@article {pmid37259937,
year = {2024},
author = {De, SK},
title = {Novel Pyrimidin-4-yl-3-amino-pyrrolo[3,4-c]pyrazoles as Protein Kinase C Inhibitors for Treating Diseases.},
journal = {Current medicinal chemistry},
volume = {31},
number = {8},
pages = {1036-1039},
doi = {10.2174/0929867330666230531164754},
pmid = {37259937},
issn = {1875-533X},
mesh = {Humans ; *Protein Kinase Inhibitors/chemistry/therapeutic use/pharmacology ; *Pyrazoles/chemistry/therapeutic use/pharmacology ; *Protein Kinase C/antagonists & inhibitors/metabolism ; Animals ; Neoplasms/drug therapy ; Cardiovascular Diseases/drug therapy ; *Pyrimidines/chemistry/therapeutic use/pharmacology ; Central Nervous System Diseases/drug therapy ; Inflammation/drug therapy ; },
abstract = {This patent describes the series of compounds and their pharmaceutically acceptable salts, such as compound K7 (as a representative potent compound). These protein kinase C selective inhibitors are useful for treating diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease, dermatological disease, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.},
}

Humans
*Protein Kinase Inhibitors/chemistry/therapeutic use/pharmacology
*Pyrazoles/chemistry/therapeutic use/pharmacology
*Protein Kinase C/antagonists & inhibitors/metabolism
Animals
Neoplasms/drug therapy
Cardiovascular Diseases/drug therapy
*Pyrimidines/chemistry/therapeutic use/pharmacology
Central Nervous System Diseases/drug therapy
Inflammation/drug therapy

@article {pmid42551683,
year = {2026},
author = {Gao, J and Xu, Y and Jiang, W and Wang, Z and Wang, L and Zhang, H},
title = {Adenosine monophosphate-activated protein kinase: A golden mediator of exercise in metabolic dysfunction-associated diseases (review).},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153885},
doi = {10.1016/j.ijbiomac.2026.153885},
pmid = {42551683},
issn = {1879-0003},
abstract = {Metabolic diseases represent a major threat to human health and are largely associated with excessive energy intake and insufficient energy expenditure. Increasing evidence indicates that obesity, diabetes, metabolic dysfunction-associated fatty liver disease, sarcopenia, Alzheimer's disease, and cancer are closely associated with metabolic dysfunction. Extensive clinical studies and therapeutic strategies have been developed for the prevention and treatment of these disorders. Among these approaches, targeted regulation of cellular energy homeostasis has emerged as a widely recognized strategy, with adenosine monophosphate-activated protein kinase (AMPK) identified as an important therapeutic target for metabolic disease intervention. With the growing development of sports medicine, exercise has become a preferred non-pharmacological approach for the prevention and management of metabolic dysfunction-related diseases, with its beneficial effects largely mediated through AMPK activation. However, the mechanisms by which exercise modulates AMPK and its subtypes in different tissues and diseases remain incompletely understood. Therefore, this narrative review retrieved English-language literature published up to May 2026 from the PubMed, Web of Science, and Scopus databases. A search strategy was constructed using the terms "AMPK", "exercise", "obesity", "diabetes", "NAFLD/MASLD", "sarcopenia", and "Alzheimer's disease" and the corresponding tissues associated with these metabolic diseases. A comprehensive analysis was conducted focusing on AMPK and its subtypes. In this narrative review, we synthesize current research on how exercise modulates AMPK in different tissues and subtype-specific functions, summarizing and analyzing existing evidence that may provide a theoretical basis for subtype-targeted therapeutic strategies (including exercise therapy and pharmacological therapy) for metabolic dysfunction-related diseases.},
}

@article {pmid42551762,
year = {2026},
author = {Lin, S and Xue, M and Xu, C and Sheng, C and Wang, T and Sun, J and Chen, Y and Lian, J and Zhang, T and Wang, W},
title = {White and gray matter microstructural alterations in subjective cognitive decline: an exploratory study using TBSS and GBSS.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112070},
doi = {10.1016/j.brainresbull.2026.112070},
pmid = {42551762},
issn = {1873-2747},
abstract = {OBJECTIVE: Subjective cognitive decline (SCD), which may represent the preclinical stage of Alzheimer's disease (AD) in a subset of individuals, lacks objective biomarkers, thus hindering the implementation of early intervention for AD. This study tentatively explored the potential value of neurite orientation dispersion and density imaging (NODDI) in assessing the microstructural integrity of gray matter (GM) and white matter (WM) in SCD.

METHODS: We enrolled 47 SCD subjects and 30 healthy controls (HCs). Through the TBSS and GBSS analysis based on NODDI, the neurite density index (NDI) and orientation dispersion index (ODI) were used to evaluate the microstructural integrity of GM and WM. NODDI parameters were extracted from multiple brain regions to assess their diagnostic utility in distinguishing SCD from HCs.

RESULTS: In WM microstructure, NDI of the genu of corpus callosum was decreased, and the ODI of the left posterior thalamic radiation and posterior corona radiata were decreased. In GM microstructure, the NDI of the left hippocampus, amygdala and parahippocampal gyrus were decreased, whereas the ODI of the rolandic operculum, opercular part of inferior frontal gyrus, and precentral gyrus were increased. Logistic regression analysis results showed that the NDI value of GM, the ODI value of GM and the ODI value of WM were independent predictors and the combination of the three parameters had the best classification effect.

CONCLUSION: This exploratory study suggests that NODDI may detect microstructural differences in GM and WM associated with SCD. These preliminary findings provide hypothesis-generating clues for future research into potential imaging markers for identifying SCD individuals. Additional studies are necessary to confirm these preliminary results.},
}

@article {pmid42551772,
year = {2026},
author = {Muedano-Sosa, A and Trujillo-Pineda, M and Ruiz-Pérez, S and Cervera, A and González-Barrios, R and Arias, C and Flores-León, M},
title = {In silico analysis of transcriptomic datasets reveals nonlinear gene expression trajectories in aging microglia and Alzheimer's disease.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113263},
doi = {10.1016/j.exger.2026.113263},
pmid = {42551772},
issn = {1873-6815},
abstract = {BACKGROUND: Neuroinflammation, a key factor in aging and neurodegeneration, is characterized by the increased activation of microglia, the brain's resident immune cells. Microglia play a central role in maintaining brain homeostasis, and their dysregulation during aging is increasingly implicated in the onset and progression of Alzheimer's disease (AD). However, the molecular mechanisms underlying microglial state transitions across physiological and pathological aging remain poorly understood.

METHODS: To address this gap, we conducted an in silico comparative transcriptomic study using publicly available datasets from two murine bulk RNA-seq including wild-type (WT) and APP/PS1 transgenic (Tg) mice at multiple ages, one human scRNA-seq dataset with multiple ages, and data obtained from SCAD-Brain.

RESULT: Our analyses revealed that physiological microglial aging is characterized by dynamic, non-linear gene expression trajectories, whereby genes involved in mitochondrial function, lysosomal degradation, and immune response follow a mirror-like pattern across aging. This mirror-like behavior was conserved in human microglial data across ages. In contrast, this adaptive pattern was disrupted at late-stage pathological aging in Tg mice, where sustained alterations in inflammatory, mitochondrial, and lysosomal pathways became more pronounced. Consistent with these findings, genes dysregulated in Tg mice showed similar expression trends in AD patients in the SCAD-Brain database.

CONCLUSION: These results suggest that middle age may represent a critical transition stage preceding neuroinflammation and neurodegeneration, making it an attractive window to identify preventive or therapeutic targets in early AD. Collectively, this study identifies candidate pathways and genes that warrant further experimental validation in the context of AD and age-related neurodegeneration.},
}

@article {pmid42551778,
year = {2026},
author = {Jaiswal, V and Deb, N and Latif, F and Shrestha, AB and Garimella, V and Shama, N and Jitta, SR and Naz, S and Kumar, T and Khan, S and Perone, F and Mattumpuram, J and Ang, SP},
title = {Association between PCSK9 targeted therapy and the risk of stroke and dementia: A Meta-Analysis of Randomized Controlled Trials.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2026.06.034},
pmid = {42551778},
issn = {1555-7162},
abstract = {BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeted therapies have been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels and circulating PCSK9. However, its effect on cerebrovascular outcomes, especially stroke and dementia, has not been well established to date.

METHODS: We conducted a systematic literature search of electronic databases for relevant randomized controlled trials (RCTs) from inception through January 2025. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model, and a p-value of <0.05 was considered statistically significant.

RESULTS: A total of 22 RCTs with 64,116 patients were included in the study. Pooled analysis showed that PCSK9-targeted therapy significantly reduced the risk of all-cause stroke (OR, 0.78 (95% CI: 0.68-0.90), P < 0.001) and ischemic stroke (OR, 0.77 (95% CI: 0.63-0.94), P=0.01). However, no significant association was observed for the risk of hemorrhagic stroke (OR, 1.16 (95%CI: 0.70-1.93), P=0.56), transient ischemic attack (OR, 0.98 (95%CI: 0.48-2.06), P= 0.95), dementia (OR, 0.77 (95%CI: 0.14-4.28), P=0.76), dementia of Alzheimer's type (OR, 0.81 (95%CI: 0.14-4.70), P=0.82), and Parkinson's disease (OR, 0.82 (95%CI: 0.11-6.37), P=0.85).

CONCLUSION: PCSK9 targeted therapies appear to reduce the risk of stroke; however, no significant association was observed for the risk of dementia and Parkinson's disease.},
}

@article {pmid42551844,
year = {2026},
author = {Xie, Q and Zhang, J and Wang, Y and Huang, J and Lin, F and Weng, RL and He, H and Chen, Q and Xu, H},
title = {CiteSure: retrieval-augmented large language models for faithful biomedical citation recommendation.},
journal = {Journal of the American Medical Informatics Association : JAMIA},
volume = {},
number = {},
pages = {},
doi = {10.1093/jamia/ocag122},
pmid = {42551844},
issn = {1527-974X},
support = {R01AG073435/NH/NIH HHS/United States ; R01LM013519/NH/NIH HHS/United States ; R01AG080429/NH/NIH HHS/United States ; 1K99LM01402/NH/NIH HHS/United States ; 1K99LM014614-01/NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: Accurate citation of relevant publications is essential for scientific integrity in biomedical research. Large language models (LLMs) excel at text generation but often hallucinate fabricated or inaccurate citations. Retrieval-augmented generation (RAG) can mitigate these errors, yet current approaches lack semantic precision in evidence retrieval. This study aims to develop a domain-specific RAG system for reliable, context-specific biomedical citation recommendations.

MATERIALS AND METHODS: We introduce CiteSure, a sentence-level citation recommendation tool designed to deliver reliable, evidence-based, and context-specific references using LLMs. CiteSure utilizes a 2-stage retrieval-augmented generation (RAG) framework, combining a domain-specific dense retriever (BioLLM2Vec) and reranker (BioRankLLaMA), adapted from LLaMA3-8B-Instruct using biomedical-specific training data. CiteSure leverages the complementary strengths of retrieval and generative LLM models, ensuring factual precision and contextual alignment. We evaluated CiteSure on a curated Alzheimer's disease dataset, comparing it to standalone LLMs and traditional retrieval-based methods.

RESULTS: CiteSure achieved 100% factual accuracy and the highest relevance score of 77.50%, outperforming all baselines. BioLLM2Vec retrieved relevant articles with over 80% accuracy in the top 100 candidates. BioRankLLaMA consistently outperformed baseline rerankers across MAP, MRR, and Precision@5 metrics, confirming the benefit of domain-specific adaptation and contrastive fine-tuning.

DISCUSSION AND CONCLUSION: Our results demonstrate that CiteSure, built on a 2-stage retrieval-augmented generation framework, effectively integrates domain-specific retrieval with LLM-based generation to achieve substantial improvements over baseline approaches. Our work underscores the importance of domain-specific adaptation in biomedical citation recommendation and provides publicly available datasets, models, and code for support future research.},
}

@article {pmid42552038,
year = {2026},
author = {Peter L, IR and Chatterjee, D and Chrishone, AF and Francis, D},
title = {Metabolic therapeutic targets in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {1-32},
doi = {10.1016/bs.irn.2026.05.010},
pmid = {42552038},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism/physiology/drug effects ; *Brain/metabolism ; *Mitochondria/metabolism ; Glucose/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder marked not only by amyloid-β and tau pathology, but also by profound disturbances in brain energy metabolism that arise early in disease progression. Accumulating evidence indicates that impairments in glucose utilization, insulin signaling, and mitochondrial function precede neurodegeneration and contribute directly to synaptic failure and cognitive decline. This chapter presents a comprehensive overview of Alzheimer's disease through the lens of metabolic dysfunction, highlighting disrupted neuronal bioenergetics as a central and unifying feature of pathogenesis. We examine key metabolic pathways implicated in AD, including cerebral glucose hypometabolism, brain insulin resistance, impaired glycolysis, mitochondrial oxidative phosphorylation deficits, oxidative stress, and altered mitochondrial dynamics. The chapter further discusses therapeutic strategies aimed at restoring metabolic homeostasis, such as insulin sensitization, enhancement of glucose transport, activation of mitochondrial biogenesis, modulation of the electron transport chain, and the use of mitochondria-targeted antioxidants. In parallel, alternative energy approaches-including ketone metabolism, fatty acid oxidation, and pentose phosphate pathway activation-are explored as promising avenues to bypass glucose-dependent energy deficits and reinforce neuronal resilience. Emerging directions in metabolic therapeutics are also highlighted, including combination treatment strategies, NAD[+]-sirtuin and AMPK signaling, and the expanding role of the gut microbiome-brain metabolism axis. By integrating insights from experimental models, neuroimaging studies, and clinical trials, this chapter underscores the potential of metabolic interventions to enable early, disease-modifying strategies for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
Animals
*Energy Metabolism/physiology/drug effects
*Brain/metabolism
*Mitochondria/metabolism
Glucose/metabolism

@article {pmid42552040,
year = {2026},
author = {Chaurasia, V and Das Modak, S and Singh, GK and Modi, G},
title = {A comprehensive review on therapeutics and diagnostic agents targeting acetyl and butyryl cholinesterases for AD.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {145-198},
doi = {10.1016/bs.irn.2026.05.017},
pmid = {42552040},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/enzymology/metabolism ; *Butyrylcholinesterase/metabolism/drug effects ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; Animals ; *Acetylcholinesterase/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive, irreversible, and multifaceted neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairment, posing a major global health challenge. Its multifactorial pathology includes cholinergic dysfunction, amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Among these, impairment of the cholinergic system, characterized by reduced acetylcholine levels, plays a crucial role in cognitive deficits. The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which hydrolyze acetylcholine, are closely involved in disease progression and serve as important therapeutic and diagnostic targets in AD. This book chapter provides a comprehensive overview of therapeutic and diagnostic agents targeting AChE and BChE in AD, and discusses small-molecule inhibitors, multifunctional ligands, and emerging strategies to modulate cholinesterase activity and restore cholinergic neurotransmission, alleviating disease symptoms. In addition, the chapter highlights advances in diagnostic approaches using fluorescent probes, particularly near-infrared (NIR) probes, for selective detection and imaging of AChE and BChE, including their molecular design, photophysical properties, enzyme selectivity, and mechanisms of action, all of which are critically examined. Targeting AChE and BChE offers a dual advantage in AD by enabling both symptomatic treatment and early-stage diagnosis. This chapter aims to present a clear and comprehensive overview of recent advances in therapeutic and diagnostic approaches, offering meaningful insights for researchers in developing effective strategies for the treatment and monitoring of AD.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/enzymology/metabolism
*Butyrylcholinesterase/metabolism/drug effects
*Cholinesterase Inhibitors/pharmacology/therapeutic use
Animals
*Acetylcholinesterase/metabolism/drug effects

@article {pmid42552041,
year = {2026},
author = {Khodve, G and Raval, S and Banerjee, S},
title = {Intestinal microbiota in neurodegeneration and ageing: Mechanisms, pathways, and therapeutic interventions.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {199-229},
doi = {10.1016/bs.irn.2026.05.015},
pmid = {42552041},
issn = {2162-5514},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy ; *Aging/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *Dysbiosis/metabolism/immunology ; *Brain-Gut Axis/physiology ; Probiotics ; Brain/metabolism ; },
abstract = {The human gut microbiota represents a complex ecosystem of trillions of microorganisms with profound implications for neurological health. Emerging evidence demonstrates that dysbiosis, an imbalance in microbial composition and function, plays a crucial role in the pathogenesis of neurodegenerative diseases and age-related cognitive decline. This chapter summarizes current knowledge of the microbiota-gut-brain axis (MGBA) and elucidates how intestinal microbes and their metabolites communicate with the central nervous system via neural, immune, endocrine, and metabolic pathways. We examine the mechanistic links between gut dysbiosis and specific neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Multiple sclerosis (MS). Furthermore, we explore age-related changes in the microbiota and their contributions to neuroinflammation, immunosenescence, and cognitive decline. Finally, we evaluate therapeutic interventions targeting the microbiota, including probiotics, prebiotics, synbiotics, and dietary modulation as promising strategies to prevent and ameliorate neurodegenerative pathology. The chapter provides a comprehensive summary of how microbiota-targeted approaches may delay ageing and neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy
*Aging/metabolism/immunology
*Gastrointestinal Microbiome/physiology
Animals
*Dysbiosis/metabolism/immunology
*Brain-Gut Axis/physiology
Probiotics
Brain/metabolism

@article {pmid42552042,
year = {2026},
author = {Milmile, M and Singh, S and Pandey, A and Pawar, G and Petkar, P and Chander, Y and Mishra, R and Chawla, R},
title = {Brain energy crisis in Alzheimer's and Parkinson's disease: Nanotechnology as a therapeutic strategy.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {231-271},
doi = {10.1016/bs.irn.2026.05.016},
pmid = {42552042},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/metabolism/drug therapy/therapy ; *Energy Metabolism/physiology/drug effects ; *Alzheimer Disease/metabolism/drug therapy/therapy ; Animals ; *Brain/metabolism/drug effects ; *Nanotechnology/methods ; Mitochondria/metabolism ; Nanoparticles ; Oxidative Stress ; Drug Delivery Systems/methods ; },
abstract = {Alzheimer's disease and Parkinson's disease are increasingly recognized as disorders marked not only by protein aggregation but by a sustained failure of brain energy metabolism. Years before overt cognitive or motor symptoms emerge, neurons begin to experience impaired glucose utilization, mitochondrial dysfunction, and declining ATP production. Because the brain is highly energy-dependent, even subtle metabolic disturbances can disrupt synaptic function, impair neuronal signaling, and trigger oxidative stress. As mitochondrial efficiency declines, reactive oxygen species accumulate, inflammatory pathways become chronically activated, and damaged cellular components are insufficiently cleared, creating a vicious cycle that accelerates neurodegeneration. Conventional metabolic therapies, including antioxidants and mitochondrial cofactors, have produced limited clinical success, largely due to poor penetration across the blood-brain barrier and lack of specificity for vulnerable neuronal populations and intracellular targets such as mitochondria. Nanotechnology introduces a more precise therapeutic strategy by enabling targeted delivery of metabolic modulators directly to the brain. Engineered nanocarriers can be designed to cross biological barriers, enhance drug stability, and release therapeutic agents in a controlled or stimuli-responsive manner within diseased regions. Advanced systems including polymeric nanoparticles, lipid-based carriers, intranasal nano formulations, biomimetic vesicles, and catalytic nanozymes offer the ability to simultaneously modulate oxidative stress, restore mitochondrial function, and regulate neuroinflammation. By integrating delivery precision with metabolic intervention, neuro-nanomedicine shifts the therapeutic focus from symptomatic management toward addressing the underlying bioenergetic crisis. Although challenges remain in safety validation, scalability, and clinical translation, targeted nanotherapeutic strategies hold significant promise for transforming the treatment landscape of these debilitating neurodegenerative disorders.},
}

Humans
*Parkinson Disease/metabolism/drug therapy/therapy
*Energy Metabolism/physiology/drug effects
*Alzheimer Disease/metabolism/drug therapy/therapy
Animals
*Brain/metabolism/drug effects
*Nanotechnology/methods
Mitochondria/metabolism
Nanoparticles
Oxidative Stress
Drug Delivery Systems/methods

@article {pmid42552043,
year = {2026},
author = {Jain, V and Bharti, S},
title = {The potential of HDAC inhibitors for Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {273-298},
doi = {10.1016/bs.irn.2026.01.005},
pmid = {42552043},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Animals ; *Histone Deacetylases/metabolism ; Epigenesis, Genetic/drug effects ; *Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative condition characterized by cognitive deterioration, memory loss, and persistent neuroinflammation. Notwithstanding considerable scientific advancements, current therapy strategies predominantly address symptoms and are ineffective in arresting illness progression. Recent studies have demonstrated the crucial role of epigenetic changes, especially histone modifications, in the pathophysiology of Alzheimer's disease. Removal of the acetyl group from histones and non-histone proteins by histone deacetylases (HDACs) plays a pivotal role in the regulation of gene expression, synaptic plasticity, and neuronal survival. Such changes lead to dysregulated HDAC activity, which is further associated with significant clinical characteristics of Alzheimer's disease, including amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. In Alzheimer's disease and other neurodegenerative diseases, the histone acetylation equilibrium is markedly disrupted, resulting in a shift towards hypoacetylation, which further inhibits the production of neuroprotective genes. Pharmacological inhibition of HDACs can reinstate hyperacetylation, therefore facilitating neuroprotective effects. This chapter explores the therapeutic potential of HDAC inhibitors in relation to Alzheimer's disease. This chapter also focuses on various HDAC isoforms associated with disease progression and explores the detailed mechanism by which HDAC inhibitors affect the epigenetic regulation and neuronal function. Preclinical investigations focusing on the role of HDAC inhibitors in mitigating neuroinflammation and Alzheimer's diseases, with a special focus on HDAC inhibitors in clinical trials, present intriguing opportunities for therapeutic advancement. The chapter further explores various challenges such as off-target effects, restricted isoform specificity, and inadequate blood-brain barrier permeability. To address these constraints, various strategies such as isoform-selective inhibitors, targeted delivery methods, and combination treatments are also explored. Thus, the chapter provides in-depth information on the role of HDAC inhibitors, which hold significant potential as disease-modifying agents in the treatment of Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Histone Deacetylase Inhibitors/pharmacology/therapeutic use
Animals
*Histone Deacetylases/metabolism
Epigenesis, Genetic/drug effects
*Neuroprotective Agents/pharmacology

@article {pmid42552044,
year = {2026},
author = {Singh, AK and M R, S and P S, A and Krishnamoorthi, S and Iyaswamy, A and Durairajan, SSK},
title = {The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {299-361},
doi = {10.1016/bs.irn.2026.06.002},
pmid = {42552044},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Energy Metabolism/physiology ; *Mitochondria/metabolism ; *tau Proteins/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease process resulting in progressive cognitive deterioration and synaptic dysfunction. The primary research approach in AD has traditionally focused on amyloid- pathology however an increasingly evidence suggests that tau protein is a key mediator of neuronal damage via a direct action on mitochondrial bioenergetics. In this chapter we look at the nature of the tau-mitochondrial interface, and propose a paradigm of tau-induced energy failure in AD. Physiologically tau provides stability to the microtubules and is involved in transport mechanisms within cells. In AD, tau is excessively post-translationally modified hyperphosphorylated and truncated tau species form toxic oligomers that incorrectly translocate to mitochondria, interacting pathologically with critical proteins such as voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocase (ANT), impeding the mitochondrial ATP/ADP exchange and reducing oxidative phosphorylation efficiency. Tau also further damages mitochondria by excessive fission, inhibition of axonal transport and Inhibition of mitophagy by interrupting PINK1-Parkin signaling. In turn, the build-up of dysfunctional mitochondria leads to ROS production, mtDNA damage and calcium imbalance creating a vicious cycle toward oxidative stress and tau pathology. At the cellular level they cause an energy depletion of the synapse and at the systems level cause glucose hypometabolism and activation of neuroinflammation. The chapter additionally discusses novel therapeutic approaches that target both tau and mitochondrial abnormalities, namely antisense oligonucleotides (ASO), mitochondria targeted compounds and mitophagy modifiers, stressing that it would be more effective to utilize a cocktail of these inhibitors. As a whole, in the context of decreased bioenergetics, the tau-mitochondria axis is an important factor to consider in the successful treatment of AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Energy Metabolism/physiology
*Mitochondria/metabolism
*tau Proteins/metabolism
Animals

@article {pmid42552045,
year = {2026},
author = {Khodadadi, S and Rezaeimanesh, N and Ariyae Motahar, A and Yousefi, F and Avateffazeli, M and Montazeri-Shatouri, R and Hosseini, E and Sahab Negah, S and Naser Moghadasi, A},
title = {Brain energy metabolism changes and neuropsychological impairment in Parkinson disease vs Alzheimer disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {33-66},
doi = {10.1016/bs.irn.2026.06.001},
pmid = {42552045},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/metabolism/complications ; *Energy Metabolism/physiology ; *Alzheimer Disease/metabolism/complications ; *Brain/metabolism ; Animals ; *Cognitive Dysfunction/metabolism/etiology ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, posing a significant public health risk. Although they are separate diseases, they have similar neuropsychological characteristics. Despite making up only a small portion of total body mass, the brain requires a disproportionately large amount of energy to maintain neuronal activity, synapse function, and cellular homeostasis. Disruption of energy metabolism is thus a major contributor to neurodegeneration. Energy metabolism has a wide-ranging impact on brain function, including cognitive and psychological processes, and gets increasingly compromised in neurodegenerative disorders. This chapter aims to offer a thorough overview of the link between altered brain energy metabolism and neuropsychological impairment in AD and PD.},
}

Humans
*Parkinson Disease/metabolism/complications
*Energy Metabolism/physiology
*Alzheimer Disease/metabolism/complications
*Brain/metabolism
Animals
*Cognitive Dysfunction/metabolism/etiology

@article {pmid42552046,
year = {2026},
author = {Yadav, N and Banerjee, J and Tiwari, M and Dixit, A},
title = {Brain lipid dysregulation as a driver of energy metabolism failure in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {363-396},
doi = {10.1016/bs.irn.2026.02.004},
pmid = {42552046},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Energy Metabolism/physiology ; Animals ; *Lipid Metabolism/physiology ; *Brain/metabolism ; Mitochondria/metabolism ; },
abstract = {Alzheimer's Disease (AD) is becoming more widely recognized as a condition of brain energy metabolism, wherein lipid dysregulation plays a crucial, although unrecognized, role. In addition to functioning as structural elements of neuronal membranes, lipids such as phospholipids, sphingolipids, and cholesterol play a crucial role in regulating mitochondrial bioenergetics, synaptic activity, and membrane-associated signaling pathways. In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates. These alterations intensify oxidative stress, impair glucose and ketone utilization, and stimulate neuroinflammatory pathways that further diminish metabolic capacity. Progress in lipidomics has uncovered disease-specific lipid signatures, providing a fresh understanding of the relationship between lipid homeostasis and neuronal energy loss. Despite extensive focus on amyloid and tau, lipid-mediated bioenergetic failure remains underrepresented in integrative AD models; this chapter addresses this gap and consolidates existing information connecting lipid modifications to metabolic dysfunction in AD, emphasizing molecular pathways and prospective treatment strategies aimed at lipid metabolism to re-establish bioenergetic equilibrium.},
}

Humans
*Alzheimer Disease/metabolism
*Energy Metabolism/physiology
Animals
*Lipid Metabolism/physiology
*Brain/metabolism
Mitochondria/metabolism

@article {pmid42552047,
year = {2026},
author = {Mittal, R and Priya, and Banerjee, J and Dixit, A},
title = {Metabolic dysregulation in Alzheimer's disease: Mechanisms, markers, and therapeutic prospects.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {397-434},
doi = {10.1016/bs.irn.2026.05.011},
pmid = {42552047},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy ; Biomarkers/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Glucose/metabolism ; *Brain/metabolism ; },
abstract = {Metabolic dysregulation has emerged as a crucial pathogenic factor that contributes in progression of Alzheimer's disease (AD), and is often found to precede classical AD's pathologies, the amyloid-β accumulation and hyperphosphorylated tau proteinopathies. The key metabolic underpinnings associated with Alzheimer's disease (AD) includes cerebral glucose hypometabolism, insulin resistance, mitochondrial dysfunction, altered lipid metabolism, vascular and systemic metabolic impairments, disrupted amino acid and nitrogen metabolism driving secondary metabolic disturbances. The chapter outlines the current evidences on dysregulated metabolic processes, and highlights emerging metabolic biomarkers that are identified through advanced neuroimaging modalities, plasma/cerebrospinal fluid (CSF) profiles, lipidomic signatures and markers of mitochondrial impairment, underscoring their diagnostic and prognostic potential. Furthermore, the chapter discusses about the therapeutic prospects targeting metabolic pathways, addressing current challenges in development of therapeutic strategies, reinforcing the need for integrative and precision-based interventions for early diagnosis and disease modifying therapeutic strategies in AD.},
}

Humans
*Alzheimer Disease/metabolism/therapy
Biomarkers/metabolism
Animals
Amyloid beta-Peptides/metabolism
Glucose/metabolism
*Brain/metabolism

@article {pmid42552048,
year = {2026},
author = {Baskar, G and Kandasamy, M},
title = {Energetic crisis, mitochondrial vulnerability and disruption of lactate shuttle in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {67-89},
doi = {10.1016/bs.irn.2026.05.012},
pmid = {42552048},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; Animals ; *Energy Metabolism/physiology ; *Mitochondria/metabolism/pathology ; *Lactic Acid/metabolism ; *Neurons/metabolism ; Astrocytes/metabolism ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) has traditionally been characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Emerging evidence reveals that metabolic dysfunction represents a key pathological feature central to disease progression. Mitochondrial dysfunction in AD leads to impaired electron transport chain activity and reduced level of adenosine triphosphate (ATP) synthesis, preceding neurodegeneration and structural abnormalities in cognitive centres of the brain. Early glucose hypometabolism and lactate deprivation or interference with their utilization represent a primary bioenergetic failure driving mitochondrial dysfunction and neuroinflammation prior to the clinical manifestation of AD. While the brain relies on lactate as a prominent energy substrate, astrocytic metabolic defects lead to impaired neuronal energy homeostasis, thereby promoting neurodegeneration. In turn, this metabolic uncoupling could also be associated with defects in regenerative mechanisms by impairing adult neurogenesis in the hippocampus due to energy deprivation, accounting for memory deficits. This chapter discusses the evidence for the energetic crisis in AD, focusing on the disruption of the astrocyte-neuron lactate shuttle (ANLS), hypometabolism of glucose, and mitochondrial vulnerability, as interconnected pathogenic mechanisms. We emphasise cerebral bioenergetic metabolic failure as a central driver of cognitive decline, arising from irreversible reactive gliosis and neuroblastosis mechanisms and highlight various therapeutic options, including restoration of ANLS to mitigate the pathogenesis and memory loss in AD.},
}

Humans
*Alzheimer Disease/metabolism
Animals
*Energy Metabolism/physiology
*Mitochondria/metabolism/pathology
*Lactic Acid/metabolism
*Neurons/metabolism
Astrocytes/metabolism
*Brain/metabolism

@article {pmid42552066,
year = {2025},
author = {Liu, Y and Poon, CH and Tse, LSR and Roy, J and So, CT and Tong, BC and Yao, KM and Tipoe, GL and Steinbusch, H and Aquili, L and Kalueff, A and Cheung, KH and Fung, ML and Lim, LW},
title = {Homeostatic DNMT3a Activity Is Required to Restore Cognition and Hippocampal DNA Methylation in the 5xFAD Model of Alzheimer's Disease.},
journal = {Aging and disease},
volume = {17},
number = {5},
pages = {2710-2739},
doi = {10.14336/AD.2025.0283},
pmid = {42552066},
issn = {2152-5250},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/drug therapy ; DNA Methyltransferase 3A ; *Hippocampus/metabolism ; *DNA Methylation/drug effects ; Disease Models, Animal ; Mice ; *DNA (Cytosine-5-)-Methyltransferases/metabolism/genetics ; *Cognition/drug effects/physiology ; Mice, Transgenic ; Methionine/pharmacology ; Spatial Memory/drug effects ; Homeostasis ; Male ; Neuronal Plasticity/drug effects ; },
abstract = {Dysregulation of DNA methylation has been implicated in Alzheimer's disease (AD), making the manipulation of DNA methylation processes a promising therapeutic strategy. DNA methyltransferase 3a (DNMT3a), one of the two de novo DNMTs, is involved in learning and memory. However, it remains elusive whether and how alterations in DNMT3a expression contributes to AD pathogenesis. In this study, we investigated the consequences of DNA methylation dysregulations in the hippocampus of 5xFAD mouse model of AD and explored the use of L-methionine (MET) supplement to restore DNA methylation dysregulations. The 5xFAD model exhibited spatial memory impairments accompanied by global DNA hypomethylation and dysregulated hippocampal expression of DNA methyltransferases (DNMT) and demethylases. Prolonged treatment with MET rescued memory deficits, reduced amyloid-β load, decreased neuroinflammation, restored the expression of plasticity-regulating genes and proteins, and enhanced serotonergic neurotransmission. DNMT3a knockdown diminished the pro-cognitive effects of MET and independently impaired spatial memory and hippocampal neuroplasticity in both wildtype and 5xFAD mice. Interestingly, DNMT3a overexpression also had detrimental effects on spatial memory and hippocampal neuroplasticity in both genotypes. Our findings demonstrate that methyl supplementation can be a promising therapeutic strategy for AD patients with brain DNA hypomethylation and that maintaining DNMT3a homeostasis is crucial for normal cognitive functions and the pro-cognitive effects of MET.},
}

Animals
*Alzheimer Disease/genetics/metabolism/drug therapy
DNA Methyltransferase 3A
*Hippocampus/metabolism
*DNA Methylation/drug effects
Disease Models, Animal
Mice
*DNA (Cytosine-5-)-Methyltransferases/metabolism/genetics
*Cognition/drug effects/physiology
Mice, Transgenic
Methionine/pharmacology
Spatial Memory/drug effects
Homeostasis
Male
Neuronal Plasticity/drug effects

@article {pmid42552207,
year = {2026},
author = {Chen, R and Pan, C and Mao, X and Zhang, Y and Chen, G and Xu, M and Nivar, J and Tao, Y and Cao, H and JunLi, },
title = {Retraction notice to "Chloride intracellular channel 4 blockade improves cognition in mice with Alzheimer's disease: CLIC4 protein expression and tau protein hyperphosphorylation" [Int. J. Biol. Macromol. 278 (2024) 134972].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153849},
doi = {10.1016/j.ijbiomac.2026.153849},
pmid = {42552207},
issn = {1879-0003},
}

@article {pmid42552272,
year = {2026},
author = {Turrisi, R and Cammarasana, S and Paccini, M and Patanè, G and , },
title = {Super-Resolution of Through-Plane Undersampled MRIs in Alzheimer's Disease Diagnosis.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02159-9},
pmid = {42552272},
issn = {2948-2933},
support = {ECS00000035//Ministero dell'Università e della Ricerca/ ; 2022WK7NHC//Ministero dell'Università e della Ricerca/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder and the leading cause of dementia worldwide. Learning-based techniques applied to magnetic resonance imaging (MRI) have recently shown strong potential for automated diagnosis. Accurate classification typically relies on high-resolution (HR) 3D MRI acquired with thin axial slices to reduce partial-volume artefacts, capture fine anatomical details, and improve diagnostic performance. However, acquiring such data is time-consuming, costly, and prone to motion artefacts and patient discomfort. Super-resolution methods offer a promising alternative by reconstructing HR 3D images from lower-resolution scans and enabling shorter acquisition times. In this study, we propose a novel pipeline that applies super-resolution to through-plane undersampled 3D magnetic resonance images and demonstrates that the resulting volumes preserve Alzheimer's disease diagnostic accuracy comparable to that achieved using fully sampled HR scans. We compare different state-of-the-art super-resolution methods from distinct methodological families, with the best-performing method achieving an F1 score of 65.6, close to the HR reference of 65.7 and substantially higher than the low-resolution baseline of 55.9. Furthermore, we investigate whether standard image quality metrics (e.g. pixel-based metrics) are sufficient to assess the contribution of super-resolution to the clinical evaluation of Alzheimer's disease. To this end, we compare them with machine learning-based measures, such as maximum mean discrepancy, and surface-based metrics derived from segmented anatomical structures, highlighting their limitations in clinically oriented evaluations.},
}

@article {pmid42552337,
year = {2026},
author = {Ma, N and Stieler, J and Hilbrich, I and Vogel, T and Hilgeroth, A and Briel, D and Schaefer, M and Holzer, M and Metelmann, M},
title = {NanoBiT screening identifies the azaoxafluorene VT11 as potent tau interaction inhibitor.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42552337},
issn = {2045-2322},
mesh = {*tau Proteins/metabolism/antagonists & inhibitors/chemistry ; Humans ; Protein Binding/drug effects ; Tauopathies/drug therapy/metabolism ; Biosensing Techniques ; },
abstract = {Tauopathies are neurodegenerative disorders characterized by accumulating misfolded, insoluble tau protein aggregates in neurons or glial cells. In this study, we screened the Spectrum Collection and other compound libraries for inhibitors of tau self-interaction using a structural complementation reporter system (NanoLuciferase Binary Technology). Resulting candidates were tested in dose-response assays and evaluated for cell toxicity and microtubule destabilization. Further, a seed-induced tau interaction biosensor assay and a cell-free tau Real-Time Quaking-Induced Conversion assay have been established to study their effects on the kinetics of tau interaction and aggregation, respectively. The substances ritanserin, 3-methoxycatechol, gambogic amide, azaoxafluorenes VT11, and NS 185 and thieno[2,3-d][1.3]oxazine B6/55 showed a concentration-dependent tau self-interaction inhibition without relevant cell toxicity or microtubule destabilization. Ritanserin, VT11, NS 185 and B6/55 blocked tau interaction in the seed-induced tau interaction biosensor assay. Finally, the cell-free tau RT-QuIC assay displayed highest inhibitory potential for VT11. Thus, the azaoxafluorene VT11 seems to be a promising candidate for further investigations as tau interaction inhibitor to address a pivotal pathological process in Alzheimer's disease and other tauopathies.},
}

*tau Proteins/metabolism/antagonists & inhibitors/chemistry
Humans
Protein Binding/drug effects
Tauopathies/drug therapy/metabolism
Biosensing Techniques

@article {pmid42552384,
year = {2026},
author = {Klimmt, J and Cardoso Gonçalves, C and Montgomery, JV and Müller, SA and Bublitz, M and Filser, S and Paeger, L and Nuscher, B and Dannert, A and Roeber, S and Pravata, V and Schifferer, M and Shrouder, JJ and Schulz, N and González-Gallego, J and Cappello, S and Misgeld, T and Plesnila, N and Beltrán, E and Herms, J and De Domenico, E and Beyer, MD and Schultze, JL and Haass, C and Lichtenthaler, SF and Carraro, C and Paquet, D},
title = {A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42552384},
issn = {1546-1726},
support = {ADR AD2019604S//BrightFocus Foundation (BrightFocus)/ ; 16LW047//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; },
abstract = {Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.},
}

@article {pmid42552390,
year = {2026},
author = {Lucey, BP and Howell, MJ},
title = {Losing sleep over glia: new mechanisms for Alzheimer-related sleep disruption.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42552390},
issn = {1759-4766},
}

@article {pmid42552421,
year = {2026},
author = {Liao, K and Xie, M and Ibáñez, CF},
title = {p75 neurotrophin receptor signaling through the RhoA/ROCK pathway contributes to Tau-mediated neurodegeneration.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42552421},
issn = {1476-5578},
support = {X2026t/77//Royal Swedish Academy of Sciences (Kungl. Vetenskapsakademien)/ ; },
abstract = {Therapeutic development in Alzheimer's Disease (AD) has for the most part been focused on reducing β-amyloid load. Nevertheless, neurofibrillary tangles (NFTs), produced by aggregation of hyper-phosphorylated Tau protein, correlate with neurodegeneration and cognitive impairment significantly better than amyloid accumulation in AD patients. Here we report that P301S mice, a model of Tau-mediated neurodegeneration, carrying mutant variants of the p75 neurotrophin receptor (p75[NTR]) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75[∆DD], lacking the death domain, and triple mutant p75[KKEA], unable to interact with RhoGDI, decreased insoluble Tau species, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75[C259A], a variant unresponsive to neurotrophins but still competent for RhoA signaling induced by myelin-derived ligands, did not afford any neuroprotection. P301S neurons expressing p75[∆DD] or p75[KKEA], but not p75[C259A], showed reduced phospho-Tau and ROCK and GSK3β activity, the two main kinases responsible for Tau phosphorylation. In line with this, treatment with myelin-associated glycoprotein (MAG) enhanced Tau phosphorylation and ROCK activity in P301S neurons expressing wild type p75[NTR] or p75[C259A], but not p75[∆DD] or p75[KKEA]. Together, these results indicate that p75[NTR] contributes to AD Tauopathy by enhancing the activity of the RhoA-ROCK pathway.},
}

@article {pmid42552687,
year = {2026},
author = {Koychev, I and Rowe, JB and Amin, J and Arsland, D and Archer, H and Barber, R and Burns, A and Coulthard, E and Deasy, C and Dunne, R and Fox, N and Humphrey, SH and Jenkinson, J and Jones, D and Kennelly, S and Khan, F and Krishnan, MSP and Malhotra, P and McFarlane, B and McGuinness, B and Mummery, C and Pennington, C and Perry, JR and Raczek, G and Rasmussen, J and Ritchie, C and Taylor, JP and Underwood, BR and Venkataraman, AV and Raymont, V},
title = {Interpreting evolving evidence in Alzheimer's disease: implications for dementia clinicians.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-2},
doi = {10.1192/bjp.2026.10750},
pmid = {42552687},
issn = {1472-1465},
}

@article {pmid42552722,
year = {2026},
author = {Kotah, JM and Lima, MT and Dragt, EC and Voulgaroglou, A and Brouwer, N and Holtman, IR and Kooistra, SM and Eggen, BJL},
title = {Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1.},
journal = {Glia},
volume = {74},
number = {10},
pages = {e70210},
doi = {10.1002/glia.70210},
pmid = {42552722},
issn = {1098-1136},
support = {WE.03-2025-06//Alzheimer Nederland/ ; WE.03-2020-03//Alzheimer Nederland/ ; //Stichting De Cock-Hadders/ ; MODEM 10510032120006/ZONMW_/ZonMw/Netherlands ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Humans ; *Cell Communication/physiology ; *Brain/metabolism/pathology ; *Osteopontin/metabolism/genetics ; Signal Transduction/physiology ; Male ; Female ; Aged ; Plaque, Amyloid/pathology/metabolism ; Aged, 80 and over ; },
abstract = {Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell-cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1, and while this pathway was also present in control samples, microglia-microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia-microglia signaling predict AD-specific induction of GAS6-AXL signaling (from inflammatory and ribosomal microglia), and SPP1-ITGAV/ITGB5 signaling (from disease-associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
Humans
*Cell Communication/physiology
*Brain/metabolism/pathology
*Osteopontin/metabolism/genetics
Signal Transduction/physiology
Male
Female
Aged
Plaque, Amyloid/pathology/metabolism
Aged, 80 and over

@article {pmid42552749,
year = {2026},
author = {Boustani, M and Klein, EG and Zimmer, JA and Wang, H and Engle, SE and Phipps, A and Japha, M and Schilling, T and Hartry, A and , },
title = {Further data to address the Alzheimer's coverage with evidence development questions.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71724},
doi = {10.1002/alz.71724},
pmid = {42552749},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; United States ; *Medicare ; *Antibodies, Monoclonal, Humanized/therapeutic use ; },
abstract = {INTRODUCTION: Medicare patients currently access amyloid-targeting therapies for Alzheimer's disease through the class-based National Coverage Determination (NCD) with coverage with evidence development (CED) established in 2022. Evidence addressing the stated CED questions was previously published in a 2024 review; however, the original 2022 NCD remains unchanged.

METHODS: Update the previously published review responding to the CED questions by summarizing recently published donanemab and lecanemab extension data and new safety-related data.

RESULTS: New evidence addresses each of the three CED questions. Extension data show that the benefit of amyloid-targeting therapy continues to accrue with no new safety signals observed. Safety analyses identified baseline risk factors for amyloid-related imaging abnormalities (ARIA). Further, a more gradual donanemab titration regimen decreased risk of ARIA-edema/effusions.

DISCUSSION: With CED questions addressed, reconsideration of the class-based NCD is scientifically justified.

CLINICAL TRIAL REGISTRATION: NCT04437511, NCT05738486, NCT03887455.},
}

*Alzheimer Disease/drug therapy
Humans
United States
*Medicare
*Antibodies, Monoclonal, Humanized/therapeutic use

@article {pmid42552750,
year = {2026},
author = {Fernández-Lebrero, A and Jiménez-Balado, J and García-Escobar, G and Contador, J and Estraguès-Gázquez, I and Peraferrer-Montesinos, L and Manero-Borràs, RM and Gramegna, LL and Viles, M and Campello, AR and Ortiz-Romero, P and de Diego, M and Del Campo, M and Torres-Torronteras, J and Jiménez-Moyano, E and Blasco-Forniés, H and Suárez-Calvet, M and Ois, A and Puig-Pijoan, A and Navalpotro-Gómez, I},
title = {Plasma p-tau217 detects Alzheimer's disease co-pathology in cerebral amyloid angiopathy: Comparison to CSF biomarkers in the ANGMAR cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71709},
doi = {10.1002/alz.71709},
pmid = {42552750},
issn = {1552-5279},
support = {PI21/00194//the Fondo de Investigación Sanitaria (FIS)/ ; ERA-CVD_JTC2020-015//the European Research Area Network on Cardiovascular Diseases/ ; AC20/00001//the European Research Area Network on Cardiovascular Diseases/ ; CP25/00015//Miguel Servet program/ ; 948677//the European Research Council (ERC)/ ; PI22/00456//Instituto de Salud Carlos III (ISCIII)/ ; 847648 (LCF/BQ/PR21/11840004)//"la Caixa" Foundation/ ; },
mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; *Cerebral Amyloid Angiopathy/blood/pathology/complications/cerebrospinal fluid/diagnostic imaging ; *Alzheimer Disease/blood/cerebrospinal fluid/pathology/complications/diagnostic imaging/diagnosis ; Female ; Biomarkers/blood/cerebrospinal fluid ; Male ; Aged ; Magnetic Resonance Imaging ; Cohort Studies ; Phosphorylation ; Aged, 80 and over ; Middle Aged ; Brain/pathology ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer's disease (AD), generating mixed vascular-neurodegenerative phenotypes. Plasma phosphorylated tau (p-tau)217 is a robust biomarker of AD, but its performance in CAA remains unclear.

METHODS: We studied 231 participants, including 50 patients with CAA (Boston v2.0), 154 with AD, and 27 cognitively unimpaired controls. Plasma p-tau217 was measured on an automated platform and compared to cerebrospinal fluid (CSF)-defined AD status. Associations with magnetic resonance imaging (MRI) markers of CAA burden were evaluated.

RESULTS: Among CAA participants, 29 met CSF criteria for AD co-pathology. Plasma p-tau217 discriminated CAA patients with and without AD co-pathology (area under the curve = 0.920) and showed no association with MRI markers of CAA burden. Predefined cut-offs (≥ 0.27 pg/mL and ≥ 0.34 pg/mL) yielded high accuracy for identifying AD co-pathology within CAA.

CONCLUSIONS: Plasma p-tau217 shows high diagnostic accuracy for identifying AD co-pathology in CAA and is not associated with MRI markers of CAA burden, supporting its specificity for AD-related pathology.},
}

Humans
*tau Proteins/blood/cerebrospinal fluid
*Cerebral Amyloid Angiopathy/blood/pathology/complications/cerebrospinal fluid/diagnostic imaging
*Alzheimer Disease/blood/cerebrospinal fluid/pathology/complications/diagnostic imaging/diagnosis
Female
Biomarkers/blood/cerebrospinal fluid
Male
Aged
Magnetic Resonance Imaging
Cohort Studies
Phosphorylation
Aged, 80 and over
Middle Aged
Brain/pathology

@article {pmid42552753,
year = {2026},
author = {Hutten, CG and Beck, T and Evans, D and Rajan, KB},
title = {The role of polygenic risk in Alzheimer's disease prediction for African Americans.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71712},
doi = {10.1002/alz.71712},
pmid = {42552753},
issn = {1552-5279},
support = {R01AG073627/AG/NIA NIH HHS/United States ; R01AG058679/AG/NIA NIH HHS/United States ; UH2AG083289/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/ethnology ; *Black or African American/genetics ; Genetic Risk Score ; Female ; Male ; *Genetic Predisposition to Disease ; Aged ; White People/genetics ; *Multifactorial Inheritance/genetics ; Risk Factors ; Aged, 80 and over ; Apolipoprotein E4/genetics ; European People ; },
abstract = {INTRODUCTION: African Americans (AAs) face a higher risk of Alzheimer's disease and related dementias (ADRD) than European Americans (EUs), yet the utility of polygenic risk scores (PRS) in AAs remains underexplored.

METHODS: A standardized dementia PRS was evaluated in the Chicago Health and Aging Project (n = 4336; 61% AA) for associations with ADRD and cognitive trajectories over 8.4 years.

RESULTS: PRS predicted ADRD more strongly in EUs (c-index 0.86) than AAs (0.77); however, it conferred higher risk in AAs (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.04-1.78) compared to EU (HR = 1.13, 95% CI: 0.88-1.44). The PRS remained predictive among AAs after apolipoprotein E (APOE) ε4 adjustment (HR = 1.53, 95% CI: 1.03-2.27). Higher PRS associated with lower baseline cognition and faster decline (p < 0.05).

DISCUSSION: PRS conferred greater ADRD risk in AAs and comparable rates of cognitive decline, despite stronger discrimination in EUs, adding to the limited knowledge of genetic contributions to ADRD risk among AAs beyond APOE ε4 alleles.},
}

Humans
*Alzheimer Disease/genetics/ethnology
*Black or African American/genetics
Genetic Risk Score
Female
Male
*Genetic Predisposition to Disease
Aged
White People/genetics
*Multifactorial Inheritance/genetics
Risk Factors
Aged, 80 and over
Apolipoprotein E4/genetics
European People

@article {pmid42552789,
year = {2026},
author = {Piras, F and Serra, L and Caltagirone, C and Giove, F},
title = {The disconnectome as target in Alzheimer disease: a promising framework or a premature end-point?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag262},
pmid = {42552789},
issn = {1460-2156},
}

@article {pmid42552845,
year = {2026},
author = {Wang, X and Li, Y and Ye, J and Lian, H and Li, T and Wang, J},
title = {Lymphedema and Alzheimer's Disease: Connecting Through the "Peripheral-Central Lymphatic System".},
journal = {Lymphatic research and biology},
volume = {},
number = {},
pages = {15578585261471251},
doi = {10.1177/15578585261471251},
pmid = {42552845},
issn = {1557-8585},
abstract = {The connection between the peripheral lymphatic system (PLS) and the central lymphatic system (CLS) plays a crucial role for the overall circulatory system. Notably, there are several similarities between lymphedema and Alzheimer's disease (AD). Accumulating evidence suggests that lymphedema might be associated with AD, potentially influencing its progression through mechanisms related to the peripheral-central lymphatic circulation. This review summarizes the lymphatic system's structure, function, and drainage pathways, emphasizing how aging and blockage of the CLS can exacerbate the progression of AD. Additionally, we discuss the relationship between lymphedema and AD, highlighting the significance of the PLS-CLS and exploring lymphaticovenous anastomosis as a promising treatment for both lymphedema and AD.},
}

@article {pmid42553105,
year = {2026},
author = {Rubinshtein, R and Obied, B and Salti, T and König, AI and Zahavi, A and Goldenberg-Cohen, N},
title = {Longitudinal assessment of intraocular pressure in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1858031},
pmid = {42553105},
issn = {1664-2295},
abstract = {OBJECTIVES: Glaucoma and Alzheimer's disease (AD) are major neurodegenerative disorders with increasing evidence of shared pathogenic pathways. Glaucoma involves progressive optic nerve degeneration and irreversible vision loss, often associated with elevated intraocular pressure (IOP) but also occurring independently of it. AD, the leading cause of dementia, results in progressive cognitive and functional decline, with vision disturbances including visual field defects. Epidemiological studies report higher co-prevalence of glaucoma and AD in older adults. This study longitudinally assessed IOP in a transgenic AD mouse model to determine whether AD-related amyloid pathology inherently drives alterations in ocular pressure.

METHODS: Ten young (25 weeks old; 9 males, 1 female) and fifteen aged 5xFAD (57-60 weeks old; 5 males and 10 females) transgenic mice, a well-established amyloidogenic model of AD, were examined. Age-matched control groups included ten young wild type (WT) mice (9 males and 1 female) and fourteen aged WT mice (7 males and 7 females). IOP was measured repeatedly without anesthesia using a rebound tonometer (Icare Tonolab) calibrated for mice. Four IOP measurement sessions were performed at days 1, 36, 55, and 77, with all measurements conducted during midday hours (11:00-14:00) to minimize circadian variability.

RESULTS: IOP remained stable across most groups and time points. Aged 5xFAD mice exhibited transient, statistically significant fluctuations, characterized by an initial decrease at day 36 followed by a return to baseline levels. Age-matched WT mice showed no significant longitudinal changes. When comparing between groups, the only significant difference was observed at day 36, where aged 5xFAD mice demonstrated significantly lower IOP than aged WT controls.

CONCLUSIONS: 5xFAD mice did not exhibit sustained IOP elevation compared with WT controls, with aged animals displaying only transient fluctuations that likely reflect physiological or measurement variability. These results suggest that amyloid-driven pathology in this model is not accompanied by chronic ocular hypertension. Consequently, our findings support the hypothesis that visual dysfunction in AD models may occur independently of elevated intraocular pressure, though the specific overlapping mechanisms between AD and glaucoma warrant cautious interpretation and further investigation.},
}

@article {pmid42553297,
year = {2026},
author = {Li, Q and You, M},
title = {Targeting mitochondria for the treatment of neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1835506},
pmid = {42553297},
issn = {1662-4548},
abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.},
}

@article {pmid42553403,
year = {2026},
author = {Fan, JD and Fu, Y and Li, QY and Zhang, ZQ and Zhao, YL and Hao, Q and Tan, L and Tan, MS and , },
title = {Association of cerebrospinal fluid amphiphysin-1 levels with cognition and Alzheimer's disease pathology biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1875646},
pmid = {42553403},
issn = {1663-4365},
abstract = {INTRODUCTION: Amphiphysin-1 (AMPH), an accessory component of the clathrin-mediated endocytosis (CME) machinery, plays a critical role in synaptic vesicle recycling and membrane dynamics and has been implicated in Alzheimer's disease (AD) risk. However, its relationship with core AD biomarkers and disease progression remains unclear.

METHODS: In this study, we examined the associations between cerebrospinal fluid (CSF) AMPH and core AD biomarkers (CSF amyloid-β42 [Aβ42], phosphorylated tau [P-tau], and total tau [T-tau]), cognitive performance, neurodegeneration, and clinical progression in 723 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were categorized according to the AT(N) framework into stage 0, stage 1, stage 2, and suspected non-AD pathophysiology (SNAP).

RESULTS: AMPH exhibited stage-dependent alterations across the AD continuum, characterized by lower levels in stage 1, and elevated levels in stage 2 and SNAP. Cross-sectionally, CSF AMPH was positively associated with core CSF biomarkers. Longitudinal analyses showed that, among amyloid-negative individuals, higher baseline AMPH was associated with faster decreases in CSF Aβ42 and increases in P-tau and T-tau. In the overall cohort, higher baseline AMPH was associated with accelerated hippocampal atrophy and cognitive decline, and with an increased risk of clinical progression (HR = 1.21, 95% CI: 1.05-1.37).

DISCUSSION: In ADNI, CSF AMPH was associated with biological changes across the AD continuum, cognitive decline, hippocampal atrophy, and clinical progression. These findings may provide complementary information for understanding disease progression.},
}

@article {pmid42553595,
year = {2026},
author = {Tamvaka, N and Scotton, W and Lilley, MT and Shoai, M and Gavrielatos, M and Heckman, MG and Soto-Beasley, AI and Roemer, SF and Baker, MC and Rademakers, R and Murray, ME and Dickson, DW and Hardy, JA and Cook, CN and Rohrer, JD and Ross, OA and , and , },
title = {Evaluating MAPT p.A152T as a risk factor for the 3R tauopathy Pick's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag266},
pmid = {42553595},
issn = {2632-1297},
abstract = {Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick's disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer's disease and progressive supranuclear palsy, but its role in Pick's disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick's disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick's disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer's disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick's disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.},
}

@article {pmid42553702,
year = {2026},
author = {Morgan, J and Aarons, T and Mukhopadhyay, A and Lace, G},
title = {Distinct brain extracellular vesicle microRNA profiles differ in frontotemporal dementia and Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag277},
pmid = {42553702},
issn = {2632-1297},
abstract = {Dementia is a syndrome caused by various diseases including Alzheimer's disease (AD) and frontotemporal dementia (FTD) with an estimated global prevalence of 60 million individuals. Recently, therapeutic development in the dementia field has accelerated, with the introduction of monoclonal antibody therapeutics such as Lecanemab and Donanemab. However, AD and FTD patients are still either diagnosed too late to benefit from available therapies or are misdiagnosed due to the clinical overlap between dementia subgroups making therapeutic intervention challenging. This highlights a real need to improve early diagnostic tools of neurodegenerative disease (ND) biomarkers. A potential source of such biomarkers come from small extracellular vesicles (sEVs), groups of cell-derived, lipid-bound assemblies with the capability to cross the blood-brain barrier (BBB) and known to carry pathogenic proteins associated with AD and FTD. A known cargo of sEVs is microRNA (miRNA), regulatory molecules that post-transcriptionally silence gene expression including transcripts of autophagic systems, processes which dysfunction in dementia-causing diseases leading to toxic aggregate build-up, causing neurodegeneration. The targeting of functional machineries in macroautophagy (MA) and chaperone-mediated autophagy (CMA) by different miRNA may vary between AD and FTD mutations, leading to potential biomarkers of disease being highlighted. Through isolating sEVs from the frontal cortex of post-mortem brain tissue of AD, FTD-MAPT, FTD-C9orf72, FTD-GRN and no-disease control patients (Manchester Brain Bank), miRNA cargoes were analysed and compared using real-time quantitative PCR (RT-qPCR). Seven autophagy-associated miRNA candidates (MA: miR-124-3p, miR-30a-5p, miR-128-3p; and CMA: miR-224-5p, miR-373-5p, miR-106a-3p and miR-26b-5p) were tested to identify dementia sub-group variations, used alongside small RNA-sequencing to explore broader miRNA variation within sEV populations. Of the miRNA tested miR-224-5p (P = 1.76 × 10[-5]) and miR-106a-3p (P = 0.033) showed significant group differences, and further significant pairwise comparison differences [miR-224-5p: AD fold change (FC) = 4.29, MAPT FC = 7.62; miR-106a-5p: AD FC = 5.59] when compared with no disease controls and other dementia subgroups, potentially showing initial diagnostic and differentiating potential. Small RNA-sequencing results revealed 8 AD, 2 FTD-GRN, 52 FTD-MAPT and 12 FTD-C9orf72 differentially expressed sEV-miRNAs when compared with no disease controls. Further direct comparisons between AD versus FTD mutation-derived sEV cargoes, and even FTD mutation versus FTD mutation-derived sEV cargoes, identified additional miRNA with differentiating capabilities. These findings demonstrate sEV-derived miRNA signatures vary across dementia sub-types and suggest potential roles of sEV cargoes in both disease diagnostics and identifying drivers of ND, such as autophagic impairments and signalling pathways.},
}

@article {pmid42553791,
year = {2026},
author = {Mehdi, MR and Al-Qassab, ZMS and Sabuni, O and Rai, M and Patel, T and Patel, R and Iftikhar, L},
title = {Exploring the Link Between Obstructive Sleep Apnea and Neuropsychiatric Disorders: Role of Neuroinflammatory Mechanisms.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112096},
pmid = {42553791},
issn = {2168-8184},
abstract = {Obstructive sleep apnea syndrome (OSAS) is a prevalent sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction during sleep, resulting in intermittent reductions or complete cessation of airflow. These interruptions reduce oxygen saturation and disrupt normal sleep architecture, frequently resulting in daytime fatigue and adverse health outcomes. Recent research has provided increasing evidence that OSAS may be associated with neuroinflammation, defined as inflammation within the brain and nervous system. Such neuroinflammation may contribute to the development of conditions including depression, anxiety, Alzheimer's disease, and Parkinson's disease. This narrative review examines the association between OSAS and neuroinflammation and outlines the potential biological mechanisms involved. Intermittent hypoxemia and recurrent sleep fragmentation are thought to promote oxidative stress, neuroinflammation, and neuronal injury, ultimately contributing to impaired memory, executive function, emotional regulation, and overall neurological function. Over time, these processes can impair memory, executive function, emotional regulation, and overall neurological function. The review also highlights key risk factors and clinical manifestations and emphasizes the importance of early diagnosis and intervention for OSAS. Evidence from both experimental animal studies and human clinical studies is discussed to highlight current understanding while distinguishing established findings from emerging hypotheses. In summary, this review indicates that neuroinflammation may represent an important mechanistic pathway linking OSAS with depression, anxiety, cognitive impairment, and neurodegenerative disorders. However, much of the available evidence remains associative, and further longitudinal and biomarker-driven studies are required to clarify causal relationships and determine the long-term impact of interventions such as continuous positive airway pressure (CPAP) therapy. Improved understanding of these mechanisms may facilitate earlier diagnosis, risk stratification, and the development of targeted therapeutic strategies for individuals with OSAS.},
}

@article {pmid42553843,
year = {2026},
author = {Sharma, S and Sharma, S and Raghuvanshi, V and Kumari, S and Singh, S and Butcher, RJ and Srikrishna, S and Katiyar, D},
title = {Design, synthesis, and evaluation of pyrano[3,2-c]coumarin derivatives for simultaneous targeting of amyloid-β42 and acetylcholinesterase in transgenic AD model of Drosophila.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42553843},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving amyloid-β (Aβ) aggregation, cholinergic dysfunction, oxidative stress, mitochondrial impairment, and progressive neuronal loss. Consequently, the development of multi-target-directed ligands (MTDLs) capable of modulating multiple pathological pathways simultaneously has emerged as a promising therapeutic strategy. In this context, the present study describes the design, synthesis, and biological evaluation of a novel series of pyrano[3,2-c]coumarin derivatives 4a-n as dual Aβ42 and acetylcholinesterase (AChE) targeting anti-AD agents. Compounds 4a-n showed significant protection by inhibiting tissue specific Aβ42 aggregation in a transgenic AD model of Drosophila. In particular, compounds 4g and 4i were identified as potential lead compounds for targeting AD. These compounds inhibited endogenous Aβ42 aggregation and exhibited a significant rescue of eye phenotypes at respective effective concentrations (ECs) (4g, 46% rescue at EC = 250 µM and 4i, 65% rescue at EC = 50 µM). Furthermore, compounds 4g and 4i effectively reduced lipid-peroxidation, which was determined by assessing thiobarbituric acid reactive substances (TBARS) levels, at 25 and 50 µM, respectively, and reactive oxygen species (ROS). Compounds 4g and 4i also exhibited AChE inhibitory activity, with IC50 values of 0.02652 and 0.0268 µM, respectively. In silico molecular docking studies of 4i with Aβ42 (PDB ID: 1IYT) and AChE (PDB ID: 4EY4) also corroborated their anti-AD activity. Therefore, the present study indicated these compounds, especially 4i, could be promising lead candidates for AD drug development.},
}

@article {pmid42554173,
year = {2026},
author = {Yıldırım, N and Güven Aksu, NM and Perk, BÖ and Can Eke, B},
title = {Plasma Concentrations of Amyloid-β Peptides, BACE-1, and Tau Proteins in Alzheimer's Disease.},
journal = {Turkish journal of pharmaceutical sciences},
volume = {},
number = {},
pages = {},
doi = {10.4274/tjps.galenos.2026.68256},
pmid = {42554173},
issn = {2148-6247},
abstract = {OBJECTIVES: The aim of this study was to compare, using ELISA, plasma levels of amyloid beta (Aβ)40, Aβ42, beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), total tau (t-tau), and phosphorylated tau (p-tau), as well as the Aβ42/Aβ40 ratio, between patients with Alzheimer's disease (AD) and healthy controls, and to evaluate their diagnostic performance in relation to demographic and lifestyle factors.

MATERIALS AND METHODS: This study is a single-center, cross-sectional, case-control study. Twenty-four individuals diagnosed with AD and 37 healthy volunteers included in the study. Alongside the analysis of plasma samples obtained from the participants, demographic data were analyzed to assess the potential influence of lifestyle and environmental factors on disease development.

RESULTS: Analysis of the case data showed that increasing age was a risk factor for AD, higher education level was associated with an increased risk of AD, and tea consumption was inversely associated with AD. While age is a well-known risk factor, both the increased risk of AD associated with higher education and the relatively protective effect of tea consumption against AD are supported by the literature. Evaluation of the levels of Aβ40, Aβ42, BACE-1, t-tau, and p-tau and of the Aβ42/Aβ40 ratio revealed no significant differences between the patient and control groups. Additionally, Aβ40, Aβ42, BACE-1 showed correlations in both the control and Alzheimer's groups, whereas t-tau did not.

CONCLUSION: None of the investigated plasma biomarkers (Aβ40, Aβ42, BACE-1, t-tau, p-tau, and the Aβ42/Aβ40 ratio) discriminated Alzheimer's patients from healthy controls, with all receiver operating characteristic area under the curve values below 0.62. These findings indicate that in this cohort, plasma levels of these individual markers did not provide diagnostic value; larger longitudinal studies including cerebrospinal fluid comparisons and multi-marker panels are needed.},
}

@article {pmid42554188,
year = {2026},
author = {Zhang, H and Zhang, Y and Cheng, Y and Liu, Q and Meng, X and Wang, D and Li, M},
title = {Docosahexaenoic acid improves cognitive function and reduces neuronal apoptosis in an Alzheimer's disease mouse model: association with reduced oxidative stress and telomere attrition.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1028415X.2026.2700765},
pmid = {42554188},
issn = {1476-8305},
abstract = {OBJECTIVE: Given the global aging intensification, age-related chronic diseases like Alzheimer's disease (AD) severely harm the elderly's health, with unclear pathogenesis and no effective drugs. Thus, this study intervened in APP/PS1 mice with docosahexaenoic acid (DHA) feeds of different doses to explore DHA's effects on the mice's cognitive function and nerve cell apoptosis, aiming to find the ways to prevent or delay the elderly's cognitive decline.

METHODS: Six-month-old APP/PS1 mice were divided into 4 groups: wild control (WT), model control (Con), low-dose DHA (DHA-L), and high-dose DHA (DHA-H). After intervention, the study evaluated mice's cognitive function, determined brain AD-related protein and free fatty acid levels, assessed neuronal degeneration and apoptosis, measured telomere oxidative damage, telomere length, and brain oxidative stress levels.

RESULTS: (1) DHA shortened water maze escape latency, increased platform crossings and target quadrant residence time, and reduced the expression of AD-related proteins (APP, Aβ, etc.) (P < 0.05); (2) It improved brain neuronal degeneration and apoptosis (P < 0.05); (3) It enhanced brain antioxidant capacity, regulated SOD, LPO, and MDA levels, and reduced DNA and telomere oxidative damage (P < 0.05); (4) It prolonged brain telomere length (P < 0.05).

CONCLUSION: DHA supplementation can improve cognitive decline in AD model mice, and the mechanism may be that DHA supplementation alleviates oxidative stress-mediated telomere wear in brain tissue, thereby inhibiting apoptosis of neuronal cells. These conditions provide a scientific basis for the elderly and people with cognitive impairment to prevent or alleviate cognitive impairment with reasonable intake of DHA.},
}

@article {pmid42554237,
year = {2026},
author = {Maestre, GE and Patel, NK and Pirela, RV and Hilsabeck, RC and Stine, K and Epps, FR and Garcia, N and Santiago-Mejias, S and Reyes, R and Satizabal, CL and Mejia-Arango, S and Sullivan, AC and Oropeza, O and Gireud-Goss, M and Rodriguez, H and Trevino, H and Ramirez, A and Young, VM and Alliey-Rodriguez, N and LaRoche, A and Martinez-Menendez, CJ and Tanner, JA and Otto, L and Garza-Parker, C and Garza, N and Flores, M and Casas, N and Robles, S and Davila, A and Maestre, CA and Shipp, E and Melgarejo, JD and de Erausquin, GA and Williams-Blangero, S and Seshadri, S},
title = {Engagement of understudied populations as community change: The South Texas ADRC model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71695},
doi = {10.1002/alz.71695},
pmid = {42554237},
issn = {1552-5279},
support = {P30AG066546/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Texas ; *Alzheimer Disease ; Hispanic or Latino ; *Patient Selection ; Community-Institutional Relations ; Focus Groups ; Rural Population ; Registries ; },
abstract = {Many populations experiencing the highest burdens of Alzheimer's disease and related dementias remain understudied, in part because traditional recruitment and retention models are insufficient to support sustained engagement. The Outreach, Recruitment, and Engagement Core (OREC) of the South Texas Alzheimer's Disease Research Center reconceptualized participant recruitment as a long-term system change in a Hispanic-majority, urban-rural region. OREC institutionalizes shared power through community advisory governance, aligns research protocols with local lived realities (through patient navigators, community health workers/promotores, and decentralized access points), and employs a data-driven feedback loop for continuous improvement. In 1 year, 46 outreach events touched 10,134 individuals (71% Hispanic) and generated 172 new registry enrollments. Qualitative engagement (focus groups/key-informant interviews) progressed to high-sensitivity topics (e.g., brain donation), signaling maturation of trust. This shift from outreach to reciprocity infrastructure reflects a systems-level change, one that lowers barriers, builds trust, and enables research participation to become routine rather than exceptional.},
}

Humans
Texas
*Alzheimer Disease
Hispanic or Latino
*Patient Selection
Community-Institutional Relations
Focus Groups
Rural Population
Registries

@article {pmid42554250,
year = {2026},
author = {Song, W and Liu, X and Yu, T and Xiang, Y and Fu, P and Wu, M and Yin, X and Zhang, X and Chen, Z},
title = {Early identification of vascular cognitive impairment from a multimodal perspective: a combined diagnosis from targeted cognitive assessments, imaging biomarkers, and molecular fluid biomarkers to ecological behavioral characteristics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71667},
doi = {10.1002/alz.71667},
pmid = {42554250},
issn = {1552-5279},
support = {81960221//National Natural Science Foundation of China/ ; 82260249//National Natural Science Foundation of China/ ; 202311506//Jiangxi Provincial Health Commission Science and Technology Plan project/ ; 2022A322//Jiangxi Provincial Administration of Traditional Chinese Medicine science and technology plan project/ ; 20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; JXJG-24-17-20//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; JXJG-24-17-2//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; JXYJG-2024-140//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Early Diagnosis ; *Cognitive Dysfunction/diagnosis ; Neuroimaging ; Machine Learning ; *Dementia, Vascular/diagnosis ; Neuropsychological Tests ; },
abstract = {Vascular cognitive impairment (VCI), the second leading cause of dementia, is characterized by heterogeneous pathophysiology and a potentially reversible early phase, underscoring the need for timely identification. This review synthesizes advances across four complementary domains - targeted cognitive assessments, imaging biomarkers, molecular fluid biomarkers, and ecological behavioral characteristics - conceptualized as the TIME framework. Emerging markers, including the peak width of skeletonized mean diffusivity (PSMD), oxygen extraction fraction, brain-derived extracellular vesicles, and digital gait metrics, enable the detection of microvascular injury before overt cognitive decline. Given the limitations of single modalities, we advocate for multimodal integration via machine learning to capture the disease continuum from vascular insult to clinical impairment. Establishing a standardized, pathophysiologically anchored classification system, analogous to the AT(N) framework in Alzheimer's disease, is essential to advance precision risk stratification and early intervention in VCI.},
}

Humans
*Biomarkers/cerebrospinal fluid
Early Diagnosis
*Cognitive Dysfunction/diagnosis
Neuroimaging
Machine Learning
*Dementia, Vascular/diagnosis
Neuropsychological Tests

@article {pmid42554263,
year = {2026},
author = {Kim, BH and Lee, H and Kim, J and Seo, SW and Nho, K and , },
title = {Epigenetic aging in Alzheimer's disease: Relation to proteome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71732},
doi = {10.1002/alz.71732},
pmid = {42554263},
issn = {1552-5279},
support = {P30AG010133/NH/NIH HHS/United States ; P30AG072976/NH/NIH HHS/United States ; R01AG081951/NH/NIH HHS/United States ; R01LM012535/NH/NIH HHS/United States ; U01AG06857/NH/NIH HHS/United States ; U01AG24904/NH/NIH HHS/United States ; U01AG072177/NH/NIH HHS/United States ; U19AG074879/NH/NIH HHS/United States ; RS-2020-KH106434//Korea Dementia Research Center (KDRC)/ ; RS-2025-02223212//Korea Health Industry Development Institute (KHIDI)/ ; 2024-ER1003-02//Korea National Institute of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/cerebrospinal fluid ; *Epigenesis, Genetic ; *Aging/genetics ; *Proteome ; DNA Methylation ; Proteomics ; Biomarkers/cerebrospinal fluid ; Female ; Male ; Aged ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) arises from heterogeneous biological processes, and long-term environmental exposures may become biologically embedded, as reflected in epigenetic clocks.

METHODS: We calculated blood DNA methylation-based epigenetic clocks and constructed protein co-abundance networks of cerebrospinal fluid (CSF) proteomics data. We performed association analysis of epigenetic age acceleration with network modules, followed by functional and cell-type enrichment analyses, association analyses of hub proteins with AD endophenotypes, and pseudotime trajectory analysis.

RESULTS: Six network modules were significantly associated with epigenetic age acceleration and were enriched in pathways related to neuronal connectivity, proteostasis, immune activation and remodeling, immune signaling, and immunoepigenetic regulation. Hub proteins demonstrated significant associations with baseline amyloid/tau/neurodegeneration biomarkers and longitudinal cognitive changes. Pseudotime analysis revealed continuous, non-linear variation in epigenetic age acceleration along the inferred trajectory.

DISCUSSION: Our CSF proteomics study identified neuronal, proteostatic, and immune-related molecular signatures associated with epigenetic age acceleration in AD.},
}

Humans
*Alzheimer Disease/genetics/cerebrospinal fluid
*Epigenesis, Genetic
*Aging/genetics
*Proteome
DNA Methylation
Proteomics
Biomarkers/cerebrospinal fluid
Female
Male
Aged

@article {pmid42554285,
year = {2026},
author = {Benussi, A and Bracca, V and Premi, E and Cantoni, V and Palacino, F and Saccavini, A and Cotelli, MS and Binetti, G and Manenti, R and Alberici, A and Gasparotti, R and Ashton, NJ and Zetterberg, H and Blennow, K and Ghidoni, R and Borroni, B},
title = {Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71722},
doi = {10.1002/alz.71722},
pmid = {42554285},
issn = {1552-5279},
support = {//University of Brescia, Italy/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; },
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Magnetic Resonance Imaging ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood ; Aged ; Middle Aged ; Neurofilament Proteins/blood ; Disease Progression ; Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Supranuclear Palsy, Progressive/pathology ; },
abstract = {BACKGROUND: The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.

METHODS: We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data.

RESULTS: Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.

CONCLUSIONS: This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.},
}

Humans
Female
*Biomarkers/blood
Male
Magnetic Resonance Imaging
*Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood
Aged
Middle Aged
Neurofilament Proteins/blood
Disease Progression
Glial Fibrillary Acidic Protein/blood
Atrophy/pathology
Brain/pathology/diagnostic imaging
Neuropsychological Tests
Supranuclear Palsy, Progressive/pathology

@article {pmid42554607,
year = {2026},
author = {Wang, J and Xie, W and Yang, L and Wang, Z and Huang, Y and Huang, P and Liu, Y and Hu, J},
title = {Systematic Multi-Level Analyses Decode the Arthritis-Neurodegeneration Axis With In Vivo Validation.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76930},
doi = {10.1002/advs.76930},
pmid = {42554607},
issn = {2198-3844},
support = {82272544//National Natural Science Foundation of China/ ; 81672218//National Natural Science Foundation of China/ ; BK20251945//Natural Science Foundation of Jiangsu Province/ ; },
abstract = {Arthritis may influence neurodegenerative risk, but directionality and mediators remain unclear. This study integrates population survival analysis, Mendelian randomization, transcriptomic mapping, and mouse perturbation to map osteoarthritis (OA)/rheumatoid arthritis (RA) links with five neurodegenerative outcomes and prioritize mediators. In 310 162 European-ancestry UK Biobank participants, Cox models associate OA with higher risks of Alzheimer's disease (AD; hazard ratio: 1.13, 95% confidence interval: 1.04-1.22), Parkinson's disease (PD; 1.10, 1.00-1.21), and disorders of autonomic nervous system (DANS; 1.36, 1.06-1.74), and RA with higher AD risk (1.37, 1.13-1.67) (all p < 0.05), but not incident PD. Mendelian randomization prioritizes a modest protective genetic effect of RA on PD (odds ratio: 0.93, 0.88-0.99; p = 0.015), without reverse causation. Transcriptome-wide association and colocalization analyses identify shared RA-PD genes and prioritize Ring Finger Protein 40 (RNF40). In a collagen-induced arthritis (CIA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, CIA attenuates dopaminergic injury, whereas systemic Rnf40 knockdown alleviates arthritis but exacerbates Parkinsonian pathology. Endogenous RNF40 is induced in arthritic joints but remains stable in midbrain. These cross-layer data define arthritis-neurodegeneration connections and nominate RNF40 as a context-dependent joint-brain candidate linking inflammatory arthritis with dopaminergic vulnerability.},
}

@article {pmid42554796,
year = {2026},
author = {Ray, A and Agarwal, K and Jha, S and Singh, AM and Majumder, S and Lodh, E and Chowdhury, T and , },
title = {miRNA-mRNA Interaction Network Analysis in Alzheimer's Disease for Biomarker Discovery.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42554796},
issn = {1559-1166},
mesh = {*Alzheimer Disease/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Humans ; *RNA, Messenger/genetics/metabolism ; *Gene Regulatory Networks ; Biomarkers/metabolism ; Transcriptome ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by widespread dysregulation of gene expression and regulatory pathways. MicroRNAs (miRNAs) act as key post-transcriptional regulators by modulating messenger RNAs (mRNAs), and their disruption can influence synaptic function, neuroinflammation, and neuronal survival. In this study, we present a transcriptomic-driven framework in which differentially expressed genes (DEGs) are identified from gene expression data and integrated with curated miRNA-target interaction databases to infer putative AD-associated miRNA-mRNA regulatory signatures and potential candidate biomarkers. Transcriptomic and clinical data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and the GEO dataset GSE48552 was used as supplementary support to assess the consistency of observed transcriptomic patterns. Using an exploratory differential expression threshold with Welch's t-test and FDR correction, 123 candidate dysregulated genes (34 up-regulated, 89 down-regulated) were identified between AD and cognitively normal controls. To further assess robustness, threshold-sensitivity and cross-method concordance analyses were conducted, supporting the presence of a reproducible core transcriptional signal within the broader discovery-level DEG set. Experimentally validated and predicted miRNA-target interactions were integrated using miRTarBase, yielding 1,669,089 miRNA-gene interactions involving 3,055 unique miRNAs, with strong enrichment toward down-regulated gene targeting. Functional enrichment analysis revealed convergence of miRNA-regulated genes on synaptic signaling, neuronal communication, intracellular transport, apoptosis, oxidative stress, and PI3K-Akt/MAPK-related pathways. A bipartite putative miRNA-mRNA regulatory network (2,207 nodes connected by 11,437 edges, including 2,104 miRNAs and 103 significant genes) was constructed and analyzed using centrality metrics, prioritizing candidate hub genes, including PBX1 and KREMEN1, which were subsequently interpreted in the context of neuronal transcriptional regulation, Wnt-related signalling, synaptic vulnerability, and AD-associated pathway enrichment. Finally, supervised machine learning models trained on selected molecular features showed discriminative performance in the held-out test set, with Random Forest, Gradient Boosting, and LightGBM achieving the highest ROC-AUC values, indicating strong capability in distinguishing AD from control samples. Overall, the framework provides a biologically interpretable strategy for biomarker discovery, prioritizing AD-associated candidate biomarkers and putative regulatory interactions while highlighting targets for future experimental and clinical validation.},
}

*Alzheimer Disease/genetics/metabolism
*MicroRNAs/genetics/metabolism
Humans
*RNA, Messenger/genetics/metabolism
*Gene Regulatory Networks
Biomarkers/metabolism
Transcriptome

@article {pmid42554848,
year = {2026},
author = {Neha, and Aran, KR},
title = {Epitranscriptomic imprints on glial cell polarization: METTL3/IGF2BP2 axis as a driver of neurodegeneration in Alzheimer's disease.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42554848},
issn = {1432-2072},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving synapse dysfunction, neuronal death and disorientation of cognitive processes that are caused by the accumulation of amyloid-β (Aβ) along with aberrant phosphorylation of tau. Aberrant proteolytic processing of amyloid precursor protein (APP) promotes Aβ production, which is pro-oxidant, activates microglia, and promotes chronic neuroinflammation. In parallel, neurofibrillary tangle formation, microtubule destabilisation, and impaired axonal transport are the consequences of pathological tau phosphorylation, which together are associated with accelerated neuronal degeneration. Recent findings implicate epitranscriptomic Dysregulation as an important, but understudied, component of AD pathobiology. In particular, emerging evidence suggests that the expression and activity of METTL3 are dynamically regulated throughout the course of AD, with up- or down-regulation at different disease stages, in specific brain regions, and across cell types, indicating that METTL3 signalling is dysregulated rather than uniformly increased or decreased in AD pathogenesis. Therefore, the changes in m6A deposition mediated by METTL3 could be different in various pathological contexts and cell types, with different downstream consequences in terms of neuronal survival, glial activation and inflammatory signalling. Context-dependent dysregulation of this regulatory axis drives a pronounced elevation in important pro-inflammatory mediators and promotes pyroptosis, including NLRP3, IL-1β, and STAT3, thereby enhancing glial activation, inflammasome assembly and caspase-dependent neuronal death. Integrating the Ab-mediated pathology, tau-mediated cytoskeletal dysfunction and chronic neuroinflammation, the METTL3/IGF2BP2 pathway defines a convergence point that helps break down neuronal homeostasis and plasticity. This review compiles new mechanistic truths of how m[6]A-dependent RNA regulation contributes to the progression of AD and discusses therapeutic opportunities of METTL3/IGF2BP2 axis targeting for novel RNA-based therapies for neurodegenerative disease.},
}

@article {pmid42492825,
year = {2026},
author = {Bunch, TJ and May, HT and Muhlestein, JB and Anderson, JL and Le, V and Woller, SC and Cutler, MJ and Mahajan, R and Targueta, GP and Gurol, ME and Knowlton, K},
title = {Concussion AF trial: Longitudinal assessment of brain injury biomarkers and cognitive decline in elderly patients with atrial fibrillation.},
journal = {Heart rhythm},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.hrthm.2026.07.019},
pmid = {42492825},
issn = {1556-3871},
abstract = {BACKGROUND: Atrial fibrillation (AF) is associated with cognitive impairment. Serum biomarkers to detect subclinical brain injury or predict dementia in patients with anticoagulated AF are understudied.

OBJECTIVE: This study aimed to quantify neural injury biomarkers and assess their ability to predict incident dementia or moderate cognitive decline in patients with AF.

METHODS: Prospective longitudinal study of 120 patients with AF (mean age 71.1 ± 10.7 years; 62.5% male) without baseline dementia. Assessments at baseline and at 6, 12, and 24 months (60% completed all visits). Cognitive and functional measures included the Mini-Mental State Examination (MMSE), the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11), the Disability Assessment for Dementia, and quality-of-life measures. Serum biomarkers measured were glial fibrillary acidic protein, neuron-specific enolase (NSE), tau, S100 calcium-binding protein B (S100B), and spectrin N-terminal fragment (SNT145). The primary endpoint was incident dementia (MMSE score <24 with memory-related quality-of-life impact). The secondary endpoint was moderate cognitive decline defined as >30% worsening in ADAS-cog11 or >30% decline in the Disability Assessment for Dementia.

RESULTS: Comorbidities were common: hypertension 64.2%, heart failure 23%, diabetes 16%, and sleep apnea 30.8%; 2 had previous stroke. No participants met the criteria for incident dementia; 3 had an MMSE score of <24 without quality-of-life impact. At 24 months, 9 of 72 (12.5%) exhibited moderate cognitive decline by ADAS-cog11. Biomarkers indicated chronic subclinical stress rather than acute injury: S100B was persistently elevated (baseline 0.18 ± 0.23; 24 months 0.18 ± 0.19 pg/mL). SNT145 was elevated (baseline 2.85 ± 3.73; 24 months 2.36 ± 1.86 ng/mL). NSE and tau remained within normal ranges; inflammatory markers were persistently elevated. Changes in biomarker levels did not correlate with cognitive decline.

CONCLUSION: Over 2 years, dementia incidence was low but 12.5% experienced moderate cognitive decline. Persistent elevations of S100B and SNT145 suggest ongoing subclinical brain injury in patients with anticoagulated AF without acute spikes in traditional stroke markers such as NSE.},
}

@article {pmid42545971,
year = {2026},
author = {Salas-Venegas, V and Ramírez-Carreto, RJ and Chavarría, A},
title = {Senescence Associated With Neurodegeneration: Simultaneous Assessment of β-gal Activity And Nissl Stain In Histological Sections of Rodent Brain.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {233},
pages = {},
doi = {10.3791/70676},
pmid = {42545971},
issn = {1940-087X},
mesh = {Animals ; *beta-Galactosidase/metabolism/analysis ; *Cellular Senescence/physiology ; *Neurodegenerative Diseases/pathology/enzymology ; *Brain/pathology/enzymology/metabolism ; Rats ; Staining and Labeling/methods ; Neurons/pathology/enzymology ; Mice ; },
abstract = {Cellular senescence is a physiological process characterized by irreversible cell cycle arrest that impairs tissue regeneration and function. This phenomenon has emerged as a key driver of neurodegeneration, fueled by the accumulation of senescent cells within the central nervous system (CNS). Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype (SASP) that sustains chronic neuroinflammation and disrupts the neuronal microenvironment. Consequently, essential processes such as neurogenesis, synaptic plasticity, and neuronal survival are compromised. An extensive body of literature associates cellular senescence with several neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis, and acute neuronal-related damage, such as cerebral ischemia or traumatic brain injury. The combined assessment of senescence-associated β-galactosidase (SA-β-gal) activity and Nissl staining in histological sections provides a comprehensive approach to evaluate cellular senescence and neuronal integrity simultaneously within the same tissue context. This strategy enables precise spatial correlation between the accumulation of senescent cells in specific vulnerable regions (e.g., the hippocampus or cortex) and neuronal loss or tissue damage. By integrating a functional marker of senescence with a classical indicator of neuronal morphology and density, this approach strengthens the interpretative robustness of the analysis. Moreover, it enables a more accurate characterization of the relationship between senescent burden and neurodegenerative changes, maximizing the information yield from limited tissue samples. Moreover, this protocol can determine how senescent cell accumulation occurs in response to interventions (pharmacological, genetic manipulation, etc.) in rodent models of neurodegenerative diseases, thereby providing a powerful tool to analyze this contribution to their pathophysiology.},
}

Animals
*beta-Galactosidase/metabolism/analysis
*Cellular Senescence/physiology
*Neurodegenerative Diseases/pathology/enzymology
*Brain/pathology/enzymology/metabolism
Rats
Staining and Labeling/methods
Neurons/pathology/enzymology
Mice

@article {pmid42546187,
year = {2026},
author = {Chaudhari, NN and Vega Huerta, OM and Bhattacharya, S and Chowdhury, NF and Irimia, A and , },
title = {Deep learning maps local brain aging in relation to cognition across human adulthood.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {32},
pages = {e2532233123},
doi = {10.1073/pnas.2532233123},
pmid = {42546187},
issn = {1091-6490},
support = {R01 AG 079957//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *Deep Learning ; *Aging/physiology/pathology ; Female ; Aged ; *Cognition/physiology ; Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/physiology/pathology ; Male ; Alzheimer Disease/diagnostic imaging/physiopathology/pathology ; Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology ; Middle Aged ; Brain Mapping/methods ; Adult ; Aged, 80 and over ; },
abstract = {Brain aging, the strongest risk factor for Alzheimer's disease (AD), varies across cortical regions. Global brain age (GBA), an imaging-derived measure of neuroanatomic decline, reduces structural aging to a single summary value. This can potentially obscure regional patterns of cognitive vulnerability preceding AD. This study introduces a deep-learning architecture trained on the [Formula: see text]-weighted MRIs of 14,748 cognitively normal (CN) participants from multiple sites to estimate local brain age (LBA) at voxel level. By mapping spatial variations in brain aging, the model reveals relatively advanced aging in frontal and temporal lobes compared to parietal and occipital regions. Beyond aging in CN aging adults ([Formula: see text]), findings reveal a pattern of progressively advanced frontotemporal aging as a function of neurodegeneration stage, ranging from mild cognitive impairment (MCI, [Formula: see text]) to AD ([Formula: see text]). Compared to CN adults, key cortical and subcortical structures known to manifest early AD pathology exhibit significantly older LBAs in both early MCI and AD ([Formula: see text]). Deviations from normative regional aging are significantly associated with cognitive performance supported by neural processes linked to those regions ([Formula: see text]), thereby relating anatomic aging to functional outcomes. By quantifying regional variations in brain aging, this framework extends GBA models to provide anatomically interpretable measures that can improve characterization of typical and pathological aging.},
}

Humans
*Deep Learning
*Aging/physiology/pathology
Female
Aged
*Cognition/physiology
Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/physiology/pathology
Male
Alzheimer Disease/diagnostic imaging/physiopathology/pathology
Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology
Middle Aged
Brain Mapping/methods
Adult
Aged, 80 and over

@article {pmid42546216,
year = {2026},
author = {Thangavel, M and Masurkar, AV},
title = {Nuclear garbage disposal: An unexpected role for amyloid precursor protein in Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {32},
pages = {e2619791123},
doi = {10.1073/pnas.2619791123},
pmid = {42546216},
issn = {1091-6490},
}

@article {pmid42546232,
year = {2026},
author = {Kropp, E and Varkanitsa, M and Stein, TD and Turk, K and Alosco, ML and Tripodis, Y and Romero, JR and Kiran, S and Budson, AE and , and Charidimou, A},
title = {Diagnostic Accuracy of the Boston Criteria v2.0 in Memory Clinic Patients: An MRI-Neuropathology Validation Study.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218314},
doi = {10.1212/WNL.0000000000218314},
pmid = {42546232},
issn = {1526-632X},
mesh = {Humans ; Female ; *Magnetic Resonance Imaging ; Male ; Aged ; Retrospective Studies ; *Cerebral Amyloid Angiopathy/diagnostic imaging/diagnosis/pathology/complications ; Aged, 80 and over ; Sensitivity and Specificity ; *Brain/pathology/diagnostic imaging ; *Memory Disorders/diagnostic imaging/etiology ; Alzheimer Disease ; },
abstract = {BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy (CAA) is common in older adults and frequently contributes to cognitive impairment and dementia. Existing in vivo diagnostic criteria for CAA (Boston Criteria) were developed primarily in patients with intracerebral hemorrhage, and their performance in memory clinic populations remains uncertain. The updated Boston Criteria v2.0 incorporate nonhemorrhagic MRI markers intended to improve case detection. We evaluated the diagnostic accuracy of the Boston Criteria v1.5 and v2.0 against neuropathologically confirmed CAA in memory clinic patients.

METHODS: We performed a retrospective diagnostic accuracy study of participants from the Alzheimer's Disease Neuroimaging Initiative and National Alzheimer's Coordinating Center, selected based on availability of required brain MRI and autopsy-based neuropathology data. Patients were classified as no, possible, or probable CAA according to the Boston Criteria v1.5 and v2.0. The primary reference standard was moderate-to-severe neuropathologic CAA; analyses using any neuropathologic CAA were secondary/exploratory. Diagnostic performance was assessed using sensitivity, specificity, predictive values, likelihood ratios, F1 scores, accuracy, and area under the (receiver-operating characteristic) curve (AUC), with formal comparisons between criteria versions.

RESULTS: Eighty patients were included (mean age: 81 years, interquartile range 74-86 years; 36.2% female, ∼80% with dementia and Alzheimer disease). Using moderate-to-severe CAA as the neuropathologic reference standard, probable CAA by Boston Criteria v1.5 had a sensitivity of 32% (95% CI 15%-50%), specificity 87% (77%-95%), and AUC 0.59 (0.49-0.69). Using the Boston Criteria v2.0, the corresponding values were 43% (25%-62%), 83% (72%-92%), and 0.63 (0.52-0.74), respectively. No overall performance measures were significantly different between the criteria versions. Secondary analyses using any neuropathologic CAA showed similar patterns.

DISCUSSION: In memory clinic patients, both Boston Criteria versions showed only modest overall diagnostic performance against neuropathology. Compared with v1.5, Boston Criteria v2.0 showed a numerical shift toward greater sensitivity at the expense of specificity but no clear overall gain in accuracy. These findings support cautious, context-dependent interpretation of MRI-based CAA criteria in memory clinic settings and highlight the need for additional biomarkers to improve in vivo diagnosis in nonhemorrhagic populations.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, in memory clinic populations, Boston Criteria v2.0 show a trade-off between sensitivity and specificity for probable CAA diagnosis, with only modest overall diagnostic accuracy for identifying moderate-to-severe neuropathologically defined CAA.},
}

Humans
Female
*Magnetic Resonance Imaging
Male
Aged
Retrospective Studies
*Cerebral Amyloid Angiopathy/diagnostic imaging/diagnosis/pathology/complications
Aged, 80 and over
Sensitivity and Specificity
*Brain/pathology/diagnostic imaging
*Memory Disorders/diagnostic imaging/etiology
Alzheimer Disease

@article {pmid42546668,
year = {2026},
author = {Wuensche, TE and Stotz, S and Battisti, UM and Herth, MM},
title = {Pretargeted imaging beyond the blood-brain barrier: From concept to reality.},
journal = {Nuclear medicine and biology},
volume = {158-159},
number = {},
pages = {109653},
doi = {10.1016/j.nucmedbio.2026.109653},
pmid = {42546668},
issn = {1872-9614},
abstract = {Pretargeted positron emission tomography (PET) is emerging as a transformative approach for imaging biologics in the brain, overcoming the limitations of direct radiolabeling. Conventional methods with long-lived radionuclides suffer from high radiation exposure, off-target accumulation, and suboptimal imaging properties. Pretargeting separates the targeting from the imaging step, enabling the use of short-lived radionuclides such as fluorine-18, the clinical gold standard, and thereby allowing high-contrast, low-dose imaging. Realizing this strategy in the brain remains challenging due to the restrictive blood-brain barrier, pharmacokinetic constraints, and the requirement for efficient in vivo click chemistry. Recent progress spanning in silico design, in vitro validation, and in vivo studies has now demonstrated successful pretargeting with BBB-shuttled antibodies and antisense oligonucleotides in rodents, non-human primates, and Alzheimer's disease models. Together, these studies demonstrate that what was once considered utopian has now become reality.},
}

@article {pmid42546694,
year = {2026},
author = {Balak, CD and Schlachetzki, JCM and Lana, AJ and West, E and Hong, C and DuGal, J and Zhou, Y and Li, B and Spann, NJ and Saisan, P and Sarsani, V and Kleemann, KL and Zhang, X and Pasillas, MP and O'Brien, S and Bokor, JA and Gordts, PLSM and Butovsky, O and Stevens, B and Kamme, F and Glass, CK},
title = {Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.},
journal = {Immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.immuni.2026.07.008},
pmid = {42546694},
issn = {1097-4180},
abstract = {Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.},
}

@article {pmid42546822,
year = {2026},
author = {Ghaderi, S and Mohammadi, S and Iturria-Medina, Y},
title = {Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110765},
doi = {10.1016/j.mri.2026.110765},
pmid = {42546822},
issn = {1873-5894},
abstract = {Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.},
}

@article {pmid42546862,
year = {2026},
author = {Zahran, A and Bdair, M and Milhem, F and Jallad, H and Awartani, A and Khaled, A and Salah, Q and Jamaleddin, R and Thouqan, L and Aldarak, S},
title = {Neurocognitive Outcomes and Survival with High- vs Low-Intensity Statins in Stroke Survivors: A Propensity Score-Matched Cohort (2010-2025).},
journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association},
volume = {},
number = {},
pages = {108721},
doi = {10.1016/j.jstrokecerebrovasdis.2026.108721},
pmid = {42546862},
issn = {1532-8511},
abstract = {BACKGROUND: Stroke survivors face elevated risks of cognitive decline and dementia. Whether initiating high-intensity versus low/moderate-intensity statins after stroke confers additional neurocognitive benefit-beyond vascular risk reduction-remains uncertain.

METHODS: Retrospective propensity-matched cohort in TriNetX Research (104 U.S. healthcare organizations). Adults ≥18 years with stroke (ICD-10-CM I60/I61/I63) who received a statin within 7 days were included.

EXPOSURE: high-intensity versus low/moderate intensity. One-to-one matching on 24 covariates.

PRIMARY OUTCOME: time to first diagnosis of any dementia within 5 years from day 30. Secondary: Alzheimer's disease, vascular dementia, and all-cause mortality. Hazard ratios with 95% CIs were estimated.

RESULTS: Of 254,711 eligible patients (148,198 high-intensity; 106,513 low/moderate), matching yielded 206,416 patients (103,208 per group) with good balance (all SMDs <0.10). Over 5 years, incident dementia occurred in 6.6% of the high-intensity group (6,816/103,208) vs 6.9% of the low/moderate group (7,104/103,208) (HR 0.954, 95% CI 0.923-0.986; P=0.005). High-intensity therapy was associated with lower risk of AD (HR 0.882, 95% CI 0.826-0.943; P<0.001) and lower all-cause mortality (HR 0.945, 95% CI 0.926-0.965; P<0.001). There was no significant difference for vascular dementia (HR 1.047, 95% CI 0.996-1.100; P=0.072).

CONCLUSION: Initiation of high-intensity statins within 7 days of stroke was associated with modestly lower 5-year dementia and mortality; randomized trials are needed to confirm causality and define agent- and subtype-specific effects.},
}

@article {pmid42546867,
year = {2026},
author = {Wong, MS and Wang, J and Lin, YH and Wu, CW and Chen, HY and Lu, KC},
title = {Glaucoma and Neurodegenerative Disease Risk: A 10-Year Assessment of Real-World Global Data.},
journal = {American journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajo.2026.07.051},
pmid = {42546867},
issn = {1879-1891},
abstract = {PURPOSE: To evaluate 10-year risk trajectories of newly diagnosed neurodegenerative diseases among glaucoma patients across age-stratified cohorts and clinical subtypes.

DESIGN: Retrospective cohort study.

METHODS: Using TriNetX data (2005-2025), glaucoma patients were propensity-matched 1:1 to controls based on baseline demographics, comorbidities, medications, and laboratory metrics. Outcomes were defined using International Classification of Diseases, Tenth Revision codes. Risks for mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia (VD), unspecified dementias, and Parkinson's disease (PD) were assessed. Cohorts were stratified by age (<45 vs >65 years) and subtype (primary open-angle [POAG], primary angle-closure [PACG], and normal-tension [NTG] glaucoma).

MAIN OUTCOME MEASURES: 1-, 3-, 5-, and 10-year hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: Among 384,256 matched pairs, glaucoma correlated with elevated 10-year risks for AD (HR = 1.485; 95% CI,1.427-1.546; P < .001), VD (HR = 1.213; 95%CI, 1.159-1.27; P < .001), and a delayed PD risk peaking at 10 years (HR = 1.115; 95%CI, 1.066-1.167; P < .001). AD and VD risks emerged early in late-onset glaucoma but showed delayed emergence in early-onset patients, where AD risk peaked at 10 years (HR = 2.320; P = .03). Subtype analysis revealed no significant AD associations for POAG (HR = 1.044; P = .10), PACG (HR = 1.096; P = .13), or NTG (HR = 1.097; P = .19). However, VD risk was elevated in POAG (HR = 1.203; 95% CI, 1.129-1.281; P < .001) and PACG (HR = 1.224; 95% CI, 1.056-1.419; P = .007), but not NTG (P = .08). MCI risk increased in POAG (HR = 1.201; 95% CI, 1.120-1.288; P < .001) and NTG (HR = 1.235; 95% CI, 1.089-1.401; P = .001). NTG demonstrated the only significant PD association (HR = 1.283; 95% CI, 1.043-1.577; P = .018), while POAG (P = .05) and PACG (P = .58) showed no correlation. All 3 subtypes maintained significant associations with unspecified dementia (all P < .05).

CONCLUSIONS: Glaucoma is observationally associated with subsequent neurodegenerative diagnoses, with statistical trajectories varying by onset age and clinical subtype. These findings indicate population-level correlations rather than causal mechanistic linkages.},
}

@article {pmid42546888,
year = {2026},
author = {Aggarwal, P and Sarkar, S},
title = {Neuron-specific suppression of aberrantly active Toll-NFκB signalling mitigates pathogenic tau hyperphosphorylation via Gsk-3β in Drosophila.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {168393},
doi = {10.1016/j.bbadis.2026.168393},
pmid = {42546888},
issn = {1879-260X},
abstract = {Chronic brain ailments like Alzheimer's disease and Frontotemporal dementia, together referred to as tauopathies, are strongly influenced by neuroinflammation, an age-associated functional anomaly. Neuroinflammation arising from a dysfunctional innate immune response, such as Toll-NFκB signalling, is implicated in modulating tau pathophysiology, with limited understanding of the molecular mechanisms. Pathogenic hyperphosphorylation of tau and its aggregation into neurotoxic species is considered as a central trigger of tau pathology; however, the mechanistic association between these pathogenic events and the Toll signalling remains largely unexplored. We examined the status of the Toll signalling in Drosophila tauopathy models and evaluated whether its modulation modifies disease severity. We present compelling evidence that neuronal expression of pathogenic human tau causes aberrant activation of the Toll signalling. In line, its additional upregulation further aggravates disease severity, while genetic downregulation of Toll components remarkably alleviates both structural and functional deficits. We subsequently noted that knockdown of the Toll pathway attenuates pathogenic tau hyperphosphorylation in a site-specific manner, largely coinciding with restoration of physiological activity of Gsk-3β/Akt/PP2Ac signalling, a relatively less explored molecular axis in neurons. Our study posits a potential contribution of neuron-intrinsic altered Toll signalling cascade in tau pathogenesis, warranting further exploration of this evolutionarily conserved pathway as a therapeutic target.},
}

@article {pmid42546917,
year = {2026},
author = {Liang, Y and Zhi, T and Fan, B and Wu, Y and Wu, L and Xie, Z and Yang, Y and Mu, R and Wu, X},
title = {Activation and increased hippocampal GPR55 prevents cognitive deficits in male APP/PS1 mice.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111129},
doi = {10.1016/j.neuropharm.2026.111129},
pmid = {42546917},
issn = {1873-7064},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive decline. G protein-coupled receptor 55 (GPR55) has been linked to cognitive regulation, yet its precise role in AD pathogenesis remains unclear.

OBJECTIVES: Here, we investigated the role of GPR55 in AD and its molecular mechanism.

METHODS: This study utilized APP/PS1 and GPR55 knockout (GPR55KO) mice to investigate the role and possible mechanism of GPR55 in AD.

RESULTS: We observed progressive reduction of GPR55 levels in the hippocampus of aging APP/PS1 mice. Conversely, hippocampal GPR55 overexpression rescued cognitive deficits, neuroinflammation, and impairment of synaptic plasticity in APP/PS1 mice. Moreover, GPR55 activation reduced neuronal death and memory impairments in APP/PS1 mice. In addition, aged GPR55KO mice showed cognitive deficits, but hippocampal GPR55 reexpression improved cognition. We also demonstrated that GPR55 activation mitigates Aβ1-42-induced synaptic damage and apoptosis in HT22 cells. Further studies revealed that in both animal and cell models, the activation levels of P-AKT/AKT and P-GSK3β/GSK3β were significantly decreased, and the activation level of P-ERK/ERK was markedly increased, while upregulation of GPR55 reversed this trend.

CONCLUSIONS: These results indicate that hippocampal GPR55 may improve cognitive dysfunction by regulating the AKT/GSK3β and ERK signaling pathways, highlighting its crucial role in AD.},
}

@article {pmid42546981,
year = {2026},
author = {Jaganathan, R and Vijayakumar, S and Chen, Y and Ye, J and Bakthavatchalam, P and Wankar, D and Yang, C and Iyaswamy, A and Li, M},
title = {New insights on microglial lysosomal acidification: A therapeutic target of neurodegenerative diseases.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107555},
doi = {10.1016/j.nbd.2026.107555},
pmid = {42546981},
issn = {1095-953X},
abstract = {BACKGROUND: Microglia, the resident immune cells of the central nervous system (CNS), maintain brain homeostasis and respond to pathological insults. Microglial dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Impaired lysosomal function, particularly defective lysosomal acidification, leads to the accumulation of undegraded material, thereby promoting neuroinflammation and neuronal damage.

PURPOSE: This review examines the mechanisms governing lysosomal acidification in microglia and evaluates its potential as both a therapeutic target and a prognostic biomarker in neurodegenerative diseases.

METHODS: The literature on microglial lysosomal acidification, lysosomal pH regulation, autophagy, and neurodegeneration was searched in PubMed, Scopus, and Web of Science. Relevant mechanistic, preclinical, and translational studies were critically appraised and synthesized.

RESULTS: Lysosomal acidification is increasingly recognized as a key regulator of microglial function and homeostasis. Defective acidification, driven by dysregulation of the vacuolar H+-ATPase (V-ATPase) proton pump, TFEB/TFE3 signaling pathways, and lysosomal ion channels such as TRPML1 and TMEM175, impairs autophagic flux and substrate degradation, facilitating the accumulation of neurotoxic aggregates including amyloid-β and α-synuclein. Emerging evidence suggests that the degree of microglial lysosomal acidification may serve as a prognostic biomarker for disease progression and therapeutic response. Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models.

CONCLUSION: Restoration of microglial lysosomal acidification represents a promising therapeutic strategy for neurodegenerative diseases. A deeper understanding of the molecular mechanisms regulating lysosomal acidification in microglia may facilitate the identification of novel biomarkers and therapeutic targets, ultimately contributing to the development of innovative interventions for neurodegenerative disorders.},
}

@article {pmid42547074,
year = {2025},
author = {Mimenza-Alvarado, AJ and Vazquez-Guajardo, M and Martínez-Bravo, LE and Aguilar Navarro, SG},
title = {The state of Alzheimer's disease in Mexico: current challenges and directions for diagnosis and treatment.},
journal = {Gaceta medica de Mexico},
volume = {161},
number = {6},
pages = {558-568},
doi = {10.24875/GMM.25000128},
pmid = {42547074},
issn = {0016-3813},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Mexico/epidemiology ; Biomarkers/blood ; tau Proteins ; Disease Progression ; },
abstract = {Alzheimer's disease (AD) is a major public health challenge in Mexico, with cases expected to rise significantly by 2050. For years, AD lacked major medical advances, but the emergence of plasma biomarkers and disease-modifying therapies has shifted the paradigm from symptomatic treatment to altering disease progression. While these advances are promising, they present substantial challenges for developing countries such as Mexico. The availability and interpretation of new biomarkers must be carefully managed, ensuring their use only in individuals with cognitive impairment rather than for asymptomatic screening. Furthermore, the presence of core biomarkers such as phosphorylated tau 217 in asymptomatic individuals should be considered, indicating "at-risk" status rather than biological AD. Although plasma biomarkers offer new opportunities, cerebrospinal fluid remains the only validated tool in Mexico for confirming amyloid pathology. In addition, two disease-modifying therapies are now approved in Mexico, but defining appropriate candidates, balancing potential benefits against risks, and monitoring treatment response remain significant challenges, especially in the absence of amyloid positron emission tomography imaging. Addressing these issues is critical to ensuring that new diagnostic and therapeutic strategies are effectively and equitably integrated into Mexico's healthcare system. Accordingly, there is an urgent need for the development of public policies and diagnostic infrastructure to ensure the safe, affordable, and sustainable implementation of these advances in countries such as Mexico.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology
Mexico/epidemiology
Biomarkers/blood
tau Proteins
Disease Progression

@article {pmid42547271,
year = {2026},
author = {Kim, B and Miller, C and Dhingra, S and Al-Ghezi, M and Wilson, E and Bhatt, NK},
title = {Vocal Fold Atrophy in Patients With Alzheimer's Disease and Related Dementias.},
journal = {The Laryngoscope},
volume = {},
number = {},
pages = {},
doi = {10.1002/lary.70761},
pmid = {42547271},
issn = {1531-4995},
support = {K08AG090629//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {OBJECTIVES: Alzheimer's disease and related dementias (AD/ADRD) can lead to deterioration in voice and swallowing. Vocal fold atrophy (VFA), seen with aging and neurodegenerative disease, results in thin/bowed vocal folds with incomplete glottic closure during voicing and swallowing, leading to breathy voice from air leakage. Magnitude of VFA in AD/ADRD has not been previously studied. This study compared endoscopic measures of VFA in AD/ADRD patients with age-matched controls.

METHODS: Thirteen patients with a diagnosis of AD (n = 3), Lewy body dementia (n = 3), vascular dementia (n = 1), or multiple-etiology dementias (n = 6) presenting to a tertiary laryngology practice were included in this cross-sectional study. Demographics, Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V), Voice Handicap Index-10, and stroboscopic still images were obtained. Images were analyzed for bowing index (BI), normalized glottal gap area (NGGA), and normalized mucosal wave amplitude (NMWA). Two age-matched controls were selected for each patient, yielding 13 AD/ADRD patients and 26 controls (1:2 ratio).

RESULTS: Mean age for patients was 80 ± 10 years. AD/ADRD patients demonstrated higher BI scores compared with controls (4.51; 95% CI [1.39, 7.63]; p = 0.008). AD/ADRD patients displayed significantly lower NMWA values (-8.2; 95% CI [-9.8, -6.6]; p < 0.0001). No significant difference seen in NGGA between groups (0.26; 95% CI [-1.69, 2.43]; p = 0.7).

CONCLUSION: This is the first study to quantify VFA in AD/ADRD patients. Endoscopic measures revealed significant atrophic differences compared with age-matched controls. These measures may serve as potential laryngeal indicators of neurodegenerative involvement in ADRD, though larger studies are needed to establish clinical utility.},
}

@article {pmid42547528,
year = {2026},
author = {Carlsson, A and Axell, E and Wallerstein, J and Thacker, D and Olsson, U and Linse, S},
title = {Human chaperone DNAJB6b suppresses tau fibril formation through co-aggregation.},
journal = {Communications chemistry},
volume = {9},
number = {1},
pages = {},
pmid = {42547528},
issn = {2399-3669},
abstract = {The aggregation of the tau protein into intraneuronal fibrillar tangles is closely associated with the pathology of Alzheimer's disease. The endogenous defense system against this process includes molecular chaperones, among which DNAJB6b has emerged as a key component. Using a tau model system comprising the tau fragment 304-380C322S, which spans the amyloidogenic core of ex vivo Alzheimer's disease fibrils, we investigated the impact of DNAJB6b on tau fibril formation. Here, we show that DNAJB6b potently delays tau aggregation by co-assembling with small tau aggregates and by binding to mature fibrils, thereby reducing their ability to catalyze further fibril growth. This interplay between tau and the chaperone results in greatly reduced fibril formation rate and a lower final fibril mass, which we interpret as increased tau solubility. Moreover, solution-state NMR spectroscopy confirms that DNAJB6b does not interact with tau monomers.},
}

@article {pmid42547581,
year = {2026},
author = {Behrangi, N and Stadler, MS and Reinbach, C and Burkert, L and Hawlitschka, A and Kaddatz, H and Wenzel, L and Llovera, G and Wree, A and Hoornaert, C and Ponsaerts, P and Splietker, U and Brandenburg, LO and Amor, S and Tauber, SC and Bohn, A and Schmitz, C and Kipp, M and Hochstrasser, T},
title = {CD44 as a Conserved Biomarker and Functional Modulator of Neuroinflammation in Multiple Sclerosis and Beyond.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42547581},
issn = {1559-1182},
mesh = {Animals ; *Multiple Sclerosis/metabolism/pathology ; *Hyaluronan Receptors/metabolism ; Humans ; Encephalomyelitis, Autoimmune, Experimental/metabolism/pathology ; *Biomarkers/metabolism ; Mice, Inbred C57BL ; *Neuroinflammatory Diseases/metabolism/pathology ; Female ; Cuprizone ; Mice ; },
abstract = {Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination, blood-brain barrier disruption, and leukocyte infiltration. The transmembrane glycoprotein cluster of differentiation 44 (CD44) has been implicated in neuroinflammation, but its functional role remains unclear. Here, we examined CD44 expression and function across both non-immune-mediated and immune-mediated MS animal models, including cuprizone-induced demyelination, experimental autoimmune encephalomyelitis (EAE), and combined cuprizone/EAE (Cup/EAE), as well as in human MS tissue and cerebrospinal fluid (CSF), using immunohistochemistry, flow cytometry and enzyme-linked immunosorbent assay. CD44 expression increased in parallel with demyelination and was most pronounced in the forebrain of Cup/EAE mice, where it localized to perivascular cuffs and lesion-associated parenchyma. CD44 expression co-localized to IBA1[+] microglia/monocytes and CD3[+] T cells. Flow cytometry analyses revealed high CD44 expression on myeloid-derived suppressor cells and regulatory T cells, which further increased upon immune activation. On the functional level, Cd44-deficient mice exhibited exacerbated disease severity in EAE, accompanied by increased immune cell infiltration and tissue damage. In human MS samples, CD44 expression and soluble CD44 levels in CSF were significantly elevated. Notably, CD44 upregulation was also observed in other neurological disease models, including ischemic stroke and APPswe/PS1dE9 mice, a model of Alzheimer's disease. Together, these findings identify CD44 as a conserved marker of neuroinflammatory activity and a context-dependent regulator of neuroinflammation with partially protective functions, rather than an exclusively pro-inflammatory molecule, highlighting its potential relevance in MS and related neurological disorders.},
}

Animals
*Multiple Sclerosis/metabolism/pathology
*Hyaluronan Receptors/metabolism
Humans
Encephalomyelitis, Autoimmune, Experimental/metabolism/pathology
*Biomarkers/metabolism
Mice, Inbred C57BL
*Neuroinflammatory Diseases/metabolism/pathology
Female
Cuprizone
Mice

@article {pmid42547584,
year = {2026},
author = {Phénix, J and Sarty, I and Katz, MS and Vázquez Cobá, A and Marure Rojano, AE and Nie, H and Kerksiek, A and Jerry, I and Berger, CS and Kiss, RS and Lütjohann, D and Pastor, WA and Poirier, J and Munter, LM and , },
title = {Reducing CETP activity prevents memory decline in an Alzheimer's disease mouse model.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42547584},
issn = {1757-4684},
support = {PJT-162302//Canadian Institutes of Health Research (CIHR)/ ; PJT-175306//Canadian Institutes of Health Research (CIHR)/ ; PJT-186080//Canadian Institutes of Health Research (CIHR)/ ; PJT 153287//Canadian Institutes of Health Research (CIHR)/ ; PJT-178210//Canadian Institutes of Health Research (CIHR)/ ; RR172187//WFF | Weston Brain Institute (WBI)/ ; 32565//Canada Foundation for Innovation (CFI)/ ; 17-02//ASC | Alzheimer Society Research Program (ASRP)/ ; RGPIN-2015-04645//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 356162//FRQ | Santé (FRQS)/ ; 1017734//Secretaría de Ciencia, Humanidades, Tecnología e Innovación (Secihti, Conacyt), Ciudad de México, México/ ; },
abstract = {Epidemiological studies have shown that lower activity of the cholesteryl ester transfer protein (CETP) correlates with reduced Alzheimer's disease (AD) risk. While small-molecule CETP inhibitors like evacetrapib have previously been assessed for cardiovascular diseases, their involvement in AD has not been investigated. Here, we establish CETP as a novel pharmacological target for AD treatment. Using CETP transgenic mice crossed to a mouse model of amyloidosis and administering evacetrapib, we provide evidence that CETP inhibition maintained memory independent of classic AD markers, likely through maintained vascular health, while increasing hippocampal cholesterol and altering plasma lipoproteins. Using proteomic data of cerebrospinal fluid (CSF) from cognitively unimpaired individuals at risk for AD in the PResymptomatic EValuation of Experimental or Novel Treatments for AD (PREVENT-AD) cohort, we confirm that our mouse model reflects physiological changes in pre-symptomatic human subjects. We propose the repurposing of CETP inhibitors as an effective therapeutic strategy to delay or prevent cognitive impairment in AD.},
}

@article {pmid42547702,
year = {2026},
author = {Alsubaie, MG and Luo, S and Shaukat, K and Zhang, W},
title = {Biomarker-Conditioned Vision Transformers with Deformable Biomarker Attention for Alzheimer's Disease Classification.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
pmid = {42547702},
issn = {2948-2933},
abstract = {Alzheimer's disease (AD) classification from structural magnetic resonance imaging (MRI) remains challenging, particularly when distinguishing mild cognitive impairment (MCI) from both cognitively normal (CN) ageing and established AD. Multimodal approaches that combine imaging with clinical information are promising, but most confine the influence of clinical variables to the classifier head, so biomarkers cannot shape spatial feature extraction inside the imaging encoder. We propose a bimodal deep learning framework operating on two input sources: 3D T1-weighted structural MRI and tabular clinical assessment scores. A biomarker encoder maps the clinical scores into a conditioning representation that modulates vision transformer patch tokens through spatial rescaling and cross-attention throughout feature extraction. Within selected transformer layers, deformable biomarker attention (DBA) acts as an internal cross-modal modulation pathway rather than a third input modality, enabling sparse biomarker-guided spatial sampling from the 3D MRI feature grid. The framework was evaluated on ADNI data under strict subject-wise train, validation and test splits, so that repeated scans from the same individual never crossed partitions. On the held-out test set, the model achieved 95.68% accuracy, 95.39% macroprecision, 94.65% macrorecall and 95.01% macro F1 score, exceeding all comparison methods reproduced under the same protocol. Prediction uncertainty was higher for misclassified cases, and rejecting the most uncertain cases raised retained set accuracy to 98.31% at 85.03% coverage. Performance degraded gradually rather than catastrophically when clinical scores were with-held, falling to 93.20% accuracy with all five biomarkers imputed. These results indicate that within-encoder biomarker conditioning improves AD classification and yields uncertainty-aware predictions that may support decision-making in clinical research settings.},
}

@article {pmid42547799,
year = {2026},
author = {Kubota, M and Kurose, S and Tagai, K and Momota, Y and Ichihashi, M and Endo, H and Seki, C and Moriguchi, S and Yamamoto, Y and Kataoka, Y and Goto, R and Tamura, T and Shiwaku, H and Matsuoka, K and Suzuki, H and Onaya, M and Tokuda, T and Uchida, H and Takahashi, H and Kawamura, K and Zhang, MR and Higuchi, M and Takahata, K},
title = {High prevalence of tau pathologies in late-onset psychosis: A PET study.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42547799},
issn = {1476-5578},
support = {22H02998//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19H03583, 24K02379//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 24K02374//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JPMJMS2024//MEXT | Japan Science and Technology Agency (JST)/ ; JP24wm0625001, JP24zf0127012, JP24wm0625304//Japan Agency for Medical Research and Development (AMED)/ ; },
abstract = {Late-onset psychosis (LOP) exhibits distinct clinical features compared with younger-onset psychosis. Although postmortem and epidemiological studies have suggested an association between LOP and neurodegenerative processes, particularly tauopathies, in vivo evidence remains limited. This study aimed to investigate the involvement of Alzheimer's disease (AD) and non-AD tauopathies in LOP using amyloid PET and tau PET with florzolotau (18F) ([18]F-florzolotau; also known as [18]F-APN-1607 or [18]F-PM-PBB3), a tracer capable of detecting a broad range of tau pathologies. Thirty-seven patients with LOP and 47 age-matched controls underwent PET scans with [11]C-PiB and [18]F-florzolotau to assess group differences in amyloid beta (Aβ) and tau accumulation. Diagnostic effects on regional [18]F-florzolotau standardized uptake value ratios (SUVRs) were assessed. Associations between regional SUVRs and cognitive and clinical features were examined separately in Aβ-positive and Aβ-negative subgroups. Patients exhibited significantly higher positivity rates for both Aβ (13 of 37 patients, 35.1%) and tau (24 patients, 64.9%) than controls (one of 47 controls, 2.1% for Aβ and seven controls, 14.9% for tau). A significant diagnostic effect was observed on regional [18]F-florzolotau SUVRs (P = 0.004), with post-hoc analyses revealing increased tracer retention in the parietal cortex. This diagnostic effect remained robust when the analysis was restricted to Aβ-negative participants (P = 0.002). Among Aβ-positive patients, greater parietal tau burden was associated with lower Frontal Assessment Battery scores. In conclusion, this in vivo PET study demonstrated a high prevalence of AD-like and non-AD-like tau accumulation patterns in LOP, suggesting that LOP may be associated with heterogeneous tau-related neurodegenerative processes.},
}

@article {pmid42547900,
year = {2026},
author = {Xiang, M and Cao, SY and Sun, XH and Hu, JW and Lv, MZ and Li, JY and Li, W},
title = {Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42547900},
issn = {2047-9158},
support = {LJKMZ20221207//Department of Education of Liaoning Province/ ; 2023-02216//the Swedish Research Council/ ; 1494/2023, 1663/2025//Parkinsonfonden/ ; FO2023-0397, FO2025-0296//The Brain Foundation/ ; 82371273, 82361138574, 31800898, 81430025, and U1801681//National Natural Science Foundation of China/ ; 2024JH6/100800008//department of Science and Technology of Liaoning Province/ ; },
mesh = {Humans ; *Brain/metabolism/pathology ; Animals ; *Insulin Resistance/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer's and Parkinson's diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR-neurodegeneration axis at its mechanistic roots.},
}

Humans
*Brain/metabolism/pathology
Animals
*Insulin Resistance/physiology
*Neurodegenerative Diseases/metabolism/pathology
alpha-Synuclein/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42548036,
year = {2026},
author = {Peña-Tauber, A and Hernández Arriaza, R and Reil, D and Muntaner, M and Park, J and Grenier-Boley, B and Hulsman, M and Amouyel, P and Bellenguez, C and Charbonnier, C and Deleuze, JF and Dols-Icardo, O and Hardy, J and Holstege, H and Nicolas, G and Mead, S and Wagner, M and Ramirez, A and Sims, R and van Swieten, J and Willams, J and Lambert, JC and Khosla, C and Le Guen, Y and Greicius, MD},
title = {Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78303},
pmid = {42548036},
issn = {1531-8249},
abstract = {OBJECTIVE: ATP-binding cassette transporter A1 (ABCA1) has been associated with Alzheimer's disease (AD), but the mechanisms by which it impacts disease risk are unknown. ABCA1 is known to bind apolipoprotein E (ApoE) and catalyze apolipoprotein lipidation. We explored whether genetic variants altering ABCA1 function interact with APOE isoforms to modify AD risk.

METHODS: Using data from the Alzheimer's Disease Sequencing Project (ADSP), UK Biobank, and the Alzheimer Disease European Sequencing consortium, we assessed the impact of ABCA1 variants on AD risk in APOE subgroups and tested for statistical interactions with APOE ε2 and ε4 in an all-APOE cohort. We first examined damaging nonsynonymous ABCA1 variants previously associated with AD. We then constructed a measure of predicted ABCA1 activity based on HDL-associated variants and tested its association with AD risk. Finally, we explored potential pathogenic mechanisms of missense variants of interest.

RESULTS: Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding.

INTERPRETATION: Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026.},
}

@article {pmid42548078,
year = {2026},
author = {Vöglein, J and Levin, J and Brendel, M},
title = {Amyloid-Related Imaging Abnormalities (ARIA) in Alzheimer's Disease.},
journal = {Deutsches Arzteblatt international},
volume = {123},
number = {13},
pages = {366},
doi = {10.3238/arztebl.m2025.0204},
pmid = {42548078},
issn = {1866-0452},
}

@article {pmid42548576,
year = {2026},
author = {Suffian, M and Mammone, N and Ieracitano, C and Tripodi, GG and Pascarella, A and Ferlazzo, E and Morabito, FC},
title = {EEGDecoder-x: an explainable deep learning framework for cross-subject EEG-based detection of Alzheimer's and Creutzfeldt-Jakob disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1851752},
pmid = {42548576},
issn = {1664-2295},
abstract = {Early detection of neurodegenerative diseases is critical. Distinguishing early-stage Creutzfeldt-Jakob disease (CJD) from "mimics" like Alzheimer's disease (AD) remains a major challenge; while EEG is valuable in advanced CJD, early-stage abnormalities are often non-specific and overlap with other rapidly progressive dementias. Deep learning offers promising EEG-based diagnostic solutions, but clinical adoption requires transparent decision-making, the interpretability of the features learned by deep learning models is equally important. In this context, careful model design and explainability are essential. In this paper, we propose a novel interpretable framework, EEGDecoder-x, for decoding EEG signals from subjects with Alzheimer's disease, Creutzfeldt-Jakob disease, and healthy controls, while providing insight into the model's learned characteristics. The EEGDecoder-x framework comprises two main components: a hybrid attention network for disease decoding (EEGDecoder-Net) and an explainability module (EEGDecoder-XAI). EEGDecoder-Net combines a convolutional neural network with a dual attention mechanism, followed by a classification layer, enabling efficient spatio-temporal feature extraction. EEGDecoder-XAI provides a comprehensive local and global explanations of the network's learning process for spatio-temporal dimensions. We validate the proposed framework using a Leave-One-Subject-Out evaluation paradigm, achieving 97.22% classification accuracy on a dataset of 36 subjects (12 with AD, 12 with CJD, and 12 healthy controls), and outperforming the baseline models, demonstrating both the effectiveness and interpretability of EEGDecoder-x.},
}

@article {pmid42548677,
year = {2026},
author = {Zhao, J and Zhang, M and Vidano, C and Takarabe, C and Bonakdarpour, B},
title = {Musical Museum: an integrative approach to emotional, intellectual and social stimulation for individuals with Alzheimer's disease and related disorders and their caregivers.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1849901},
pmid = {42548677},
issn = {1664-2295},
abstract = {INTRODUCTION: Musical Museum is a concert series that features live music and short music appreciation lectures in a socially safe setting designed for individuals with neurocognitive disorders (NcDs) and their caregivers. This program was created to provide emotional well-being, intellectual stimulation and social interaction. In this manuscript, we present our viable methodology, satisfaction ratings, implementation practicality, exploratory outcomes, and plans for future quantitative research on this program.

METHODS: Participants, which included individuals with NcDs, their caregivers and other program supporters, experienced hourlong sessions with diverse music (both familiar and unfamiliar), enhanced by verbal introductions providing historical and musical context. Post-concert receptions encouraged social interaction. Anonymous surveys assessed satisfaction, pleasure, intellectual stimulation, likelihood to recommend and change in mood. Participants also provided open-ended feedback to evaluate logistics to determine practicality.

PRELIMINARY RESULTS: Musical Museum sessions require operational, logistical, and artistic components including venue setup, audiovisual support, communications, printed materials, staffing, and performance planning. Attendance data and expenses were tabulated to assess practicality and acceptability. In surveys, participants reported high satisfaction, pleasure, intellectual stimulation and likelihood to recommend. Participants' perceived mood significantly improved post-session, and they showed appreciation of the social benefits of the program in open-ended questions.

DISCUSSION: Over 11 completed sessions, implementation of Musical Museum proved to be practical in terms of operational, logistical, and artistic components. Largely positive survey feedback and consistent interest and attendance suggested acceptability to individuals with NcDs and their caregivers. Future directions include a controlled quantitative trial integrating psychosocial and neurophysiologic measures to examine efficacy and underlying mechanisms beyond participant-reported acceptability as well as assessment of the program's longitudinal impact on participant well-being.},
}

@article {pmid42548715,
year = {2026},
author = {Su, TS and Su, KP and Hsueh, PR and Lai, ZL and Chen, CM and Lai, YC and Chen, CS and Nian, X and Chang, YW and Tsai, ST},
title = {Memory training through Chinese classics recitation for individuals with subjective cognitive decline: study protocol for a pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1830299},
pmid = {42548715},
issn = {1663-4365},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is a preclinical condition associated with an increased risk of dementia and Alzheimer's disease, with no consensus regarding effective therapeutic interventions to date. As the global burden of aging-related neurodegenerative diseases continues to rise, early intervention has become increasingly critical. Cognitive training has been proposed as a promising behavioral intervention; however, few studies have integrated multimodal assessments to elucidate its underlying neurobiological and psychological mechanisms, particularly within the educational system that shapes cognitive reserve and learning strategies across the lifespan. This pilot study aims to estimate effect sizes for future definitive trials, assess the feasibility and acceptability of the intervention and multimodal evaluations, and generate hypotheses regarding the relationship between recitation practice and clinical biomarkers.

METHODS: A total of 60 individuals with subjective cognitive decline will be enrolled in a randomized, assessor-blinded, controlled pilot study. Participants will be randomly assigned to either an intervention group or a non-active control group prior to baseline assessment. The intervention group will undergo a six-month structured recitation training program. Both groups will undergo short-term follow-up after the intervention, and long-term follow-up annually post-intervention. Multimodal assessments will include neuropsychological testing, functional magnetic resonance imaging (fMRI), electroencephalography (EEG), blood biomarker profiling, gut microbiota analysis, and fecal metabolomics.

DISCUSSION: This study protocol outlines a randomized, assessor-blinded, controlled pilot study designed to advance understanding of the feasibility of Chinese Classics recitation training on both physiological and psychological outcomes in individuals with subjective cognitive decline. The findings are expected to provide mechanistic insights into non-pharmacological interventions and to address the current underrepresentation of Asian populations in neuroscience research.

CLINICAL TRIAL REGISTRATION: We registered this randomized controlled trial on ClinicalTrials.gov on March 11, 2026, under the identifier NCT07463391.},
}

@article {pmid42548797,
year = {2026},
author = {Pan, Z and Shen, Y and Peng, D and Tang, L and Ran, T and Liu, Y and Zeng, X and Liu, H},
title = {Caenorhabditis elegans in neuroscience: from neural communication to neurodegenerative disease modeling.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1865186},
pmid = {42548797},
issn = {1663-4365},
abstract = {Consistent with humans and other metazoans, the nematode Caenorhabditis elegans (C. elegans) undergoes progressive structural and functional decline during aging. Possessing highly conserved genetic pathways that share extensive homology with human genes, and characterized by a streamlined, fully mapped connectome, C. elegans has emerged as a robust model for dissecting the mechanisms underlying neuronal aging and degeneration. In this review, we summarize the intrinsic advantages of C. elegans as a model organism, highlighting its readily quantifiable behavioral phenotypes, short lifespan, and genetic tractability. We elaborate on its foundational neural communication architecture and its unique utility in constructing molecular models of neurodegenerative diseases. Additionally, we explore the integration of this model system with high-throughput pharmacological screening, environmental toxicology evaluations, and advanced genomic sequencing technologies. Ultimately, this synthesis aims to provide a comprehensive framework for investigating neurodegenerative mechanisms and facilitating clinical translation under specific stress conditions, particularly hypoxia.},
}

@article {pmid42548880,
year = {2026},
author = {Alhowail, AH},
title = {Dapagliflozin and cognitive impairment: pharmacological mechanisms, translational evidence, and future directions.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1895764},
pmid = {42548880},
issn = {1663-9812},
abstract = {Cognitive impairment increasingly emerges at the intersection of type 2 diabetes mellitus, vascular brain injury, chronic kidney disease, heart failure, and neurodegeneration, prompting interest in therapies that modify shared metabolic and inflammatory drivers of brain vulnerability. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor widely used in type 2 diabetes and cardiorenal disease, has attracted attention as a candidate modulator of cognitive decline because its established peripheral pharmacology extends beyond glucose lowering to include natriuresis, blood pressure reduction, weight loss, improved insulin resistance, reduced oxidative and inflammatory stress, and favorable cardiorenal effects. In this review, we examine the pharmacological basis by which these systemic actions could influence the neurovascular unit, mitochondrial homeostasis, glial activation, autophagy-related signaling, and synaptic plasticity pathways implicated in cognitive impairment. We summarize preclinical evidence suggesting that dapagliflozin can improve cognitive performance and modulate pathways such as AMPK-mTOR, Wnt/β-catenin, CREB/BDNF, oxidative stress responses, and neuroinflammatory signaling in experimental models, while also critically evaluating the limitations of these models. We then assess the current human evidence, distinguishing observational studies that suggest lower dementia risk from randomized clinical evidence that has not yet established a definitive cognition-related benefit. We argue that dapagliflozin should currently be viewed not as a proven cognitive therapeutic, but as a mechanistically plausible metabolic-neurovascular intervention whose relevance may be greatest in metabolically vulnerable phenotypes. Finally, we outline key translational challenges, including uncertainty regarding direct central target engagement, the need for biomarker-enriched trial designs, and the importance of integrating pharmacological, vascular, and neurodegenerative frameworks in future studies.},
}

@article {pmid42548982,
year = {2026},
author = {Piccarducci, R and Mainardi, M and Marchetti, L},
title = {Editorial: New horizons in Alzheimer's disease research: combining cell, gene, and emerging therapies.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1919555},
pmid = {42548982},
issn = {2296-858X},
}

@article {pmid42549172,
year = {2026},
author = {Liu, BB and Wang, HC and He, YL and Zhang, LJ and Meng, DL and Fu, Y and Wang, MY and Zhang, W},
title = {Inhibition of amyloid β aggregation by venetoclax: a computational and in vitro experimental approach.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42549172},
issn = {2046-2069},
abstract = {The aggregation of amyloid β-protein (Aβ) plays a key role in the pathological progression of Alzheimer's disease (AD). Given the current absence of effective therapeutic strategies, the drug repurposing approach provides novel insights into the treatment of AD. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, has demonstrated remarkable efficacy in the treatment of hematological malignancies, characterized by well-defined pharmacokinetic properties and a favorable safety profile. However, its effects and molecular mechanisms in the treatment of AD remain unexplored. Here, we investigated the potential of venetoclax in the inhibition of Aβ aggregation and elucidated its underlying mechanism. The inhibitory effect of venetoclax on Aβ aggregation was assessed using thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy. Cellular assays were performed to evaluate the neuroprotective effects of venetoclax against Aβ42-induced neurotoxicity and oxidative stress. Molecular dynamics (MD) simulations were conducted to explore the molecular interactions between venetoclax and Aβ42 peptides. Venetoclax significantly inhibited Aβ aggregation, reduced fibril formation, and decreased β-sheet content at molar ratios of 2 : 1 and 1 : 1 (Aβ : venetoclax). Cellular assays showed that venetoclax attenuated Aβ42-induced neurotoxicity and oxidative stress. MD simulations revealed that venetoclax stabilized Aβ peptides via hydrogen-bonding networks, increasing solvent accessibility and reducing hydrophobic interactions. Venetoclax inhibited Aβ aggregation and mitigated Aβ-induced neurotoxicity by stabilizing Aβ peptide dynamics. These findings support the potential of venetoclax as a repurposed therapeutic candidate for AD.},
}

@article {pmid42549443,
year = {2026},
author = {Kamiya, M and Osawa, A and Kagaya, H and Kondo, I},
title = {The effects of tabletop gaming on patients with mild cognitive impairment and Alzheimer's disease: A feasibility study.},
journal = {Fujita medical journal},
volume = {12},
number = {3},
pages = {215-221},
pmid = {42549443},
issn = {2189-7255},
abstract = {OBJECTIVES: This study examined the feasibility of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) performing gaming tasks.

METHODS: Ten patients with MCI and nine patients with AD participated. Gaming and tabletop tasks were the two types of interventions designed for this study. Following a randomized crossover design, the two interventions were conducted at a rate of 1 hour per week for 4 weeks. The Genki! Ha•tsu•ra•tsu Trepachi-table (TOYOMARU INDUSTRY CO., LTD., Aichi, Japan) device was used for the gaming intervention. Using this table-shaped gaming device with cognitive training components, one to four players can compete in various gaming challenges on a touchscreen mounted on the top of the table. For the tabletop task intervention, patients completed arithmetic and spot-the-difference exercises as cognitive training activities. A visual analog scale was used to quantify mood before and after each intervention session, and a reaction scale measuring the "autonomy" and "degree of participation" of patients was completed after each intervention.

RESULTS: The gaming intervention significantly increased the visual analog scale score of the AD group (p=0.031). The MCI group had significantly higher autonomy reaction scale scores during the gaming intervention than the AD group (p=0.007).

CONCLUSIONS: Activities using gaming technology may enhance the willingness and mood of senior citizens with diminished cognitive capabilities and could potentially support ongoing brain training.},
}

@article {pmid42549510,
year = {2026},
author = {Silva, A and Silva, S and Macedo, J and Moreira, P and Baptista, D and Bicker, J and Fortuna, A and Liberal, J and Rodrigues, B and Resende, R and Vitorino, I and Santos, AE and Neves, BM and Pereira, C and Cruz, MT},
title = {Intranasal Administration of Isoeugenol Improves Memory Deficits in APP/PS1 Old Mice-A Role Beyond Nrf2 Activation?.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {15},
pages = {e72186},
doi = {10.1096/fj.202601575R},
pmid = {42549510},
issn = {1530-6860},
support = {LA/P/0058/2020//MEC | Fundação para a Ciência e a Tecnologia (FCT)/ ; UID/04539/2025//MEC | Fundação para a Ciência e a Tecnologia (FCT)/ ; UID/PRR/4539/2025//MEC | Fundação para a Ciência e a Tecnologia (FCT)/ ; },
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Eugenol/analogs & derivatives/administration & dosage/pharmacology ; Mice ; Administration, Intranasal ; *Memory Disorders/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Mice, Transgenic ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Presenilin-1/genetics/metabolism ; Male ; Disease Models, Animal ; Microglia/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD), a neurodegenerative disorder and the most common cause of dementia, has no cure or effective treatment; thus, identification of disease-modifying therapeutics is crucial. Nrf2 is a master controller of homeostatic functions whose activity is compromised in AD. Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify cysteine residues in the thiol-rich Keap1, and many are Michael acceptors, such as low-molecular-weight (LMW) skin allergens. However, LMW allergens-induced Nrf2 activation in a pharmacological setting has only recently attracted attention, exemplified by the clinical success of Dimethyl Fumarate. Hence, we investigated, for the first time, the potential of the skin allergen Isoeugenol to activate Nrf2 and reverse selected AD hallmarks, both in vitro and in vivo, in AD-specific models. In vitro studies were performed using microglia cells exposed to LPS and neuronal cells overexpressing human APP with Swedish mutation, to evaluate Isoeugenol's potential in decreasing neuroinflammation and activating the Nrf2 pathway, respectively. In vivo studies were conducted in 10-month-old AD double-transgenic mice (APP/PS1), which were intranasally administered Isougenol. Isoeugenol's pharmacokinetic and pharmacodynamic profile, and its effect on mice cognition were evaluated. The results showed that Isoeugenol (1) activated Nrf2 in AD neuronal cells (likely involving AKT signaling); (2) exhibited antioxidant and Nrf2-dependent anti-inflammatory activity, which was abolished after Nrf2 silencing; (3) exhibited good pharmacokinetic and pharmacodynamic profiles; (4) reduced the levels of Aβ peptides in vitro and in vivo; (5) reduced triglyceride and LDL cholesterol levels in treated mice; and (6) improved the memory deficits in old mice. This is the first study reporting Isoeugenol's intranasal administration, and on specific AD mice models. Overall, the results reinforce Isoeugenol as a pleiotropic molecule, with great potential for AD treatment.},
}

Animals
*NF-E2-Related Factor 2/metabolism
*Eugenol/analogs & derivatives/administration & dosage/pharmacology
Mice
Administration, Intranasal
*Memory Disorders/drug therapy/metabolism
*Alzheimer Disease/drug therapy/metabolism
Humans
Mice, Transgenic
*Amyloid beta-Protein Precursor/genetics/metabolism
*Presenilin-1/genetics/metabolism
Male
Disease Models, Animal
Microglia/metabolism/drug effects

@article {pmid42549671,
year = {2026},
author = {Du, X and Yi, G and Ren, Y and Zhang, Z and Mi, H},
title = {Generalized Multilevel Multisource Functional Regression With an Application to Alzheimer's Disease.},
journal = {Statistics in medicine},
volume = {45},
number = {18-19},
pages = {e70688},
doi = {10.1002/sim.70688},
pmid = {42549671},
issn = {1097-0258},
support = {21BTJ044//National Social Science Fund of China/ ; 12371267//National Natural Science Foundation of China/ ; ZK-2026-fw-18//College of Advanced Interdisciplinary Studies, National University of Defense Technology/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; Bayes Theorem ; *Principal Component Analysis ; Computer Simulation ; Regression Analysis ; Longitudinal Studies ; Models, Statistical ; Disease Progression ; Neuroimaging ; },
abstract = {With population aging, Alzheimer's disease has gained increasing attention. Advances in medical technology and longitudinal studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) have generated diverse follow-up data, which can be viewed as multilevel multisource functional data for understanding disease progression. In this paper, we propose a new estimation method for the multilevel multisource functional principal components. This method first applies the multilevel functional principal component analysis on the univariate multilevel functional data, then obtains the estimation of the principal components of the multilevel multisource functional principal component model based on the relationship between the univariate and the multisource principal component models, thus realizing the multisource-component-based two-stage estimation of the generalized multilevel multisource functional regression model. We also further consider Bayesian estimation based on the two-stage estimation. Numerical simulations and empirical analyses show that both the proposed multisource-component-based two-stage estimation and Bayesian estimation methods work well. Compared to the multisource-component-based two-stage estimation methods, the classification performance of Bayesian estimation is significantly improved.},
}

*Alzheimer Disease/diagnostic imaging
Humans
Bayes Theorem
*Principal Component Analysis
Computer Simulation
Regression Analysis
Longitudinal Studies
Models, Statistical
Disease Progression
Neuroimaging

@article {pmid42549715,
year = {2026},
author = {Manabe, Y},
title = {A Diagnostic Pitfall in the Era of Amyloid-Targeting Therapy: Creutzfeldt-Jakob Disease Masquerading as Biologically Defined Alzheimer's Disease.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70202},
doi = {10.1111/psyg.70202},
pmid = {42549715},
issn = {1479-8301},
}

@article {pmid42549923,
year = {2026},
author = {Takahashi, M and Abe, T and Fujii, M},
title = {Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.},
journal = {Molecular and cellular biology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/10985549.2026.2705871},
pmid = {42549923},
issn = {1098-5549},
abstract = {Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.},
}

@article {pmid42550250,
year = {2026},
author = {Li, G and Li, Y},
title = {Psychological and neurological benefits of physical activity: impact on mental health, Parkinson's disease, and Alzheimer's disease.},
journal = {Brain structure & function},
volume = {231},
number = {7},
pages = {},
pmid = {42550250},
issn = {1863-2661},
mesh = {Humans ; *Alzheimer Disease/psychology/physiopathology/metabolism ; *Parkinson Disease/psychology/physiopathology/therapy ; *Mental Health ; *Exercise/psychology/physiology ; *Brain/physiopathology/metabolism ; Animals ; Exercise Therapy ; },
abstract = {This review synthesizes current evidence on the psychological and neurological benefits of physical activity, with emphasis on mental health, Parkinson's disease (PD), and Alzheimer's disease (AD). Physical inactivity is increasingly recognized as a modifiable risk factor that may exacerbate neuroinflammatory and metabolic dysfunctions associated with these conditions. Structured exercise has been shown to activate muscle-brain signaling pathways, including neurotrophic factors (BDNF, IGF-1, VEGF), immune modulation (IL-6, IL-10), metabolic regulators (PGC-1α, SIRT1), and peripheral mediators such as myokines and gut-brain axis components. For mental health, exercise is associated with reductions in depressive, anxiety, and stress-related symptoms, potentially through HPA-axis recalibration, neurotransmitter remodeling (serotonin, dopamine), and enhanced endocannabinoid signaling. These changes are supported by fMRI and EEG studies showing improved prefrontal-limbic connectivity and cognitive resilience. In PD, exercise interventions are linked to improvements in motor control, balance, and mood, likely mediated by dopaminergic integrity, neurotrophic support, and anti-inflammatory effects, with multimodal programs (aerobic, resistance, and dance-based) often demonstrating superior outcomes. In AD, mid-life physical activity has been associated with reduced dementia risk in epidemiological studies; proposed mechanisms include enhanced amyloid/tau clearance, glymphatic function, and synaptic adaptation, with some RCTs reporting hippocampal volume preservation and improved network connectivity. Shared mechanisms across conditions include neurotrophic upregulation and anti-inflammatory effects, whereas distinct pathways involve dopaminergic circuit remodeling in PD and glymphatic facilitation in AD. Clinical translation through FITT principles (frequency, intensity, time, type) requires personalized prescriptions, strong adherence strategies, and multidisciplinary integration. Despite methodological heterogeneity and limitations in the existing trials, structured physical activity emerges as a scalable, non-pharmacological intervention with potential for prevention, symptom management, and neuroprotection. Larger, well-designed studies are needed to optimize its application and clarify long-term disease-modifying effects.},
}

Humans
*Alzheimer Disease/psychology/physiopathology/metabolism
*Parkinson Disease/psychology/physiopathology/therapy
*Mental Health
*Exercise/psychology/physiology
*Brain/physiopathology/metabolism
Animals
Exercise Therapy

@article {pmid42550339,
year = {2026},
author = {Yu, H and Liu, X and Liu, J and Tang, D},
title = {Kaempferol-Conjugated Manganese Oxide Nanocomposites Mitigate Aluminium Chloride-Induced Neurobehavioral Impairments in a Rat Model of Alzheimer's disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42550339},
issn = {1559-1166},
mesh = {Animals ; *Oxides/chemistry/therapeutic use/pharmacology/administration & dosage ; *Manganese Compounds/chemistry/therapeutic use/administration & dosage/pharmacology ; *Alzheimer Disease/drug therapy ; Humans ; Rats ; Aluminum Chloride/toxicity ; *Antioxidants/therapeutic use/pharmacology/chemistry ; *Kaempferols/chemistry/therapeutic use/pharmacology/administration & dosage ; *Nanocomposites/therapeutic use/chemistry/administration & dosage ; *Neuroprotective Agents/therapeutic use/chemistry/pharmacology/administration & dosage ; Male ; Chlorides/toxicity ; Cell Line, Tumor ; Blood-Brain Barrier/metabolism ; },
abstract = {The neurodegenerative illness Alzheimer's disease (AD) causes cognitive decline. The production of oxidative stress in neurons is thought to play a role in the emergence of AD. The antioxidants, including kaempferol, reduce the course of AD; however, their use is limited by poor bioavailability. Kaempferol-conjugated manganese oxide nanocomposites (KMF@PEG-MnO2 NCs) exhibit enhanced protective effects against AD compared to free kaempferol. In this study, the potential of KMF@PEG-MnO2 NCs as an anti-Alzheimer's disease (AD) agent was explored through in silico and experimental approaches. The effective preparation of KMF@PEG-MnO2 NCs was validated by FT-IR, XRD, DLS, and SEM-EDX characterization techniques. The influence of KMF@PEG-MnO2 NCs on antioxidant capacity using the DPPH assay, reactive oxygen species (ROS) quantification with the SH-SY5Y cell line, and determining the amyloid β disaggregation was determined. Additionally, blood-brain barrier permeability was assessed with brain endothelial cells, and an anticholinesterase study was performed to explore its potential for treating Alzheimer's disease. Surface characterization revealed a spherical shape of the nanoparticle. DPPH and FR assay showed a substantial rise in antioxidant defence for KMF@PEG-MnO2 NCs compared to KMF. Anti-aggregation studies demonstrated the nanoparticle's ability to inhibit Aβ fibrils. Additionally, the BBB permeability assay indicated that the nanoparticle can permeate the BBB. Furthermore, in vivo studies demonstrated that KMF@PEG-MnO2 NCs protected against cognitive and synaptic deficits in AlCl3-induced AD rats (AlCl3-AD). KMF@PEG-MnO2 NCs significantly reduced AChE activity. Furthermore, it markedly reduced the brain's levels of nitric oxide (NO) while increasing the function of superoxide dismutase (SOD) and catalase (CAT) activities. Overall, the findings suggest that KMF@PEG-MnO2 NCs may serve as a promising therapeutic candidate for AD management.},
}

Animals
*Oxides/chemistry/therapeutic use/pharmacology/administration & dosage
*Manganese Compounds/chemistry/therapeutic use/administration & dosage/pharmacology
*Alzheimer Disease/drug therapy
Humans
Rats
Aluminum Chloride/toxicity
*Antioxidants/therapeutic use/pharmacology/chemistry
*Kaempferols/chemistry/therapeutic use/pharmacology/administration & dosage
*Nanocomposites/therapeutic use/chemistry/administration & dosage
*Neuroprotective Agents/therapeutic use/chemistry/pharmacology/administration & dosage
Male
Chlorides/toxicity
Cell Line, Tumor
Blood-Brain Barrier/metabolism

@article {pmid42550363,
year = {2026},
author = {Sood, A},
title = {A Review on Structural Insights into NLRP3 and NEK7: Domain Architecture, Subcellular Localization, and Their Interaction in Inflammasome Assembly and Signaling.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42550363},
issn = {1559-1182},
mesh = {*NIMA-Related Kinases/metabolism/chemistry ; Humans ; *Inflammasomes/metabolism/chemistry ; Animals ; *Signal Transduction/physiology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/chemistry ; Protein Domains ; },
abstract = {The NLRP3 inflammasome plays an important role in the innate immune system that mediates caspase-1 activation and the subsequent secretion of the pro inflammatory cytokines IL-1β and IL-18 in response to microbial infections and cellular stress. Aberrant activation of the NLRP3 inflammasome has been implicated in a range of inflammatory and metabolic disorders, including cryopyrin-associated periodic syndromes (CAPS), Alzheimer's disease, type 2 diabetes, and atherosclerosis. NLRP3 activation can be triggered by diverse stimuli and involves multiple cellular events, such as ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS) generation, and lysosomal damage. A critical regulator of NLRP3 activation is NEK7, a serine/threonine kinase also known for its role in mitotic spindle formation and cytokinesis. Structurally, NEK7 exhibits a partially assembled regulatory spine (R-spine), consistent with an inactive kinase state. However, a mutant form of NEK7 engineered to stabilize the R-spine retains catalytic activity and has been crystallized in complex with compound 51- an ATP-competitive, small-molecule chemical inhibitor that targets both NEK2 and NEK7. Interestingly, wild-type NEK7 crystallized in both apo form and with compound 51 showed variable R-spine conformations, while NEK7 displayed a uniform, partially stacked R-spine configuration. Despite the structural similarity in compound 51 binding between NEK2 and NEK7, subtle differences in ligand orientation reveal potential avenues for designing isoform-selective inhibitors. In this review, we comprehensively examine the structural domains and subcellular localizations of NLRP3 and NEK7, and highlight how their interaction promotes inflammasome assembly. I also discuss recent insights from cryo-electron microscopy (cryo-EM), X-ray crystallography, and molecular modeling studies that illuminate the conformational dynamics of the NLRP3-NEK7 complex. Additionally, we explore the crosstalk between the STING pathway and inflammasome signaling, and address key unanswered questions that may guide future research into therapeutic modulation of these essential protein-protein interactions.},
}

*NIMA-Related Kinases/metabolism/chemistry
Humans
*Inflammasomes/metabolism/chemistry
Animals
*Signal Transduction/physiology
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/chemistry
Protein Domains

@article {pmid42550365,
year = {2026},
author = {Talebi Taheri, A and Motamedzadeh, A and Zahedi, E and Farasat, A and Dadgostar, E and Aschner, M and Khanifar, H and Rahmati-Dehkordi, F and Tamtaji, OR},
title = {Therapeutic potential of spirulina and its bioactive compound phycocyanin in neuropsychiatric disorders.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42550365},
issn = {1573-4978},
mesh = {*Spirulina/chemistry/metabolism ; *Phycocyanin/therapeutic use/pharmacology ; Humans ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Mental Disorders/drug therapy/metabolism ; Oxidative Stress/drug effects ; },
abstract = {Neuropsychiatric disorders are of great health concerns, and despite the availability of drugs, effective therapies are poor, emphasizing the need for novel therapeutics. Among the natural substances screened for neuromodulation properties, Spirulina platensis, a cyanobacterium, and its main bioactive compound (phycocyanin) have attracted great attention. Substantial evidence demonstrates that spirulina and phycocyanin possess neuroprotective properties by targeting multiple interconnected cellular and molecular pathways, including apoptosis, oxidative stress, neuroinflammation, and regulators of synaptic plasticity. Consequently, these compounds have shown therapeutic potential in experimental models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, epilepsy, schizophrenia, depression, and autism spectrum disorder. Herein, we summarize various cellular and molecular pathways which are affected by spirulina and phycocyanin in neuropsychiatric disorders.},
}

*Spirulina/chemistry/metabolism
*Phycocyanin/therapeutic use/pharmacology
Humans
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
*Mental Disorders/drug therapy/metabolism
Oxidative Stress/drug effects

@article {pmid42550584,
year = {2026},
author = {Huchegowda, R and Harbishettar, V and Sinha, P and Das, S and Pt, S and John, JP},
title = {Vitamin B12, Homocysteine, and Cognitive Function in the Older Adults Attending a Tertiary Geriatric Psychiatry Center: A Retrospective Case Notes-Based Study.},
journal = {Journal of nutrition in gerontology and geriatrics},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/21551197.2026.2713421},
pmid = {42550584},
issn = {2155-1200},
abstract = {BACKGROUND: Cognitive impairment in older adults has been linked to low serum Vitamin B12 (B12) and elevated homocysteine (HCY) levels, but evidence remains inconclusive. This study examined their relationship with cognitive impairment among older adults in India.

METHODS: This retrospective case note-based study included 96 subjects: cognitively normal (n = 21), Alzheimer's disease (AD; n = 42), and other cognitive disorders (n = 33). The mean age was 70.1 (± 8.9) years, with 58% males. Cognitive function was assessed using the Hindi Mental Status Examination (HMSE). Serum B12 (pg/ml) and HCY (micromol/L) levels were measured. Pearson's correlation, multiple linear regression, and bootstrapped mediation analyses were performed.

RESULTS: Elevated HCY (>15 micromol/L) was seen in 72%, and low B12 (<200 pg/mL) in 33%. The mean HMSE score was 16.9 (± 8.5). No significant correlation was found between HMSE scores and HCY (r = -0.006, p = 0.95) or B12 (r = 0.12, p = 0.23). HCY levels were higher in cognitively impaired groups than controls, but not significantly. Regression analysis showed gender as a significant predictor, while B12, HCY, and age were not.

CONCLUSION: B12 and HCY levels were not independently associated with cognitive performance. No significant moderation effect between B12 and HCY on HMSE scores was observed.},
}

@article {pmid42550597,
year = {2026},
author = {Cruz-Gonzalez, S and Okpala, O and Gu, E and Gomez, L and Mews, M and Vance, JM and Cuccaro, ML and Cornejo-Olivas, MR and Feliciano-Astacio, BE and Byrd, GS and Haines, J and Pericak-Vance, MA and Griswold, AJ and Bush, WS and Capra, JA},
title = {Methylation clocks fail to generalize across genetically admixed individuals.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.105343},
pmid = {42550597},
issn = {2050-084X},
support = {F31AG090006/AG/NIA NIH HHS/United States ; R35GM127087/GM/NIGMS NIH HHS/United States ; R01AG070935/AG/NIA NIH HHS/United States ; U01AG076482/AG/NIA NIH HHS/United States ; U01AG072579/AG/NIA NIH HHS/United States ; R01AG070864/AG/NIA NIH HHS/United States ; R01AG072547/AG/NIA NIH HHS/United States ; U19AG074865/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *DNA Methylation ; *Epigenesis, Genetic ; *Alzheimer Disease/genetics ; *Aging/genetics ; White People/genetics ; Female ; CpG Islands ; Black or African American/genetics ; European People ; Quantitative Trait Loci ; },
abstract = {Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimer's disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here, we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts. The clocks are less accurate at predicting age in genetically admixed cohorts compared to the White cohort, especially for those with substantial African ancestry. This decreased accuracy holds in >2500 individuals of European and African ancestry from three additional datasets. The clocks also fail to consistently identify age acceleration in admixed AD cases compared to controls. To explore potential causes for the lack of generalization of the clocks, we intersected clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data from global populations. We find differential methylation between African and European ancestry individuals is common for clock CpGs. Genetic variants rarely disrupt clock CpGs between populations, but a substantial fraction of clock CpGs have meQTL with significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk when applied across populations and suggest avenues for improving their portability by considering differences in genetic and epigenetic patterns across human populations.},
}

Humans
*DNA Methylation
*Epigenesis, Genetic
*Alzheimer Disease/genetics
*Aging/genetics
White People/genetics
Female
CpG Islands
Black or African American/genetics
European People
Quantitative Trait Loci

@article {pmid42550766,
year = {2026},
author = {Tuokkola, T and Parkkola, R and Koikkalainen, J and Vahlberg, T and Kaprio, J and Lötjönen, J and Eero, V and Rinne, J},
title = {A magnetic resonance imaging analysis of cognitively discordant monozygotic and dizygotic twins: a comparative study of visual rating method and tensor-based morphometry.},
journal = {Acta radiologica (Stockholm, Sweden : 1987)},
volume = {},
number = {},
pages = {2841851261438991},
doi = {10.1177/02841851261438991},
pmid = {42550766},
issn = {1600-0455},
abstract = {BackgroundAtrophy of the medial temporal lobes and deep gray matter, along with ventricular enlargement, are typical structural magnetic resonance imaging (MRI) findings in the brains of patients with Alzheimer's disease (AD). However, there are few twin studies on this subject.PurposeTo determine whether the visual rating method (VRM) and tensor-based morphometry (TBM) can detect the structural brain changes in monozygotic and dizygotic twin pairs discordant for memory performance.Material and MethodsA total of 12 monozygotic and 24 same-sex dizygotic twin pairs discordant for memory performance and 44 cognitively healthy non-twin volunteers were studied.ResultsSignificant within-twin pair differences in brain atrophy were detected in the medial temporal lobes and ventricular areas (both with VRM and TBM), and in deep gray matter structures (TBM only). When monozygotic and dizygotic twin pairs were analyzed separately, the differences were not statistically significant.ConclusionOur study yielded promising TBM results in distinguishing memory-discordant co-twins in temporal and deep gray matter atrophy. In addition, the findings confirm the assumption that AD affects twins in the same way, independent of genes. Studies with larger twin cohorts would better reveal possible differences between monozygotic and dizygotic twin pairs.},
}

@article {pmid42550855,
year = {2026},
author = {López-Dequidt, I and Leira, Y and Cinza-Sanjurjo, S and Rey-Aldana, D and Jiménez, I and Campos, F and Sobrino, T and Castillo, J and Rodríguez-Yáñez, M},
title = {Circulating MMP-7 is associated with cognitive decline in individuals with vascular risk factors.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474103},
doi = {10.1177/13872877261474103},
pmid = {42550855},
issn = {1875-8908},
abstract = {BackgroundVascular risk factors contribute substantially to late-life cognitive impairment and interact with neurodegenerative processes underlying dementia. Blood-brain barrier (BBB) dysfunction has emerged as a key mechanism linking vascular pathology to cognitive decline; however, circulating biomarkers reflecting BBB remodeling remain incompletely characterized.ObjectiveTo explore the association between circulating markers of BBB remodeling, amyloid-β (Aβ)1-40 and longitudinal cognitive decline in individuals with vascular risk factors.MethodsIn this prospective cohort study, 101 individuals (mean age 71 ± 5 years; 59.4% women) with long-standing hypertension and/or type 2 diabetes mellitus underwent serial assessment of serum BBB-related biomarkers (matrix metalloproteinases [MMPs], TIMP-1 and soluble tumor necrosis factor-like weak inducer of apoptosis [sTWEAK]), Aβ1-40, brain MRI, and standardized cognitive testing (Mini-Mental State Examination and Addenbrooke's Cognitive Examination Version V) over a mean follow-up of 24 ± 4.9 months. Cognitive decline was defined as a clinically meaningful reduction in global cognitive scores.ResultsTwelve participants (11.9%) developed cognitive decline. Higher serum MMP-7 levels at 12 months were independently associated with subsequent cognitive decline after adjustment for age, sex and baseline cognition (adjusted OR 2.13; 95% CI 1.09-4.13; p = 0.026). Baseline levels of Aβ1-40, MMP-9, and sTWEAK were associated with lower cognitive performance.ConclusionsElevated circulating MMP-7 at 12 months was associated with cognitive decline suggesting a potential role for BBB remodeling in vascular contributions to cognitive impairment. These findings should be considered exploratory and require validation in larger studies.},
}

@article {pmid42550989,
year = {2026},
author = {Casarini, A and Ballerini, A and Maramotti, R and Tondelli, M and Carbone, C and Chiari, A and Vinceti, G and Bedin, R and Urbano, T and Malagoli, M and Genovese, M and Scolastico, S and Giovannini, G and Pugnaghi, M and Orlandi, N and Molinari, MA and Meletti, S and Zamboni, G and Vaudano, AE},
title = {Cognitive and Biomarker Signatures of Late-Onset Temporal Lobe Epilepsy: Toward Non-Alzheimer Neurodegenerative Mechanisms.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218356},
doi = {10.1212/WNL.0000000000218356},
pmid = {42550989},
issn = {1526-632X},
mesh = {Humans ; Female ; *Epilepsy, Temporal Lobe/cerebrospinal fluid/diagnostic imaging/psychology/complications/pathology ; Male ; Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; tau Proteins/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Middle Aged ; Neurofilament Proteins/cerebrospinal fluid ; Neuropsychological Tests ; *Cognition ; Cohort Studies ; Age of Onset ; },
abstract = {BACKGROUND AND OBJECTIVES: Late-onset unexplained epilepsy (LOUE) represents a substantial proportion of epilepsies with onset after 50 years and often manifests as temporal lobe epilepsy (LO-TLE). Although a link with Alzheimer disease (AD) has been suggested, only a subset of LO-TLE shows AD-related biomarkers, indicating biological heterogeneity. This study aims to characterize the cognitive and CSF phenotype of LO-TLE and compare it with healthy controls (HCs) and patients with mild cognitive impairment due to AD (MCI-AD).

METHODS: This Italian cross-sectional cohort study included LO-TLE patients with normal CSF β-amyloid (Aβ) biomarkers, MCI-AD, and age-matched and sex-matched HC. Participants underwent structural MRI, neuropsychological assessment, and CSF biomarkers assay, including neurofilament light chain (NfL) and the phosphorylated-to-total tau ratio (p/t-tau). Cortical thickness and subcortical volumes were quantified from structural MRI. Cognitive performance was summarized using principal component analyses. Group differences in imaging, cognition, and CSF biomarkers were assessed, and associations between CSF markers and cognition were examined within groups.

RESULTS: The study included 18 LO-TLE, 24 MCI-AD, and 17 HC. LO-TLE showed preserved cortical thickness and subcortical volumes comparable with HC, whereas MCI-AD exhibited widespread cortical thinning and medial temporal atrophy. Despite normal imaging, LO-TLE showed lower performance compared with HC in episodic memory (t(53) = -7.79, pFDR < 0.001), short-term memory (t(53) = -2.94, pFDR = 0.007), language (t(53) = 4.12, pFDR < 0.001), and executive functions (t(53) = -3.76, pFDR < 0.001), while attention was preserved. Global cognitive performance further distinguished LO-TLE from MCI-AD, with the former group performing better (t(53) = 4.21, pFDR < 0.001). LO-TLE CSF profiles were characterized by low NfL levels and a p/t-tau ratio below the proposed cutoff of 0.17, whereas MCI-AD showed pathologic Aβ and tau alterations, elevated NfL, and p/t-tau ratio above 0.17. In LO-TLE, a higher p/t-tau ratio was associated with better performance on global cognition (rs = 0.585, pFDR = 0.032) and short-term memory (rs = 0.588, pFDR = 0.032), whereas no associations emerged in MCI-AD.

DISCUSSION: LO-TLE with normal CSF AD biomarkers is characterized by distinct cognitive and biological features compared with MCI-AD, suggesting a disease process independent of AD. The low p/t-tau ratio may reflect alternative pathophysiologic mechanisms and warrants further investigation in larger longitudinal studies to clarify the underlying pathology and clinical trajectories.},
}

Humans
Female
*Epilepsy, Temporal Lobe/cerebrospinal fluid/diagnostic imaging/psychology/complications/pathology
Male
Biomarkers/cerebrospinal fluid
Cross-Sectional Studies
tau Proteins/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging
Magnetic Resonance Imaging
*Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging
Amyloid beta-Peptides/cerebrospinal fluid
Aged
Middle Aged
Neurofilament Proteins/cerebrospinal fluid
Neuropsychological Tests
*Cognition
Cohort Studies
Age of Onset

@article {pmid42551144,
year = {2026},
author = {Li, J and Gao, Y and Guan, Z and Cheng, T and Wu, R and Yu, H and Yang, A and Xu, M and Wang, Y and Yang, P and Wang, T and Ma, G and Lei, B},
title = {Deep Cross-Branch Multi-Modal Fusion Network for early Alzheimer's diagnosis.},
journal = {Artificial intelligence in medicine},
volume = {181},
number = {},
pages = {103497},
doi = {10.1016/j.artmed.2026.103497},
pmid = {42551144},
issn = {1873-2860},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder where early diagnosis is pivotal for effective intervention, yet it is hindered by subtle pathological feature differences among AD subtypes and severe class imbalance in medical imaging datasets. Existing structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) multimodal fusion methods for AD diagnosis mostly adopt simple concatenation or summation without fine-grained cross-modal alignment and interaction. To address these issues, we propose a Deep Cross-Branch Multi-Modal Fusion Network (DCMFNet) for early AD diagnosis. We first preprocess sMRI and rs-fMRI to extract ROI-based features, then perform dimension unification and normalization to realize cross-modal feature alignment. A novel Deep Cross-branch Multi-modal Feature Fusion (DCMF) module with three parallel branches and a dual-pathway cross-modal branch is designed to fully mine complementary and correlated cross-modal information, and the fused features are input into a Transformer encoder for classification. Moreover, we introduce the Logit Adjustment Cross-Entropy (LACE) loss to mitigate class imbalance by correcting decision boundaries based on class prior probabilities, enhancing the recognition of minor classes. The model is evaluated on a private clinical dataset. Experimental results show that DCMFNet outperforms traditional machine learning methods and state-of-the-art deep learning models in six binary AD subtype classification tasks, with the LACE loss and DCMF module effectively alleviating class imbalance and improving cross-modal feature representation. This work provides a reliable multimodal fusion framework for early AD diagnosis and reduces the diagnostic burden on healthcare professionals.},
}

@article {pmid42551412,
year = {2026},
author = {Furtado, J and Schneeberger, M},
title = {When lactate speaks: Rewiring astrocyte-neuron metabolism in Alzheimer's disease.},
journal = {Cell metabolism},
volume = {38},
number = {8},
pages = {1527-1528},
doi = {10.1016/j.cmet.2026.05.007},
pmid = {42551412},
issn = {1932-7420},
mesh = {*Astrocytes/metabolism ; *Alzheimer Disease/metabolism/pathology ; Humans ; *Neurons/metabolism ; Animals ; *Lactic Acid/metabolism ; Glycolysis ; Glucagon-Like Peptide-1 Receptor/metabolism ; },
abstract = {Metabolic dysfunction is a defining but poorly understood feature of Alzheimer's disease. Du et al. show that a brain-penetrant GLP-1 receptor agonist rewires astrocyte-neuron metabolic coupling through lactate-driven histone lactylation, linking astrocytic glycolysis to neuronal lipid homeostasis and positioning metabolite signaling as a therapeutic axis in neurodegeneration.},
}

*Astrocytes/metabolism
*Alzheimer Disease/metabolism/pathology
Humans
*Neurons/metabolism
Animals
*Lactic Acid/metabolism
Glycolysis
Glucagon-Like Peptide-1 Receptor/metabolism

@article {pmid42551536,
year = {2026},
author = {Lei, Y and Liu, L and Tang, Y},
title = {How do energy metabolism disorders and neuroinflammation collectively contribute to the pathogenesis of Alzheimer's disease?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103287},
doi = {10.1016/j.arr.2026.103287},
pmid = {42551536},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), as the leading cause of dementia, poses an increasingly severe socioeconomic burden in the context of global ageing. Traditionally defined by amyloid-β and tau pathology, it's increasingly recognized as a systems disorder in which impaired glucose metabolism, mitochondrial dysfunction, and neuroinflammation interact across neural cell types and disease stages. However, the interaction among these three mechanisms, their role in promoting the classical pathology of AD, and their verification in major neural cell types remains unclear. This review summarizes the alterations in glucose metabolism and mitochondrial metabolism in neurons, astrocytes and microglia in AD and their relationship with neuroinflammation, while also discussing some unaddressed questions, outlining therapeutic strategies, and future promising directions. Biomarkers that reflect disease stage and pathological status, multitarget therapeutic strategies, individualized precision medicine, and the integration of pharmacological with non-pharmacological interventions represent particularly promising directions for the future.},
}

@article {pmid42551552,
year = {2026},
author = {Kumar, V and Arulsamy, S and Sharma, S and Kumar, S and Kakoty, V},
title = {Covalent small-molecule RNA targeting in Alzheimer's disease: computational strategies, challenges and opportunities.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104758},
doi = {10.1016/j.drudis.2026.104758},
pmid = {42551552},
issn = {1878-5832},
abstract = {RNA dysfunction is increasingly recognized as an upstream driver of Alzheimer's disease pathology, and covalent small molecules that engage pathogenic RNA structures are emerging as a therapeutic strategy. In addition to its role as a template, RNA governs amyloid-β production, the tau isoform balance and neuroinflammation through aberrant splicing, noncoding RNA activity and epitranscriptomic modification. The irreversible engagement of these structures enables modulation with sustained target occupancy. This analysis examines how covalent docking, molecular dynamics and AI-enabled screening can be combined to identify electrophilic RNA binders, using the microtubule-associated protein tau exon 10 splicing regulatory element and the amyloid precursor protein 5'-UTR as concrete reference points. It assesses the determinants of nucleophilic reactivity in folded RNA, the electrophilic modules with demonstrated RNA reactivity and the barriers of selectivity, brain delivery and translational validation.},
}

@article {pmid42541674,
year = {2026},
author = {Kewal, A and Rajput, MS and Shah, J and Gandhi, D},
title = {Valorization of 2-aminoethoxydiphenyl borate as a neurotherapeutic agent: modulation of calcineurin, TRPC1 and MARK2/GSK-3β signaling in scopolamine-triggered tauopathy.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42541674},
issn = {1568-5608},
support = {(IP/2023-24/68)//Nirma University Funded Minor Research Project Scheme. Directorate of Research, Nirma University, Ahmedabad, India/ ; },
abstract = {In Alzheimer's disease (AD), amyloid beta (Aβ) plaques and hyperphosphorylated tau tangles drive neurodegeneration and cognitive decline. Disrupted calcium homeostasis-particularly via transient receptor potential canonical-1 (TRPC1) channels-contributes to tauopathy and disease progression. This study investigated the therapeutic potential of 2-aminoethoxydiphenyl borate (2-APB), a modulator of TRP channels, in a scopolamine-induced rat model of AD. Adult Wistar rats were assigned to six groups: normal control, disease control (scopolamine 2.5 mg/kg), three 2-APB treatment groups (2.5, 5.0 and 10.0 mg/kg) and a donepezil group (5.0 mg/kg), each with six animals. Treatments lasted three weeks. Cognitive performance was assessed using the Morris water maze, memory consolidation and open field tests. Biochemical assays measured acetylcholinesterase (AChE), calcineurin, oxidative stress markers (GSH, MDA) and inflammatory cytokines (TNF-α, IL-6, IL-1β). Protein and gene expression analyses (Western blot, qRT-PCR) evaluated tau, GSK-3β, TRPC1, MARK2, and calcineurin A/PPP3CA, alongside histopathological and immunohistochemical studies. 2-APB treatment significantly reduced pro-inflammatory cytokines, alleviated neuroinflammation, and decreased oxidative stress. Cognitive function improved, correlating with normalized AChE activity and preserved neuronal structure. At the molecular level, 2-APB reduced tau hyperphosphorylation at Ser396 and Thr231, likely through suppression of TRPC1-associated calcium entry and consequent modulation of calcium-dependent kinases (MARK2) and phosphatases (calcineurin), as well as the GSK-3β pathway. However, given that 2-APB is a broad-spectrum calcium signaling modulator - known to act on IP3 receptors, SOCE/ORAI pathways, and multiple TRPC subtypes in addition to TRPC1-the present findings provide supportive evidence linking TRPC1 modulation to the observed neuroprotective effects. Although, the involvement of additional interconnected signaling mechanisms cannot be excluded and these findings should be interpreted within the context of 2-APB's pleiotropic pharmacological profile. Downregulation of TRPC1 and calcineurin A/PPP3CA gene expression supported 2-APB's role in restoring calcium balance and mitigating tau pathology. These results highlight 2-APB's potential in addressing key AD features-tauopathy, oxidative stress, neuroinflammation and cognitive impairment-warranting further preclinical and clinical research as a potential therapeutic for AD and related tauopathies.},
}

@article {pmid42541877,
year = {2026},
author = {Salama, RS and Hulshizer, CA and Crowson, CS and Lennon, RJ and Rocca, WA and George, RJ and Frechette, N and Allen, M and Myasoedova, E},
title = {Menopause status and its role in incident Alzheimer's disease and related dementias, rheumatoid arthritis (RA) disease severity, and overall mortality in women with RA.},
journal = {Seminars in arthritis and rheumatism},
volume = {80},
number = {},
pages = {153051},
doi = {10.1016/j.semarthrit.2026.153051},
pmid = {42541877},
issn = {1532-866X},
abstract = {INTRODUCTION/OBJECTIVES: We aimed to investigate associations between menopausal characteristics, including age at menopause and cause (natural vs. artificial), with long-term outcomes in women with rheumatoid arthritis (RA), incident Alzheimer's disease and related dementias (ADRD), RA severity, and overall mortality. We hypothesized that atypical menopausal characteristics increase ADRD risk and disease severity.

METHODS: Women with incident RA in 1980-2014 who were ≥50 years of age at RA incidence were included. Menopause cause and age at menopause (categorized as <45, 45-54, ≥55 years) were abstracted from medical records. Associations between menopausal characteristics and ADRD, extra-articular manifestations (ExRA), erosions, cardiovascular events, and mortality were evaluated using Cox models. Associations with clinic visits for flares and remissions were assessed using mixed-effects models. Data were collected using the Rochester Epidemiology Project medical records-linkage system.

RESULTS: Both early/premature and late menopause were associated with nonsignificant near two-fold increases in ADRD risk. In addition, early/premature (HR 2.40; 95% CI 1.15-5.01) and late menopause (HR 2.17; 95% CI 1.01-4.66) significantly increased severe ExRA risk. Menopausal characteristics were not associated with presence of erosions or mortality. Artificial menopause was associated with fewer cardiovascular events and fewer visits for RA remission. Early/premature menopause was associated with fewer remission visits (OR 0.50; 95% CI 0.29-0.87).

CONCLUSION: Women with early/premature and late menopause had nonsignificant, increased risk of incident ADRD. Menopausal characteristics had significant associations with RA severity and cardiovascular events, and may be relevant contextual factors in long-term risk assessment for women with RA.},
}

@article {pmid42541965,
year = {2026},
author = {Vanderlip, CR and Lingad, JN and Treadwell, Z and Loritsch, JM and Illeck, CL and Ubele, MF and Boaz, K and Mefford, JL and Jones, ED and Perpich, JA and McCarty, K and Meacham, B and Bembenek Bailey, SA and Puskás, LG and Bresch, F and Powell, DK and Norris, CM and Head, E and Stark, CEL},
title = {Amyloid-associated cognitive trajectories in aging dogs mirror early changes in humans.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {99-108},
doi = {10.1016/j.neurobiolaging.2026.07.009},
pmid = {42541965},
issn = {1558-1497},
abstract = {Amyloid-β (Aβ) accumulation begins many years before the onset of clinical symptoms in Alzheimer's disease (AD). Studies in humans suggest that unimpaired individuals with elevated Aβ exhibit subtle changes in cognitive trajectories over time, particularly in memory. Identifying animal models that recapitulate these early changes is critical for translational research on preclinical AD. Here, we hypothesized that aging dogs, which naturally accumulate Aβ, show similar patterns to those observed in humans. Forty-three beagles underwent longitudinal cognitive testing on tasks assessing spatial memory, landmark discrimination, and reversal learning, while Aβ burden was measured using cerebrospinal fluid Aβ42/40. Parallel analyses were conducted in cognitively unimpaired older adults from the Harvard Aging Brain Study (n = 287) using Aβ PET imaging and neuropsychological assessments. Despite no baseline differences, dogs with lower CSF Aβ42/40 showed worse longitudinal trajectories on a spatial memory task. No comparable effects were observed for landmark discrimination or reversal learning. Using a data-driven approach, Low CSF Aβ42/40 dogs were more likely to be classified in the Lower trajectory group than High CSF Aβ42/40 dogs. A similar pattern emerged in humans: Aβ+ individuals showed lower memory trajectories compared to Aβ- individuals. Across species, memory deficits were characterized by reduced benefits of practice effects rather than abrupt decline. Together, these findings suggest that aging dogs show Aβ-associated memory trajectories that parallel patterns observed in cognitively unimpaired older adults and support the canine model as a valuable translational platform for studying the earliest stages of AD.},
}

@article {pmid42542073,
year = {2026},
author = {Oriquat, G and Rizaev, J and Abdulqader, AF and Kadhim, AA and Jamuna, KV and Singhal, D and Bainsal, N and Mansurova, N},
title = {Gut microbiota and brain health: Disease-specific pathways and emerging therapeutic strategies.},
journal = {Multiple sclerosis and related disorders},
volume = {113},
number = {},
pages = {107407},
doi = {10.1016/j.msard.2026.107407},
pmid = {42542073},
issn = {2211-0356},
abstract = {The microbiota-gut-brain axis (MGBA) has emerged as a dynamic, bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS) through neural, immune, endocrine, and metabolic mechanisms. Increasing evidence indicates that alterations in gut microbial communities are associated with a wide range of neurological disorders; however, the strength of this association varies across diseases, and many mechanistic observations still rely predominantly on experimental models rather than human studies. This review provides an overview of current evidence regarding the role of the gut microbiota in maintaining CNS homeostasis, with particular emphasis on intestinal barrier function, immune modulation, vagal and enteric communication, and the generation of biologically active microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitter-related compounds. Studies in both clinical and experimental settings have reported disease-specific microbial signatures in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorders, and amyotrophic lateral sclerosis. In parallel, microbiota-directed interventions-including probiotics, prebiotics, dietary approaches, fecal microbiota transplantation, and strategies targeting microbial metabolites-have produced encouraging findings in preclinical studies and early-stage clinical investigations. Nevertheless, considerable heterogeneity in study populations, experimental methodologies, and therapeutic protocols continues to limit the translation of these findings into routine clinical practice. Collectively, current evidence supports the MGBA as a valuable framework for understanding neurological diseases while underscoring the need for rigorously designed longitudinal studies and well-controlled clinical trials to define its therapeutic relevance better.},
}

@article {pmid42542107,
year = {2026},
author = {Sui, JZ and Yin, WW and Yu, HH and Hu, H and Wei, LL and Zhang, JS and Wang, FY and Tan, L and Xue, M and Zhao, B and , },
title = {Trajectories of sleep disturbance in older adults and their associations with clinical and pathological outcomes in AD: A longitudinal study.},
journal = {Sleep medicine},
volume = {147},
number = {},
pages = {109168},
doi = {10.1016/j.sleep.2026.109168},
pmid = {42542107},
issn = {1878-5506},
abstract = {BACKGROUND: Sleep disturbance is a core feature of affective and neurodegenerative disorders. This study tracks long-term sleep disturbance trajectories and their links to incident Alzheimer's disease (AD) and longitudinal clinical and pathological changes.

METHODS: A total of 774 non-demented participants from the ADNI cohort were included. Sleep disturbance (NPI sleep item) trajectories over 8 years were identified via group-based trajectory modeling. Cox proportional hazards regression was used to estimate the risk of incident AD. Linear mixed-effects models were used to assess longitudinal changes in cognition, structural magnetic resonance imaging, amyloid-β positron emission tomography (Aβ-PET), fluorodeoxyglucose (FDG)-PET, and cerebrospinal fluid (CSF) biomarkers.

RESULTS: Three trajectories emerged: "Low-stable" (37.2%), "High-peaked" (21.0%), and "Moderate-increasing" (41.8%). Compared to those without sleep disturbance, a significantly elevated risk of incident AD was associated with "High-peaked" (hazard ratio [HR] = 3.28; 95% confidence interval [CI] = 1.89-5.70; p < 0.001) and "Moderate-increasing" trajectories (HR = 2.13; 95% CI = 1.28-3.53; p = 0.003) but not with the "Low-stable" trajectory (p = 0.888). Participants with "High-peaked" trajectory exhibited faster declines in cognition (MMSE, memory, executive function) (p < 0.050) and a steeper reduction in CSF Aβ1-42 levels (p = 0.038) than those with non-sleep disturbance. However, there were no significant differences between groups in the rates of hippocampal, entorhinal, or middle temporal atrophy, global Aβ-PET burden, or FDG-PET changes (p > 0.050).

CONCLUSIONS: "High-peaked" and "Moderate-increasing" sleep trajectories predict higher AD risk, faster cognitive decline, and faster Aβ1-42 reduction. Long-term monitoring of sleep behaviors is essential for identifying and stratifying individuals at high risk for AD.},
}

@article {pmid42542170,
year = {2026},
author = {Xu, X and Li, H and Zhu, Y and Fu, X and Hu, Q and Dong, X},
title = {The critical role of ceramide in mental health and psychiatric diseases.},
journal = {Pharmacology & therapeutics},
volume = {},
number = {},
pages = {109093},
doi = {10.1016/j.pharmthera.2026.109093},
pmid = {42542170},
issn = {1879-016X},
abstract = {Ceramides (Cer) are lipid signaling molecules regulating cell proliferation, differentiation, senescence and apoptosis, whose metabolic disturbance disrupts organismal homeostasis. Accumulating evidence links ceramide imbalance to psychiatric and neurodegenerative diseases, yet few systematic reviews summarize subtype-specific ceramide functions. This review outlines ceramide anabolic and catabolic pathways, compares functional distinctions among ceramides with distinct acyl chain lengths, describes substrate preferences of ceramide metabolic enzymes, and introduces ceramide detection techniques. On this basis, we discuss regulatory roles and underlying molecular mechanisms of ceramides in schizophrenia, Alzheimer's disease, epilepsy, depression, bipolar disorder and anxiety disorders, identify disease-specific effects of distinct ceramide subtypes, and provide theoretical evidence for lipid-targeted pharmacological research on psychiatric disorders.},
}