for clinical registries. We call on European clinicians, research institutions, and policy makers for a bold and coordinated action to urgently modernize diagnostic pathways and monitoring infrastructure to deliver novel AD treatments in a timely, safe, and equitable manner to all patients who may benefit.},
}

@article {pmid42395104,
year = {2026},
author = {Li, J and Zhou, FL and Chen, JJ and Lin, ZJ and Shi, X and Zhang, GG and Yang, HJ and Dong, MJ and Yi, L and Hu, J and Chen, XH},
title = {Novel PSEN1 (Q223 L) mutation causes early-onset Alzheimer's disease: A case report.},
journal = {World journal of radiology},
volume = {18},
number = {6},
pages = {116652},
pmid = {42395104},
issn = {1949-8470},
abstract = {BACKGROUND: Mutations in the PSEN1, PSEN2, and APP genes are known to cause Alzheimer's disease (AD). Among these, PSEN1 mutations are the most frequent causes of autosomal dominant early-onset AD (EOAD). Patients harboring pathogenic mutations often exhibit considerable clinical heterogeneity. Identifying novel mutations and analyzing their associations with clinical cases is crucial for advancing our understanding of the pathogenesis of AD.

CASE SUMMARY: This report describes the clinical presentation of a family with EOAD. The proband was a 43-year-old Chinese female who presented with a three-year history of cognitive decline for 3 years. Magnetic resonance imaging demonstrated diffuse cerebral cortical atrophy. Next-generation sequencing identified a novel heterozygous c.668A>T mutation in PSEN1, which resulted in a p.Gln223 Leu. cerebrospinal fluid biomarker analysis revealed abnormal levels of amyloid and tau, indicative of underlying Alzheimer's pathology. Furthermore, [18]F-flortaucipir (AV-1451) positron emission topography and [18]F-florbetapir (AV-45) positron emission topography imaging demonstrated extensive cerebral amyloid beta and tau deposition.

CONCLUSION: We report a novel pathogenic PSEN1 mutation, Q223 L, identified for the first time in a Chinese family with EOAD.},
}

@article {pmid42395191,
year = {2026},
author = {Zhang, K and Sha, L and Sun, X},
title = {Editorial: Association of diabetes mellitus with cognitive impairment and neurological disorders, volume II.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1900873},
pmid = {42395191},
issn = {1664-2392},
}

@article {pmid42395342,
year = {2026},
author = {Barrantes, FJ},
title = {Correction: Cognitive synaptopathy: synaptic and dendritic spine dysfunction in age-related cognitive disorders.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1845297},
doi = {10.3389/fnagi.2026.1845297},
pmid = {42395342},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2024.1476909.].},
}

@article {pmid42395343,
year = {2026},
author = {Terman, E},
title = {Biomarkers, diagnosis, and the meaning of disease: evaluating competing frameworks for Alzheimer's disease classification.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1841695},
pmid = {42395343},
issn = {1663-4365},
}

@article {pmid42395345,
year = {2026},
author = {Zhao, B and Zhou, R and Liu, P and Li, Q and Yan, Y and Du, J and Zhao, K and Liu, J and Wang, J and Qu, Q},
title = {FLOT1 and EEF1D: ac4C-related genes bridging Alzheimer's disease and sleep deprivation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1825164},
pmid = {42395345},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) and sleep deprivation (SD), two common conditions in the elderly, share complex molecular connections and may mutually influence each other's pathogenesis. Current drugs only relieve symptoms with limited efficacy, making it urgent to explore the shared pathological mechanisms and potential intervention targets of the two conditions. This study used bioinformatics: first screening AD-related genes associated with SD and N4-acetylcytidine (ac4C) from relevant data; then identifying key genes via Mendelian randomization (MR) analysis and machine learning; finally screening AD-related key cells with single-cell RNA sequencing (scRNA-seq) data, to provide a basis for revealing the molecular and cellular regulatory mechanisms of AD-SD comorbidity.

METHODS: This study integrated bulk RNA sequencing (RNA-Seq) and scRNA-seq data from the Gene Expression Omnibus (GEO) database to identify AD-related key genes associated with SD and ac4C. Machine learning algorithms, including MR, were applied to screen these key genes. Additionally, gene set enrichment analysis (GSEA) was conducted to explore the pathways associated with the key genes, while ssGSEA was used to assess differences in immune cell infiltration. For the scRNA-seq data, key cells involved in AD pathology were further identified. Subsequently, the differential expression of the two key genes was validated using peripheral blood samples collected from AD and SD patients.

RESULTS: Through MR analysis, machine learning algorithms, and other analytical approaches, FLOT1 and EEF1D were identified as key genes. GSEA revealed that these key genes were enriched in multiple pathways, including the lysosome pathway, chemokine signaling pathway, and leukocyte transendothelial migration. Immune cell infiltration analysis suggested that myeloid-derived suppressor cells (MDSCs) might serve as key immune cells. Additionally, scRNA-seq analysis identified microglia, CD4 + T cells, CD8 + T cells, and natural killer (NK) cells as key cell types involved in AD pathogenesis. Critically, these key genes were successfully validated in peripheral blood samples from AD and SD patients, aligning with the above analysis.

CONCLUSION: Overall, FLOT1 and EEF1D were identified as key genes associated with SD and ac4C in AD. This finding provided new grounds for the clinical diagnosis and treatment of AD.},
}

@article {pmid42395347,
year = {2026},
author = {Tang, Y and Ruan, Y and Zheng, D and Huang, Y and Qi, W and Yuan, Q and Xue, C and Xiao, C},
title = {Striatal functional connectivity alterations in mild cognitive impairment subtypes defined by CSF A/T biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1831310},
pmid = {42395347},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is the prodromal stage of Alzheimer's disease (AD), the primary cause of dementia. In addition to supporting motor and higher-order cognitive activities, the basal ganglia, particularly the caudate nucleus and putamen, may exhibit early AD-related network changes. This study investigated differences in striatal functional connectivity (FC) across MCI subtypes marked by cerebrospinal fluid (CSF) amyloid-β (Aβ42) and phosphorylated tau (p-tau) (A/T) biomarkers (A+/A- and T+/T-), along with associations among altered FC, AD pathology, and cognitive performance.

METHODS: From the ADNI database, 212 individuals with MCI were stratified into three groups: A-T- (n = 54), A+T- (n = 28), and A+T+ (n = 52). Group differences in putamen and caudate connectivity were investigated using seed-based FC analyses. Changes in FC, CSF biomarkers, and cognitive function were evaluated using partial correlation analyses. The discriminative value of FC changes was assessed using univariate and multivariate logistic regression analyses.

RESULTS: Compared with the A-T- and A+T- groups, the A+T+ group was older and showed lower episodic memory (EM) scores. The left caudate and bilateral cerebellar anterior lobes, between the right caudate and bilateral medial frontal gyrus (MFG), and between the left putamen and left MFG all had higher FC in the A+T+ group. In the A+T+ group, right caudate-MFG connectivity was positively correlated with CSF p-tau levels (r = 0.424, p = 0.012) and negatively correlated with EM scores (r = -0.38, p = 0.018). Compared with single-region models, multivariate logistic regression demonstrated superior classification performance.

CONCLUSION: Patients with MCI and coexisting CSF Aβ and tau pathologies (A+T+) exhibit increased FC in striatal-cortical circuits, which is strongly associated with tau pathology and episodic memory impairment. These findings provide neuroimaging evidence that striatal network alterations are linked to tau-related pathology in prodromal AD. Changes in striatal FC may serve as an early neurobiological indicator of AD-related MCI.},
}

@article {pmid42395350,
year = {2026},
author = {Van Skike, CE and Hernandez, SF and Hussong, SA and Miller, LR and Makhlouf, H and Muppala, AC and DeRosa, N and Jahrling, JB and Dineley, KT and Galvan, V},
title = {mTOR drives cerebrovascular dysfunction and blood-brain barrier breakdown in a model of Alzheimer's disease with cerebral amyloid angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.23.733858},
pmid = {42395350},
issn = {2692-8205},
abstract = {Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid β fibrils (Aβ) within walls of the cerebrovasculature and contributes to intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in patients with Alzheimer's disease (AD) and in non-pathological aging. Previous studies have shown that mTOR drives cerebrovascular dysfunction and cognitive impairment observed in AD, vascular cognitive impairment, and normative aging. However, the mechanisms by which mTOR contributes to CAA are unknown. Here, we show that mTOR drives the accumulation of fibrillar vascular Aβ lesions in the Tg2576 Model of AD with CAA (using equal numbers of female and male mice), which directly impair endothelium-dependent cerebrovascular reactivity. Additionally, we found that blood-brain barrier (BBB) breakdown and remodeling of tight junction proteins, dependent on mTOR, are associated with increased cerebral microhemorrhages. Finally, we show that mTOR contributes to neurovascular uncoupling in Tg2576 AD mice through nNOS dysfunction and inhibition of non-nitric oxide synthase-dependent contributions to neurovascular coupling (NVC). Contextual memory impairments were ameliorated by the mTOR inhibitor rapamycin. Improvements in memory were associated with reduced cerebrovascular Aβ fibril accumulation, enhanced endothelium-dependent vasodilation, reduced fibrillar Aβ load, restoration of BBB integrity, attenuation of intracerebral microhemorrhage, and restoration of NVC. These data indicate that mTOR drives vascular accumulation of fibrillar Aβ, including those associated with brain vasculature, and mediates cerebrovascular dysfunction in a model of AD with CAA. Thus, mTOR inhibitors represent a promising treatment option for patients with CAA and AD.},
}

@article {pmid42395371,
year = {2026},
author = {Aladeokin, AC and Jeltsch, M and Davtyan, H and Blurton-Jones, M and Koistinaho, J},
title = {Composition and activity of the proteasome in human iPSC-derived neuronal model of early-stage sporadic Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.23.734021},
pmid = {42395371},
issn = {2692-8205},
abstract = {INTRODUCTION: The proteasome is a critical cellular degradative machinery impaired in late-stage Alzheimer's disease (AD). However, the status and activity of the proteasome in early-stage sporadic AD (sAD) is unknown.

METHODS: A cellular model of human early-stage sAD was generated from sAD patient iPSC-derived cortical neurons by dual-SMAD inhibition. The iPSCs, neuroprogenitors, and cortical neurons were validated by the expressions of key markers. The level of total intraneuronal Aβ was measured by ELISA. Composition and native proteolytic activities of the proteasome in control and sAD cortical neurons were measured using complementary fluorogenic probes.

RESULTS: Control and sAD patients iPSCs expressed pluripotent markers OCT4, NANOG, and SSEA4 which induced into neuroprogenitors expressing NESTIN and PAX6. The neuroprogenitors terminally differentiated into cortical neurons expressing neuronal markers MAP2 and TUJ1, and cortical layer marker TBR1. The level of intraneuronal Aβ in the sAD cortical neurons was significantly higher compared to control. Control and sAD cortical neurons expressed native 30S, 26S, and 20S proteasome assemblies with the sAD cortical neurons displaying higher 20S assemblies. Increased active 20S assemblies was associated with higher β1, β2, and β5 proteolytic sites activities.

DISCUSSION: The significant elevation in the proteolytic activities of the β1, β2, and β5 subunits of 20S proteasome in sAD cortical neurons suggests that this may be a possible compensatory response to elevated intraneuronal Aβ.},
}

@article {pmid42395377,
year = {2026},
author = {Qiu, J and Bosch, MA and Wolfe, M and Korac, K and Rizzo, S and Stincic, TL and Farley, SE and Fitzgerald, W and Rajendran, M and Laguerre, A and Stein, F and Copenhaver, PF and Rønnekleiv, OK and Rønnekleiv-Kelly, SM and Rostovtseva, TK and Bezrukov, SM and Schultz, C and Kelly, MJ},
title = {Identifying Novel Estrogenic Mitochondrial Targets in Hypothalamic Proopiomelanocortin Neurons by Chemoproteomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.732817},
pmid = {42395377},
issn = {2692-8205},
abstract = {Loss of estrogens at menopause is linked to impaired brain metabolism and increased risk of Alzheimer's disease (AD). However, estrogen replacement therapies are limited due to the deleterious effects of estrogen on peripheral organs and increased risk of vascular dementia. We have developed a non-steroidal estrogenic compound, STX, which does not bind to the classical estrogen receptors α and β, but mimics estrogenic signaling in the central nervous system (CNS) without the peripheral reproductive actions. STX is protective against neurodegeneration in stroke and AD models, but its molecular targets are unknown. Here, we identified and validated STX neural targets using chemoproteomic, molecular biological, electrophysiological and metabolic assays of hypothalamic proopiomelanocortin (POMC) neurons. Chemoproteomic profiling identified voltage dependent anion channels (VDAC1-3) as major intracellular binding partners in mHypo43 (POMC) cells. Based on quantitative single-cell PCR, Vdac2 was identified as the dominant isoform in female hypothalamic POMC neurons. Seahorse metabolic flux analyses showed that STX potently increased glycolysis, oxidative respiration and mitochondrial ATP production in mHypo43 cells. Nanomolar concentrations of STX enhanced VDAC2 voltage-dependent gating in reconstituted lipid membranes and shifted the low-conductance states toward anion selectivity, consistent with increased ATP flux. Together, these findings reveal a mechanism for the neuroprotective effects of STX through enhancing mitochondrial bioenergetics and modulating VDAC channel properties, potentially increasing cellular energy stores. Therefore, this work identifies previously unrecognized estrogenic mitochondrial targets and provides a mechanistic basis for the neuroprotective actions of STX relevant to menopause-associated brain vulnerability.},
}

@article {pmid42395379,
year = {2026},
author = {Estrella, LD and Dasgupta, S and Gundavelli, A and Li, H and Yang, HS and Chancellor, S and Pastika, T and Abdourahman, A and Tamm, J and Yanamandra, K and Romanul, N and Liao, F and Zhao, K and Lin, G and Srinivasa, PP and Wang, X and Martin, A and Asque, E and Doering, A and Ried, JS and Talanian, RV and Kwon, T and Woodbury, ME and Grinberg, YY and Agastra, E and Oakley, DH and Hyman, BT and Serrano-Pozo, A and Zwang, T and Das, S and Bennett, RE},
title = {Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.26.734052},
pmid = {42395379},
issn = {2692-8205},
abstract = {Cerebrovascular alterations are widely observed in both Alzheimer's Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Pick's disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.},
}

@article {pmid42395391,
year = {2026},
author = {Sharma, MS and Agarwal, R and Tiwari, N and Sharma, M and Kaushik, A and , },
title = {Alzheimer's Disease Selectively Perturbs Age-Sensitive Brain Radiomic Features Across the Disease Continuum.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.732875},
pmid = {42395391},
issn = {2692-8205},
abstract = {Normal brain aging and Alzheimer's disease both involve progressive structural brain alterations, making it challenging to distinguish pathological neurodegeneration from normative aging-related atrophy. This study investigated whether Alzheimer's disease exhibits radiomic patterns that mimic, diverge from, or selectively perturb age-associated structural brain changes. T1-weighted magnetic resonance imaging scans from the Alzheimer's Disease Neuroimaging Initiative were analyzed using a region-wise radiomics framework across 10 anatomically defined brain regions. Radiomic features were extracted following automated segmentation, bias field correction, and intensity normalization. Age-associated radiomic patterns were first identified in cognitively normal subjects using Spearman correlation analysis. Features demonstrating significant age sensitivity were subsequently compared between cognitively normal and Alzheimer's disease cohorts across age bins using Welch's two-sample t-tests with permutation-based significance estimation and false discovery rate correction. Medial temporal and limbic regions, particularly the hippocampus, entorhinal cortex, and cingulum, demonstrated consistent age-aligned radiomic trajectories with systematic, statistically significant disease-related shifts across all age bins, supported by large effect sizes and bootstrap-validated confidence intervals. In contrast, several other regions demonstrated more heterogeneous and less stable patterns of group separation across age bins. Secondary analysis using late mild cognitive impairment subjects demonstrated that these radiomic divergences are detectable at the transition from normal cognition to mild cognitive impairment, with statistically significant CN-LMCI separation but no significant LMCI-AD separation, positioning the identified markers as early-stage rather than late-stage indicators of neurodegeneration. These findings indicate that Alzheimer's disease does not uniformly mimic normal aging across the brain but instead selectively perturbs radiomic features associated with normative aging trajectories. The identified markers represent promising candidates for age-adjusted radiomic biomarkers, warranting validation in independent cohorts to establish their generalisability. The fully automated nature of the analytical pipeline - spanning segmentation, feature extraction, and statistical comparison without manual annotation - may facilitate scalable validation of these biomarkers in larger neuroimaging cohorts.},
}

@article {pmid42395402,
year = {2026},
author = {Hossain, MS and Praticò, D},
title = {Temporal and Regional Circular RNA profiling in a Tauopathy Mouse Model: Implications for Tau Pathology and Neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.733253},
pmid = {42395402},
issn = {2692-8205},
abstract = {MicroRNAs (miRNA), are non-coding RNA that act as post-transcriptional regulators of gene expression in various organs including the brain where they play an important role in neurodegeneration. Circular RNAs are single-stranded, covalently closed loop RNA molecules recognized as upstream regulators of miRNA. Previous studies have shown that circRNAs are dysregulated in Alzheimer's and other neurodegenerative diseases. However, a systematic, age-and region-specific circRNA atlas in primary tauopathy is lacking. To this end, we performed comprehensive circRNA sequencing of hippocampal and cortical tissues from a model of human tauopathy, h-Tau mice, at 3, 6, and 12 months of age. We identified circRNA-miRNA sponging networks that target and regulate key tau disease-associated pathways, including kinases, phosphatases, histone deacetylase, glutamatergic and GABAergic synapse, and microglial efferocytosis. Our study demonstrates an age- and region-specific circRNA landscape in the brain of a model of human tauopathy and identify candidate circRNA-miRNA-mRNA regulatory axes converging on core tau pathological processes. These findings support the novel hypothesis that specific circRNAs have the potential to be used as biomarkers and therapeutic targets against tau-driven neurodegeneration.},
}

@article {pmid42395404,
year = {2026},
author = {Giorgio, J and Blazhenets, G and Landau, SM and Pezzoli, S and Yokoyama, JS and Soleimani-Meigooni, DN and Carrillo, MC and Grinberg, LT and Seeley, WW and Spina, S and Nudelman, KN and Apostolova, LG and Dickerson, BC and Jagust, WJ and Rabinovici, GD and Joie, R and , and , },
title = {Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.733031},
pmid = {42395404},
issn = {2692-8205},
abstract = {The standard approach to quantify amyloid (Aβ) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of Aβ-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant Aβ-PET binding. In particular, Aβ-PET positive participants who have posterior predominant binding are less likely to be APOE -ε4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant Aβ binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that Aβ-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess Aβ-PET is insufficient to capture meaningful signal from Aβ-PET imaging. This work has implications for the diagnosis and treatment of Alzheimer's disease and extends our understanding of the mechanisms governing variable Aβ-PET distribution and its downstream effects.},
}

@article {pmid42395416,
year = {2026},
author = {Wang, X and Walker, AC and Reeves, MM and Bejarano, JG and Song, Y and Dunmore, J and Yue, M and Rawlinson, B and Engelberg-Cook, E and DeTure, M and Tome, RB and Narayan, A and Bartfield, J and Graff-Radford, NR and Boeve, BF and Peterson, RC and Knopman, DS and Oskarsson, B and Day, GS and Murray, ME and Dickson, DW and Cook, C and Zhang, Y and Petrucelli, L and Josephs, KA and Prudencio, M},
title = {TDP-43 subtypes shape transcriptomic signatures in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.733827},
pmid = {42395416},
issn = {2692-8205},
abstract = {TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid β plaques in Alzheimer's disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types α and β for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.},
}

@article {pmid42395446,
year = {2026},
author = {Thomson, S and Li, XC and Walker, S and Tang, TCY and Graham, ME and Olechnowicz, SWZ and Bowden, R and , and Waugh, KA and Slawson, C and Burns, JM and Swerdlow, RH and Wilkins, HM and Shvetcov, A and Finney, CA},
title = {Patient cerebral organoids capture Alzheimer's disease proteomic biomarkers and drug targets.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.733874},
pmid = {42395446},
issn = {2692-8205},
abstract = {Patient iPSC-derived cerebral organoids are a leading human model of Alzheimer's disease, yet their proteome has never been benchmarked against human disease. Clinical cohorts now nominate thousands of biomarkers and drug targets across three proteomic platforms, and whether patient organoids capture these candidates is unknown. Here, we profile AD and control cerebral organoids containing neurons, astrocytes, and microglia on the three platforms driving clinical discovery, mass spectrometry, SomaScan, and Olink, in both conditioned media and lysate. Benchmarked against 121 studies and clinical cohorts of over 17,000 plasma, CSF, and cortex samples, patient organoids detect almost every nominated candidate and reproduce the disease-associated change in roughly one in four of the most reproducible. This convergence spans plasma, CSF, and cortex, and extends to synaptic, mitochondrial, and proteostatic biology. We provide the first multi-platform reference proteome of a patient-derived AD model, establishing it as a translationally relevant system for studying AD.},
}

@article {pmid42395472,
year = {2026},
author = {Wang, C and Ma, CT and Crotty, C and Zeng, FY and Bobkov, A and Covel, JA and Rivera, EK and Sergienko, E and Kosik, KS and Olson, SH and Jackson, MR and Rauch, JN},
title = {High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.24.733881},
pmid = {42395472},
issn = {2692-8205},
abstract = {The cellular uptake and propagation of tau are central features of tauopathies, including Alzheimer's disease, and are mediated by the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1). While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined. Here, we establish a quantitative and scalable framework to interrogate the tau-LRP1 interaction and identify small-molecule modulators. We engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region mediating tau interaction, and developed multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, to measure LRP1-BD4 interactions with tau and a known peptide ligand. Across assay formats, we observe consistent binding affinities in the nanomolar range and demonstrate competitive displacement by tau, receptor-associated protein (RAP), and a peptide ligand, supporting overlapping binding interfaces. Leveraging these platforms, we performed small molecule high-throughput screening and identified a set of candidate inhibitors of the LRP1-BD4-tau interaction. Selected compounds reduced tau uptake in a cellular assay, phenocopying competitive inhibition by tau and a peptide ligand. Together, these studies define the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface and establish an integrated discovery pipeline linking mechanistic characterization to functional cellular outcomes. This work provides a foundation for the development of therapeutic strategies targeting LRP1-mediated tau uptake.},
}

@article {pmid42395483,
year = {2026},
author = {Zhang, W and Wang, L and Franzmann, EJ and Chen, XS},
title = {Multivariate Random Forests for Cross-Modal Multi-Omics Integration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.732933},
pmid = {42395483},
issn = {2692-8205},
abstract = {Multi-omics studies are widely used across many areas of biomedical research. In many diseases, some signals are shared across data types, while others are strongest in a single omics layer. Current multi-omics clustering methods often either merge all data types into a single representation, which can blur biology that is strong in one layer, or rely on linear structure that may miss more complex relationships across data types. We introduce multiRF, a random-forest-based method that handles complex data types and separates shared and modality-specific structure for multi-omics data. multiRF learns sample similarities across omics layers from multivariate random forests, combines them across data types, and uses the resulting weights to estimate the part of each omics layer that is predictable from the others. The remaining residual is treated as modality-specific signal, allowing shared and modality-specific similarities to be clustered separately. In simulations, multiRF recovered shared clusters as well as or better than established integrative methods while more reliably separating modality-specific signal under nonlinear data structures. In TCGA head and neck squamous cell carcinoma, the shared component aligned with the main subtype structure across established reference classifications, while gene- and miRNA-specific components revealed additional immune and developmental biology. In the ADNI cohort with matched blood DNA methylation and structural MRI, the shared cross-modal aging signal was associated with future conversion to mild cognitive impairment or Alzheimer's disease, and a DNAm-specific residual signal showed exploratory additional information. These results show that multiRF can recover a common disease axis while retaining biologically meaningful signals specific to one data type. multiRF is available as an open-source R package at https://github.com/novawz/multiRF.},
}

@article {pmid42395514,
year = {2026},
author = {Wu, A},
title = {Discrete Cognitive Resolution in Alzheimer's Disease: Cross-Cohort Reanalysis of ADNI and NACC Longitudinal Data.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.733215},
pmid = {42395514},
issn = {2692-8205},
abstract = {INTRODUCTION: Do continuous cognitive totals capture patient-relevant transitions, or does decline have discrete structure?

METHODS: We formalize a discrete cognitive resolution (DCR) model in which decline is loss of binary discriminative coordinates, with deterministic emissions tying items to a shared low-dimensional mask. Using natively discrete item-level data (ADAS-Cog, 688 ADNI participants; MoCA sub-items, 13,323 NACC participants), we tested pre-specified signatures by out-of-sample log-loss against continuous-drift, per-item, and mixed-effects IRT competitors, with a coordinate-label permutation null (S2).

RESULTS: DCR beat both pre-specified baselines (ADNI 0.436 vs 0.965; NACC 0.566 vs 0.602). S2 was decisive in ADNI (AUC 0.782; null 0.529, P < .001); in NACC the signal concentrated in orientation (AUC 0.718). Mixed-effects IRT achieved lower log-loss than DCR.

DISCUSSION: Cognitive decline shows discrete coordinate structure when items are single-coordinate probes. The claim is structural, not predictive; encoding is decisive.},
}

@article {pmid42395537,
year = {2024},
author = {Wang, R and Maloney, B and Nho, K and Beck, J and Counts, SE and Lahiri, DK},
title = {Human microRNA-153-3p targets specific neuronal genes and is associated with the risk of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.09.07.611728},
pmid = {42395537},
issn = {2692-8205},
abstract = {Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid β precursor protein (APP) and α-synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3-UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cells and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with reduced AD probability, while elevated REST may associate with a greater AD probability. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reducing APP, SNCA, and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.},
}

@article {pmid42395556,
year = {2026},
author = {Fields, EA and Kim, CY and Nett, RS},
title = {Ancient origins of alkaloid biosynthesis in medicinal clubmosses.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.21.733354},
pmid = {42395556},
issn = {2692-8205},
abstract = {The plant kingdom is rich with medicinal natural products that are complex and difficult to access. Discovering how plants build these molecules can be challenging, especially for biosynthetic pathways that have unusual chemical transformations or require intricate coordination among cellular compartments. Here, we leveraged 300 million years of metabolic conservation to uncover how medicinal clubmosses organize extracellular and intracellular alkaloid biosynthesis to produce the Alzheimer's disease therapeutic huperzine A (HupA). We reveal not only scaffold-forming enzymes that form key precursors to hundreds of clubmoss alkaloids, but also an essential transporter that connects metabolism across the plasma membrane to enable complete HupA biosynthesis. Our results demonstrate how ancient evolutionary conservation can be used to identify cryptic biosynthetic components and unexpected cellular organization in plant specialized metabolism.},
}

@article {pmid42395576,
year = {2026},
author = {Taimouri, M and Ravindra, V},
title = {Normative brain-state trajectories reveal deviation from healthy aging in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.19.733190},
pmid = {42395576},
issn = {2692-8205},
abstract = {Distinguishing healthy brain aging from early neurodegenerative disruption remains a major challenge in Alzheimer's disease. Here, we used resting-state fMRI from the Alzheimer's Disease Neuroimaging Initiative to model large-scale brain-state dynamics relative to a cognitively normal aging reference. A Hidden Markov Model trained exclusively on cognitively normal adults defined latent connectivity states, and a generalized additive model estimated an age-adjusted reference trajectory of transition entropy. Mild cognitive impairment and Alzheimer's disease showed progressively greater deviation from this reference, with the strongest disruption in Alzheimer's disease. A single absolute-deviation score retained much of the predictive information contained in higher-dimensional dynamic features, supporting its use as a compact and interpretable candidate biomarker of altered brain-state organization. These findings suggest that Alzheimer's disease is associated with measurable departure from healthy dynamic brain aging, providing an interpretable framework for future longitudinal and clinically validated studies.},
}

@article {pmid42395621,
year = {2026},
author = {Ferhat, A and Messaoudi, M and Guelifet, K and Amor, IB and Zahnit, W and Bendrihem, KA and Zeraib, A and Ouakouak, H and Benmohamed, M and Ferhat, MA and Larkem, I and Alsaeedi, H and Khan, AAP and Bechelany, M and Tian, F and Barhoum, A},
title = {Chemical profiling and in silico evaluation of a Matricaria chamomilla L. extract: exploring its antioxidant, antibacterial, antidiabetic, anti-inflammatory, and anticholinergic activities.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1852820},
pmid = {42395621},
issn = {2296-861X},
abstract = {INTRODUCTION: This study aimed to investigate the phytochemical composition and multifunctional therapeutic potential of a hydroethanolic extract of Matricaria chamomilla L. collected from the semi-arid region of Algeria. The research focused on evaluating its antioxidant, antimicrobial, antidiabetic, anti-inflammatory, neuroprotective, and potential anticancer activities.

METHODS: Total polyphenol and flavonoid contents were determined using spectrophotometric methods. The phytochemical profile was characterized by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Antioxidant activity was assessed using DPPH and galvinoxyl radical scavenging assays. Antimicrobial activity was evaluated against bacterial and fungal strains using inhibition zone measurements. Enzyme inhibitory activities against α-amylase, acetylcholinesterase, and butyrylcholinesterase were investigated in vitro. Anti-inflammatory activity was evaluated through protein denaturation inhibition and carrageenan-induced paw edema assays. Molecular docking studies were performed to assess the interactions of identified compounds with breast cancer targets ERα and HER2.

RESULTS: The extract contained high levels of total polyphenols (41.9 mg gallic acid equivalent/g extract) and flavonoids (17.1 mg rutin equivalent/g extract). LC-MS/MS analysis identified several bioactive compounds, including caffeic acid, gallocatechin gallate, and apigenin-7-O-glucoside. The extract exhibited moderate antioxidant activity, with IC50 values of 324.4 μg/mL and 22.7 μg/mL for DPPH and galvinoxyl assays, respectively. Strong antimicrobial effects were observed against Staphylococcus aureus (22 mm inhibition zone) and Candida albicans (18 mm inhibition zone). The extract also demonstrated potent inhibitory activities against α-amylase (IC50 = 440.6 μg/mL), acetylcholinesterase (IC50 = 3.11 μg/mL), and butyrylcholinesterase (IC50 = 28.7 μg/mL), surpassing standard inhibitors. In vitro anti-inflammatory activity reached 98.4% inhibition of protein denaturation at 2000 μg/mL, while in vivo edema inhibition reached 38.81%. Molecular docking revealed strong binding affinities of α-tocopherol and apigenin-7-O-glucoside toward ERα and HER2 receptors.

DISCUSSION: The findings demonstrate that Matricaria chamomilla L. possesses significant pharmacological potential due to its rich phytochemical composition and broad-spectrum biological activities. The observed antioxidant, antimicrobial, enzyme inhibitory, anti-inflammatory, and molecular docking results suggest that this plant could serve as a promising natural source for the development of therapeutic agents targeting diabetes, neurodegenerative disorders, microbial infections, and breast cancer. Further pharmacological and clinical investigations are warranted to validate these bioactivities and support future drug development applications.},
}

@article {pmid42395725,
year = {2026},
author = {Liu, HC and Lin, CY and Ho, CS and Chang, JF and Lee, KH and Yang, SY},
title = {Immunomagnetic reduction detects amyloid β 1-42, but neither x-42 nor 1-y.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42395725},
issn = {2046-2069},
abstract = {Amyloid β 1-42 peptide (Aβ1-42) is listed in the diagnostic guidelines as a plasma analyte for evaluating amyloid neuropathology in Alzheimer's disease. Owing to its ultralow concentrations in plasma, ultrasensitive analytical technologies have been developed for its accurate detection. Immunomagnetic reduction (IMR) is an ultrasensitive assay. In contrast to conventional immunoassays, which involve pairs of primary antibodies against the C-terminal and N-terminal domains of Aβ1-42 for achieving high specificity, IMR utilizes a single primary antibody against the C-terminal domain of Aβ1-42. Thus, IMR may be used to assay not only Aβ1-42 but also other Aβ peptides, such as Aβ x-42. In this work, the specificity of assaying Aβ1-42 using IMR was investigated. The binding specificities between the C-terminal antibody used in the IMR reagent and Aβ peptides were examined through western blot analysis. Furthermore, the interference effects of other Aβs on Aβ1-42 quantification using IMR were explored. The analytical performance, including the analytical curve, low limit of detection, high limit of detection, and storage stability of the reagents, was investigated. The C-terminal antibody only binds to Aβ1-42, and not to Aβ3-42, pyroglutamate-modulated Aβ3-42 (Aβp3-42), Aβ1-55, Aβ1-38, Aβ3-40, or Aβ1-40. The IMR Aβ1-42 assay developed using this antibody also demonstrated high selectivity for Aβ1-42. The lower and upper limits of detection for assaying Aβ1-42 were 17 fg mL[-1] and 30 000 pg mL[-1], respectively. Furthermore, the storage stability of the IMR Aβ1-42 reagent at 2-8 °C was at least 440 days. These results reveal that the IMR assay of Aβ1-42 exhibits high sensitivity and high specificity enabling precise measurement of Aβ1-42 concentrations in human plasma.},
}

@article {pmid42395838,
year = {2026},
author = {Moeller, S and Singsank, K and Goodwin, G and Lafont-Tanner, D and Lawrence, E and Renn, B and John, S},
title = {Multiracial participants in Alzheimer's research: scoping review and recommendations.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70276},
pmid = {42395838},
issn = {2352-8737},
abstract = {Evidence suggests that Alzheimer's disease (AD) presents differently across ethnoracial groups, producing disparate risk and resilience profiles that may be measured through neuropsychological data. Extant AD research primarily examines monoracial groups, despite the fact that Multiracial individuals make up more than 10% of the US population. Failure to incorporate data from Multiracial participants (those endorsing two or more racial identities) limits research and clinical efforts to address AD in minoritized communities. A scoping review examined the use of neuropsychological data from Multiracial participants within AD research. Three databases were searched (APA PsycInfo, Embase, and Web of Science) for studies containing ethnoracially minoritized groups. Two independent researchers reviewed articles and included studies that met the following criteria: published in 2000 (the year the US Census formally allowed self-identification of multiple races) or later, in English, US-based cohort (as race is a social construct), reported neuropsychological data, and the research was AD-related. Searches yielded 855 original articles. Following abstract review, 484 articles were screened in full, resulting in 19 articles that met the inclusion criteria. Most excluded articles (66.67%) contained vague racial descriptions (e.g., use of an undefined Other Race group), making it difficult to know whether Multiracial participants existed in the dataset. Roughly one-third (29.03%) of articles were excluded because they described only monoracial groups. Analysis of neuropsychological outcomes showed that most articles included Multiracial participant data in larger group-level analyses (e.g., normal cognition versus dementia) or grouped their data with other, less represented ethnic or racial groups (e.g., Other Races). This review demonstrates the paucity of research and need for intentional consideration of the inclusion of Multiracial participants in AD research. Recommendations to improve reporting of data from Multiracial participants are offered, including considerations for the anticipation and adaptation to changes in the social definitions of ethnicity and race.},
}

@article {pmid42395866,
year = {2026},
author = {Sidharth, A and Shin, D},
title = {The role of SUMOylation in regulating proteins that drive neuronal disease progression.},
journal = {Biochemistry and biophysics reports},
volume = {47},
number = {},
pages = {102687},
pmid = {42395866},
issn = {2405-5808},
abstract = {SUMOylation is a post-translational modification in which a Small Ubiquitin-like Modifier (SUMO) protein is reversibly attached to a lysine residue on a target protein in an ATP-dependent process. This modification can affect the function of target proteins by enhancing their stability or changing cellular translocation, thereby making SUMOylation a critical regulator in the pathogenesis of multiple diseases. The functional consequences of SUMOylation, however, are highly context dependent. In Alzheimer's disease, SUMOylation stabilizes proteins that drive disease progression and enhances neurotoxicity, thereby exacerbating these conditions. Similarly, in Progressive Supranuclear Palsy, SUMO-1 conjugation stabilizes truncated tau and blocks its ubiquitination, whereas SUMO-2/3 conjugation promotes Tau clearance and recovery from neuroinflammation, illustrating how distinct SUMO paralogues can exert opposing effects within the same disease. Conversely, increased SUMOylation can be neuroprotective in cerebral ischemia and Parkinson's disease by promoting autophagic clearance of pathogenic proteins. Beyond alterations in protein stability, aberrant SUMOylation can also lead to mis-localization of target proteins, which has been identified as a pathogenic mechanism in disorders such as Huntington's disease and Amyotrophic Lateral Sclerosis that results in impaired clearance and pathogenic buildup, which results in neuronal death. From a therapeutic standpoint, the SUMO inhibitor TAK-981 has shown promise in both Multiple Sclerosis and in pre-clinical glioblastoma models, underscoring the translational potential of targeting of this pathway. This review examines the multifaceted role of SUMOylation across diverse neurological conditions, evaluates the therapeutic potential of SUMO inhibitors and activators, and highlights the opportunities and challenges of modulating this pathway in currently incurable neurological disorders.},
}

@article {pmid42396039,
year = {2026},
author = {Yang, SY and Liu, HC and Chiu, MJ and Chang, JF and Ho, CS and Lee, KH},
title = {Changes in Plasma Amyloid β 1-42 Peptide and Total Tau Protein from Normal Cognition to Sever-Stage Alzheimer's Disease Using an Immunomagnetic Reduction Assay.},
journal = {ACS omega},
volume = {11},
number = {25},
pages = {36855-36865},
pmid = {42396039},
issn = {2470-1343},
abstract = {Measurements of plasma biomarkers are included in current guidelines for the diagnosis of Alzheimer's disease. Amyloid β 1-42 peptide (Aβ1-42) and tau protein are the key analytes. By using the ultrasensitive immunomagnetic reduction (IMR) assay, the combination of Aβ1-42 and total tau protein (T-Tau), i.e., Aβ1-42xT-Tau, effectively discriminates cognitively unimpaired (CU) individuals from patients with amnestic mild cognitive impairment (aMCI) and early-stage Alzheimer's disease dementia (eADD). However, the accuracy of plasma Aβ1-42xT-Tau in distinguishing mild/severe ADD (m-sADD) decreases. In this work, the dynamic changes in individual and combined plasma Aβ1-42 and T-Tau in CU, aMCI, eADD, and m-sADD individuals were investigated. One hundred thirty-nine individuals, including 66 CU, 24 aMCI, 26 eADD, and 23 m-sADD patients, were enrolled to investigate the distributions of plasma Aβ1-42 and T-Tau using IMR. In addition, 13 autopsies were performed to investigate the evolution of plasma Aβ1-42 and T-Tau with increasing Aβ plaque density in the brain. CU subjects had 249.8 ± 103.7 (pg/mL)[2] for plasma Aβ1-42xT-Tau. aMCI, eADD, and m-sADD patients had plasma Aβ1-42xT-Tau of 583.4 ± 139.2, 1061.1 ± 402.9, and 884.7 ± 488.9 (pg/mL)[2], respectively. Plasma Aβ1-42xT-Tau levels clearly increase from CU to aMCI to eADD patients. Similar changes in plasma Aβ1-42xT-Tau are correlated with high densities of Aβ plaques in the postmortem brain. Further analysis revealed that the dynamic changes in plasma Aβ1-42xT-Tau from CU to m-sADD patients are mainly attributed to T-Tau neuropathology. The results of the autopsy study suggest that the fibrillization of soluble tau proteins is accelerated at high Aβ plaque densities, possibly contributing to the dynamic change in plasma biomarkers from eADD to m-sADD. Measurements of individual or combined plasma Aβ1-42 and T-Tau using IMR show high sensitivity (>0.9) and high specificity (>0.9) for assessing aMCI and eADD patients. By using stepwise cutoff values, the prediction of staging CU, aMCI, or eADD is feasible in clinical practice.},
}

@article {pmid42396279,
year = {2026},
author = {Teo, MH and Taong, MRQ and Kan, CN and Tan, CH and , },
title = {Cognitive and Neuroimaging Biomarker Intra-Individual Variability in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.21.26356195},
pmid = {42396279},
abstract = {BACKGROUND: Greater cognitive intra-individual variability (IIV) reflects increased heterogeneous performance across cognitive domains and has been linked to a higher risk of Alzheimer's disease (AD). However, it remains unclear whether cognitive IIV is linked to heterogeneous dispersion of regional AD pathology. Hence, we aimed to examine the association between cognitive IIV and AD neuroimaging biomarker IIV.

METHODS: This study included participants with normal cognition (CN) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative. Cognitive IIV was computed as the within-person standard deviation of five domain-specific neuropsychological test z-scores. Four neuroimaging biomarker IIV metrics were similarly derived using regional amyloid-β (n = 1,021), tau (n = 719), cortical thickness (n = 2,148), and combined amyloid-tau-neurodegeneration (ATN, n = 258). Associations between cognitive IIV and each biomarker IIV were evaluated using linear regression models, adjusted for relevant covariates.

RESULTS: Higher cognitive IIV was associated with greater biomarker IIV across amyloid-β (β = 0.039, SE = 0.014, p = .006), tau (β = 0.196, SE = 0.033, p < .001), cortical thinning (β = 0.036, SE = 0.008, p < .001), and ATN (β = 0.176, SE = 0.043, p < .001). Interaction analyses revealed that the associations of cognitive IIV with tau IIV, cortical thickness IIV, and ATN IIV were stronger in MCI than CN individuals. Significant interactions between cognitive IIV and biomarker positivity status showed that the effect with amyloid-β IIV was attenuated in A- (β = 0.004, SE = 0.014, p = .78) but that the effect with tau IIV remained robust even in T-individuals (β = 0.088, SE = 0.022, p < .001).

CONCLUSION: Elevated cognitive IIV is associated with greater heterogeneity in cortical dispersion of AD-related pathology, particularly in prodromal AD and in the presence of abnormal pathology. As a novel measure that captures variation in topographical scattering of AD pathological burden across the cortex, AD biomarker IIV may offer research and clinical utility beyond evaluating absolute biomarker load or thresholds.},
}

@article {pmid42396292,
year = {2026},
author = {Hernandez-Rasco, F and Ruiz, R and de Rojas, I and Puerta, R and Garcia-Mayor, C and Espinosa-Oliva, AM and García-Revilla, J and Bayon, P and Rivera-Ramos, A and Oualit, FR and Jiménez, S and Saez, ME and de Pablos, RM and Zhao, F and Olive, C and Sanz, P and Montalbán, X and Valero, S and Cano, A and Fernández, MV and Wells, AM and Cavazos, JE and Seshadri, S and Boada, M and Mañes, S and Heneka, MT and Vitorica, FJ and Ramirez, A and Venero, JL and Ruiz, A},
title = {Human IL-34 Deficiency Primes Microglia Toward Alzheimer's Disease-Associated States.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.21.26346696},
pmid = {42396292},
abstract = {BACKGROUND: Genome-wide association studies (GWAS), with independent replication in large European consortia, have identified a common nonsense variant in IL-34 (Y213X) as a genetic risk factor for late-onset Alzheimer's disease (AD). However, the biological consequences of this IL-34 mutation in humans, its prevalence in the population, and the mechanisms by which IL-34-Y213X alters microglial homeostasis, cerebrospinal fluid (CSF) proteomic networks, and amyloid pathology remain poorly understood.

METHODS: We combined human genetics, cerebrospinal fluid (CSF) and serum proteomics, transcriptomics, large-scale phenome-wide association analyses, and preclinical experimental models to define the impact of human IL-34 deficiency. IL-34 concentrations were first quantified in CSF and serum from deeply phenotyped AD cohorts stratified by the common IL-34-Y213X nonsense variant. IL-34 levels and IL-34-Y213X status were then integrated with unbiased CSF proteomic networks and AD biomarkers. Transcriptomic profiling of purified microglia from IL-34 knockout mice was performed to assess disease-associated microglial programs. Using APP/PS1 mice lacking IL-34, we examined the effects of IL-34 deficiency on microglial survival, tiling, and plaque encapsulation. Finally, we performed postmortem analyses of temporal cortex from AD patients carrying IL-34-Y213X to assess microglial density, spatial organization, and plaque-associated responses.

FINDINGS: IL-34-Y213X was a strong, dose-dependent loss-of-function (LOF) allele that reduced IL-34 levels by up to 2.5 standard deviations in CSF and serum and was common in multiple populations. IL-34 deficiency reshaped CSF proteomic networks, downregulating axon guidance and microglial support modules while upregulating inflammatory and extracellular matrix signatures, and showed pleiotropic associations with neurological, inflammatory, and metabolic traits. Transcriptomic analysis of sorted microglia from healthy 9-month-old IL-34KO compare to wild-type mice revealed a profound pro-inflammatory and disease-associated microglial transcriptional program enriched for disease-associated microglia (DAM) signatures, inflammatory pathways, and AD risk genes including APOE, CLU, and CASS4 . In APP/PS1 mice, genetic IL-34 deletion selectively depleted homeostatic gray-matter microglia, disrupted microglial tiling, and impaired plaque encapsulation, resulting in altered amyloid structure and enhancing neuritic injury. Concordantly, AD patients homozygous for IL-34-Y213X displayed markedly reduced cortical microglial density and increased microglial spatial dispersion, indicating a breakdown of the microglial network organization in the human brain.

INTERPRETATION: A common human IL-34 LOF variant creates a naturally occurring model of IL-34 deficiency that links microglial survival, CSF network signatures, and amyloid pathology in both mice and humans. Importantly, IL-34 deficiency alone is sufficient to induce inflammatory, AD-associated microglial states beyond simply reducing microglial number. These findings identify IL-34/CSF1R signaling as a critical determinant of microglial resilience and a potential upstream pathway linking human genetic variation to AD susceptibility, highlighting IL-34-dependent pathways as promising targets for disease modification.

FUNDING: This work was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades/FEDER/UE (PID2024-157400OB-I00) and FORTALECE program (FORT23/00008; Instituto de Salud Carlos III, Spain) to RRL and JLV, ISCIII of Spain co-financed by FEDER funds (European Union) through grants PI24/00308 (JV) and CIBERNED collaborative grant 2022/01 to JV, PID2023-147125OB-I00 and CEX2023-001386-S (Severo Ochoa Programme) to SMTBC. A.R. is supported by STAR Award. University of Texas System. Tx, United States, The South Texas ADRC. National Institute of Aging. National Institutes of Health. USA. (P30AG066546), the Keith M. Orme and Pat Vigeon Orme Endowed Chair in Alzheimer's and Neurodegenerative Diseases (2024-2025) and Patricia Ruth Frederick Distinguished Chair for Precision Therapeutics in Alzheimer's and Neurodegenerative Diseases (2025-2028). AR is also supported by the Agency for Innovation and Entrepreneurship (VLAIO) grant N° PR067/21 for the HARPONE project and the ADAPTED project the EU/EFPIA Innovative Medicines Initiative Joint Undertaking Grant N° 115975 and CIBERNED (ISCIII).},
}

@article {pmid42396302,
year = {2026},
author = {Mounié, A and Sato, K and Nakashima, S and Niimi, Y and Iwatsubo, T},
title = {Study partner profile effects on CDR-SB change in anti-amyloid therapy evaluation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.26356066},
pmid = {42396302},
abstract = {INTRODUCTION: The Clinical Dementia Rating Sum of Boxes (CDR-SB), a primary outcome in anti-amyloid therapy (AAT) trials, integrates information from participants and study partners. CDR-SB scores may vary by study partner characteristics, but their impact on 18-month change interpretation remains unclear.

METHODS: Using the NACC Uniform Data Set, we fitted linear mixed-effects calibration models in an Alzheimer's disease (AD)-primary early symptomatic cohort and propagated study partner-associated coefficients through Monte Carlo simulations. We estimated components of 18-month CDR-SB change under observed profile changes, simulated follow-up imbalance in a common female living-with profile, and tipping-point scenarios. Analyses were repeated in amyloid-positive and trial-like cohorts.

RESULTS: The AD-primary cohort included 15,061 participants and 7,683 baseline-to-18-month pairs. Observed profile changes generated a negligible cohort-level component (mean 0.0014 points, 95% simulation interval 0.0006 to 0.0022). Simulated follow-up imbalance generated differences of 0.014 to 0.071 points across 10% to 50% reassignment. Under the primary calibration model, generating a 0.45-point difference, equal to the reported Clarity AD CDR-SB group difference, required median net imbalance >100% and was feasible in 48% of iterations. Amyloid-positive and trial-like cohorts had lower median tipping points but wider intervals, reflecting coefficient imprecision.

DISCUSSION: In the large AD-primary cohort, observed study partner profile changes and simulated follow-up imbalance generated CDR-SB differences that were small relative to the 0.45-point Clarity AD benchmark. Biomarker-confirmed estimates were less stable because of coefficient imprecision. These findings suggest limited impact under typical AD-primary conditions but support systematic study partner profile collection and sensitivity analyses in observational and external-comparator CDR-SB studies for AAT evaluation.},
}

@article {pmid42396303,
year = {2026},
author = {Lim, J and Islam, R and Raghavan, D and Omofojoye, B and Rodriguez, AD and Kiarashi, Y and Hershenberg, R and Clifford, GD and Kwon, H},
title = {Wearable sensing for quantifying cognitive and balance functions in naturalistic movements of older adults with mild cognitive impairment in therapeutic environments.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.26355980},
pmid = {42396303},
abstract = {UNLABELLED: Mild cognitive impairment (MCI) is a clinically important stage preceding Alzheimer's disease and related dementias, in which cognitive and balance functions are commonly evaluated using standard clinical assessments such as the Montreal Cognitive Assessment (MoCA) and Mini-Balance Evaluation Systems Test (Mini-BESTest). These assessments are administered episodically by clinicians and may miss functional changes during everyday movement. Recent studies and prior work in the Charlie and Harriet Shaffer Cognitive Empowerment Program (CEP), a therapeutic environment supporting lifestyle intervention and naturalistic social interaction, suggest that wearable and passive behavioral sensing can monitor movement patterns associated with cognitive and balance function in older adults with MCI. However, it remains unclear whether passive waist-mounted IMU data collected during naturalistic movement and social interaction can quantify clinician-rated cognitive and balance outcomes, particularly at the subdomain level, in an interpretable and demographically fair manner. To address this gap, we analyzed weekly IMU recordings collected over 6 months from 44 older adults with MCI in the CEP and trained tree-based ensemble regression models to estimate MoCA and Mini-BESTest total and subdomain scores, with interpretability and demographic fairness evaluation. Our models achieved RMSEs of 3.677 for MoCA and 3.672 for Mini-BESTest, benchmarked against Minimal Detectable Change and Minimal Clinically Important Difference thresholds. Feature importance analysis showed distinct movement signal properties across assessments, with general movement intensity features most informative for MoCA and temporal gait features led by cadence most informative for Mini-BESTest. Demographic bias analysis identified sex-related model bias, mitigated through post-processing while maintaining performance. This study supports the feasibility of wearable-based estimation of clinical assessment scores in older adults with MCI during naturalistic activity, with comparable performance between sexes after bias mitigation. This advances the validation of passive sensing for home monitoring to support clinical decision-making and personalized interventions.

AUTHOR SUMMARY: Mild cognitive impairment (MCI) is an early stage of cognitive decline that may precede Alzheimer's disease and related dementias. Cognitive and balance changes are usually evaluated during clinical visits, but clinical assessments may miss functional changes that occur during everyday movement. In this study, we examined whether waist-worn motion sensors could be used to estimate standard cognitive and balance assessment scores in older adults with MCI during naturalistic activity in a therapeutic program. We used machine learning models to analyze movement patterns collected over six months and evaluated whether the models could estimate total and subdomain scores from the Montreal Cognitive Assessment and Mini-Balance Evaluation Systems Test. We also examined which movement features were most informative, whether estimations differed by sex or race, and whether post-processing bias mitigation reduced these differences. Our findings suggest that passive wearable sensing may provide useful information about cognitive and balance function of older adults with MCI in naturalistic settings. With further validation, this approach could support future monitoring and triage tools by helping identify individuals with MCI who exhibit concerning movement or balance changes and may benefit from more detailed clinical evaluation.},
}

@article {pmid42396306,
year = {2026},
author = {Gomar, JJ and Gordon, ML and Christen, E and Giliberto, L and Keehlisen, L and Gong, M and Hoehn, N and Morley, E and O'Neil, A and Wuelfing, D and Malyavantham, K and Greenwald, B and Marambaud, P and Adrien, L and Jimenez, H and Davies, P and Koppel, J},
title = {Blood-Based Biomarkers Predict Differential Longitudinal Decline in Alzheimer's Disease Psychosis: Evidence from Two Cohorts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.26355956},
pmid = {42396306},
abstract = {INTRODUCTION: Psychosis affects 40% of individuals with Alzheimer's disease (AD) and is associated with accelerated cognitive decline. Blood-based biomarkers, particularly plasma phosphorylated tau (ptau), have demonstrated utility in predicting cognitive decline in AD, with ptau217 showing superior performance in many studies. However, whether these biomarkers predict differential cognitive trajectories in AD with psychosis (ADP) remains unknown.

METHODS: Two independent cohorts were analyzed: Alzheimer's Disease Neuroimaging Initiative (ADNI; n=659: 172 cognitively unimpaired [CU], 406 AD, 81 ADP) and Litwin-Zucker Research Center (LZ; n=142: 68 CU, 57 AD, 17 ADP) with 6-year follow-up. Psychosis was defined by non-zero Neuropsychiatric Inventory delusions or hallucinations scores. In ADNI, plasma ptau181, ptau217, ptau231, amyloid-β42/40, GFAP, and NfL were quantified using NULISA. In LZ, ptau181, ptau205, ptau212, ptau217, amyloid-β42/40, GFAP, and NfL were quantified using Simoa. Linear mixed-effects models assessed prediction of cognitive decline across memory, language, visuospatial, and executive function domains.

RESULTS: In ADNI, baseline ptau181 predicted differential ADP decline in language (p<0.05), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted language (p<0.05) and visuospatial (p<0.05) decline; GFAP predicted language (p<0.05) and visuospatial (p<0.05) decline; and NfL visuospatial decline (p=0.01). In LZ, ptau181 predicted decline in memory (p<0.05), language (p<0.0001), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted memory (p<0.05) and visuospatial (p<0.05) decline; and GFAP predicted language decline (p<0.05). Johnson-Neyman analyses revealed ADP-AD divergence at low ptau181 thresholds in ADNI, while LZ showed crossover patterns with steeper ADP decline at low biomarker levels that attenuated at high levels where AD decline was steeper.

DISCUSSION: ADP exhibited accelerated cognitive decline across domains driven by a distinct biomarker landscape compared to non-psychotic AD. Plasma ptau181 demonstrated broader domain-specific associations with decline in ADP than other blood-based biomarkers and associated exclusively with executive function impairment, indicating its unique utility for predicting cognitive trajectories in this pathophysiological subtype.},
}

@article {pmid42396312,
year = {2026},
author = {Wang, Q and Jiang, M and Luna, A and Niu, X and Nan, Y and Sun, Q and Perrin, RJ and Franklin, E and Cruchaga, C and Flores, S and Benzinger, TLS and Wang, Y},
title = {Histologically validated diffusion MRI signatures of neuroinflammation and neurodegeneration in Alzheimer disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.26354743},
pmid = {42396312},
abstract = {UNLABELLED: Noninvasive neuroinflammation measurement remains a major barrier for Alzheimer disease (AD) therapeutics. We present generalized diffusion basis spectrum imaging (g-DBSI), a diffusion MRI framework that decomposes the tissue signal into biologically interpretable microstructural compartments. In postmortem Knight ADRC brains, g-DBSI-derived restricted isotropic fraction (RIF) and restricted anisotropic fraction (RAF) mapped cellularity and neurofilament density, while their ratio (RIF/RAF) tracked inflammatory cell density and peri-plaque amyloid-beta with higher specificity and regional consistency than RIF alone. In 112 living Knight ADRC participants stratified by PET amyloid, g-DBSI metrics showed amyloid-dependent trajectories: in low-amyloid individuals, RIF and RAF rose together with amyloid, consistent with early neuropil expansion and glial elaboration, whereas in high-amyloid individuals, RIF/RAF increased, and RAF declined, indicating established neuroinflammatory remodeling and neurofilament loss. CSF proteomics linked RIF/RAF to glia-enriched immune and vascular pathways, supporting g-DBSI as a clinically compatible MRI biomarker of neuroinflammation and neurodegeneration in AD.

TEASER: g-DBSI provides noninvasive MRI biomarkers of neuroinflammation and neurodegeneration in AD, validated by histopathology and CSF proteomics.},
}

@article {pmid42396323,
year = {2026},
author = {Vasiljevic, E and Schmitz, LL and Engelman, CD},
title = {Early-life nutritional environment is associated with late-life cognition in the Health and Retirement Study, a pellagra epidemic natural experiment.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.26355481},
pmid = {42396323},
abstract = {Early-life exposures are important to several late-life health outcomes. We sought to study the effect of an in utero nutritional environment and its interaction with Alzheimer's disease (AD) genetic risk on late-life cognitive function. We used a natural experiment created by the pellagra epidemic, a nutritional disease caused by a vitamin B 3 deficiency, to evaluate the association between in utero pellagra epidemic exposure and late-life cognitive function in the Health and Retirement Study (N = 18,285). We also evaluated whether the in utero exposure could modify the AD polygenic score's (PGS) effect on cognition. In utero pellagra epidemic exposure was significantly associated with cognition (β = -0.025). However, these effects were not isolated to the prenatal period as exposure during childhood periods also had an effect. The interaction between the in utero exposure and the AD PGS was significant, where the genetic effect on cognition was amplified with increasing (progressively worse) in utero exposure levels. These associations imply that the early-life nutritional environment affects late-life cognitive function and that these effects can modify genetic risk.},
}

@article {pmid42396324,
year = {2026},
author = {French, SR and Culwell, GC and Wiskoski, HE and Arias, JC and Zahra, S and Escareno, CE and Heitkamp, EN and Garcia, AR and Vidana, P and Quijada, JB and Kasparov, R and Vitali, F and Bedrick, EJ and Mushtaq, R and Alexander, GE and Weinkauf, CC},
title = {Reliable quantification of renal function from frozen blood samples.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.12.26355531},
pmid = {42396324},
abstract = {BACKGROUND: Differences in renal function may affect Alzheimer's disease (AD) blood biomarker levels independent of AD pathology. Although renal function was unaccounted for in foundational AD blood biomarker studies, there is potential to address this through quantification of estimated glomerular filtration rate (eGFR) from frozen serum and plasma samples. However, the validity of eGFR evaluation from long-term frozen blood samples is unknown.

METHODS: Adults aged 50-85 with ≥2 vascular risk factors were recruited from vascular surgery or cardiology clinics in Tucson, Arizona from 2022-2025. Individuals with creatinine assessments in point-of-care whole blood (POC-WB) and frozen serum and plasma samples using the iSTAT (Abbott) were included. eGFR was calculated using the 2021 CKD-EPI creatinine equation without race. Agreement between POC-WB and frozen blood samples was assessed using Cohen's kappa with linear weights.

RESULTS: 134 participants (mean age: 72.6 ± 7.5 years, 39.6% female, 23.1% chronic kidney disease) had POC-WB eGFR available. Frozen serum and plasma samples had strong agreement with POC-WB for eGFR (Kw= 0.90-0.95, P<0.001). Pre-analytical factors had minimal effect on eGFR differences between POC-WB and frozen blood samples.

CONCLUSIONS: Renal function can be assessed from frozen blood samples with high consistency to POC-WB, which may be particularly relevant for interpretation of AD blood biomarkers in general aging and vascular populations who often have impaired renal function.},
}

@article {pmid42396326,
year = {2026},
author = {Ferreira-Atuesta, C and Schubert, KM and Noain, D and Draganski, B and Galovic, M and , },
title = {Association of antiseizure medication with lower amyloid and tau burden.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.26356204},
pmid = {42396326},
abstract = {Network hyperexcitability is increasingly implicated in prodromal Alzheimer's disease and may be suppressed by antiseizure medications (ASMs). ASMs are widely prescribed to older adults, yet whether their use relates to Alzheimer's-disease biomarkers at the population level is unknown. In 52,537 participants in the National Alzheimer's Coordinating Center (NACC) study, we compared cerebrospinal-fluid biomarkers, amyloid and tau positron emission tomography (PET) between ASM users and non-users using inverse-probability-of-treatment weighting with gradient-boosted propensity scores. ASM users showed directionally lower amyloid across multiple brain regions, amplifying markedly in APOE ε4 carriers (Centiloid β = -25.7, p = 0.007). All three temporal tau-PET composites were significantly lower in users (META-temporal β = -0.05, p = 0.01). The amyloid finding replicated independently in the the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (Centiloid β = -8.6, p = 0.01), whereas four comparator drug classes showed no amyloid signal. These convergent observational findings provide a quantitative framework for evaluating ASMs as candidate disease-modifying agents in Alzheimer's disease.},
}

@article {pmid42396344,
year = {2026},
author = {Das, A and Lakhani, C and Mazeeva, VM and Raj, T and Knowles, DA},
title = {An empirical Bayes framework for burden and dispersion association tests helps prioritize rare variants associated with Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.15.26354742},
pmid = {42396344},
abstract = {Rare genetic variants provide critical insight into the mechanisms underlying complex diseases, yet their study is limited by inherent statistical challenges, particularly in the noncoding genome where functional prioritization remains difficult. Here, we introduce parmigiano , an empirical Bayesian framework that systematically integrates functional annotations into existing rare variant association tests (RVATs), jointly learning annotation weights and a global variant filter threshold to enable trait-informed variant prioritization. We apply parmigiano to Alzheimer's disease (AD) whole-genome sequencing data (12,900 cases and 23,846 controls) and perform both coding and noncoding RVATs, leveraging AD-relevant cell-type-specific predictions of variant regulatory effect. Integrating parmigiano significantly increases association yield across five existing RVATs, uncovering 23 candidate AD genes - 19 uniquely detected by our framework -including SIGLEC10 and HUNK . Associations detected by parmigiano replicate more reliably in held-out data than those from the original RVATs and show higher overlap with known AD associations. parmigiano offers a unified, computationally efficient approach to variant prioritization, enabling scalable, interpretable rare variant analyses across coding and noncoding regions.},
}

@article {pmid42396347,
year = {2026},
author = {Gel, A and Phillips, E and Hausle, I and Thropp, P and Tosun, D and , },
title = {MCH-Guard: Multimodal Machine Learning Framework for Risk Stratification of Cerebral Microhemorrhage Risk in the Alzheimer's Disease Neuroimaging Initiative.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.26355972},
pmid = {42396347},
abstract = {BACKGROUND: Efficient cerebral microhemorrhage (MCH) monitoring is critical for anti-amyloid therapy safety due to ARIA-H risk. We developed MCH-Guard, a multimodal machine-learning framework, to stratify MCH risk using ADNI data (N=813).

METHODS: Nested models integrated clinical history, fluid biomarkers, and imaging to predict MCH presence, incidence, and stability.

RESULTS: The comprehensive model detected baseline MCH with high accuracy (AUC 0.86). Notably, the "minimal" model (M1), utilizing only demographics and clinical history, achieved robust performance (AUC 0.82). Longitudinal models predicted time-to-onset (R [2] =0.68) and stratified four-year risk. Furthermore, we identified a transient vascular instability phenotype-where MCH status fluctuates- which was strongly predicted by hepatic factors.

CONCLUSIONS: MCH-Guard offers a flexible clinical decision-support tool for optimizing spontaneous MCH & ARIA surveillance. The strong performance of the clinical-only M1 model supports equitable risk assessment in resource-limited settings, while the characterization of vascular instability addresses a critical confounder in safety monitoring.},
}

@article {pmid42396431,
year = {2025},
author = {Ganitidis, T and Vlontzou, ME and Athanasiou, M and Nikita, KS and Davatzikos, C},
title = {Source-Free Active Learning for Adapting Alzheimer's Diagnostic Deep Learning Models Across Neuroimaging Cohorts.},
journal = {... IEEE-EMBS International Conference on Biomedical and Health Informatics. IEEE-EMBS International Conference on Biomedical and Health Informatics},
volume = {2025},
number = {},
pages = {},
pmid = {42396431},
issn = {2641-3590},
abstract = {Alzheimer's Disease (AD) classification across multiple neuroimaging sites faces significant challenges due to domain shifts arising from variations in data acquisition protocols, imaging devices, and population demographics. While large-scale multi-site datasets offer unprecedented opportunities for developing robust diagnostic models, the heterogeneity between sites often leads to poor model generalization. This work proposes an uncertainty-informed active learning framework for Source-Free (SF) Domain Adaptation (DA) to classify cognitively normal individuals and AD patients across different neuroimaging studies. The proposed approach leverages Monte Carlo dropout to estimate prediction uncertainty and guide the selection of the most informative samples from the target domain for model adaptation, eliminating the need for source domain data during deployment. The framework was evaluated on a large-scale dataset comprising 3,177 participants from five neuroimaging studies (ADNI-1, ADNI-2/3, PENN, AIBL, and OASIS) with 145 regional brain volume measurements. The uncertainty-based active learning approach achieved the highest median AUC of 91.4% across all source-target combinations, outperforming baseline models (89.7%) and demonstrating superior performance compared to other SF and Source-Aware (SA) DA methods. Additionally, the distribution shifts between studies were quantified using maximum mean discrepancy to evaluate the effectiveness under variable inter-site shift. The results demonstrate that SF methods can achieve comparable or superior performance to SA approaches while addressing privacy constraints inherent in medical imaging applications.},
}

@article {pmid42396515,
year = {2026},
author = {Hwang, E and Shim, HS and Kim, SC and Nam, MH and Hyeon, SJ and Kim, HJ and Kim, JE and Park, HJ and Woo, J and Hwang, EM and Stein, T and Lee, J and Choi, JH and Ryu, H},
title = {Basal forebrain parvalbumin neuron dysfunction links network oscillation deficits to hippocampal pathology in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10027900/v1},
pmid = {42396515},
issn = {2693-5015},
abstract = {Background Basal forebrain (BF) degeneration is a key pathological feature of Alzheimer's disease (AD) and is closely associated with cognitive decline. Although parvalbumin (PV)-expressing neurons are abundant in the BF and are important regulators of cortical network activity, their contribution to AD pathogenesis remains poorly understood. Methods To investigate the role of BF-PV neurons in AD, we examined the effects of PV knockdown in the BF of APP/PS1 mice. Electrophysiological recordings, behavioral analyses, retrograde tracing, hippocampal transcriptome profiling, and integrative computational analyses, including meta-correlation analysis and artificial neural network (ANN) modeling, were performed to assess the impact of BF-PV loss on neural network activity, hippocampal pathology, and cognitive function. Results BF-PV knockdown disrupted theta oscillations and theta-gamma coupling in the parietal cortex and impaired hippocampal synaptic activity and memory-related behaviors in mice. Retrograde tracing demonstrated that BF neuronal circuits project directly to the hippocampus. Transcriptome analysis revealed that BF-PV knockdown increased amyloidosis- and microvessel-associated gene signatures while reducing synaptic plasticity-related gene expression in the hippocampus. Furthermore, meta-correlation analyses and ANN modeling indicated that BF-PV dysfunction strongly predicts hippocampal pathology, disrupted EEG coupling, and behavioral abnormalities in AD mice. Conclusions These findings identify BF-PV neuronal dysfunction as an important contributor to hippocampal pathology, neural network dysregulation, and cognitive impairment in AD, highlighting BF-PV neurons as a potential mechanistic link between BF degeneration and AD progression.},
}

@article {pmid42396669,
year = {2026},
author = {Wu, M and Li, Y},
title = {Exercise and fluoxetine in Alzheimer's disease: Molecular mechanisms of synergistic and antagonistic effects (Review).},
journal = {International journal of molecular medicine},
volume = {58},
number = {3},
pages = {},
doi = {10.3892/ijmm.2026.5908},
pmid = {42396669},
issn = {1791-244X},
mesh = {*Alzheimer Disease/drug therapy/metabolism/therapy/pathology ; Humans ; *Fluoxetine/therapeutic use/pharmacology ; Animals ; *Exercise/physiology ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid‑β deposition, tau pathology, synaptic dysfunction, neuronal loss and neuroinflammation. Regular physical activity is a key non‑pharmacological strategy that can ameliorate cognitive impairment and multiple AD‑related pathological features across experimental models by improving mitochondrial function and quality control, strengthening antioxidant defenses, suppressing neuroinflammation and supporting synaptic plasticity. These effects are closely linked to enhanced neurotrophic signaling and cerebrovascular regulation, both of which contribute to resilience against AD‑associated cognitive decline. Fluoxetine, a selective serotonin reuptake inhibitor widely prescribed for depression, has also shown potential benefits in AD models, including modulation of mitochondrial and redox homeostasis, inflammatory signaling and neuroplasticity. The present review integrates evidence on the convergent and divergent molecular targets of exercise and fluoxetine within core AD pathways, highlighting scenarios in which combined interventions may produce synergistic effects, as well as conditions that could lead to antagonistic effects. By mapping shared nodes and potential points of interference, the present review aims to clarify mechanistic hypotheses and inform the design of optimized, clinically translatable strategies that integrate lifestyle and pharmacological approaches for AD.},
}

*Alzheimer Disease/drug therapy/metabolism/therapy/pathology
Humans
*Fluoxetine/therapeutic use/pharmacology
Animals
*Exercise/physiology
Oxidative Stress/drug effects
Mitochondria/metabolism/drug effects
Selective Serotonin Reuptake Inhibitors/therapeutic use

@article {pmid42397410,
year = {2026},
author = {Zhang, Y and Zhang, J and Xu, S},
title = {Correction to: Multiscale characterization and classification of Alzheimer's disease via integration of brain fingerprint radiomics and graph‑theoretical network metrics.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00234-026-04102-9},
pmid = {42397410},
issn = {1432-1920},
}

@article {pmid42397523,
year = {2026},
author = {Chakole, VR and Sen, P},
title = {Overexpression of human interleukin 6 in NaCl inducible bacterial system and its characterization.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
pmid = {42397523},
issn = {1559-0291},
support = {RGEMS seed fund 2025-26//Vellore Institute of Technology, Vellore/ ; },
abstract = {Human Interleukin-6 (hIL6) is a multifunctional cytokine that plays a central role in host defence system due to its wide range of immune and hematopoietic activities. hIL-6 stimulates the inflammatory and autoimmune processes in many diseases such as multiple sclerosis, diabetes, atherosclerosis, Alzheimer's disease, systemic lupus erythematous, multiple myeloma, prostate cancer & rheumatoid arthritis. Due to its clinical and research relevance, production of recombinant hIL-6 in biologically active state is considerably important. In this study, we reported successful cloning, transformation, expression, purification and characterization of hIL-6 by using salt inducible expression system i.e. GJ1158. The hIL6 was subcloned from pcDNA3.1 into the prokaryotic expression vector pRSET-B and transformed in GJ1158. Recombinant expression of protein was done by NaCl at mid-log phase. Cobalt-NTA affinity chromatography (IMAC) and S-200 size exclusion chromatography (SEC) were used to obtain approx. 95% purified hIL6 protein (1.5 mg; 18.8% overall recovery). The recombinant hIL-6 was confirmed by western blotting and MALDI-TOF MSMS while functional validation was done by ELISA and MTT assay. The study establishes a cost effective and environmentally favourable strategy for producing recombinant hIL-6 in a prokaryotic host without compromising structural and functional properties. This expression system can used to produce hIL-6 for research, diagnostic and potential therapeutic applications.},
}

@article {pmid42397646,
year = {2026},
author = {Ardah, MT and Yaseen, BM and Malathi, H and Ray, S and Thyagarajan, R and Shankhyan, A and Eshmetov, R and Ataullaev, Z and Mishra, MK},
title = {Targeted nanomedicine strategies for Alzheimer's disease therapy.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {42397646},
issn = {2731-9229},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and is characterized by amyloid-beta deposition, tau pathology, synaptic dysfunction, and progressive cognitive decline. Currently approved symptomatic therapies, including acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine, provide modest and time-limited benefit and do not directly modify upstream disease drivers. This review synthesizes recent nanomedicine strategies that aim to bridge this gap by integrating biomarker-oriented nanosensors and imaging probes for earlier detection with targeted nanocarriers designed to overcome delivery barriers, particularly the blood-brain barrier, while improving pharmacokinetics and limiting off-target exposure. We highlight converging design principles, including stimulus-responsive release, receptor- and ligand-guided targeting, biomimetic coatings, and organelle-focused delivery to mitochondria and lysosome-autophagy pathways. Beyond repackaging existing agents, nano-enabled approaches are discussed in relation to amyloid and tau clearance or neutralization, redox and mitochondrial rescue, microglia-centered immunomodulation, and regenerative support for neuronal and neurovascular repair. To move beyond a descriptive overview, this review presents a stage-informed and pathology-guided framework for matching nanomedicine design to amyloid-predominant, tau-dominant, neuroinflammatory, mitochondrial, and advanced neurovascular phenotypes. We also evaluate translational constraints, including long-term safety, biodistribution, reproducibility, immunogenicity, scalable manufacturing, regulatory characterization requirements, and the trade-off between biological sophistication and clinical manufacturability. Finally, we distinguish platforms with nearer-term translational potential, such as selected lipid, polymeric, and extracellular vesicle-based systems, from exploratory multifunctional inorganic or highly complex biomimetic designs. This balanced framing clarifies where nanomedicine may realistically advance disease-modifying therapy while identifying evidence gaps that still limit translation.},
}

@article {pmid42397694,
year = {2026},
author = {Liu, X and Li, M and Wei, Z and Shang, T and Zou, W},
title = {Border-Associated Macrophages in CNS Health and Disease: A Comprehensive Review of Ontogeny, Heterogeneity, and Functional Plasticity at Neural Interfaces.},
journal = {ASN neuro},
volume = {18},
number = {1},
pages = {2687503},
doi = {10.1080/17590914.2026.2687503},
pmid = {42397694},
issn = {1759-0914},
mesh = {Animals ; *Macrophages/immunology/metabolism/physiology ; Humans ; *Central Nervous System/immunology/metabolism ; *Neuronal Plasticity/physiology ; *Central Nervous System Diseases/immunology/pathology ; },
abstract = {Border-associated macrophages (BAMs) represent a specialized population of tissue-resident immune cells strategically positioned at the critical interfaces between the central nervous system (CNS) and peripheral circulation, including the meninges, choroid plexus, and perivascular spaces. As frontline sentinels of the neuroimmune system, BAMs perform essential functions in immune surveillance, barrier integrity maintenance, and homeostatic regulation, yet their unique biology and disease-associated roles remain incompletely characterized compared to parenchymal microglia. This review aims to synthesize current knowledge on BAM ontogenetic origins, compartment-specific heterogeneity, transcriptional programs, and functional outputs in both health and neurological disorders. We conducted a comprehensive literature analysis integrating findings from lineage tracing studies, single-cell RNA sequencing, spatial transcriptomics, and functional interrogation in animal models of disease. The results reveal that BAMs exhibit remarkable cellular diversity shaped by distinct ontogenetic origins-primarily yolk sac-derived erythro-myeloid progenitors with variable contributions from fetal liver and postnatal monocytes depending on anatomical compartment. Compartment-specific marker combinations (CD206, LYVE1, CD163, MHCII) define functionally distinct subsets, and core transcriptional regulators including PU.1 and IRF8 maintain BAM identity while CSF-1/IL-34-CSF1R signaling governs survival and renewal. In neurological disorders including ischemic stroke, Alzheimer's disease, multiple sclerosis, and brain tumors, BAMs display pronounced double-edged roles, transitioning from protective homeostatic guardians to pathogenic drivers depending on disease stage and microenvironmental context. This comprehensive analysis establishes a unified framework for understanding BAM biology and identifies critical opportunities for developing subset-specific therapeutic strategies targeting these interface macrophages in neurological diseases.},
}

Animals
*Macrophages/immunology/metabolism/physiology
Humans
*Central Nervous System/immunology/metabolism
*Neuronal Plasticity/physiology
*Central Nervous System Diseases/immunology/pathology

@article {pmid42397748,
year = {2026},
author = {Barata, MA and Guimas Almeida, C},
title = {Protocol for semi-automatic quantitative bioimaging analysis of synapse loss.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104675},
doi = {10.1016/j.xpro.2026.104675},
pmid = {42397748},
issn = {2666-1667},
abstract = {Synapse loss correlates with cognitive decline in neurodegenerative diseases like late-onset Alzheimer's disease. We developed a semi-automated workflow to quantify synapse loss in primary mouse neurons. The protocol includes culturing neurons on coverslips, using short hairpin RNA (shRNA)-expressing lentivirus, maintaining cultures, and labeling excitatory and inhibitory presynaptic markers by immunofluorescence. Image acquisition and analysis using Fiji/ComDet macros enable region of interest selection, neurite length measurement, puncta detection, and quantification of synapse density, size, and intensity following Bin1 knockdown. For complete details on the use and execution of this protocol, please refer to Barata et al.[1].},
}

@article {pmid42398025,
year = {2026},
author = {Zhai, W and Zhou, D and Yuan, Z and Ji, J},
title = {PLNFGL: Joint Estimation of Multi-Condition Gene Networks from Single-cell RNA-seq Data.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag485},
pmid = {42398025},
issn = {1367-4811},
abstract = {MOTIVATION: Graphical models have been widely used in bioinformatics to infer the conditional dependence structure among random variables, but traditional Gaussian graphical models (GGMs) are suboptimal for single-cell RNA sequencing (scRNA-seq) due to dropout events and distributional mismatch. Moreover, most existing methods estimate networks under a single condition, limiting their utility in multi-condition studies.

RESULTS: We propose PLNFGL (Poisson Log-Normal Fused Graphical Lasso), a joint network estimation framework for scRNA-seq data. PLNFGL uses a multivariate Poisson log-normal model to accommodate dropout effects and estimates the covariance via moment methods. A joint graphical model is then employed to infer condition-specific precision matrices. Simulations show improved estimation accuracy. Applications to scRNA-seq data of Alzheimer's disease and spatial transcriptomics of lung cancer reveal cell-type-specific interaction networks. Edge set enrichment enables pathway analysis, validating known interactions and highlighting novel disease-related targets. This work provides a powerful tool for the integrative analysis of scRNA-seq data.

The R implementation of PLNFGL is available at https://github.com/jijiadong/PLNFGL, and an archival version is available on Zenodo at https://doi.org/10.5281/zenodo.20744172.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid42398038,
year = {2026},
author = {Hoang, MN and Kim, L and Fisher, L and DuBose, L and Ory, MG and Lee, S and Falohun, T and Fan, Q},
title = {Exploring Informal Caregivers' Perception of the Olera Digital Caregiving Assistance Platform for Dementia Care: Mixed Methods Evaluation Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e92967},
doi = {10.2196/92967},
pmid = {42398038},
issn = {2561-326X},
mesh = {Humans ; *Caregivers/psychology/statistics & numerical data ; *Dementia/psychology/therapy/nursing/complications ; Female ; Middle Aged ; Male ; Aged ; *Perception ; Surveys and Questionnaires ; Qualitative Research ; Adult ; Digital Health ; Aged, 80 and over ; Digital Media ; Mobile Applications/standards ; Internet ; },
abstract = {BACKGROUND: Informal caregivers of people living with dementia often experience high rates of caregiver burnout while providing care. Although there are many websites and mobile apps available to help caregivers, many do not use digital tools. The Olera platform was developed to be an easily adoptable web-based support tool, connecting caregivers with long-term services and supports, financial assistance, and educational resources. The platform was developed based on the Build-Measure-Learn framework with input from caregiver needs assessments and usability studies.

OBJECTIVE: This study aims to evaluate the quantitative and qualitative feedback of informal caregivers of people living with dementia on the second iteration of the Olera platform. The primary objective was to assess caregivers' acceptance of this caregiving platform. The secondary objective was to use qualitative methods to explore (1) the study cohort's challenges in daily caregiving to determine and compare them with prior literature, (2) their experience when using the Olera platform, and (3) their attitudes toward integrating artificial intelligence in caregiver services for future studies and platform development.

METHODS: Caregivers were recruited through various sources and screened for eligibility through an initial survey. Participants used the platform for 4 weeks and completed a survey with an adapted Technology Acceptance Survey (TAS) and qualitative open-ended questions at the end of the testing period. TAS responses were summarized with descriptive statistics, while ANOVAs, t tests, and linear regressions were used to compare the differences in the overall TAS scores by caregiver characteristics. Qualitative feedback data on the platform's usefulness were analyzed via a thematic analysis framework approach.

RESULTS: A total of 65 caregivers in the United States completed the study, with a mean age of 59.9 (SD 9.8) years. The majority were female (61/65, 95.3%), non-Hispanic or Latino White (45/65, 69.2%), and the adult child of their care recipient (42/65, 64.6%). Evaluation of the Olera platform showed a high acceptance rate, with each TAS item scoring above 5.0 and an overall TAS score of 5.83 (SD 0.85) out of 7. Higher platform use frequency was associated with higher TAS ratings in technology acceptance (F3,61=7.88, P<.001). Thematic analyses elicited the caregiving challenges, evaluation of the Olera platform, and feedback on artificial intelligence-assisted support.

CONCLUSIONS: The Olera platform is an example of a beneficial web-based tool, though key features were requested to be included in the next iteration. Additionally, data supported prior findings regarding informal caregiver challenges and the insufficiency of conventional support mechanisms, indicating a need for more innovative digital solutions. Future research and development efforts using the Build-Measure-Learn approach are necessary to further iterate the platform's key features, enhance the tool, involve more informal caregivers in its improvements, and serve as a model for customizable, person-centered online care support.},
}

Humans
*Caregivers/psychology/statistics & numerical data
*Dementia/psychology/therapy/nursing/complications
Female
Middle Aged
Male
Aged
*Perception
Surveys and Questionnaires
Qualitative Research
Adult
Digital Health
Aged, 80 and over
Digital Media
Mobile Applications/standards
Internet

@article {pmid42398039,
year = {2026},
author = {McKenna, M and Torous, J and Rozenblit, E and Flathers, M and Ryan, S and Byun, AJS and Lim, C},
title = {Real-Time Smartphone Monitoring Assessments as a Cognitive Biomarker of Alzheimer Disease: Protocol for a Development Study.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e93259},
doi = {10.2196/93259},
pmid = {42398039},
issn = {1929-0748},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Smartphone ; Pilot Projects ; Biomarkers/analysis ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Female ; Cognition ; },
abstract = {BACKGROUND: The diagnosis and monitoring of Alzheimer disease (AD) currently rely on clinician-administered, in-person, and cross-sectional pen-and-paper cognitive assessments. While clinically validated, these measures are time-intensive, infrequently administered, and limited in their ability to detect early, subtle, or short-term cognitive changes. Thus, more frequent, ecologically valid assessments are critical to improving sensitivity to early cognitive impairment and disease progression.

OBJECTIVE: This study aims to develop and pilot a smartphone-based assessment battery that combines active cognitive assessments with passive smartphone sensor data (eg, steps, sleep) and survey data to identify and longitudinally characterize cognitive impairment associated with AD.

METHODS: We developed a suite of digitized versions of standard cognitive tests alongside novel, game-based cognitive tests within the mindLAMP platform. Uniquely, these tests integrate into the platform's mobile survey and digital phenotyping capabilities to produce a comprehensive assessment tool capable of simultaneously tracking self-reported, behavioral, and cognitive symptoms in real time. These tools were unified within the Smartphone Monitoring Assessment in Real Time-Alzheimer's framework. Across a 6-month pilot study involving individuals with mild cognitive impairment or mild AD, we will examine the feasibility, acceptability, and longitudinal adherence to these assessments. We will compare digital cognitive and passive data streams against standard clinical assessments to evaluate their usefulness in detecting cognitive impairment and change over time.

RESULTS: Recruitment began in April of 2025. As of February 2026, 13 participants with mild cognitive impairment or AD (mean age 72.8, SD 6.5 y, 8 male) and 12 controls (mean age 71.6, SD 7.8 y, 6 male) have been enrolled; recruitment is ongoing. Preliminary analyses on participant compliance, passive data, and variations in game scores are in progress. Data analysis is expected to be completed by mid-2026, and we anticipate results to be published in 2027. This study is funded by the a2 Pilot Awards, a subaward of funding given to the Trustees of the University of Pennsylvania under the a2 Collective, beginning in April 2024.

CONCLUSIONS: Smartphone-based cognitive assessments, when combined with digital phenotyping, offer a scalable and ecologically valid approach to detecting and monitoring AD in real-world settings. This framework has the potential to enhance early detection, enable continuous monitoring, and support future machine learning-based automated identification of cognitive impairment, ultimately facilitating earlier and more personalized care.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
*Smartphone
Pilot Projects
Biomarkers/analysis
*Cognitive Dysfunction/diagnosis
Neuropsychological Tests
Female
Cognition

@article {pmid42398140,
year = {2026},
author = {Zhu, Q and Ye, N and Huang, L and Wang, H and Zhao, Q and Ma, L and She, G and Mu, L and Shi, W},
title = {A nanowire-based fluorescent sensor for detecting hydrogen peroxide (H2O2) dyshomeostasis in cell body and synapse of Alzheimer's disease (AD) cell model.},
journal = {Talanta},
volume = {311},
number = {},
pages = {130250},
doi = {10.1016/j.talanta.2026.130250},
pmid = {42398140},
issn = {1873-3573},
abstract = {Revealing the levels of hydrogen peroxide (H2O2) in neuron's cell body and synapse with high spatial resolution is very important not only for clarifying the pathways between the fluctuation of H2O2 and neurotoxicity of amyloid-β oligomers (AβOs), but also for further understanding the pathogenesis of Alzheimer's disease (AD). Herein, a single nanowire-based H2O2 fluorescent sensor has been designed and developed by covalently modifying H2O2-responsive molecules onto the surface of silicon nanowires (SiNWs). The sensor features high spatial resolution, excellent selectivity and high sensitivity. By positioning SiNW sensors into both cellular compartments, respectively, the AβOs-induced alterations of H2O2 levels in cell body and synapse of neurons are detected. It is found that H2O2 levels in cell body and synapse are gradually elevated with prolonging AβOs exposure. Moreover, the elevation of H2O2 in synapse occurs prior to the increase in cell body. It is demonstrated that the clathrin-mediated endocytosis serves as a prime pathway mode for transporting exogenous AβOs into the cells, and plays a critical role in preferentially elevating H2O2 levels in synapse. The method developed in this work for monitoring H2O2 with high spatial resolution will be beneficial for exploring the critical role of H2O2 in AD pathogenesis.},
}

@article {pmid42398193,
year = {2026},
author = {Saumur, TM and Ashraf, H and Mathers, KE and Wagner, B},
title = {Pharmacotherapy for Alzheimer's Disease and Dementias in Long-Term Care: A Real-World EHR Study.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {9},
pages = {106293},
doi = {10.1016/j.jamda.2026.106293},
pmid = {42398193},
issn = {1538-9375},
abstract = {OBJECTIVES: To characterize contemporary pharmacologic medication order patterns for Alzheimer's disease (AD) and related dementias (ADRD) among US long-term care (LTC) residents and to examine facility- and resident-level factors associated with treatment.

DESIGN: Retrospective and observational study.

SETTING AND PARTICIPANTS: Electronic health record data from 1,675,873 LTC residents in the PointClickCare Life Sciences clinical database included 295,946 with a documented ADRD diagnosis in skilled nursing facilities in the United States who remained in facility at the end of the study window (January-April 2025).

METHODS: Residents were classified as treated/untreated based on the presence of ≥1 ADRD medication order as outlined by the Alzheimer's Association. Analyses incorporated demographics, comorbidities, medication burden, and facility characteristics. Multivariate logistic regression estimated the odds of having an ADRD medication order.

RESULTS: Overall, 82.0% of residents with ADRD had ≥1 order for ADRD medication. Treatment was most common among residents with Lewy body dementia (91.1%) and early onset AD (90.3%) and least frequent among Asian (72.3%), Native Hawaiian, or Other Pacific Islander (74.6%) and short-stay residents (75.6%). Treated residents exhibited a higher medication burden (mean, 8.6 vs 6.3). Diagnoses for other chronic conditions as well as specific ADRD subtypes strongly impacted probability of treatment; diabetes was associated with lower odds of treatment, whereas ADRD subtypes strongly predicted treatment.

CONCLUSIONS AND IMPLICATIONS: Approximately one-fifth of residents with ADRD did not have an ADRD medication order, and treatment varied significantly by nonclinical predictors. These findings underscore the need to investigate and understand possible treatment disparities, optimize polypharmacy management, and discover new ADRD treatments, and develop safer and more effective ADRD therapies.},
}

@article {pmid42398284,
year = {2026},
author = {Basu, R and Polsky, DE and Van Houtven, CC},
title = {Patient-Driven Grouping Model and Home Health Use Among Traditional Medicare Beneficiaries.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {8},
pages = {106327},
doi = {10.1016/j.jamda.2026.106327},
pmid = {42398284},
issn = {1538-9375},
abstract = {OBJECTIVES: In January 2020, the Centers for Medicare & Medicaid Services implemented the Patient-Driven Groupings Model (PDGM), the most substantial revision to Medicare's home health (HH) prospective payment system since its introduction in 2000. PDGM shortened the payment period from 60 to 30 days and eliminated therapy visit thresholds from payment calculations. Because Medicare's HH payment policies have historically shaped patterns of service use, payment changes under PDGM were expected to influence service intensity and episode length. The aim of this study is to examine whether PDGM influences HH utilization among Medicare beneficiaries, particularly those with Alzheimer's disease and related dementias (ADRD).

DESIGN: Cross-sectional cohort study.

SETTINGS AND PARTICIPANTS: A 20% random sample of traditional Medicare beneficiaries who used HH services in 2019 (pre-PDGM) and 2021 (post-PDGM).

METHODS: We compared total HH visits and length of stay (LOS) during a standardized 60-day episode in the pre- and post-PDGM periods. Generalized linear models were used to estimate changes in visit volume and LOS following PDGM implementation, comparing beneficiaries with ADRD and without ADRD.

RESULTS: Beneficiaries with ADRD experienced a steeper decline in total visits (from 22.4 to 17.9) compared with those without ADRD (from 18.2 to 15.4), driven by reductions in therapy visits, which fell from 12.9 to 9.9 among beneficiaries with ADRD and from 9.8 to 8.3 among those without ADRD. The average LOS within a 60-day episode also decreased after PDGM implementation. Adjusting for patient-level characteristics, beneficiaries with ADRD in the post-PDGM period received 2.04 fewer total visits, including 1.4 fewer therapy visits, than those without ADRD. These patterns differed by the severity of ADRD.

CONCLUSIONS AND IMPLICATIONS: PDGM's reimbursement changes and the shortening of the payment period may disproportionately affect Medicare beneficiaries with ADRD, underscoring the need to assess the implications for patient outcomes and future refinements of the payment policy.},
}

@article {pmid42398294,
year = {2026},
author = {Jyothi, GD and Kumar, CM and Kottala, RK},
title = {Combined transformer encoder-CNN architecture with texture features for MRI-based Alzheimer's disease detection.},
journal = {Psychiatry research. Neuroimaging},
volume = {362},
number = {},
pages = {112277},
doi = {10.1016/j.pscychresns.2026.112277},
pmid = {42398294},
issn = {1872-7506},
abstract = {Alzheimer's disease (AD) develops long before clinical symptoms appear, which highlights the need for early diagnostic tools. Current diagnostic techniques often miss the subtle structural brain changes in the early stages of AD, creating a critical gap in timely medical intervention. This paper proposes a combined modified Transformer Encoder-Convolutional Neural Network (CNN) architecture for AD detection using Magnetic Resonance Imaging (MRI). Data augmentation techniques, including rotation, zooming, brightness adjustment and flipping, are applied to increase the number of training images. Images are processed using a Modified Gaussian Filtering technique (modGFT) that implements a spatially adaptive variance to suppress noise while preserving critical anatomical edges and structural details. Relevant features, including shape features, Improved Median Robust Extended Local Binary Pattern (ImpMRELBP) and Pyramid Histogram of Oriented Gradients (PHOG) features, are extracted. The ImpMRELBP descriptor highlights boundaries and captures meaningful texture variations. These features are input into a hybrid modTransEncd-CNN detection model. The model incorporates batch normalization and an enhanced attention module, improving training speed, stability and generalization. The results from both models are merged using soft voting for AD classification. Experimental results demonstrate that the proposed modTransEncd-CNN method outperforms traditional models, achieving 96% accuracy.},
}

@article {pmid42398379,
year = {2026},
author = {Mosquera Losada, ME and Martín, JP and Mariño, AO and Gómez-Conesa, A},
title = {Aetiological diagnosis of cognitive impairment in older adults: The role of geriatric nursing and factors associated with its detection.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {72},
number = {},
pages = {104157},
doi = {10.1016/j.gerinurse.2026.104157},
pmid = {42398379},
issn = {1528-3984},
abstract = {AIMS: To quantify the proportion of residents with cognitive impairment who receive an aetiological diagnosis during their stay in nursing homes, to identify associated sociodemographic and stay-related factors, and to evaluate the association between geriatric specialist availability and aetiological diagnosis METHODS: Retrospective observational cohort study with up to 24 months of follow-up across eight nursing homes in Pontevedra, Spain. Participants were aged ≥60 years, had cognitive impairment at admission and no prior aetiological diagnosis (n = 98). The primary outcome was receipt of an aetiological diagnosis during the stay.

RESULTS: An aetiological diagnosis was recorded in 26/98 residents (26.5%). Among those diagnosed, dementia accounted for 69.2%; vascular dementia predominated (55.5%), followed by Alzheimer's disease (22.2%); in 22.2% the subtype was not recorded. Median length of stay was longer in residents who received a diagnosis (24 vs 5.5 months; p < 0.01). In bivariate analyses, the presence of a geriatric nurse and a geriatrician was associated with a greater likelihood of receiving an aetiological diagnosis.

CONCLUSIONS: Only one quarter of residents with cognitive impairment received an aetiological diagnosis during their stay, indicating considerable scope for improvement. Longer length of stay and the presence of healthcare professionals specialised in geriatrics were associated with higher diagnostic rates.},
}

@article {pmid42398400,
year = {2026},
author = {Xin, Z and Tan, H and Xu, Y and He, P and Wang, Z and Bu, X and Wu, H},
title = {Design, synthesis and evaluation of dual modulators targeting glutaminyl cyclase and cannabinoid CB2 receptor.},
journal = {European journal of medicinal chemistry},
volume = {317},
number = {},
pages = {119115},
doi = {10.1016/j.ejmech.2026.119115},
pmid = {42398400},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is the major cause of dementia and one of the most common chronic diseases affecting aging populations. As such, novel and effective therapeutic agents are urgently needed to address this growing public health challenge. Given the involvement of glutaminyl cyclase (QC) and cannabinoid type 2 receptor (CB2R) dysregulation in AD progression, we designed, synthesized, and evaluated a series of biphenyl carboxamide derivatives as dual modulators targeting QC and CB2R. In vitro assays showed that most of the 35 compounds exhibited notable QC inhibitory and CB2R agonistic activity; for example, compound 18 demonstrated potent activity against both targets (QC, IC50 = 0.65 ± 0.07 μM; CB2R, EC50 = 0.32 ± 0.04 μM). Structure-activity relationship analysis indicated that the amide-linked motif (R[1]) is critical for CB2R agonistic potency, while the introduction of a methoxy group (R[2]) on the biphenyl scaffold enhances activity against both targets. Molecular docking further supported the interactions between these compounds and their respective protein targets. Taken together, these dual modulators targeting QC and CB2R warrant further investigation as potential therapeutic candidates for AD.},
}

@article {pmid42398567,
year = {2026},
author = {Quach, B and Salehi, S and Roufegarinejad, R and Guleria, VS and Mante, M and Florio, J and Rissman, RA and Winston, CN},
title = {Neuropathological and functional impact of astrocyte-derived extracellular vesicles in an aged model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115893},
doi = {10.1016/j.expneurol.2026.115893},
pmid = {42398567},
issn = {1090-2430},
abstract = {Extracellular vesicles (EVs) are lipid-bound particles that transfer cargos between cells. While plasma neuronal-derived EVs (NEVs) from individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have been reported to exhibit high pathogenic potential, this study examined the impact of astrocyte-derived EVs (AEVs) in an aged AD mouse model. Plasma AEVs were isolated from cognitively normal control (CNC), MCI, and AD individuals using GLAST-based immunocapture and AEV size, purity, and tetraspanin were validated by flow cytometry, nanoparticle tracking, and super-resolution microscopy. AEVs pooled by clinical cohort were injected into the hippocampus of 6-month-old female PSAPP mice. Behavioral, biochemical, and neuropathological outcomes were assessed 6 months later. Rotarod assessment revealed significant impairment in motor coordination (p < 0.0001) in mice receiving MCI- and AD-AEVs compared with those receiving CNC-AEVs. While Morris water maze (MWM) also demonstrated that CNC-AEVs injected mice exhibited a trend toward increased target quadrant entries and faster escape latencies, these measures did not reach did not reach statistical significance. No overt changes were observed in the staining of amyloid plaque burden (6E10), and astrogliosis (GFAP). Immunoblotting of 82E1 and 22C11 confirmed Aβ/AAP levels remained similar across all injected mice, whereas increased cortical tau accumulation was observed in MCI- and AD-AEV injected mice. Cerebellar synaptic density (SY-38) remained unchanged. These findings suggest that while human-derived AEVs can precipitate early tau-related changes and motor coordination deficits, they do not significantly alter overall amyloidosis or astrocyte-reactivity at this time point. Further investigation is required to determine the viability of AEVs as biomarkers or therapeutic targets given the subtle nature of the observed structural pathology.},
}

@article {pmid42398608,
year = {2026},
author = {Chen, L and Kang, X and Deng, W and Zhang, Y and Zhao, Y and Song, C and Yang, Z},
title = {Structural characterization of a branched α-glucan from Pseudostellaria heterophylla and its neuroprotective effect against Alzheimer's disease via regulating the microbiota-gut-brain axis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153352},
doi = {10.1016/j.ijbiomac.2026.153352},
pmid = {42398608},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options. Emerging evidence highlights the gut-brain axis as a promising target, and natural polysaccharides offer multi-target advantages. Here, we isolated and structurally characterized PF30-3, a homogeneous branched α-D-glucan (69.91 kDa) from Pseudostellaria heterophylla, featuring a (1 → 4)-α-d-glucopyranosyl backbone with (1 → 4,6)-α-d-glucopyranosyl branching points. In LPS-stimulated RAW264.7 macrophages, 200 μg/mL PF30-3 significantly inhibited nitric oxide release, restored cell viability, and rebalanced inflammatory cytokines. The in vivo efficacy was first validated in an Aβ1-42-induced zebrafish AD-like model, where 20 mg/kg PF30-3 effectively rescued spatial memory and learning impairments. These findings were further translated to 5 × FAD mice, in which oral administration of 50 mg/kg PF30-3 for 24 consecutive days significantly improved the recognition and spatial memory without observable acute toxicity. Mechanistically, PF30-3 reduced cerebral Aβ deposition in vivo, an effect not attributable to direct aggregation inhibition as shown by ThT and CD assays. Instead, PF30-3 exerted its effects through multiple indirect pathways, including inhibition of glial cell hyperactivation, repair of intestinal barrier integrity, rebalancing of serum inflammatory cytokines, and remodeling of gut microbiota composition, characterized by a decreased Firmicutes/Bacteroidota ratio and enrichment of beneficial genera such as Muribaculum, Bacteroides, and Prevotellaceae_UCG-001. Correlation analyses linked these microbial shifts to improved cognitive outcomes and reduced neuroinflammation. Collectively, these findings demonstrate that PF30-3 exerts neuroprotective effects through modulation of the microbiota-gut-brain axis, highlighting it as a promising natural polysaccharide-based candidate for AD therapy.},
}

@article {pmid42121377,
year = {2026},
author = {Shieu, B and Neidre, DB and Song, L and Delgado, RE and Cary Reid, M and Gaugler, JE and White, CL},
title = {Latino family caregivers: "it's what we do-we take care of our own".},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {81},
number = {8},
pages = {},
pmid = {42121377},
issn = {1758-5368},
support = {#2021318//RRF Foundation for Aging/ ; },
mesh = {Humans ; *Caregivers/psychology ; *Hispanic or Latino/psychology ; *Dementia/nursing/ethnology ; Female ; Aged ; Community-Based Participatory Research ; Male ; Qualitative Research ; Middle Aged ; Texas/ethnology ; Aged, 80 and over ; Adult ; },
abstract = {OBJECTIVES: To better understand the interplay of culture and family caregiving among Latinos, we explored the perceptions of caregivers of persons living with dementia on how their culture informs the care they provide.

METHODS: This study used a descriptive qualitative design to explore the perceptions of Latino family caregivers of persons living with dementia. A Community-Based Participatory Research (CBPR) approach underpinned the study design and execution, with a Latino Caregiver Advisory Council (LCAC) engaged in study design, recruitment, and interpretation. Individual semi-structured interviews were conducted via Zoom with Latino family caregivers of persons living with dementia from South Central Texas, in either English or Spanish. The interview guide consisted of questions about participants' perceptions of caregiving and culture. Content analysis was used to analyze the transcripts.

RESULTS: Among 13 caregivers, we identified two overarching themes, "The Influence of Culture on Caregiving" and "Barriers to Care," that together illustrate how cultural values serve as a profound source of both resilience and distress. We identified key subthemes related to the influence of culture (i.e., motivations for providing care, who provides this care, and where it is provided) and barriers to care (i.e., cultural beliefs about dementia, structural barriers to accessing resources, and systemic financial challenges).

DISCUSSION: Our findings indicate that culture can be a source of strength and a source of stress for Latino family caregivers. These results highlight the need for tailored caregiver support intervention programs that recognize the cultural influence shaping how families give and receive care.},
}

Humans
*Caregivers/psychology
*Hispanic or Latino/psychology
*Dementia/nursing/ethnology
Female
Aged
Community-Based Participatory Research
Male
Qualitative Research
Middle Aged
Texas/ethnology
Aged, 80 and over
Adult

@article {pmid42385986,
year = {2026},
author = {Millhauser, GL and Singewald, K and Smart, A and Pavlovici, F},
title = {Isotope-Edited ESEEM: A New Method for Probing Copper Binding Sites in Neurodegenerative Proteins.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113310},
doi = {10.1016/j.jbc.2026.113310},
pmid = {42385986},
issn = {1083-351X},
abstract = {The interactions between intrinsically disordered domains in neurodegenerative proteins are often stabilized by the inclusion of physiologic metal ions such as copper or zinc. Characterizing the metal ion coordination environment in such cases is critical for assessing the stability and organization of these relevant protein-protein interactions but is challenging given the lack of regular molecular order of the relevant protein domains. We recently developed a new pulsed Electron Paramagnetic Resonance (EPR) approach that takes advantage of Electron Spin Echo Envelope Modulation (ESEEM) with selective [15]N isotope labeling. Histidine side chains with [14]N or [15]N coordinated to Cu[2+] give distinct, fully resolvable signals in both ESEEM and its two-dimensional companion method HYSCORE. The approach was applied to the cellular prion protein, PrP[C], to investigate how its otherwise neurotoxic, disordered N-terminal domain is regulated through a Cu[2+] linkage to its globular C-terminal domain. Sortase-mediated ligation created an expressed murine prion protein with segmental [15]N-labeling exclusive to the N-terminal domain. Isotope-edited ESEEM identifies the specific His residues from both domains that participate in this essential regulatory process. Extending this approach to hetero-protein complexes focused on how Cu[2+] may facilitate the interaction between PrP[C] and the Aβ peptide, a dominant component of senile plaques in Alzheimer's disease. Combining [15]N-labeled PrP[C] with unlabeled Aβ, shows that both proteins simultaneously coordinate Cu[2+] with Aβ contributing a single His side chain. Collectively, this review highlights isotope-edited ESEEM as an effective method for achieving residue-specific insights into metal coordination within structured and disordered protein complexes.},
}

@article {pmid42386071,
year = {2026},
author = {Del Castillo, IL and Garcia-Martin, J and Gutierrez, A and Moreno-Gonzalez, I},
title = {Amylin at the crossroads of type 2 diabetes and neurodegenerative diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103226},
doi = {10.1016/j.arr.2026.103226},
pmid = {42386071},
issn = {1872-9649},
abstract = {Type 2 diabetes (T2D) is traditionally viewed as a metabolic disease centered on insulin resistance and β-cell failure. However, growing evidence supports its reclassification as a systemic proteinopathy, in which the aggregation of amylin (islet amyloid polypeptide, IAPP) emerges as a key pathogenic event. In this review, we examine the shift toward an IAPP-centric model of disease, highlighting how IAPP misfolding and aggregation drive β-cell dysfunction independently of, and in parallel with, metabolic stress. We integrate recent advances in the structural biology of IAPP to provide a mechanistic framework for its cytotoxicity. IAPP aggregation disrupts cellular homeostasis through membrane damage, proteostasis imbalance, mitochondrial dysfunction, oxidative and ER stress, and inflammation, ultimately leading to progressive β-cell loss. Beyond the pancreas, we position IAPP as a molecular bridge between peripheral metabolic stress and neurodegeneration. Through prion-like cross-seeding, IAPP interacts with Aβ, tau, α-synuclein, and PrP, linking T2D as a major risk factor for neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. We review emerging therapeutic strategies, including long-acting non-fibrillating analogues that suppress endogenous secretion, cross-amyloid inhibitors, conformation-specific immunotherapies, and synthetic chaperones. Finally, we discuss structure-based and AI-driven diffusion models as tools to design binders that selectively mask the amyloidogenic core while preserving the homeostatic function of IAPP. Given the projected magnitude of T2D, targeting the IAPP-neurodegeneration axis through early detection and midlife intervention is essential to mitigating the impending socioeconomic impact of combined metabolic and cognitive decline.},
}

@article {pmid42386101,
year = {2026},
author = {Kitagawa, T and Kamagata, K and Uchida, W and Takabayashi, K and Andica, C and Rui, Z and Ozawa, T and Hagiwara, A and Akashi, T and Sano, K and Wada, A and Tanaka, Y and Hosoi, R and Kanzawa, J and Aoki, S and , },
title = {Investigating tau-related white matter degeneration in Alzheimer's disease using fixel-based analysis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107518},
doi = {10.1016/j.nbd.2026.107518},
pmid = {42386101},
issn = {1095-953X},
abstract = {Alzheimer's disease involves the accumulation of amyloid-β and tau proteins, with tau-related white matter degeneration potentially contributing to cognitive impairment. This study investigated the relationship between regional tau deposition and white matter degeneration using fixel-based analysis and examined whether white matter changes mediate tau-related cognitive decline. We analyzed data from 285 participants in the Alzheimer's Disease Neuroimaging Initiative, classified based on amyloid and tau biomarker status into four groups: 141 amyloid-negative tau-negative cognitively unimpaired (A - T - CU), 58 amyloid-positive tau-negative cognitively unimpaired (A + T - CU), 49 amyloid-positive tau-positive mild cognitive impairment (A + T + MCI), and 37 amyloid-positive tau-positive dementia (A + T + Dementia). Fixel-based analysis metrics included fiber density, log-transformed fiber-bundle cross-section, and their combined measure derived from diffusion MRI. These were evaluated in relation to [18]F-flortaucipir tau PET standardized uptake value ratios and multiple cognitive assessments. Results showed that A + T + MCI and A + T + Dementia participants exhibited significantly reduced fixel-based metrics in subcortical white matter adjacent to cortical regions with high tau deposition, particularly in temporal and frontal areas (FDR-corrected p < 0.05), with more widespread reductions in A + T + Dementia. Mediation analysis revealed that white matter degeneration across multiple subcortical white matter regions adjacent to temporal, insular, and parietal cortices significantly and partially mediated the relationship between regional tau deposition and cognitive decline, accounting for 6.3-19.7% of the total effect. These findings suggest that tau-related white matter degeneration in regions adjacent to heavily affected cortical areas partially contributes to cognitive impairment in Alzheimer's disease.},
}

@article {pmid42386501,
year = {2026},
author = {Karlovich, E and Priemer, DS and Rhodes, CH and Perl, DP and Tanji, K and Goldman, JE},
title = {Non-Alzheimer Aβ deposits in the human CNS: Implications with hypoxia and related conditions.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70120},
doi = {10.1111/bpa.70120},
pmid = {42386501},
issn = {1750-3639},
support = {//Thompson Family Foundation/ ; HU00012120007//Uniformed Services University of the Health Sciences/ ; 312159-1.00-66531//Henry M. Jackson Foundation/ ; //Department of Defense Uniformed Services University Brain Tissue Repository and Neuropathology Program/ ; },
abstract = {We recently reported the deposition of Aβ in the frontal cortex of individuals who died of acute coronavirus disease 2019 (COVID-19), or who did not have COVID-19 but had respiratory distress, or infants with severe cardiac malformations. These Aβ deposits were not the senile, neuritic core "plaques" of Alzheimer's disease (AD) and did not stain for Thioflavin-S or with antibodies to phosphorylated tau protein. Here, we examined multiple sections of the brains of such individuals, finding these non-Alzheimer Aβ deposits (NADAs) predominantly in the isocortex, including frontal, temporal, insular, and occipital, but also in subcortical structures such as the diencephalon, cerebellum, brainstem, and spinal cord, albeit many fewer. NADAs also appeared around blood vessels and within blood vessel walls, but did not incite an inflammatory response. We also examined brains of individuals with metabolic and mitochondrial diseases that lead to hypoxic damage and one individual with severe hyperthermia. All had NADAs identical to the ones we previously reported. These Aβ deposits somewhat resemble the amorphous or diffuse plaques or deposits that have been thought to be associated with early stages of AD, but they are morphologically distinguishable and appear in brains of young individuals who have no Alzheimer pathology. We suggest that the deposits are associated with hypoxia or related mechanisms of injury.},
}

@article {pmid42386668,
year = {2026},
author = {Mascioli, D and Mancini, M and Conti, M and Bissacco, J and Buttarazzi, V and Simonetta, C and Avvento, F and Veltri, F and Nesci, V and Bernardini, S and Sancesario, GM and Centonze, D and Stefani, A and Pierantozzi, M and Schirinzi, T},
title = {Alzheimer's Disease Cerebrospinal Fluid Biomarkers Predict Survival in Progressive Supranuclear Palsy.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70418},
pmid = {42386668},
issn = {1531-8257},
support = {PNRR-M4C2-I1.3 Project PE_00000019 "Heal Italia"//Italian Ministry of University and Research (MIUR)/ ; PRIN Bando 2022 Prot. 20222FYK9R//Italian Ministry of University and Research (MIUR)/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD)-related pathology may co-occur in progressive supranuclear palsy (PSP), although its clinical and prognostic impact is unclear.

OBJECTIVES: To assess whether cerebrospinal fluid (CSF) AD biomarker profiles at diagnosis predict severity and survival in PSP.

METHODS: CSF amyloid-β42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) levels from 85 newly-diagnosed PSP patients and 59 controls were assessed by the amyloid/tau/neurodegeneration (AT[N]) framework, and the p-tau/Aβ42 ratio (AD+ if ≥0.08), and implemented in a survival analysis through Kaplan-Meier, Cox regression, and LASSO-Cox modeling.

RESULTS: AD CSF signature was identified in 5.9% and 18.8% of PSP patients, according to AT(N) and ratio, respectively. It was unrelated to phenotype or severity but strongly predicted survival, with AD+ patients showing markedly shorter survival. The p-tau/Aβ42 ratio was the strongest independent predictor of mortality, together with phenotype and smoking.

CONCLUSIONS: AD-related CSF signature defines a biological PSP subgroup with shortened survival. The p-tau/Aβ42 ratio offers a pragmatic prognostic tool for patient stratification. © 2026 International Parkinson and Movement Disorder Society.},
}

@article {pmid42386678,
year = {2026},
author = {Walton, AM and Moss, D and Chai, HW and Stephan, AT and Gamaldo, AA and Ross, LA and Phillips, CB},
title = {The moderating role of personality in the associations between delay discounting and technology use among older adults.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag123},
pmid = {42386678},
issn = {1758-5368},
abstract = {OBJECTIVES: Delay discount rate (DDR), or the devaluation of a future reward as the delay to its receipt increases, often leads individuals to favor smaller, immediate rewards over larger, delayed ones. Older adults' technology use may reflect delay discounting, with short-term ease favored over long-term benefits, and personality traits such as openness or neuroticism further modifying these associations. However, these relationships in older adults' decision-making remain unexplored. Therefore, this study examined (1) associations of DDR with social media and mobile application use, and (2) whether the relationships were moderated by personality traits in a sample of community-dwelling adults aged 55+ years (N = 119, Mage=68.63).

METHODS: Measures included the Monetary Choice Questionnaire, Mobile Application Use Questionnaire, one item from The Australian National University Alzheimer's Disease Risk Index to assess social media use, and the Big Five Personality Inventory.

RESULTS: Linear regression analyses revealed that greater DDR was associated with higher social media and mobile app use (p < 0.001). Neuroticism and openness significantly moderated the relationship between DDR and mobile app (p = .017) and social media use (p = .008), respectively.

DISCUSSION: Results suggest a greater delay discount rate is associated with more frequent technology use among participants with lower levels of neuroticism and openness. This study contributes to an initial understanding of the combined effects of stable and alterable factors that can impact older adults' willingness to use technology, allowing for the development of more refined strategies to promote healthy engagement.},
}

@article {pmid42386680,
year = {2026},
author = {Guleria, VS and Winston, CN},
title = {Primary cilia-extracellular vesicle crosstalk in Alzheimer's disease: Emerging mechanisms and biomarker potential.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71645},
pmid = {42386680},
issn = {1552-5279},
support = {R00AG0703900/NH/NIH HHS/United States ; U19AG074879/NH/NIH HHS/United States ; U19AG024904/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Cilia/metabolism/pathology ; *Extracellular Vesicles/metabolism ; Biomarkers/metabolism ; Animals ; Signal Transduction/physiology ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition marked by cognitive decline and synaptic issues. Recent studies show primary cilia (PCs), sensory organelles present on the surface of most mammalian cells, act as a critical regulators of brain homeostasis and signaling. PCs act as a signaling hubs for pathways like G protein-coupled receptor, Hedgehog, Wnt, and neuroinflammation. When PCs are depleted or dysfunctional, they impair the processing of amyloid precursor protein, tau phosphorylation, synaptic signaling, and neuron-glia communication, leading to tau tangles, neuroinflammation, and amyloid beta plaques that drive AD progression. Beyond their role in signal transduction, PCs also regulate the biogenesis, release, and cargo selection of extracellular vesicles (EVs), and dysfunctional EV-PC crosstalk may contribute to AD progression. Examining PC-derived EVs offers pathway-specific insights into early ciliary and neuroinflammatory issues. This review consolidates evidence on PCs' multifaceted role in AD pathogenesis and suggests their potential as an early biomarker.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Cilia/metabolism/pathology
*Extracellular Vesicles/metabolism
Biomarkers/metabolism
Animals
Signal Transduction/physiology
Brain/metabolism

@article {pmid42386684,
year = {2026},
author = {Hazan, J and Liu, KY and Howard, R},
title = {What should convince a clinician of disease modification in Alzheimer's disease clinical trials?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71643},
pmid = {42386684},
issn = {1552-5279},
support = {//The Blood Biomarker Challenge (UCL ADAPT study)/ ; //University College London Hospitals Biomedical Research Centre/ ; CRTF2023B-003//Alzheimer's Research UK/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; *Clinical Trials as Topic ; },
abstract = {The recent publication of extension data from post-regulatory trials of amyloid-lowering antibody therapies, such as donanemab and lecanemab, requires clinicians to critically appraise trial designs and analyses in order to evaluate claims made by authors and sponsors of disease modification. This Perspective outlines the challenges with assessing claims of disease course modification, provides a framework for their evaluation, reviews the different trial designs and analytical approaches used to test or support them, and proposes a practical appraisal checklist for evaluating studies.},
}

Humans
*Alzheimer Disease/drug therapy/therapy
*Clinical Trials as Topic

@article {pmid42386726,
year = {2026},
author = {Pola, I and Akinyemi, T and Tan, K and Olalusi, O and Traichel, W and Giacomucci, G and Yaria, J and Rahmouni, N and Ogunde, G and Oguntiloye, O and Macedo, AC and Fagbemi, A and Cadmus, E and Therriault, J and Popoola, F and Paddick, SM and Dotchin, C and Kisoli, A and Walker, R and Ogunronbi, M and Olujobi, D and Famuyiwa, O and Akinyemi, J and Owolabi, M and Udeh-Momoh, CT and Ladokun, O and Griswold, A and Romero-Ortuno, R and Pericak-Vance, M and Ogunniyi, A and Debette, S and Lawlor, B and Ashton, NJ and Kalaria, R and Zetterberg, H and Rosa-Neto, P and Akinyemi, RO and Benedet, AL},
title = {Plasma proteomic profiles of Alzheimer's disease and neurodegeneration in African cohorts.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74971-4},
pmid = {42386726},
issn = {2041-1723},
abstract = {Alzheimer's disease and related dementia (ADRD) represents a growing public health burden, especially in low- and middle-income countries. Yet, most studies focus on Non-Hispanic white (NHW) populations from high-income countries. This study investigates plasma proteomic signatures associated with amyloid pathology in African populations. Nigerian older adults from the VALIANT study and participants from a Tanzanian study, with available biomarker quantification in plasma are employed. For proteomic comparison, participants from the Canadian TRIAD cohort are included, capturing a distinct population. Here, we show that multiple proteins are differentially abundant in the plasma of p-tau217-positive individuals and in the different cognitive groups, with findings largely consistent amongst African cohorts. Comorbidities are significantly associated with protein levels and differences in plasma biomarkers levels are found between sexes. Lastly, VALIANT and TRIAD show both shared and unique protein profiles in relation to amyloid-pathology. These findings support the utility of fluid biomarkers in ADRD in African populations.},
}