@article {pmid41942597,
year = {2026},
author = {Sharef, H and Almoiqli, MS and Jalal, A and Mazi, W and Ibrahim, B and Alrehaili, A and Aljowni, MA and Alessa, AH and Fakhre, N and Alharbi, OA and Alsulami, RA and Albarqi, MM and Baata, M},
title = {Eco-engineered bio-imprinted polymer for selective aluminum sequestration in wastewater.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41942597},
issn = {2045-2322},
abstract = {Aluminum (Al) poisoning in wastewater poses a significant environmental and public health threat, with potential association to neurological diseases such as Alzheimer’s. Conventional remediation methods often rely on synthetic materials with environmental drawbacks. This study presents a sustainable alternative by synthesizing ion-imprinted polymers (IIPs) from chia seed extract, a biobased resource rich in functional groups. Using Al (III) ions as a template and epichlorohydrin as a crosslinker, IIPs with specific sites for capturing aluminum. These IIPs demonstrated performance superior to non-imprinted polymers (NIPs), achieving a maximum adsorption capacity of 188.7 mg/g and a removal efficiency of 96.02%. Optimal conditions were found to be a pH of 5.5, a temperature of 30 °C, and a 30-minute contact time. Statistical analysis through ANOVA confirmed the significance of the findings (p < 0.001). The adsorption process conformed to the Langmuir, Freundlich, Temkin, and Sips isotherm models, as well as the pseudo-first-order, pseudo-second-order, intraparticle diffusion, and Elovich kinetic models, suggesting a monolayer, endothermic, and spontaneous characteristic. The IIPs also proved highly reusable, maintaining their effectiveness over 10 regeneration cycles. These results demonstrate that chia seed-based IIPs provide a biobased, selective, and reusable approach for aluminium removal from wastewater, offering a balance between sustainability and adsorption efficiency.},
}

@article {pmid41998752,
year = {2026},
author = {Zhang, Z and Xu, C},
title = {Airborne pollutants and risk of neurodegenerative diseases: a global systematic review and meta-analysis.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41998752},
issn = {1758-9193},
support = {LZZX2025-02//Linzhi Science and Technology Program Project/ ; 2023ZD0503500//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; O88RA205YA//Innovation Project of State Key Laboratory of Resources and Environmental Information System/ ; },
abstract = {BACKGROUND: The relationship between airborne pollutants and subtypes of neurodegenerative disorders remains poorly understood. This study aims to assess the associations between major air pollutants and the risk of multiple neurodegenerative disease outcomes.

METHODS: We searched three databases (PubMed, Web of Science, and Scopus), with the most recent update on February 21st, 2026. We included studies involving adults (without the disease at baseline) with exposure to air pollutants such as PM2.5, PM10, NO2, NOx, and O3, and outcomes related to all-cause dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), and vascular dementia (VaD). Data extracted included study details, population characteristics, and risk of bias, assessed using a modified Newcastle-Ottawa Scale. Hazard ratios (HR) and 95% confidence intervals (CIs) were pooled using random-effects models.

RESULTS: Among 24,196 identified records, 49 studies met the inclusion criteria. The included studies covered populations from North America, Europe, Asia and Oceania, providing a broad global perspective. A per-increment relationship was found between air pollution and incidence of all-cause dementia. For each 1 µg/m³ increase in PM2.5, the pooled HR for all-cause dementia was 1.07 (95% CI: 1.02–1.12), with weaker but positive associations for AD (HR: 1.03, 95% CI: 1.01–1.05), PD (HR: 1.02, 95% CI: 1.00-1.04) and VaD (HR: 1.03, 95% CI: 1.01–1.05). PM10 exposure was positively associated with AD risk (HR: 1.02, 95% CI: 1.00-1.03, per 1 µg/m³ increase). In addition, NO2 was associated with increased risks of all-cause dementia (HR: 1.05, 95% CI: 1.00-1.11) and VaD (HR: 1.14, 95% CI: 1.01–1.28) per 10 µg/m³ increase.

CONCLUSIONS: Our findings indicate that pollutants, particularly PM2.5, PM10, and NO2, are associated with an increased risk of neurodegenerative diseases. These results provide strong evidence supporting the role of air quality in achieving Sustainable Development Goals (SDGs) 3 and 13, aiming to reduce the dementia burden and improve air quality globally.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02050-3.},
}

@article {pmid42204869,
year = {2026},
author = {Donley, G and Hsiao, J and Balintfy, J and Silverberg, N},
title = {Four decades of Alzheimer's disease discoveries, data, and research resources: The NIH Alzheimer's Disease Research Center Program.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71511},
doi = {10.1002/alz.71511},
pmid = {42204869},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/history/diagnosis ; *Biomedical Research/history ; History, 20th Century ; History, 21st Century ; *National Institute on Aging (U.S.) ; National Institutes of Health (U.S.) ; United States ; },
abstract = {The Alzheimer's Disease Research Centers (ADRC) program, funded by the National Institute on Aging (NIA), is a national network for conducting cutting-edge basic, clinical, and translational Alzheimer's disease (AD) and AD-related dementias (ADRD) research. ADRCs collect clinical, biomarker, neuroimaging, and autopsy data on thousands of longitudinally followed research participants and the well-characterized data and samples generated by the ADRCs are readily available to the research community. Beyond conducting research, the primary objectives of the ADRC program are to train the next generation of multidisciplinary AD/ADRD researchers and share information with the public, including the latest findings and opportunities to participate in clinical studies. This article provides an overview of the 40-year history of the ADRC program, from its establishment by Congress in 1984 to now, highlighting the AD/ADRD scientific achievements enabled by the ADRCs, the data, samples, and resources that ADRCs provide, and future directions for the program.},
}

Humans
*Alzheimer Disease/history/diagnosis
*Biomedical Research/history
History, 20th Century
History, 21st Century
*National Institute on Aging (U.S.)
National Institutes of Health (U.S.)
United States

@article {pmid42204876,
year = {2026},
author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A},
title = {Scalable markers for early cognitive decline: Plasma p-tau217, subjective cognitive concerns, and digital testing: Results from the A4/LEARN studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71505},
doi = {10.1002/alz.71505},
pmid = {42204876},
issn = {1552-5279},
support = {//public-private philanthropic partnership/ ; //National Institutes of Health/National Institute on Aging/ ; //Eli Lilly and Company/ ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; //Avid and Cogstate/ ; },
mesh = {Humans ; Aged ; *Cognitive Dysfunction/diagnosis/blood ; *tau Proteins/blood ; Biomarkers/blood ; Female ; Male ; Aged, 80 and over ; Neuropsychological Tests ; Positron-Emission Tomography ; *Alzheimer Disease/blood ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers confirm Alzheimer's disease (AD) pathology but are impractical for large-scale screening. Plasma phosphorylated tau at threonine 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We assessed their separate and combined predictive value for cognitive decline.

METHODS: We analyzed 1064 cognitively unimpaired adults (ages 65-85 years) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4; amyloid-positive) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN; amyloid-negative) studies. Baseline assessments included apolipoprotein E (APOE) ε4 status, hippocampal volume, amyloid PET, plasma p-tau217, Cognitive Function Index (CFI), and Cogstate Computerized Battery (CCB). Cognitive impairment was defined as conversion from a Clinical Dementia Rating Global Score (CDR-GS) of 0 to ≥0.5 over 240 weeks.

RESULTS: During the follow-up, 34.1% developed cognitive impairment. Higher p-tau217, higher CFI, and lower CCB were associated with higher odds of converting to CDR-GS >0 across all cohorts.

DISCUSSION: P-tau217, CFI, and CCB each independently predict cognitive decline, offering practical, non-invasive tools for early AD risk stratification and trial enrichment.},
}

Humans
Aged
*Cognitive Dysfunction/diagnosis/blood
*tau Proteins/blood
Biomarkers/blood
Female
Male
Aged, 80 and over
Neuropsychological Tests
Positron-Emission Tomography
*Alzheimer Disease/blood
Longitudinal Studies

@article {pmid42205004,
year = {2026},
author = {Stefanacci, RG},
title = {Turning Compliance Into Action: An Augmented Intelligence-Enabled Framework for Advocacy Organizations to Drive Population Health Improvement.},
journal = {Population health management},
volume = {},
number = {},
pages = {19427891261450800},
doi = {10.1177/19427891261450800},
pmid = {42205004},
issn = {1942-7905},
abstract = {Community Health Needs Assessments (CHNAs), mandated by the Affordable Care Act for tax-exempt hospitals, represent an underutilized yet rich data source for disease-specific advocacy. This commentary proposes a novel framework in which disease advocacy organizations-such as Alzheimer's Los Angeles, the American Heart Association, and the National Alliance on Mental Illness-deploy artificial intelligence (AI) agents to systematically analyze CHNAs, identify gaps in condition-specific care, generate personalized outreach to hospital leadership, and publicly score health systems on their responsiveness to identified needs. Using Alzheimer's disease and dementia care in Los Angeles County as a primary case example, this article describes how AI-driven automation of data collection, natural language processing of CHNA documents, and coordinated advocacy campaigns can transform the current passive CHNA cycle into an active mechanism for population health improvement. The framework combines reputational accountability through public scorecards with constructive, evidence-based recommendations, creating a "carrot-and-stick" dynamic that existing literature on public performance reporting suggests can achieve engagement rates of 40%-70% and meaningful institutional change in 30%-60% of targeted systems. This approach is adaptable across chronic conditions and disease advocacy organizations, wherever publicly reported community needs data intersect with organized patient advocacy. Implications for population health management, health system quality improvement, and the responsible integration of AI in public health advocacy are discussed.},
}

@article {pmid42205980,
year = {2026},
author = {Mirzai, M and Marouf, SP and Eslami, M and Nabian, MH},
title = {Metabolic dysfunction and insulin resistance across major dementias: A comprehensive narrative review of the TyG index as a predictive marker.},
journal = {Metabolism open},
volume = {30},
number = {},
pages = {100474},
pmid = {42205980},
issn = {2589-9368},
abstract = {Dementia is a progressive neurodegenerative disorder and a leading cause of disability worldwide, with Alzheimer's disease (AD), vascular dementia (VaD), and Lewy body dementias (LBD) representing the most common subtypes. Its rising prevalence, driven by population aging, underscores the urgent need for accessible biomarkers to support early risk identification and prevention. Insulin resistance (IR) has emerged as a key metabolic mechanism involved in cognitive decline and neurodegeneration. The triglyceride-glucose (TyG) index, derived from routine fasting glucose and triglyceride levels, is a simple and cost-effective surrogate marker of IR. Evidence suggests that higher TyG values are associated with an increased risk of dementia, adverse neuroimaging and biomarker profiles, and cerebrovascular and neurodegenerative changes, although findings remain heterogeneous. This review summarizes the current evidence linking the TyG index to major dementia subtypes and discusses the underlying pathophysiological mechanisms and clinical implications. A graphical abstract illustrating the proposed metabolic-neurodegenerative pathways is also provided.},
}

@article {pmid42206050,
year = {2026},
author = {Deng, HX and Cao, JL and Wu, Y and Jiang, SJ and Fang, QQ and Zhu, BY and Jiang, YJ},
title = {AI-driven insights into protein misfolding and innate immunity in neurodegenerative diseases.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1814357},
pmid = {42206050},
issn = {1664-3224},
mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; *Immunity, Innate ; *Protein Folding ; Animals ; *Artificial Intelligence ; *Proteostasis Deficiencies/immunology ; },
abstract = {Neurodegenerative diseases encompass a diverse group of disorders ranging from adult-onset conditions such as Alzheimer's and Parkinson's disease to pediatric forms including neuronal ceroid lipofuscinoses (NCLs), Niemann-Pick type C (NPC), and infantile neuroaxonal dystrophy (INAD), all of which are characterized by protein misfolding and chronic neuroinflammation. During their occurrence and development, the innate immune system, especially the immune responses mediated by microglia in the central nervous system, plays a crucial regulatory role. Increasing evidence indicates that misfolded and abnormally aggregated proteins, such as β-amyloid (Aβ), Tau, α-synuclein, and TDP-43, are not only neurotoxic factors but can also act as damage-associated molecular patterns (DAMPs) recognized by innate immune receptors, thereby triggering persistent neuroinflammatory responses. However, traditional experimental and computational methods still have significant limitations in systematically analyzing the "protein misfolding-innate immune activation" mechanism. In recent years, artificial intelligence has made breakthrough progress in protein structure prediction, multi-conformation modeling, and integration of multi-omics data, providing a new research paradigm for revealing the intrinsic relationship between protein misfolding and innate immunity across the spectrum of neurodegenerative diseases. This article systematically reviews the latest applications of artificial intelligence in predicting the conformational characteristics of misfolded proteins, simulating the protein aggregation process, revealing the mechanism of innate immune perception, and reconstructing the regulatory network of neuroinflammation. It focuses on discussing the significance of deep learning models such as AlphaFold, I-TASSER, RoseTTAFold, Phyre2, and ESMFold in the field of protein structure prediction, as well as the related research on multi-modal AI technology in revealing the complex molecular mechanisms behind neurodegenerative diseases, such as combining AI with mathematical models to simulate the spread of misfolded proteins and further exploring the association with disease progression. The review also highlights the potential of AI to address the diagnostic challenges unique to pediatric neurodegenerative disorders, which, despite their rarity, collectively impose devastating lifelong burdens. In summary, AI tools not only deepen our understanding of the molecular mechanisms underlying both adult and childhood neurodegenerative diseases but also open up new avenues for developing innovative diagnostic tools and treatment methods.},
}

Humans
*Neurodegenerative Diseases/immunology/metabolism
*Immunity, Innate
*Protein Folding
Animals
*Artificial Intelligence
*Proteostasis Deficiencies/immunology

@article {pmid42206051,
year = {2026},
author = {Li, T and Guo, K and Ma, Y and Zhao, J and Cao, Y and Zhang, R and Li, X and Wei, J and Ma, Y and Zhu, Z and Zhao, D},
title = {Lipid metabolic regulation of neuroinflammation in Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1815719},
pmid = {42206051},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/pathology ; *Lipid Metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism/etiology ; Microglia/metabolism/immunology ; Brain/metabolism/immunology ; Apolipoproteins E/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau pathology, and sustained neuroinflammation. Increasing evidence indicates that dysregulated lipid metabolism is not merely a metabolic disturbance but a critical modulator of inflammatory responses driving AD pathogenesis. The brain, one of the most lipid-enriched organs, relies on tightly controlled lipid homeostasis to maintain neuronal function and synaptic integrity. Alterations in fatty acid composition, apolipoprotein E (ApoE) isoforms, lipoprotein lipase activity, and lipid-derived signaling mediators profoundly reshape microglial activation states and inflammatory cascades. Obesity, insulin resistance, and gut microbiota dysbiosis further exacerbate systemic and central lipid imbalance, amplifying neuroinflammatory signaling through cytokine networks and blood-brain barrier disruption. Notably, polyunsaturated fatty acids and lipid mediators exert dual immunomodulatory effects, influencing β-amyloid aggregation, oxidative stress, and microglial polarization. This review synthesizes recent advances in understanding how lipid metabolism modulates neuroinflammation and microglia-neuron crosstalk in AD, highlighting emerging therapeutic strategies targeting lipid-inflammation axes as promising avenues for disease modification.},
}

Humans
*Alzheimer Disease/metabolism/immunology/pathology
*Lipid Metabolism
Animals
*Neuroinflammatory Diseases/metabolism/etiology
Microglia/metabolism/immunology
Brain/metabolism/immunology
Apolipoproteins E/metabolism

@article {pmid42206189,
year = {2026},
author = {De Jaegher, S and Pinzauti, D and D'Aguanno, M and Parkinson, E and Schofield, J and Strazzeri, F and Skipp, P and Penrice-Randal, R and Kunicki, A and McCausland, B and Kipps, C and Amin, J and Biazzo, M},
title = {Identifying microbial biomarkers of neurodegeneration: a comparative study in Alzheimer's and Parkinson's disease.},
journal = {Frontiers in microbiomes},
volume = {5},
number = {},
pages = {1831956},
pmid = {42206189},
issn = {2813-4338},
abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) have been increasingly linked to alterations of the gut microbiota, although reported microbial signatures remain heterogeneous and often lack taxonomic resolution.

METHODS: In the present study, we applied full-length 16S rRNA gene sequencing to characterize gut microbiota composition in 152 individuals, including patients with AD (n = 37), PD (n = 65), and age-matched healthy controls (n = 50), using a unified bioinformatic and statistical framework with adjustment for relevant demographic covariates.

RESULTS: Alzheimer's disease was associated with a modest but significant reduction in microbial richness and Shannon diversity compared with controls, whereas no alpha diversity differences were observed in PD. Beta diversity analyses revealed significant compositional differences across diagnostic groups, driven primarily by PD and modulated by sex but not age. Species-level differential abundance analysis identified a PD-associated microbial signature characterized by reduced abundances of short-chain fatty acid-producing bacteria, including Faecalibacterium prausnitzii, Agathobacter rectalis, Roseburia intestinalis, and Faecalicatena fissicatena, together with increased abundance of Ruminococcus sp. JE7A12. In contrast, AD exhibited minimal species-level changes, with only Bacteroidales bacterium CF showing reduced abundance compared with controls.

DISCUSSION: Overall, these findings indicate that Parkinson's disease is characterized by a targeted disruption of beneficial butyrate-producing bacteria, whereas Alzheimer's disease exhibits subtler and less consistent microbiome alterations. Our results underscore the importance of species-level resolution for identifying disease-associated microbial signatures.},
}

@article {pmid42206324,
year = {2026},
author = {Muñoz, MH and Okine, J and Brown, EL and Ruggiano, N},
title = {Mapping Augmentative and Alternative Communication Applications for Dementia Care.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261451134},
doi = {10.1177/07334648261451134},
pmid = {42206324},
issn = {1552-4523},
abstract = {Although augmentative and alternative communication (AAC) technology has been proven to support communication for people living with dementia, a gap in the use of this technology for this population still exists. Therefore, this study reviewed, described, and evaluated 11 commercial applications and their appropriateness for people living with dementia, using an adapted instrument, the Mobile App Rating Scale. Findings indicated that most apps scored higher in ease of use and navigation features, and performed lowest in graphic visual appeal. In terms of credibility, only one app was created by a developer with expertise in speech-language pathology, and only one app reported any study findings in peer-reviewed literature.},
}

@article {pmid42206504,
year = {2026},
author = {Brandt, E and Koivisto, A and Pereira, P and Mustanoja, E and Auvinen, P and Saari, T and Rusanen, M and Leinonen, V and Scheperjans, F and Kärkkäinen, V},
title = {Gut Microbiome Differences Between Early Alzheimer Disease and Idiopathic Normal Pressure Hydrocephalus.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000726},
pmid = {42206504},
issn = {1546-4156},
abstract = {BACKGROUND: Alzheimer disease (AD) and idiopathic normal pressure hydrocephalus (iNPH) are neurodegenerative diseases causing memory decline. Previous studies have demonstrated an altered gut microbiome (GM) in both conditions. In this study, we compared the GM composition between the groups to find out how if the GM composition differed between the cognitively healthy individuals (CO) and AD groups, as well as between the AD and iNPH groups.

METHODS: Thirty-seven CO participants, 21 mild AD patients and 10 participants with shunted iNPH gave fecal samples, which were subjected to 16S amplicon sequencing. Then, genus-level differences were analyzed. Information about comorbidities and diet was collected, and cognitive function was evaluated.

RESULTS: Compared with the CO group, Anaerovorax and an unknown genus of the Comamonadaceae family increased, whereas Enterobacter, Absicoccus, Buttiauxella, Raoultella, and Lacticaseibacillus decreased in the AD group. Compared with the iNPH group, Paramuribaculum, an unknown genus of the Desulfovibrionaceae family, Ruficoccus and Mitsuokella increased, whereas Anaeromassilibacillus and Desulfovibrio decreased in the AD group.

CONCLUSIONS: We demonstrated differences in the GM composition between the AD and CO groups, as well as between the AD and iNPH groups. To our knowledge, this is the first report to compare the 2 neurodegenerative diseases and demonstrate GM differences.},
}

@article {pmid42206603,
year = {2026},
author = {Hayes, AMR and Bashaw, AG and Klug, ME and Kanoski, SE},
title = {Neural mechanisms linking Western diet consumption and cognitive impairment: a role for the vagus nerve.},
journal = {Clinical science (London, England : 1979)},
volume = {140},
number = {6},
pages = {1119-1135},
doi = {10.1042/CS20250034},
pmid = {42206603},
issn = {1470-8736},
support = {DK123423//HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)/ ; DK14526//HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)/ ; DK138777//HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)/ ; AG077932//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *Vagus Nerve/physiopathology/metabolism ; *Diet, Western/adverse effects ; Animals ; *Cognitive Dysfunction/physiopathology/etiology/psychology/metabolism ; *Cognition ; *Brain/physiopathology/metabolism ; Signal Transduction ; Neurotransmitter Agents/metabolism ; },
abstract = {Consumption of a Western diet containing large proportions of calories from highly palatable foods that are high in fat and sugar is causally linked with obesity and metabolic dysfunction. In addition to these widely known deficits, Western diet consumption also negatively impacts various cognitive domains, including learning and memory function (e.g. Alzheimer's and related dementias), affective processes (e.g. anxiety, depression), and reward-related behaviors. However, the underlying neurobiological mechanisms that link Western diets to impaired cognition are poorly understood. In this review, we highlight recent findings revealing the impacts of Western diet consumption on the molecular machinery and signaling of key central neuromodulators (acetylcholine, dopamine, serotonin) that contribute to the dysregulation of fundamental cognitive and behavioral processes. Based on emerging evidence, we propose that Western diet-associated perturbations in central neuromodulator signaling and associated neurocognitive impairments are driven, at least in part, by blunted gut-to-brain communication through the vagus nerve. While future research is necessary to fully elucidate this hypothesized connection, it provides a framework to advance our understanding of the mechanisms mediating diet-cognition interactions.},
}

Humans
*Vagus Nerve/physiopathology/metabolism
*Diet, Western/adverse effects
Animals
*Cognitive Dysfunction/physiopathology/etiology/psychology/metabolism
*Cognition
*Brain/physiopathology/metabolism
Signal Transduction
Neurotransmitter Agents/metabolism

@article {pmid42206989,
year = {2026},
author = {Lee, S and Kim, S},
title = {Interval From Cancer Diagnosis to Depression Onset and Risk of Dementia in Cancer Survivors.},
journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {},
number = {},
pages = {},
doi = {10.1158/1055-9965.EPI-26-0336},
pmid = {42206989},
issn = {1538-7755},
abstract = {BACKGROUND: To examine how the timing of depression after cancer diagnosis relates to the risk of all-cause dementia (ACD) and Alzheimer disease (AD), and to compare time-fixed and time-varying modeling approaches.

METHODS: We conducted a nationwide cohort study using Korean National Health Insurance Service data on 385,092 individuals aged ≥55 years diagnosed with cancer between 2009 and 2013, with no dementia or depression, followed through 2023. Depression was identified using ICD-10 codes F32-F33 and categorized by interval from cancer diagnosis. Depression was modeled as a baseline time-fixed or a time-varying exposure. The primary outcome was ACD and the secondary outcome was AD. Cox proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs), adjusting for demographic, lifestyle, and cardiometabolic factors.

RESULTS: Over a median follow-up of 11.7 years, 71,600 participants (18.6%) developed ACD. Time-fixed models suggested increased dementia risk for depression diagnosed within 5 years after cancer, but an apparent inverse association for depression diagnosed >5 years after cancer (aHR, 0.90; 95% CI, 0.87-0.93). In contrast, time-varying models showed consistently elevated risks across all depression-onset intervals, including >5 years after cancer (aHR, 2.09; 95% CI, 2.02-2.17). Results were similar for AD.

CONCLUSIONS: Depression at any time after cancer diagnosis is associated with increased dementia risk when modeled. Time-fixed analyses may introduce immortal time bias and mischaracterize risk, underscoring the importance of time-varying approaches in survivorship research.

IMPACT: Modeling post-cancer depression as a time-varying exposure clarifies dementia risk estimates and informs survivorship mental health strategies.},
}

@article {pmid42207225,
year = {2026},
author = {Ed-Day, S and Kacimi, FE and El Gui, R and Didou, L and Ibouzine-Dine, L and El Kourchi, C and Boulbaroud, S and Haddan, A and Harhar, H and Azzaoui, FZ},
title = {Erythrina caffra extract restores memory, modulates cholinergic dysfunction, neuroinflammation, and attenuates oxidative stress in cadmium-induced alzheimer's disease-like pathology in rats.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42207225},
issn = {1573-4978},
mesh = {Animals ; Oxidative Stress/drug effects ; *Plant Extracts/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Rats ; Rats, Wistar ; Cadmium/toxicity ; Male ; *Erythrina/chemistry/metabolism ; *Memory/drug effects ; Antioxidants/pharmacology ; Hippocampus/drug effects/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Acetylcholine/metabolism ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: Cadmium (Cd) is a well-established neurotoxic heavy metal. Several epidemiological studies have highlighted its involvement in the pathogenesis of Alzheimer's disease (AD). AD is a multifactorial disorder influenced by environmental factors such as heavy metals. Erythrina caffra (E. caffra) is a medicinal plant rich in bioactive compounds with anti-inflammatory, antioxidant, and anticholinesterase properties. However, its protective potential against Cd-induced neurodegeneration remains insufficiently explored. This study investigated the effects of Cd on memory, cholinergic function, oxidative stress, and neuroinflammation, as key AD-related pathophysiological features, and evaluated the therapeutic potential of E. caffra seeds ethanolic extract.

METHODS AND RESULTS: AD-like alterations were induced in Wistar rats by intracerebroventricular (ICV) administration of cadmium chloride (CdCl2). Animals were treated with E. caffra ethanolic extract (2.5 mg/kg) or memantine (20 mg/kg) by oral gavage. Behavioral, neurobiochemical, and histological analyses were performed to assess memory, cholinergic function, oxidative stress, neuroinflammation, and neuronal integrity. Cd exposure significantly impaired memory and disrupted cholinergic function, as evidenced by reduced acetylcholine (ACh) levels in the hippocampus. Moreover, it induced oxidative stress, marked by decreased catalase (CAT), superoxide dismutase (SOD), and non-protein thiols (NPSH), alongside increased proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and hippocampal neuronal loss. Treatment with E. caffra and memantine significantly ameliorated these alterations.

CONCLUSIONS: E. caffra extract demonstrates neuroprotective effects against Cd-induced AD-like pathology by modulating oxidative stress, neuroinflammation, and cholinergic dysfunction. These findings suggest its potential as a promising therapeutic candidate for mitigating neurodegenerative processes associated with AD.},
}

Animals
Oxidative Stress/drug effects
*Plant Extracts/pharmacology
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Rats
Rats, Wistar
Cadmium/toxicity
Male
*Erythrina/chemistry/metabolism
*Memory/drug effects
Antioxidants/pharmacology
Hippocampus/drug effects/metabolism
Neuroinflammatory Diseases/drug therapy/metabolism
Disease Models, Animal
Acetylcholine/metabolism
Neuroprotective Agents/pharmacology

@article {pmid42207546,
year = {2026},
author = {Zanin, J and McNeil, JJ and Rance, G},
title = {Speech-in-Noise Ability and Longitudinal Cortical Thinning in Speech-Processing Networks.},
journal = {JAMA otolaryngology-- head & neck surgery},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoto.2026.1050},
pmid = {42207546},
issn = {2168-619X},
abstract = {IMPORTANCE: Age-related hearing loss is a major modifiable risk factor for dementia, yet the neural mechanisms linking auditory dysfunction to brain aging and cognitive decline remain unclear. In particular, it is unknown whether peripheral hearing loss, central auditory processing deficits, or hearing aid use best predict neurodegenerative change in older adults.

OBJECTIVE: To determine whether hearing thresholds, speech-in-noise ability, and hearing aid use are associated with longitudinal cortical atrophy and cognitive trajectories in cognitively normal older adults.

This population-based, longitudinal cohort study with baseline and 3-year follow-up assessments was conducted among community-dwelling older adults in Australia. Participants were selected from the Aspirin in Reducing Events in the Elderly trial and categorized as having normal hearing, unaided hearing loss, or using hearing aids based on audiometry and self-reported hearing aid use. Structural magnetic resonance imaging, auditory, and cognitive data were collected between 2012 and 2017. Data were analyzed from August to October 2025.

EXPOSURES: Peripheral hearing loss assessed using better-ear 4-frequency average thresholds, central auditory processing assessed using binaural speech-in-noise performance, and hearing aid use and duration of use.

MAIN OUTCOMES AND MEASURES: Longitudinal change in cortical thickness and regional brain volumes derived from T1-weighted magnetic resonance imaging, focusing on auditory and Alzheimer disease-vulnerable regions. Global cognition was assessed using the Modified Mini-Mental State Examination.

RESULTS: A total of 312 adults (mean [SD] age, 73.5 [3.3] years; 167 [54%] female) without dementia at baseline were included. At baseline, hearing loss groups showed poorer audiometric and speech-in-noise performance but did not differ in global cognition. Over 3 years, widespread age-related cortical atrophy was observed, and poorer baseline speech-in-noise performance was associated with faster cortical thinning in inferior parietal (β = -0.002; 95% CI, -0.003 to 0.001), precuneus (β = -0.001; 95% CI, -0.002 to 0.000), middle temporal cortex (β = -0.001; 95% CI, -0.002 to -0.001), and superior temporal sulcus regions (β = -0.001; 95% CI, -0.002 to 0.000), independent of hearing thresholds and hearing aid use. There was not a statistically significant association between hearing loss/hearing aid use and longitudinal neurostructural change or cognitive decline.

CONCLUSIONS AND RELEVANCE: In this cohort study of cognitively normal older adults, central auditory processing impairment, not peripheral hearing loss or hearing aid use, was associated with accelerated cortical thinning in speech-processing networks. Speech-in-noise performance may represent an early behavioral marker of neural vulnerability preceding measurable cognitive decline.},
}

@article {pmid42207606,
year = {2026},
author = {Papamicaël, C and Gembus, V and Gourand, F and Levacher, V},
title = {Redox Heterocyclic Platforms Engineered for Brain Drug Delivery and Beyond.},
journal = {Chemical record (New York, N.Y.)},
volume = {},
number = {},
pages = {e70162},
doi = {10.1002/tcr.70162},
pmid = {42207606},
issn = {1528-0691},
abstract = {Overcoming the blood-brain barrier remains one of the most formidable challenges in the diagnosis and treatment of central nervous system disorders. In this account, we showcase our contributions to the field of redox-responsive heterocycles, most notably 1,4-dihydroquinolines and 1,4-dihydropyridines, designed as powerful platforms for targeted brain delivery. Our work builds on the chemical delivery system and bioprecursor prodrug strategies pioneered by Bodor et al. We have focused on the development of redox-activated drug carriers and "bio-oxidizable" prodrugs, which enable efficient transport of neurotransmitters, neuropeptides, and radiotracers for advanced brain imaging, as well as cholinesterase and kinase inhibitors for the treatment of Alzheimer's disease. Last but not least, these versatile heterocyclic systems offer unprecedented perspectives in synthetic methodology, driving breakthrough advances in peptide synthesis and atroposelective amide bond construction.},
}

@article {pmid42207731,
year = {2026},
author = {Queiroz, EM and Couto, CM and Ferreira, AR and de Souza, LC and Caramelli, P},
title = {Clinical presentation and diagnostic challenges of frontotemporal dementia in Brazil: A 15-year cohort study.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-23},
doi = {10.1159/000552730},
pmid = {42207731},
issn = {1423-0208},
abstract = {INTRODUCTION: Frontotemporal dementia (FTD) comprises heterogeneous neurodegenerative syndromes with limited data from low- and middle-income countries, where diagnostic delay and misdiagnosis are common.

METHODS: A retrospective cohort study was conducted of 190 patients with FTD meeting criteria for behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), or FTD-amyotrophic lateral sclerosis (FTD-ALS) who were evaluated at a publicly-funded Brazilian tertiary referral center (2009-2024). Clinical features, diagnostic trajectories, neuroimaging, genetic testing, and survival outcomes were analyzed. Standardized mortality ratios (SMRs) were calculated using IBGE 2017 life tables as a reference.

RESULTS: The cohort comprised 95 bvFTD (50.0%; 73 probable and 22 possible), 79 PPA (41.6%), and 16 FTD-ALS (8.4%) patients. Accurate initial diagnosis was achieved in only 15.8% of bvFTD patients and 17.7% of PPA patients, with Alzheimer's disease being the most common misdiagnosis (36.8% and 34.2%, respectively). Survival differed significantly between subtypes (p < 0.001), with FTD-ALS having the shortest median survival (79.0 months) compared with PPA (119.0 months) and bvFTD (144.0 months). Compared with PPA, FTD-ALS was associated with increased mortality risk (HR: 4.01; 95% CI: 1.94-8.31; p < .001). FTD patients had approximately twice the expected mortality for age- and sex-matched individuals in the general population (SMR: 1.97; 95% CI: 1.59-2.38), with the highest excess mortality in FTD-ALS patients (SMR: 4.08).

DISCUSSION: This Brazilian hospital-based cohort reveals alarming diagnostic delays despite typical clinical phenotypes and high mortality across all FTD subtypes relative to the general population. These findings highlight the need for improved FTD awareness and specialized training among healthcare providers in Brazil and similar Latin American countries, underscoring the value of hospital-based cohort studies in characterizing FTD in low- and middle-income countries.},
}

@article {pmid42207745,
year = {2026},
author = {Bhat, KMR and Lc, P and Thonse, NK and Potu, BK and Kateel, R},
title = {Neuroprotective Effects of Ginkgo biloba Extract in Neurological Disorders: Integrating Anti-Inflammatory and Antioxidant Mechanisms.},
journal = {Complementary medicine research},
volume = {},
number = {},
pages = {1-40},
doi = {10.1159/000552633},
pmid = {42207745},
issn = {2504-2106},
abstract = {BACKGROUND: Neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke are major causes of global disability and mortality. Neuroinflammation and oxidative stress play central roles in their pathogenesis. Ginkgo biloba extract (GBE), particularly the standardized formulation EGb 761, contains flavonoids and terpenoids that exert antioxidant, anti-inflammatory, and mitochondrial-protective effects. These pleiotropic actions position GBE as a promising candidate for neuroprotection.

SUMMARY: This narrative review synthesizes evidence from preclinical and clinical studies on the neuroprotective actions of GBE. Experimental data demonstrate that GBE attenuates oxidative stress by scavenging reactive oxygen species and enhancing endogenous antioxidant defenses, while simultaneously downregulating pro-inflammatory mediators through NF-κB inhibition and NLRP3 inflammasome suppression. Additional benefits include stabilization of mitochondrial function, modulation of neurotransmission, and prevention of apoptosis. Preclinical models consistently show improvements in cognition, motor function, and neuronal survival across diverse disease contexts. Clinical findings, however, are mixed: some randomized trials report improved cognition and functional outcomes in dementia and Parkinsonism, whereas others show no superiority over placebo. Variability in study design, extract standardization, and treatment regimens contribute to these discrepancies.

KEY MESSAGES: GBE exerts multifaceted neuroprotective effects through combined antioxidant, anti-inflammatory, mitochondrial, and neurotransmitter-modulating actions. Preclinical evidence strongly supports its role in mitigating pathological processes underlying Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic injury. But clinical outcomes remain inconsistent. GBE holds potential as a safe, multi-target adjunctive therapy for complex central nervous system disorders, but translation into consistent clinical practice requires further validation.},
}

@article {pmid42208123,
year = {2026},
author = {Hsu, MH and Hwang, SY and Tsai, YH and Chang, YC and Liang, CK and Chang, CY},
title = {Advancing Alzheimer Disease Prediction With Large Language Model-Based Linguistic Feature Analysis: Development and Validation Study.},
journal = {JMIR medical informatics},
volume = {14},
number = {},
pages = {e86965},
doi = {10.2196/86965},
pmid = {42208123},
issn = {2291-9694},
mesh = {Humans ; Large Language Models ; *Alzheimer Disease/diagnosis ; *Linguistics/methods ; Prediction Algorithms ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is a progressive neurodegenerative disorder with rapidly growing global prevalence. Early detection is critical for timely intervention; yet, conventional diagnostic methods remain costly and invasive. Speech-based assessment has emerged as a noninvasive alternative, as AD characteristically impairs linguistic abilities including fluency, coherence, and informational content. Recent advances in large language models (LLMs) offer new opportunities to extract structured linguistic features from transcribed speech for automated AD classification. However, existing LLM-based approaches often lack transparency and clinical interpretability, limiting their adoption in clinical workflows.

OBJECTIVE: This study aims to investigate the influence of linguistic features extracted from transcribed speech, as analyzed by LLMs, on the accuracy and interpretability of AD prediction.

METHODS: We propose a framework that leverages LLMs to analyze linguistic features extracted from transcribed speech for AD classification. Our approach focuses on 4 key aspects, including readability, fluency, richness of detail, and keyword relevance. To enhance classification accuracy, the framework integrates transcript embeddings with feature explanation embeddings, forming a comprehensive linguistic representation. We conducted extensive ablation studies to evaluate the contributions of individual features and benchmarked our framework against existing LLM-driven methodologies through pairwise explainability evaluations. Output stability was assessed across 3 independent pipeline runs. A fully local configuration (Llama 3 8B + nomic-embed-text) was tested to evaluate privacy-preserving deployment feasibility. Explainability was assessed via LLM-based pairwise comparison (Gemini-3.1-flash-lite) against the method of Bang et al across 54 correctly classified cases and by blinded evaluation from 2 neurologists.

RESULTS: The proposed framework achieved a mean precision of 91.52%, a sensitivity of 91.08%, a specificity of 96.29%, and F1-score of 91.05% across 3 independent runs on the ADReSSo 2021 dataset, outperforming existing LLM-based approaches. A fully-local configuration (Llama 3 8B+nomic-embed-text, requiring no cloud application programming interface access) achieved an F1-score of 81.58%, demonstrating framework transferability to privacy-preserving deployment environments. Keyword relevance was the most influential feature (F1-score drop of 13.22 pp when removed). Explainability evaluations showed our method was preferred in 49 out of 54 cases via Gemini-3.1-flash-lite, with human experts preferring our method in 89 of 108 blinded assessments.

CONCLUSIONS: These findings highlight that a structured linguistic feature analysis using LLMs provides a robust and interpretable framework for preliminary AD detection. Our approach offers a scalable and accessible solution that bridges artificial intelligence-driven text analysis with clinical applications, supporting early detection of cognitive decline through noninvasive assessment methods.},
}

Humans
Large Language Models
*Alzheimer Disease/diagnosis
*Linguistics/methods
Prediction Algorithms

@article {pmid42208178,
year = {2026},
author = {Burstein, ES and Olsson, R and Skold, N and Jansen, KE and Azar, M and Sandiego, C and Ridler, K and Rabiner, EA and Rhodes, G and Dey, PM and Pathak, S},
title = {Nonclinical characterization of ACP-204, a novel selective serotonin receptor subtype 2A receptor inverse agonist.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {6},
pages = {104932},
doi = {10.1016/j.jpet.2026.104932},
pmid = {42208178},
issn = {1521-0103},
abstract = {Pimavanserin was the first US Food and Drug Administration approved antipsychotic drug that does not block D2 dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT2A receptor inverse agonist that reduces the frequency of hallucinations and delusions associated with Parkinson disease. Despite these attributes, pimavanserin prolongs the QT interval at therapeutic doses, limiting the dose to 34 mg. In addition, pimavanserin has a 57-hour half-life, and reaches steady state in approximately 12 days. ACP-204 was identified as a compound with subnanomolar affinity in radioligand binding assays, and subnanomolar inverse agonist and antagonist potency at 5-HT2A receptors in cell-based functional assays. ACP-204 had 13-fold less affinity for 5-HT2C receptors in radioligand binding, and 30- to 100-fold less potency at 5-HT2C in the functional assays, and was over 1000-fold selective against over 70 other targets. ACP-204 had 9-fold lower potency inhibiting human ether-à-go-go-related gene than pimavanserin, and lower potency at Cav1.2 L-type calcium and Nav1.5 sodium channels, all channels associated with cardiovascular function. ACP-204 was active in 3 rodent models of schizophrenia, was orally active, and potently engaged with central 5-HT2A receptors in nonhuman primates. Long-term toxicity studies demonstrated wide safety margins, and pharmacokinetic modeling predicted a 14.7 to 21.7 hours half-life in humans. It is anticipated that reducing the potential for QT prolongation will allow greater dosing flexibility with ACP-204 compared with pimavanserin; additionally, a shorter half-life may provide faster onset of action because of plasma concentrations reaching steady state sooner. ACP-204 is currently being evaluated for efficacy and safety in Alzheimer disease psychosis and Lewy body dementia psychosis. SIGNIFICANCE STATEMENT: Psychotic disorders remain a major source of burden and disability worldwide, with current treatments limited by inadequate efficacy or significant side effects. ACP-204 is a novel 5-HT2A receptor inverse agonist/antagonist being evaluated clinically for its potential to treat Alzheimer disease psychosis and Lewy body dementia psychosis. Comprehensive nonclinical evaluations shown herein demonstrate that ACP-204 has optimized pharmacodynamic properties resulting in a favorable safety/tolerability profile, a broad therapeutic index, and promising effectiveness.},
}

@article {pmid42208269,
year = {2026},
author = {Saxena, S and Kaur, J and Singh, TG and Kumar, M and Awasthi, A},
title = {Beyond the brain barrier: Hybrid nanoparticles orchestrating intelligent neuro-theranostics.},
journal = {Advances in colloid and interface science},
volume = {356},
number = {},
pages = {103954},
doi = {10.1016/j.cis.2026.103954},
pmid = {42208269},
issn = {1873-3727},
abstract = {Hybrid nanoparticles (HNPs) that integrate organic and inorganic components have been recognized as one of the most sophisticated solutions in the field of nanomedicine to surpass the physiological limitations of the blood-brain barrier (BBB). By the combination of biocompatibility, flexibility, and the capacity of functionalization of the organic shells with the magnetic, optical, or structural precision of the inorganic cores, HNPs provide receptor-mediated transport, controlled drug release, and multimodal imaging with high efficiency. This review details the molecular mechanisms of HNPs crossing the BBB, such as receptor-mediated, adsorptive, carrier-mediated, and biomimetic transcytosis, and also points to the role of the advanced conjugation chemistries like EDC/NHS coupling, thiol‑gold anchoring, click reactions, and redox-cleavable linkers in enhancing targeting fidelity. The therapeutic improvements in the major neurological diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease, and glioblastoma, are discussed with the help of figures, which illustrate enhanced bioavailability, gene silencing, mitochondrial targeting, and integrated photothermal or magnetic responsiveness. Moreover, the review discusses potential diagnostic applications such as multimodal MRI/PET/NIR-II imaging, molecular biosensing, and theranostic nanoplatforms, which link the real time visualization with the targeted treatment. To conclude, we point out the upcoming directions comprising biomimetic coatings, AI guided nanoparticle design, stimuli responsive logic-gated systems, and clinically scalable biodegradable hybrids. In sum, HNPs embody a radically different strategy to precision neuro-nanomedicine, thereby providing a seamless avenue for diagnosis, targeted therapy, and continuous disease monitoring within a single intelligent nanosystem.},
}

@article {pmid42208339,
year = {2026},
author = {Coulter, K and Dash, T and Best, T and Grant, N and Ansaldo, AI and Phillips, NA and , },
title = {Multilingualism and cognitive reserve in older adults with, or at risk for, Alzheimer's disease: Evidence from resting-state functional connectivity.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {50-57},
doi = {10.1016/j.neurobiolaging.2026.05.009},
pmid = {42208339},
issn = {1558-1497},
abstract = {Speaking more than one language is hypothesized to lead to greater brain resilience in aging and Alzheimer's disease, resulting in a delay in the symptom onset of Alzheimer's disease. While previous research has used structural neuroimaging measures to explore the neural underpinnings of this protective effect, few studies have used functional brain measures. Thus, we used functional connectivity measures of resting-state fMRI data to explore the association between multilingualism and brain resilience in older adults with, or at risk for, Alzheimer's disease. Participants were selected from The Comprehensive Assessment of Neurodegeneration and Dementia Study and The Consortium for the Early Identification of Alzheimer's disease - Quebec, and included older adults who were cognitive unimpaired, those with subjective cognitive decline, mild cognitive impairment, or mild Alzheimer's disease. Half of the participants in each diagnosis group were monolingual (i.e., reported knowledge of only one language) and half were multilingual (i.e., reported knowledge of 2 or more languages). Within diagnosis groups, monolinguals and multilinguals were strictly matched on age, sex, years of education, cognitive impairment, and memory function. We examined average within-network functional connectivity of the default mode network using the CONN Toolbox. We observed reduced connectivity within the default mode network for multilinguals compared to monolinguals with Alzheimer's disease. Our finding suggests greater Alzheimer's disease neuropathology for multilingual compared to monolingual participants, despite being matched on measures of cognitive impairment and memory function. Therefore, multilingual participants show evidence of greater brain resilience by way of greater cognitive reserve compared to their monolingual peers.},
}

@article {pmid42208351,
year = {2026},
author = {Martino, ED and Maduro, S and Luchicchi, A and Wilhelmus, MMM and Orefice, NS},
title = {Distinctive characteristics of dopamine neuron release mechanisms: Insights into Parkinson's Disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119534},
doi = {10.1016/j.biopha.2026.119534},
pmid = {42208351},
issn = {1950-6007},
abstract = {Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, after Alzheimer's disease, and is characterized not only by progressive motor dysfunction but also by a wide array of non-motor symptoms that frequently emerge during the prodromal phase. These early manifestations, including cognitive and neuropsychiatric impairments, autonomic dysfunction, and sleep disturbances, contribute substantially to disease burden and often precede the onset of motor impairments by years. Although degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and α-synuclein (α-syn) pathology define the classical neuropathology of PD, the molecular basis of selective neuronal vulnerability remains incompletely understood. Growing evidence suggests that calcium (Ca[2 +]) dysregulation, mitochondrial dysfunction, oxidative stress, and impaired axonal transport converge to produce early synaptic and axonal failure. Importantly, disruptions in dopamine (DA) release, reuptake, and synaptic vesicle (SV) cycling arise well before overt nigrostriatal degeneration and long before clinically detectable DA depletion. These early presynaptic alterations are increasingly recognized as key drivers of motivational, affective, and reward-processing deficits that typify prodromal PD. In this review, we synthesize evidence supporting the hypothesis that axonal and synaptic dysfunction precedes dopaminergic cell body loss and represents a primary site of disease initiation. We focus on the molecular machinery governing presynaptic DA transmission and examine how its disruption contributes to early circuit dysfunction and progressive neurodegeneration. By looking at these early pathophysiological events, we aim to advance the understanding of PD initiation and identify potential avenues for early diagnosis and disease-modifying interventions.},
}

@article {pmid42208357,
year = {2026},
author = {Huang, B and Tang, G},
title = {Aquaporin‑4 polarization and glymphatic function in Alzheimer's disease: Mechanisms, modulators, and therapeutic strategies.},
journal = {Pathology, research and practice},
volume = {286},
number = {},
pages = {156564},
doi = {10.1016/j.prp.2026.156564},
pmid = {42208357},
issn = {1618-0631},
abstract = {Although Alzheimer's disease (AD) is traditionally viewed as a disorder of cerebral amyloid‑β (Aβ) accumulation, emerging evidence has shifted attention toward impaired clearance mechanisms as a primary driver of sporadic disease. Central to this paradigm shift is the glymphatic system and its obligate facilitator, aquaporin‑4 (AQP4), whose polarized localization at astrocytic endfeet is essential for efficient interstitial solute clearance. Loss of AQP4 polarization, termed depolarization, is consistently observed in AD mouse models as a driver of glymphatic failure and in human postmortem tissue as a correlate of protein aggregation. This review synthesizes current understanding of the molecular and cellular mechanisms that govern AQP4 polarization. We discuss the dystrophin‑associated protein complex as the primary anchoring machinery, the role of orthogonal array particle assembly and isoform switching, and the impact of post‑translational modifications. We also examine how diverse factors, including proteases, kinase signaling pathways, circadian modulators, pathological proteins, astrocyte phenotypes, and lifestyle interventions, converge to regulate AQP4 polarity. Finally, we evaluate emerging therapeutic strategies that target this axis, including pharmacological AQP4 facilitators, upstream polarity regulators such as PERK inhibitors, and non‑invasive approaches like 40 Hz gamma stimulation and exercise. By repositioning AQP4 polarization as a modifiable homeostatic checkpoint, we propose that restoring perivascular AQP4 localization represents a biologically sound strategy to enhance endogenous brain clearance and modify AD progression.},
}

@article {pmid42208551,
year = {2026},
author = {Rosenberg, A and Ngandu, T},
title = {Plasma biomarkers for Alzheimer's disease among middle-aged individuals.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2146-2147},
doi = {10.1016/S0140-6736(26)00692-6},
pmid = {42208551},
issn = {1474-547X},
}

@article {pmid42208552,
year = {2026},
author = {Therriault, J},
title = {Advancing tau-PET imaging in Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2148-2149},
doi = {10.1016/S0140-6736(26)00809-3},
pmid = {42208552},
issn = {1474-547X},
}

@article {pmid42208554,
year = {2026},
author = {Suárez-Calvet, M and Salvadó, G and de Fortuny, BB and Del Campo, M},
title = {Blood biomarkers for Alzheimer's disease: from detection to decisions.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2151-2154},
doi = {10.1016/S0140-6736(26)00909-8},
pmid = {42208554},
issn = {1474-547X},
}

@article {pmid42208558,
year = {2026},
author = {McLellan, F},
title = {Reisa Sperling: getting ahead of Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2164},
doi = {10.1016/S0140-6736(26)01033-0},
pmid = {42208558},
issn = {1474-547X},
}

@article {pmid42208562,
year = {2026},
author = {Jiang, X and Hoang, TD and Shaw, LM and Jacobs, DR and Nasrallah, IM and Bryan, RN and Yaffe, K},
title = {Alzheimer's disease neuropathology plasma biomarkers and cognition in midlife: a community-based cohort study.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2208-2216},
doi = {10.1016/S0140-6736(26)00515-5},
pmid = {42208562},
issn = {1474-547X},
mesh = {Humans ; *Alzheimer Disease/blood/pathology ; Biomarkers/blood ; Male ; Female ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; Middle Aged ; Cohort Studies ; *Cognition ; Peptide Fragments/blood ; },
abstract = {BACKGROUND: Alzheimer's disease neuropathology, characterised by amyloid β (Aβ) and phosphorylated-tau (p-tau) protein accumulation, has primarily been assessed with biomarkers in clinical samples of older adults. Less is known about plasma biomarkers of Alzheimer's disease neuropathology and their associations with cognitive outcomes in midlife in diverse community-based samples. Our goal was to address these gaps.

METHODS: In this cohort study, we analysed participants who were retained in the US Coronary Artery Risk Development in Young Adults (CARDIA) Study with available plasma biomarkers at year 35 (2020-22). We excluded participants without cognitive measures and individuals with probable dementia. Cognition in five domains was measured with standardised tests at years 30 and 35; accelerated cognitive decline in each domain was defined as a 5-year decline at least 1·5 SD greater than the cohort mean change. Plasma Aβ42, Aβ40, and p-tau217 concentrations were assayed with the use of the Fujirebio Lumipulse G1200 analyser and used to calculate the p-tau217-to-Aβ42 ratio (p-tau217/Aβ42) and Aβ42-to-Aβ40 ratio (Aβ42/40). Alzheimer's disease neuropathology status (ie, negative, intermediate, or positive) was defined based on amyloid PET-validated cutpoints for each biomarker (p-tau217/Aβ42, p-tau217, and Aβ42/40). Associations of Alzheimer's disease neuropathology with cognition (Z scores) and accelerated decline were evaluated with the use of multivariable linear and logistic regression.

FINDINGS: From the 2248 CARDIA participants who completed the year 35 visit, we randomly selected 1500 participants for plasma biomarker measurement. We excluded three participants with poor biomarker assay quality, 143 without cognitive measures, and four with probable dementia resulting in a final cohort of 1350. The mean participant age was 61 years (SD 3·6, range 53·0-69·0); 779 (58%) participants were women, 571 (42%) were men, 613 (45%) were Black, and 737 (55%) were White. Alzheimer's disease neuropathology positivity was present in 86 (6%) participants based on p-tau217/Aβ42, 196 (15%) based on Aβ42/40, and 48 (4%) based on p-tau217, and was associated with worse performance on processing speed (standardised cognitive difference comparing Alzheimer's disease neuropathology positive to negative for Aβ42/40, p-tau217, and p-tau217/Aβ42 -0·54 to -0·25; p values 0·0001 to 0·0048) and executive function (-0·42 to -0·19; p values 0·0070 to 0·049). Alzheimer's disease neuropathology positivity was also associated with increased odds of accelerated decline on verbal memory (Aβ42/40: odds ratio 4·31, 95% CI 1·71-10·9, p-tau217/Aβ42: 2·44, 1·16-5·13) and processing speed (p-tau217: 3·98, 1·71-9·3; p-tau217/Aβ42: 3·35, 1·77-6·35) compared with Alzheimer's disease neuropathology negativity. There was no association for global cognition or fluency. Although not consistent, some effect modification was observed, with stronger associations among women and Black participants and individuals with APOE ∈4.

INTERPRETATION: Alzheimer's disease neuropathology is relatively uncommon in midlife but associated with worse cognitive performance and accelerated decline and might have stronger association among some groups. Early Alzheimer's disease neuropathology detection with the use of plasma biomarkers might enable timely prevention and intervention in midlife adults including risk reduction and pharmacological therapies.

FUNDING: National Heart, Lung, and Blood Institute (75N92023D00002, 75N92023D00003, 75N92023D00004, 75N92023D00005, and 75N92023D00006), National Institute on Aging (R01AG063887, R01AG091431, R35AG071916, and K99AG083211), and the Alzheimer's Association (AARFD-23-1150636).},
}

Humans
*Alzheimer Disease/blood/pathology
Biomarkers/blood
Male
Female
*Amyloid beta-Peptides/blood
*tau Proteins/blood
Middle Aged
Cohort Studies
*Cognition
Peptide Fragments/blood

@article {pmid42208563,
year = {2026},
author = {Povala, G and Bellaver, B and Lussier, FZ and Amaral, L and Bauer-Negrini, G and Ferreira, PCL and Rocha, A and Ruppert, E and Medeiros, MS and Tissot, C and Jagust, WJ and Masdeu, JC and Fortea, J and Tudorascu, DL and Soleimani-Meigooni, DN and Lowe, V and Oh, H and Pascual, B and Gordon, BA and Rosa-Neto, P and Baker, S and Pascoal, TA and , },
title = {Comparison of [18F]flortaucipir and [18F]MK6240 for the detection of tau pathology in Alzheimer's disease (HEAD): a multicentre, prospective, cross-sectional, within-participant study.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2217-2226},
doi = {10.1016/S0140-6736(26)00417-4},
pmid = {42208563},
issn = {1474-547X},
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; *Carbolines ; Cross-Sectional Studies ; Fluorine Radioisotopes ; *Positron-Emission Tomography/methods ; Prospective Studies ; *Pyridines ; Radiopharmaceuticals ; *tau Proteins/metabolism ; Isoquinolines ; },
abstract = {BACKGROUND: Tau PET imaging has emerged as a critical biomarker for Alzheimer's disease, informing diagnosis, staging, and therapeutic selection. We investigated whether PET tracer selection alters tau detection.

METHODS: We conducted a prospective, multicentre, non-randomised, within-participant comparison of [[18]F]flortaucipir (Tauvid), currently used in clinical settings in the USA and Europe, and [[18]F]MK6240, an investigational tau PET tracer. Participants were recruited from eight north American sites and underwent tau PET, amyloid-β (Aβ) PET, and detailed cognitive assessments. Tau PET with both agents was acquired within a 45-day window. Coprimary outcomes were the discriminative accuracy for Alzheimer's disease-related cognitive impairment and the frequency of tau positivity in early medial temporal lobe (MTL) and late neocortical regions. The study is registered with ClinicalTrials.gov, NCT05361382.

FINDINGS: Between March 2, 2022, and Aug 27, 2025, 775 individuals were enrolled, with 682 completing all procedures (373 [55%] female, 309 [45%] male; 38 [6%] aged 19-27 years, 214 [31%] aged 50-65 years, and 430 [63%] aged 65-89 years). 32 (5%) participants identified as Hispanic or Latino. 637 (93%) identified as White, 24 (4%) as Black or African American, 16 (2%) as Asian, and five (1%) as other. In addition, 49 (7%) individuals were identified as being from a rural area. [[18]F]MK6240 showed greater accuracy than [[18]F]flortaucipir in distinguishing Alzheimer's disease from non-Alzheimer's disease impairment (area under the curve 0·93, 95% CI 0·89-0·95 vs 0·86, 0·75-0·91; p<0·0001). Among the older adults, tau positivity status was concordant in 560 (87%) for MTL and 603 (94%) for neocortical regions. In cognitively unimpaired participants, [[18]F]MK6240 identified twice as many MTL-positive cases as [[18]F]flortaucipir (n=54 [15%] vs n=23 [6%]). Prevalence ratio in Aβ-positive was 2·43 (95% CI 1·50-3·94; p=0·0003), identifying 23 additional cases per 100. Among discordant cases, 75 (89%) were [[18]F]MK6240-positive only and had higher Aβ burden (p<0·0001), APOEε4 frequency (p<0·0001), and cognitive impairment (p=0·0043) than those negative on both tracers. Neocortical tau positivity was more frequent with [[18]F]MK6240 than with [[18]F]flortaucipir in cognitively impaired individuals (80 [28%] vs 46 [16%]). Prevalence ratio in Aβ-positive was 1·74 (95% CI 1·32-2·29; p<0·0001), identifying 15 additional mild cognitive impairment and 21 dementia cases per 100.

INTERPRETATION: Tau PET tracer selection influences the frequency of detection of tau pathology across the ageing and Alzheimer's disease spectrum. Compared with [[18]F]flortaucipir, [[18]F]MK6240 identified more individuals with tau pathology in cognitively unimpaired and cognitively impaired individuals, with direct implications for patient stratification in clinical trials and more precise guidance for therapeutic decision-making.

FUNDING: National Institute on Aging.},
}

Aged
Aged, 80 and over
Female
Humans
Male
Middle Aged
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Amyloid beta-Peptides/metabolism
*Carbolines
Cross-Sectional Studies
Fluorine Radioisotopes
*Positron-Emission Tomography/methods
Prospective Studies
*Pyridines
Radiopharmaceuticals
*tau Proteins/metabolism
Isoquinolines

@article {pmid42208565,
year = {2026},
author = {Serrano-Pozo, A and Escott-Price, V and Grinberg, LT and Pascoal, T and Suárez-Calvet, M and Dubois, B and Sperling, RA},
title = {Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2241-2262},
doi = {10.1016/S0140-6736(26)00198-4},
pmid = {42208565},
issn = {1474-547X},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology/prevention & control ; Biomarkers ; },
abstract = {Alzheimer's disease is the leading cause of dementia and among the top ten leading causes of death in high-income countries. Exponential advances in epidemiology, genetics, diagnostic imaging and fluid biomarkers, treatment, and prevention in the last decade reinforce the notion that we are entering a new era in the clinical management of Alzheimer's disease. However, far from triumphalism, this momentum should be accelerated to achieve the goals of preventing Alzheimer's disease and arresting its progression. In this Seminar, we summarise this progress and highlight unmet needs and areas of research priority.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology/prevention & control
Biomarkers

@article {pmid42208720,
year = {2026},
author = {Kulkarni, R and Kumari, S and Sharma, P and Dhapola, R and Medhi, B and HariKrishnaReddy, D},
title = {Evaluation of the neuroprotective effects of ergosterol in a streptozotocin-induced Alzheimer's disease rat model: Insights into anti-inflammatory and antioxidant mechanisms.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115853},
doi = {10.1016/j.expneurol.2026.115853},
pmid = {42208720},
issn = {1090-2430},
abstract = {Oxidative stress and neuroinflammatory processes constitute pivotal pathogenic mechanisms in the progression of Alzheimer's disease (AD), an age-associated neurodegenerative disorder, as well as in other neurodegenerative conditions. This study is the first to integrate in-silico TLR4-targeted molecular docking of ergosterol with comprehensive in-vivo validation, thereby providing mechanistic insight into its potential role as a neuroprotective agent. The present experimental work aimed to explore the effects of ergosterol (25, 50, and 100 mg/kg body weight) and its combination with the standard drug donepezil, as an antioxidant and anti-inflammatory agent, in a streptozotocin (STZ) induced AD rat model. In silico docking studies were first performed, in which ergosterol and donepezil were docked to the TLR4 receptor (PDB ID: 2Z62). The docking scores of ergosterol and donepezil were - 3.318 and - 3.934, respectively, with MMGBSA ΔG bind scores of -36.9 and - 39.19, ergosterol demonstrated neuroprotective potential with supportive computational evidence suggesting possible TLR4 interaction. RMSD values for both ergosterol-TLR4 and donepezil-TLR4 complexes indicated stable binding interactions. In the in-vivo STZ model, ergosterol administration significantly improved memory and learning impairments, as assessed by the Morris water maze, Novel Object Recognition Test, and Elevated Plus Maze Test. It also reversed changes in glutathione and malondialdehyde levels and showed protective effects in the hippocampus. Moreover, ergosterol ameliorated neuroinflammation by reducing glial cell activation. These findings provide experimental evidence that ergosterol prevents memory loss, learning impairments, oxidative stress, and neuroinflammation in ICV-STZ rats. In conclusion, ergosterol, either alone or in combination with donepezil, may constitute a promising therapeutic strategy against AD through its dual action on oxidative stress and neuroinflammation.},
}

@article {pmid42209252,
year = {2026},
author = {Jung, D and Seo, H and Yoo, L},
title = {Artificial intelligence in nursing practice for older adults with dementia: A narrative review informed by bibliometric mapping and implications for nurse-led research.},
journal = {Journal of Korean gerontological nursing},
volume = {28},
number = {2},
pages = {125-133},
doi = {10.17079/jkgn.2026.00143},
pmid = {42209252},
issn = {2383-8086},
abstract = {PURPOSE: This narrative review aimed to (1) map the global research landscape of artificial intelligence (AI) in dementia care, (2) characterize domestic Korean research, and (3) propose priority directions for nurse-led AI research.

METHODS: International literature was retrieved from PubMed (January 2015 to December 2025; n=5,710) and analyzed using VOSviewer with the Leiden algorithm. Korean literature from RISS (n=265) was synthesized narratively.

RESULTS: Publications increased substantially since 2015, with acceleration after 2024 driven by large language models. Five thematic clusters emerged: (1) care, daily living, and digital health; (2) aging and brain structure; (3) risk prediction and clinical data; (4) early screening and behavioral biomarkers; and (5) Alzheimer's diagnosis and deep learning. Four domains were most relevant to nursing: monitoring technologies, digital biomarkers, AI chatbots for caregivers, and clinical decision support systems. Korean research concentrated on emotional support robots with methodological limitations.

CONCLUSION: Rigorous nurse-led trials with multidimensional outcomes are needed to establish AI's clinical value in dementia nursing.},
}

@article {pmid42209655,
year = {2026},
author = {Xu, Y and Wang, H and Wang, Z and Zhang, J and Stancanelli, E and Xu, Q and Hou, Y and Wang, C and Zhang, P and Gearing, M and Liu, J},
title = {Quantitative LC-MS/MS profiling reveals aberrant chondroitin sulfate in Alzheimer's disease.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10358-x},
pmid = {42209655},
issn = {2399-3642},
support = {AG087305//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; GM142304//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; AG069039, GM144019, GM148100, MH130476, AG078123, AG088409, and AG066511//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; },
abstract = {Chondroitin sulfate (CS) is an essential sulfated glycan in the brain, but standard LC-MS/MS disaccharide analysis provides only limited quantitative accuracy for detecting CS structural changes under physiological and pathophysiological conditions. Here, we incorporated eight distinct [13]C-labeled CS disaccharide calibrants into the analytical workflow. Using this enhanced approach, we identified structural alterations in both sulfation patterns and total CS abundance in pre-clinical and clinical Alzheimer's disease (AD) brain samples compared with controls. Analysis of cerebrospinal fluid (CSF) from AD patients further revealed elevated levels of the CS-E disaccharide and reduced levels of hyaluronic acid. Functionally, we found that synthetic CS-E 19-mer-but not other synthetic CS 19-mer subtypes-impaired neuronal growth, underscoring the need to pinpoint specific CS structures that contribute to neurodegeneration. Because CS abnormalities are detectable in the pre-clinical AD brain, our findings raise the possibility that CS glycans could serve as early biomarkers for AD.},
}

@article {pmid42209703,
year = {2026},
author = {Yu, J and Xu, M and Wu, XR and Kang, WB and Zou, WY and Liu, Q and Zhang, DF and Yao, YG},
title = {Convergent mitochondrial impairment and apoptosis driven by simultaneous down-regulation of multiple genes at 11p11.2 in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42209703},
issn = {1476-5578},
support = {32230021//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32300826//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024M763353//China Postdoctoral Science Foundation/ ; },
abstract = {Genome-wide association studies (GWAS) and multi-omics analyses have identified numerous risk loci and thousands of potential causal genes associated with Alzheimer's disease (AD). However, the synergistic pathogenic contributions of multiple low-risk causal genes within a single locus remain poorly understood. Polygenic synergism at the 11p11.2 locus was systematically examined in AD pathogenesis. Three causal genes (MTCH2, NDUFS3, and PSMC3) exhibited coordinated down-regulation in both AD patients and AD mouse models. Individual knockdown in cultured cells altered mitochondrial function and disrupted AD-associated pathways, as revealed by transcriptomic profiling. Integrated RNA-seq analysis and experimental validation demonstrated that the concurrent down-regulation of all three genes synergistically enhanced mitochondrial reactive oxygen species (ROS) generation and activated the caspase-7-mediated apoptotic pathway. Notably, pharmacological caspase inhibition with Q-VD-OPh attenuated neuronal apoptosis, ameliorated memory deficits, and reduced Aβ plaque deposition in APP/PS1 mice. Simultaneous down-regulation of multiple genes at the 11p11.2 locus contributed to mitochondrial dysfunction and apoptosis in AD, highlighting polygenic synergism as a key pathogenic mechanism.},
}

@article {pmid42209819,
year = {2026},
author = {Ishii, K and Yamada, T and Hanaoka, K and Kojita, Y and Kono, A and Kaida, H and Nihashi, T and Sakurai, K and Kato, T and Nakamura, A},
title = {Stage-specific regional distribution of amyloid and tau deposition across the Alzheimer's disease continuum revealed by tau-to-amyloid ratio imaging.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42209819},
issn = {1619-7089},
abstract = {BACKGROUND: Amyloid-β and tau deposition follow distinct spatial and temporal trajectories across the Alzheimer's disease (AD) continuum. Amyloid accumulation occurs early in the disease course, whereas tau pathology is more closely associated with neurodegeneration and clinical progression. Characterizing stage-specific regional divergence between amyloid and tau deposition may refine biomarker-based disease staging and improve prognostic assessment.

METHODS: We analyzed participants from the BATON study who underwent amyloid PET with [18]F-flutemetamol, tau PET with [18]F-MK-6240, and 3D MRI within a three-month interval. Participants were classified into cognitively normal amyloid-negative controls (CNA, n = 101) and the AD continuum (n = 102), comprising preclinical AD (PCA, n = 47), mild cognitive impairment due to AD (MCA, n = 24), and AD dementia (ADD, n = 31). Standardized uptake value ratios (SUVRs) were calculated using the Centiloid and CenTauR frameworks, and voxel-wise tau-to-amyloid ratio (TAR) images were generated. Voxel-wise and region-of-interest analyses were performed to compare regional patterns of amyloid deposition, tau accumulation, and TAR across disease stages.

RESULTS: Amyloid deposition was already widespread at the PCA stage, involving the frontal, posterior cingulate/precuneus, and temporal cortices. In contrast, tau deposition in PCA was largely confined to the medial temporal lobe. With progression to MCA and ADD, tau burden increased substantially and extended to the lateral temporal, parietal, and frontal cortices. TAR analysis demonstrated high values in the medial temporal cortex at the PCA stage, followed by decreasing TAR in frontal regions during MCA and a tau-dominant neocortical pattern in ADD.

CONCLUSIONS: Amyloid and tau exhibit distinct and stage-dependent regional dissociation across the AD continuum. TAR imaging effectively captures this divergence, reflecting early medial temporal tau predominance and subsequent neocortical tau expansion. These findings support the utility of integrated amyloid-tau PET metrics for refined disease staging and longitudinal therapeutic monitoring.},
}

@article {pmid42209955,
year = {2026},
author = {Reid, GA and DeBay, DR and Macdonald, IR and Laouz, AB and Pottie, IR and Darvesh, S},
title = {Molecular Imaging of Butyrylcholinesterase Associated with Amyloid-β Plaques Distinguishes 5XFAD from Wild-Type Mice: A Proof-of-Concept.},
journal = {Molecular imaging and biology},
volume = {},
number = {},
pages = {},
pmid = {42209955},
issn = {1860-2002},
support = {MOP-82798//Institute of Aging/ ; RNS- 117795//Institute of Aging/ ; MOP-119343//Institute of Aging/ ; PJT - 153319//Institute of Aging/ ; Grant No. 37854//Canadian Foundation for Innovation/ ; },
abstract = {PURPOSE: Diagnosis of Alzheimer's disease (AD) requires symptoms of dementia and accumulation of amyloid-β (Aβ) and tau in the brain. Molecular imaging of Aβ or tau in AD, though informative, is complicated by the finding that similar changes are found in brains of ~ 30% of cognitively normal older individuals. Butyrylcholinesterase (BChE), normally present in low levels in the cerebral cortex, is found in high levels associated with Aβ plaques in AD. When associated with plaques, the biochemical properties of BChE are altered. The aim of the present study was to determine if the BChE ligand, [[18]F]1-methyl-4-piperidinyl p-fluorobenzoate ([[18]F]BMP), can image BChE-associated plaques in the 5XFAD mouse model of AD and distinguish it from its wild-type (WT) counterpart.

PROCEDURES: [[18]F]BMP was synthesized and evaluated in wild-type (WT), 5XFAD and BChE knock-out (BChE-KO) mouse models for in vivo dynamic PET imaging of BChE. Time-activity curves were generated and [[18]F]BMP clearance parameters were determined. Brain, liver and urine homogenates were evaluated for [[18]F]BMP and its metabolites. Ex vivo autoradiography mapped the distribution of [[18]F]BMP brain retention.

RESULTS: In vivo PET imaging following injection of [[18]F]BMP demonstrated significantly greater brain retention of activity in 5XFAD mice compared to WT, while BChE-KO mice appeared similar to WT levels. Metabolite analysis confirmed [[18]F]BMP was metabolized in the periphery but survived in sufficient quantity to enter the brain. Ex vivo autoradiography showed [[18]F]BMP retention in the 5XFAD brain where BChE-associated plaques were prominent.

CONCLUSIONS: These results demonstrate that PET imaging of BChE-associated plaques is feasible, offering an avenue to evaluate the role(s) of BChE in AD pathogenesis and progression to complement the existing AD biomarker framework.},
}

@article {pmid42210035,
year = {2026},
author = {Weerawarna, PM and Jesudason, CD and Lobb, KL and Mason, ER and Gu, X and Chu, S and Richardson, TI},
title = {Curated set of tool compounds to probe PYK2 and FAK signaling in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71508},
doi = {10.1002/alz.71508},
pmid = {42210035},
issn = {1552-5279},
support = {U54AG065181//National Institute on Aging of the National Institutes of Health/ ; },
mesh = {*Focal Adhesion Kinase 2/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy ; *Signal Transduction/drug effects ; Humans ; Animals ; *Microglia/drug effects/metabolism ; *Focal Adhesion Kinase 1/metabolism/antagonists & inhibitors ; Phagocytosis/drug effects ; *Protein Kinase Inhibitors/pharmacology/pharmacokinetics ; Mice ; },
abstract = {INTRODUCTION: Proline-rich tyrosine kinase 2 (PYK2) and focal adhesion kinase (FAK) are non-receptor tyrosine kinases implicated in Alzheimer's disease (AD), but their functional role in microglia remains understudied. Selective pharmacological tools are required for preclinical studies leading to translational therapeutic development.

METHODS: We evaluated potent and selective inhibitors described in publications and patents, synthesized or procured representative compounds, and profiled them in kinase assays. In vitro physicochemical and pharmacokinetic (PK) properties were assessed, and functional effects were studied in microglial phagocytosis assays using HMC3 and BV2 microglia cellular models.

RESULTS: Biochemical profiling confirmed potent and selective inhibition, consistent with reported data, though assay-dependent differences in apparent selectivity were observed. Most compounds showed favorable physicochemical and PK properties. In HMC3 assay, the PYK2-selective tool compounds showed that strong stimulation of phagocytosis and parallel cell counts declined at non-toxic concentrations.

DISCUSSION: This curated set of well-characterized inhibitors provides a validated toolkit to probe PYK2/FAK biology in AD-relevant models.},
}

*Focal Adhesion Kinase 2/metabolism/antagonists & inhibitors
*Alzheimer Disease/metabolism/drug therapy
*Signal Transduction/drug effects
Humans
Animals
*Microglia/drug effects/metabolism
*Focal Adhesion Kinase 1/metabolism/antagonists & inhibitors
Phagocytosis/drug effects
*Protein Kinase Inhibitors/pharmacology/pharmacokinetics
Mice

@article {pmid42210251,
year = {2026},
author = {Langness, VF and Simmons, DA and Kaur, S and Massa, SM and Longo, FM},
title = {Taming the "death receptor": translating the first-in-class p75[NTR] modulator LM11A-31 from basic biology, across broad preclinical models, to clinical proof-of-concept.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08276-x},
pmid = {42210251},
issn = {1479-5876},
abstract = {BACKGROUND: The p75 neurotrophin receptor (p75[NTR]) is a critical regulator of diverse biological processes. Depending on the cellular context, p75[NTR] can promote trophic or degenerative signaling, which can influence a broad spectrum of pathological conditions, including neurodegenerative diseases, inflammatory/infectious conditions, and various central and peripheral nervous system injuries. These attributes of p75[NTR] and its widespread, frequently upregulated expression on affected cells and tissues, make it a compelling therapeutic target. Among various therapeutic targeting strategies, the first-in-class small molecule p75[NTR] modulator, LM11A-31, has emerged as a leading candidate and has been evaluated in 62 published preclinical studies spanning 26 distinct disease and injury models.

MAIN BODY: This review covers the foundational biology of p75[NTR] signaling and expression and all published mechanistic and preclinical studies evaluating LM11A-31, focusing on outcomes that have been reproduced across multiple studies and independent labs. Beyond its therapeutic potential, we also explore how LM11A-31 has served as a powerful pharmacological probe, significantly advancing our knowledge of p75[NTR] biology. LM11A-31 consistently reduced elevated JNK/c-Jun, NFκB, and RhoA signaling, and normalized reduced PI3K/AKT signaling in a variety of pathological conditions. It also mitigated associated disease processes, including inflammation, degeneration of neurites, synapses, and dendritic spines, and cell death. These protective effects against pathologies often improved functional outcomes, including cognitive and motor measures. Studies using LM11A-31 also uncovered emerging molecular and cellular functions of p75[NTR] by demonstrating its ability to improve autophagy, calcium and redox homeostasis, and blood-brain barrier function. Finally, a Phase 2a clinical trial applying LM11A-31 for Alzheimer's disease demonstrated a favorable safety profile and significantly slowed the progression of biomarkers related to neurodegenerative mechanisms.

CONCLUSIONS: Together, these studies expand our understanding of p75[NTR] function and support p75[NTR] modulation as a promising therapeutic strategy across diverse pathological conditions.},
}

@article {pmid42210271,
year = {2026},
author = {Guan, Y and Cheng, CH and Khanna, SD and Fader, C and Ohene, Y and Wells, JA and Koo, BB},
title = {Integrated imaging and molecular profiling reveals APOE4-associated neurovascular and glial disruptions in young adult mice.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03888-y},
pmid = {42210271},
issn = {1742-2094},
support = {HT94252410934//Department of Defense / Congressionally Directed Medical Research Programs (CDMRP) TERP/ ; },
abstract = {BACKGROUND: The Apolipoprotein-E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) and may contribute to neurodegeneration through a multi-hit hypothesis, in which vascular dysfunction, glial activation, and impaired lipid metabolism play central roles. Alterations in neurovascular unit (NVU) have emerged as an early APOE4-related phenotype, independent of amyloid and tau pathology. Astrocytes, as the primary source of APOE in the brain and key regulators of NVU homeostasis, may play a central role in these processes. This study investigates APOE4-associated NVU water exchange dynamics and astrocyte-vascular interactions using integrated in vivo MRI, ex vivo histology, and transcriptomic profiling.

METHODS: Non-contrast multimodal MRI, including multi-echo time arterial spin labeling (multi-TE ASL), T1-weighted imaging, and diffusion-weighted MRI, were applied in 6-9-month-old APOE3-KI and APOE4-KI mice. Multi-TE ASL was used to estimate regional NVU water exchange dynamics, while diffusion MRI assessed tissue microstructural alterations. Immunohistochemistry evaluated perivascular matrix metalloproteinase-9 (MMP9) activity, vascular-associated markers, astrocytic AQP4 expression, and glial reactivity. Single-nucleus RNA sequencing (snRNAseq) characterized cell-type-specific transcriptional profiles, and inferred cell-cell communication analysis between astrocytes, pericytes, and other NVU components. Integrated analyses compared MRI-derived measures with molecular and cellular findings.

RESULTS: APOE4-KI mice showed regionally specific alterations in NVU water exchange dynamics, particularly in the hippocampus, accompanied by trends toward altered microstructural complexity. Immunohistochemistry demonstrated increased perivascular MMP9 expression and evidence of extracellular matrix remodeling without prominent structural disruption of blood-brain barrier (BBB) markers in APOE4 mice. Astrocytes showed increased AQP4 expression, heightened proinflammatory gene signatures, and morphological reactivity. Molecular findings aligned with MRI, supporting the sensitivity of non-contrast MRI to early NVU alterations. Exploratory snRNAseq suggested an APOE4-enriched astrocyte subpopulation associated with immune activation and matrix-related pathways and suggested potential glial-vascular interactions that require validation in larger samples.

CONCLUSIONS: This integrated imaging and molecular analysis suggests that non-contrast multimodal MRI detects early APOE4-related changes in NVU exchange dynamics and glial-vascular interactions. By providing converging multiscale neuroimaging and cellular observations, this work provides a foundation for developing non-invasive biomarkers to monitor neurovascular vulnerability and guide early intervention strategies in individuals at risk for LOAD.},
}

@article {pmid42210357,
year = {2026},
author = {Behzad, F and Leili, FR and Ebrahimi, MJ and Moafi, M and Kenari, PB and Alizadeh, A and Adeli, S and Khosravani, M and Jadidi Kouhbanani, MA and Fahanik-Babaei, J},
title = {Plant-mediated green nanoparticles: combining nanometal and biometabolite potential for Alzheimer's treatment.},
journal = {Biomedical engineering online},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12938-026-01572-z},
pmid = {42210357},
issn = {1475-925X},
abstract = {Alzheimer's disease (AD) can cause cognitive and memory dysfunction due to insufficient acetylcholine (ACh). In principle, acetylcholinesterase (AChE) hydrolyzes ACh into acetic acid and choline, rendering the latter inactive. Acetylcholinesterase inhibitors (AChEI) are currently the main treatment strategy used to increase ACh availability and decrease the effects of cholinergic loss. The FDA has currently approved donepezil, rivastigmine, and galantamine (GAL) as AchEI drugs to treat AD. Among these drugs, only the alkaloid galantamine is found naturally among the AChEIs. The synergistic effect of plant metabolites and metal nanoparticles (MNPs) presents a promising avenue for AD treatment. Green synthesis approach leverages the unique properties of MNPs combined with the therapeutic potential of plant-derived compounds. In the present review, recent developments in nanotechnology, including the green synthesis of MNPs, have been discussed in relation to the treatment of AD. Given the recent advancements, we hope that the combination of nanotechnology and medicinal plants will eventually result in the development of highly successful strategies for the treatment of AD.},
}

@article {pmid42210358,
year = {2026},
author = {Clark, AL and Valocchi, E and McGill, MB and Lopez, FV and Chanfreau-Coffinier, C and Thomas, KR and Jester, DJ and Logue, MW and Merritt, VC},
title = {Examining the additive risk of TBI and comorbid conditions on dementia in military veterans: a retrospective cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02086-5},
pmid = {42210358},
issn = {1758-9193},
support = {IK2 CX001952/CX/CSRD VA/United States ; },
abstract = {BACKGROUND: Although traumatic brain injury (TBI) has been identified as a risk factor for Alzheimer's disease and related dementias (ADRD), not all studies have shown a clear link between TBI and ADRD, suggesting that the relationship between TBI and ADRD is complex, nuanced, and likely influenced by a multitude of factors. The purpose of this retrospective cohort study was to examine interactions between TBI history and co-occurring health conditions and health behaviors on 10-year incidence of ADRD among Veterans enrolled in the VA Million Veteran Program (MVP).

METHODS: Participants (N = 245,949) included Veterans aged ≥ 65 years at study enrollment who completed the MVP Baseline Survey and had VA electronic health record (EHR) data. Participants were followed from the date of MVP enrollment until the earliest ADRD diagnosis, death, or last visit date before the end of the observation period (January 2011 through September 2021). TBI status (TBI + vs. TBI-) and health conditions/health behaviors were characterized using a combination of MVP survey and EHR data. ADRD status (ADRD + vs. ADRD-) was based on a validated algorithm using EHR-extracted ICD codes. Cox proportional hazards regression analyses adjusted for age, sex, and education were used to assess the association between each health condition/health behavior and the hazard of ADRD in the TBI + and TBI- groups. Additive interactions between TBI and health conditions/health behaviors were tested using the relative excess risk due to interaction (RERI) statistic.

RESULTS: Among Veterans with a TBI history (n = 7,613), 12.16% developed ADRD over 10 years of follow-up; among those without TBI (n = 238,336), 4.32% developed ADRD. RERI analyses showed significant additive TBI by health condition/health behavior interactions for depression (RERI = 1.55, 95% CI = 0.96-2.15), heart attack/coronary artery disease (RERI = 0.76, 95% CI = 0.29-1.24), and physical inactivity (RERI = 0.58; 95% CI = 0.10-1.05), such that ADRD risk in Veterans with TBI was increased for those with these health conditions/health behaviors compared to those without.

CONCLUSIONS: Findings suggest that ADRD risk following TBI may be heightened in the presence of certain health conditions/health behaviors, highlighting targeted areas of intervention for potentially mitigating adverse late-life outcomes in Veterans with a history of TBI.},
}

@article {pmid42210396,
year = {2026},
author = {Romero-Murillo, S and Lachén-Montes, M and Cartas-Cejudo, P and Anaya-Cubero, E and de Miguel, M and Extramiana, L and Ferrer, I and Fernández-Irigoyen, J and Santamaría, E},
title = {Early, sex-dependent and progressive proteomic imbalance in the amygdala during Alzheimer´s disease continuum.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00930-9},
pmid = {42210396},
issn = {2042-6410},
support = {PID2023-152593OB-I00 funded by MCIU/AEI/ 10.13039/501100011033 / FEDER//Ministerio de Ciencia e Innovación/ ; 0011-1411-2023-000028//Gobierno de Navarra/ ; },
abstract = {BACKGROUND: The amygdala is involved in the emotional expression, memory processing and managing stimulatory input. Although amygdala atrophy is early evidenced in Alzheimer's Disease (AD), the molecular mechanisms disrupted in initial neuropathological stages are still unknown. In the present study, we investigated the proteomic impairment of the amygdaloid region from AD-Braak stage I-II and III-IV subjects to better understand the neuropathological processes occurred early in this area and to identify potential targets that may face AD from the beginning of the disease.

METHODS: Label-free quantitative proteomics was applied using an Orbitrap Exploris 480 mass-spectrometer in 24 postmortem amygdala specimens derived from non-demented (n = 3F/5M), AD-Braak stage I-II (n = 4F/4M) and AD-Braak stage III-IV (n = 4F/4M). Data analysis was performed using MaxQuant and Perseus software (two-way Student T-test; p < 0.05). Metascape and Ingenuity Pathway Analysis softwares were considered for biological interpretation. Connectivity map platform was used for drug repurposing analyses. Transcriptomic/proteomic data of other brain regions were obtained from AlzData, Neuropro, and Agora repositories.

RESULTS: Amygdaloid proteome of AD-Braak stage I-II and III-IV subjects compared to controls revealed a progressive proteomic impairment with a minimal overlap across Braak stages. Some of the amygdaloid DEPs were known interactors of human Aβ plaques, APP, or Tau proteins or were previously identified at transcriptional or translational level in other brain regions affected by AD. Interestingly, amygdaloid proteome was more severely affected in women than in men with a particular protein expression profile associated to each AD stage. Comparing our sex-dependent differential proteome datasets with transcriptomic data of different brain regions, we identified potential sex-specific proteins related to cognitive decline and neurodegeneration. Finally, data-driven drug repositioning using amygdaloid omics profiles unveiled that most of the small molecule candidates were neuropathological stage and/or sex-specific.

CONCLUSIONS: Early and sex-specific amygdaloid proteome dysregulation in AD highlights the consideration of a deliberate stratification by sex in future research and clinical trials to develop effective therapeutic strategies in AD for both sexes. The amygdala is a brain region involved in the expression of emotions, memory processing and managing incoming stimulus. Atrophy of this area is evidenced at the first stages of Alzheimer's Disease (AD), pointing out a potential involvement of amygdala in the pathology of this disease. However, the molecular changes occurred early in this area are not fully understood. To this end, we interrogated the proteome of amygdala postmortem samples came from subjects of early AD stages. By applying data and functional analyses, we observed a stage-dependent and progressive proteomic impairment in this area. We detected proteins differentially expressed that were already known to interact with well-stablished neuropathological proteins or were altered in other brain areas. Importantly, data stratification by sex revealed that protein expression changes of amygdala were more abundant in women than men across AD progression. After comparing our results with published data in different brain regions affected by AD, we identified sex-specific proteins that could be used as biomarkers of cognitive decline and neurodegeneration. Finally, a drug repositioning-based approach proposed candidates with the potential to reverse amygdaloid malignant AD signature more effectively in one sex than in other or just in one sex. These observations highlight the consideration to include sex differences in future research to develop more precise and effective treatments in AD.},
}

@article {pmid42210397,
year = {2026},
author = {Wan, MD and Liu, XX and Wan, TF and Liu, YW and Jiang, YL and Zou, JT and Jiao, B and Liu, QQ and Jin, L and Duan, R and Wang, Z and Hong, CG and Wang, X and Hu, XY and Liao, XX and Cao, J and Shen, L and Xie, H and Wang, ZX},
title = {Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer's disease pathology and systemic bone loss.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03854-8},
pmid = {42210397},
issn = {1742-2094},
support = {1053320231248//Postgraduate Innovative Project of Central South University/ ; 82301625//National Natural Science Foundation of China/ ; U22A20300, 82571373//National Natural Science Foundation of China/ ; 82125023, 82072504//National Natural Science Foundation of China/ ; 82272562//National Natural Science Foundation of China/ ; 2020YFC2008500//National Key R&D Program of China/ ; 2023RC3075//Science and Technology Innovation Program of Hunan Province/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.},
}

@article {pmid42210401,
year = {2026},
author = {Escamilla, S and Avilés-Granados, C and Márquez-Marco, C and Keller, M and Sánchez-Domínguez, I and Cuchillo-Ibáñez, I and Aguado, F and Zetterberg, H and Pietrzik, CU and Sáez-Valero, J},
title = {Meprin-β levels are increased in the brain and the cerebrospinal fluid of Alzheimer's disease patients.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02092-7},
pmid = {42210401},
issn = {1758-9193},
support = {PI22/01329//Fondo de Investigaciones Sanitarias/ ; CIAICO/2024/313//CIBERNED/ ; CEX2021-001165-S//"Severo Ochoa" Program for Centers of Excellence in R&D/ ; PID2022-142187OB-I00//Spanish Ministry of Science, Innovation and Universities MICINN/FEDER/ ; },
abstract = {The aim of this study is to assess the levels of meprin-β, an alternative β-secretase in the brain and cerebrospinal fluid of subjects suffering Alzheimer's disease. The full-length zymogen and the active species of meprin-β were characterized by immunoblotting and immunoprecipitation using ectodomain N-terminal and C-terminal antibodies. We examined meprin-β changes in extracts from Alzheimer's frontal cortex (n = 13, Braak stages I-II; n = 12, Braak stages III-IV; n = 12, Braak stages V-VI) compared with controls (n = 14), as well as in cerebrospinal fluid samples from Alzheimer's patients (n = 15) or non-Alzheimer's controls (n = 15). Cerebrospinal fluid meprin-β levels were also determined in 19-month old TgF344-AD and wild-type rats. Brain and cerebrospinal fluid from a Mep1b-null mouse served to characterize the specificity of the immunoreactive bands for meprin-β. Human induced pluripotent stem cell (iPSC)-derived neuronal cultures were treated with 2 μM Aβ42 for 24 h. We found that meprin-β is present in human brain extracts and cerebrospinal fluid as several distinct species, attributed to the zymogen and the mature species. These species were absent in brain and cerebrospinal fluid from a Mep1b-null mouse. No fragments of meprin-β were detected in brain extract, either in cerebrospinal fluid. Only the mature forms of meprin-β are increased in frontal cortex extracts (from Braak V-VI), but not the zymogen. The MEP1-B mRNA levels are increased in Braaks III-IV and V-VI compared with controls. The meprin-β species are increased in human neuronal cultures treated with Aβ42. Finally, we demonstrated elevated levels of the mature meprin-β in the cerebrospinal fluid of patients with Alzheimer's disease and in TgF344-AD rats. Our data support a role of meprin-β in Alzheimer's pathology.},
}

@article {pmid42210602,
year = {2026},
author = {Ruan, JY and Qi, X and Su, J and Mao, W and Xie, Y and Yu, J and Wang, J and Wu, B},
title = {Understanding Oral Health Management for People Living With Dementia: A Qualitative Meta-Synthesis.},
journal = {Gerodontology},
volume = {},
number = {},
pages = {},
doi = {10.1111/ger.70091},
pmid = {42210602},
issn = {1741-2358},
support = {P30AG083257/NH/NIH HHS/United States ; P50MD017356/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: People living with dementia often experience oral health problems, and managing oral health in this population presents numerous challenges. Although qualitative data have presented these challenges from multiple perspectives, there remains a lack of qualitative evidence synthesis. This paper aimed to synthesize available qualitative evidence on the perceptions and experiences of oral health management for people living with dementia from the perspectives of patients, their caregivers, healthcare professionals, and social workers across diverse contexts.

METHOD: This systematic review was registered in the International Prospective Register of Systematic Reviews (Registered Number: CRD420251110648). This review was conducted and reported in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Enhancing Transparency in Reporting the Synthesis of Qualitative Research statement. We searched 11 databases and grey literature sources from inception to July 2025. We included qualitative designs or mixed-methods designs in which qualitative data were analysed separately from quantitative data and that addressed oral health management for people living with dementia. Studies published in English or Chinese were eligible. Study quality was assessed using the Critical Appraisal Skills Programme checklist for qualitative studies. Data were analysed through thematic synthesis, and confidence in the evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation-Confidence in Evidence from Reviews of Qualitative Research.

RESULTS: Sixteen studies were synthesized, yielding three themes: (1) recognizing the importance of oral health for people living with dementia as a process, (2) oral health management for people living with dementia having unique requirements, and (3) learning to manage oral health for people living with dementia across multiple domains.

CONCLUSION: This review highlights critical gaps in oral health management for people living with dementia, emphasizing the need for oral health continuity of care, shared decision-making in oral health, and creating dementia-friendly oral health practice environments. These findings provide direction for practice and research aimed at improving person-centered oral care.},
}

@article {pmid42210608,
year = {2026},
author = {Torii, Y and Sekiguchi, H and Habuchi, C and Miwa, A and Arafuka, S and Takeda, K and Fujishiro, H and Yoshida, M and Iwasaki, Y and Iritani, S and Ikeda, M},
title = {Exploring the neuropathological basis of lateral ventricular enlargement in elderly patients with schizophrenia.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70079},
pmid = {42210608},
issn = {1440-1819},
support = {JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP25wm0625126//Japan Agency for Medical Research and Development/ ; JP19K17059//Japan Society for the Promotion of Science/ ; JP22K07595//Japan Society for the Promotion of Science/ ; JP26K10511//Japan Society for the Promotion of Science/ ; },
abstract = {AIM: Lateral ventricular enlargement is a robust morphological finding in schizophrenia. However, its characteristics and neuropathological basis in elderly patients remain poorly understood. We aimed to clarify the impact of neuropathologically confirmed neurodegenerative pathologies on lateral ventricular size in elderly patients with schizophrenia and explore other clinical factors potentially influencing ventricular morphology.

METHODS: We examined 31 postmortem brains from patients with schizophrenia with an onset age of <40 years. The ventricular-brain ratio (VBR) was measured using computed tomography within 3 years before death. Neuropathological evaluations of various neurodegenerative pathologies were performed according to the current diagnostic criteria, and the relationship between these pathologies, clinical factors, and VBR was examined.

RESULTS: Although Alzheimer's disease (AD) pathology increased with age, VBR did not differ significantly according to the severity of AD pathology in elderly patients with schizophrenia. Meanwhile, patients with aging-related tau astrogliopathy (ARTAG) in the medial temporal lobe exhibited a significantly higher VBR than those without. In elderly schizophrenia patients without neurodegenerative diseases, VBR was significantly correlated with illness duration but not with age at computed tomography scanning.

CONCLUSION: Lateral ventricular enlargement may occur in elderly patients with schizophrenia regardless of conventional neurodegenerative pathologies, such as AD pathology. This enlargement may be related not only to ARTAG but also to illness duration, suggesting a progressive process intrinsic to schizophrenia. This finding warrants further studies with a detailed histological assessment beyond conventional neurodegenerative pathologies to clarify the basis of ventricular enlargement in schizophrenia.},
}

@article {pmid42210804,
year = {2026},
author = {Devanand, DP and Huey, ED and Qian, M and Wei, R and Motter, JN and Nedic, L and Andrews, HF and Deliyannides, DA and Maayan, L and Graff, J and Deehan, E and Acosta, EP and Zanderigo, F and Goldberg, TE},
title = {Valacyclovir Treatment in Mild Cognitive Impairment: The VALMCI Randomized Clinical Trial.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000735},
pmid = {42210804},
issn = {1546-4156},
abstract = {BACKGROUND: Evidence from neuroscience, epidemiology, and electronic health records studies implicates herpes simplex viruses (HSV) as potentially etiologic for Alzheimer disease (AD).

METHODS: The VALMCI study was conducted in a research outpatient clinic specializing in memory disorders. The efficacy and side effects of valacyclovir 4 g/day were compared with placebo in a 12-month pilot, randomized, double-blind trial of participants with mild cognitive impairment (MCI), seropositivity to HSV1 or HSV2, and positive 18F-florbetapir PET scan.

RESULTS: Totally, 42 of 50 participants (84%) completed the trial. In linear mixed-effects model analyses with age, sex, and apolipoprotein E e4 genotype as covariates, change in the primary outcome of 18F-florbetapir PET mean SUVR was not significant with least-squares mean difference -0.01 (95% CI: -0.12 to 0.10; P=0.82). For secondary cognitive and functional outcomes, PACC composite z-score showed the least square mean difference 0.16 (95% CI: -0.17 to 0.49; P=0.32), and ADCS-ADL-PI score showed the least square mean difference 1.96 (95% CI: -0.43 to 4.34; P=0.11).

CONCLUSION: The results do not support the use of valacyclovir in the treatment of individuals with MCI with HSV seropositivity and PET amyloid positivity.},
}

@article {pmid42210866,
year = {2026},
author = {Talukdar, B and Verma, D and Packirisamy, G},
title = {Xerogel-Engineered Graphitic Carbon Nitride Interfaces Enable Aptamer-Based Detection of Salivary Lactoferrin for Noninvasive Diagnosis of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00824},
pmid = {42210866},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD), the primary cause of dementia, is a progressive neurodegenerative disorder that requires early diagnosis using noninvasive biosensing strategies. Salivary lactoferrin has consequently emerged as a compelling early-stage AD biomarker, as its dysregulated expression reflects underlying neuroinflammatory mechanisms associated with disease initiation and progression. Accordingly, we report an innovative aptamer-based electrochemical aptasensor for noninvasive and accurate biosensing of salivary lactoferrin (Lf). The design approach involves fabricating gold screen-printed electrodes (gSPEs) with in situ prepared porous graphitic carbon nitride (g-C3N4) xerogel using coprecipitation with the amino acid l-cysteine (l-Cys), followed by surface immobilization of the Lf aptamer and subsequent blocking with 6-mercapto-1-hexanol (MCH) via drop-casting. Structural and electrochemical characterizations indicate successful xerogel synthesis, where l-Cys acts as an interlayer-bridging agent, achieving high specificity and superior performance within a broad detection range of 0.5-500 μg mL[-1] based on the differential pulse voltammetry (DPV) technique. The aptasensor exhibits a significantly high sensitivity of 89.22 μA (log10 μg mL[-1])[-1] cm[-2] and a low limit of detection (LOD) of 0.34 μg mL[-1] in the artificial saliva samples. Furthermore, our fabricated sensor shows good reproducibility and repeatability with %RSD values well below 5%, thereby strengthening the utility of our novel biosensor design for applications in the timely detection of AD biomarker in body fluids, both within clinical settings as well as in point-of-care (POC) diagnostics.},
}

@article {pmid42211091,
year = {2026},
author = {Dempsey, DA and Unverzagt, FW and Xu, H and Moser, L and Gao, S and Avena-Koenigsberger, A and Chumin, EJ and Yoder, KK and Agarwal, P and Tangney, CC and Clark, DO and Saykin, AJ and Risacher, SL},
title = {MIND diet moderates the associations between cerebrovascular and neurodegenerative disease burden and cognition.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1837406},
pmid = {42211091},
issn = {2296-861X},
abstract = {INTRODUCTION: The Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet is associated with reduced dementia risk, but its role in moderating pathology-cognition relationships in high-risk populations remains unclear. This study examined associations of the MIND diet and Healthy Eating Index (HEI) with cognition and tested whether diet quality modifies the impact of brain pathology on cognitive performance.

METHODS: Sixty-six older adults (aged 60-82 years; mean education of 12 years, 65% Black, 73% female) completed MRI and the VioScreen food frequency questionnaire (FFQ). Multivariable linear regression models examined associations between diet scores (MIND, HEI-2020) and cognitive outcomes (cognition composite, memory, executive function), adjusting for age, sex, and education level. Interaction analyses cross-sectionally tested whether diet moderated relationships between structural brain pathology-white matter hyperintensity (WMH), hippocampal, and cortical volumes-and cognition, followed by post-hoc simple slopes analyses.

RESULTS: Higher MIND diet scores were independently associated with better memory performance (p < 0.05). These were significant interactions between WMH volume and MIND diet score across cognitive outcomes (all p-interactions < 0.05). Greater WMH volume was associated with worse cognitive performance at low (all p < 0.01), but not mean or high MIND diet scores (all p > 0.05). Similarly, cortical volume-cognition associations were present in those with low MIND diet scores and attenuated in those with mean or high scores. In contrast, the HEI-2020 score did not modify the effects of brain pathology on cognition, and neither diet quality measure modified hippocampal volume-cognition relationships.

CONCLUSION: The MIND diet may buffer the cognitive consequences of cerebrovascular pathology and cortical atrophy in older adults at elevated dementia risk and promote cognitive resilience over general healthy eating guidelines.},
}

@article {pmid42211120,
year = {2026},
author = {Song, H and Yang, M and Wu, S and Dai, Q and Qin, W and Xie, W and Chen, Y and Jiang, X and Zhang, X and Deng, X and Ouyang, C and Zhang, Y and Liu, X and Zhu, Y and Huang, G},
title = {Andrographolide attenuates microglial senescence in Alzheimer's disease mice by suppressing the STAT3 signaling.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116033},
pmid = {42211120},
issn = {2589-0042},
abstract = {Andrographolide (AP), a diterpenoid extracted from Andrographis paniculata, has emerged as a promising treatment for Alzheimer's disease (AD) in preclinical studies, but the underlying mechanisms remain incompletely defined. Here, we demonstrated that AP treatment improved cognition performance and reduced amyloid-β (Aβ) plaque accumulation in 5×FAD transgenic mice of both sexes, by mitigating microglial senescence. Proteomic analysis revealed that AP markedly decreased cholesterol content in the cerebral cortex. Using an in vitro low-density lipoprotein-induced senescence model, we found that AP significantly alleviated senescence in BV2 microglia while enhancing their phagocytic capacity. Mechanistically, AP mitigated microglial senescence by inhibiting STAT3 signaling. Overall, these findings identify a previously unrecognized immunometabolic mechanism for AP in the treatment of AD.},
}

@article {pmid42211344,
year = {2026},
author = {Modali, VA and Pavanya, M and Arjunan, V and Cenitta, D and Sampathila, N and Kamath, R and Chadaga, K},
title = {AlzStack: Forecasting early-onset Alzheimer's with an explainable AI system using multiple data balancing techniques.},
journal = {Global epidemiology},
volume = {11},
number = {},
pages = {100261},
doi = {10.1016/j.gloepi.2026.100261},
pmid = {42211344},
issn = {2590-1133},
}

@article {pmid42211438,
year = {2024},
author = {Gangas, P and Lennox-Chhugani, N and Alvarez, A and Aldasoro, E and Can Semerci, Y and Judica, E and Louro, C and Proença, JP and Marin, M and Calarota, E and Meidlinger, S},
title = {PROCare4Life integrated care model validation.},
journal = {Open research Europe},
volume = {4},
number = {},
pages = {3},
doi = {10.12688/openreseurope.16678.3},
pmid = {42211438},
issn = {2732-5121},
abstract = {This article focuses on reporting the methodology and results of the EU funded project PROCare4Life, whose main goal has been to develop an integrated, personalised, IT system, to empower and improve the Quality of Life of elderly people living with Parkinsons', Alzheimer's or another dementia. Research has been implemented to evaluate the results against the PROCare4Life integrated care strategy. Multimethod, quantitative, and qualitative research has been performed, benefiting from the Pilot 3 results gathered by consortium members. The article has been organised according to the research questions, which were based on the expected results by PROCare4Life that might support the future integration of care when the system is further developed and implemented into healthcare provision organisations. The PROCare4Life system is a digital tool that includes features that might support the advance of the integration of care, such as data sharing among multidisciplinary healthcare professionals and with patients and caregivers, the enhancement of direct communication among them or the constant sharing of the data monitored by the PROCare4Life system. Technology readiness levels (TRLs) 7 was achieved by the final prototype of the PROCare4Life system. Pilot representatives consider the PROCare4Life idea and underlying model of care very innovative and promising and believe it can certainly improve care practice through more enhanced integrated care. It is usable for people of different ages, conditions, and socioeconomic levels. It has been assessed to be more effective for elderly people living with Parkinson's than with dementia. Patients and caregivers indicated that the system helped them reduce their anxiety and increase their quality of life. Although overall assessment of the system by healthcare professionals was positive, divided opinions were shared on its capability to save time. Requirements for future scalability have been included in the last section.},
}

@article {pmid42211564,
year = {2026},
author = {Xu, Z and Xue, Y and Zheng, Y and Wu, B},
title = {Dementia diagnostic deserts: workforce and geographic inequities in the diagnostic pathway for cognitive impairment.},
journal = {Health affairs scholar},
volume = {4},
number = {5},
pages = {qxag109},
pmid = {42211564},
issn = {2976-5390},
abstract = {As disease-modifying therapies for Alzheimer's disease become available, ensuring equitable access to timely and accurate diagnosis of cognitive impairment is critical. This article conceptualizes "dementia diagnostic deserts," defined as geographic areas where rurality, primary care professional shortages, and high social deprivation converge to exacerbate access to the diagnostic continuum, from initial screening and comprehensive evaluation to the appropriate referral for specialist-based diagnostic confirmation. Using a multidimensional framework, we identify "Triple Disadvantage Zones" where these barriers intersect most severely, leading to diagnostic errors, characterized by failure to differentiate subjective complaints from objective impairment. This diagnostic failure produces 2 distinct forms of diagnostic inequity: delayed diagnosis for those with true pathology, and inappropriate over-testing for those who do not meet clinical criteria. Nurse practitioners and physician assistants are frontline providers in these underserved regions but face significant training gaps and practice-level infrastructure barriers. Addressing these disparities requires a multidimensional policy approach that targets the convergence of geographic, workforce, and socioeconomic barriers rather than rurality alone. We propose a coordinated policy agenda focused on comprehensive clinical triage training, appropriate reimbursement for clinician time, financial assistance for diagnostic testing, and investments in practice-level capacity for the entire diagnostic pathway and subsequent care.},
}

@article {pmid42211832,
year = {2026},
author = {Zholshybek, N and Abdurakhmanova, E and Bimakhan, A and Jumadilova, D and Baiturlin, Z and Almazan, J and Bolla, SR},
title = {Reliability and diagnostic performance of an automated MRI-based classifier compared with radiologists in Alzheimer's disease.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1821249},
pmid = {42211832},
issn = {1662-5196},
abstract = {Reliable imaging biomarkers are essential for improving early detection of Alzheimer's disease (AD). We evaluated whether an automated MRI-based classifier provides diagnostic performance comparable to expert radiologists in differentiating cognitively normal (CN) individuals from patients with AD using standardized ADNI data. Thirty-eight structural MRI datasets (20 CN, 18 AD) were analyzed. An automated multi-class volumetric classifier and two board-certified radiologists independently assigned probability scores across seven diagnostic categories. Performance was evaluated using a partial-credit scoring rule to account for probabilistic ties. Diagnostic performance for CN-AD discrimination was assessed using accuracy, sensitivity, specificity, receiver operating characteristic (ROC) analysis, inter-observer agreement metrics, Brier scores for calibration, and decision curve analysis (DCA) for clinical utility. The automated classifier achieved an accuracy of 0.66, sensitivity of 0.56, and specificity of 0.75. Radiologists demonstrated comparable performance with inherent inter-observer variability. Agreement between automated and human assessments was fair at the categorical level, with low concordance for continuous probability estimates. ROC analysis based on continuous AD probabilities demonstrated high discrimination performance for the automated model (AUC = 0.90), exceeding that of radiologists (AUC = 0.71 and 0.62). DCA indicated that the automated pipeline provides a positive net benefit as a second-opinion tool. This exploratory study emphasizes the impact of evaluation frameworks on performance metrics and supports further validation using multi-modal data in larger cohorts.},
}

@article {pmid42211838,
year = {2026},
author = {Drago, L and De La Motte, LR and Deflorio, L and Sansico, DF and Salvatici, M and Micaglio, E and Biazzo, M and Giarritiello, F},
title = {Correction: Systematic review of bidirectional interaction between gut microbiome, miRNAs, and human pathologies.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1872999},
doi = {10.3389/fmicb.2026.1872999},
pmid = {42211838},
issn = {1664-302X},
abstract = {[This corrects the article DOI: 10.3389/fmicb.2025.1540943.].},
}

@article {pmid42211879,
year = {2026},
author = {Komedera, M and Wojda, U and Kiryk, A},
title = {Cannabinoids in Alzheimer's disease: animal-human evidence and clinical pharmacology challenges.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1833021},
pmid = {42211879},
issn = {1662-5153},
abstract = {Cannabinoids have emerged as potential modulators of pathological processes in Alzheimer's disease (AD), including neuroinflammation, synaptic dysfunction, and protein aggregation. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the main phytocannabinoids from Cannabis sativa, interact with the endocannabinoid system and may influence neuronal and glial signaling pathways relevant to AD pathology. This mini review summarizes evidence from transgenic animal models and clinical studies evaluating CBD, THC, and their combination in AD. Preclinical studies show that CBD and THC reduce β-amyloid accumulation, attenuate tau phosphorylation, and regulate neuroinflammatory responses, often associated with improvements in learning and memory. Cognitive outcomes appear to depend on cannabinoid composition, with CBD or THC administered individually showing more consistent effects, while combined CBD + THC effects appear dose- and ratio-dependent. Clinical evidence in AD patients remains limited and primarily reports improvements in neuropsychiatric symptoms, such as reductions in agitation, nighttime activity, and behavioral disturbances, whereas cognitive improvements are modest. Cannabinoid-based treatments are generally well tolerated, with mild sedation, somnolence, or disorientation as the most reported adverse effects. Overall, current data support the biological plausibility of cannabinoids as modulators of neuroinflammatory and synaptic processes in AD. However, heterogeneity in formulations, dosing, and study design limits firm conclusions. Future research should focus on dose optimization, biomarker-guided clinical trials, and long-term safety assessments to better define their therapeutic potential in AD.},
}

@article {pmid42212001,
year = {2026},
author = {Wang, B and Zhang, J and Li, CH and Huang, X and Gao, RB and Peng, Y and Xie, Q and Ning, YL and Zhao, Y and Yang, N and Chen, X and Xie, YL and Zhou, YG and Lin, S and Chen, L and Li, P},
title = {Nuclear accumulation of PANK4 in hippocampal astrocytes aggravates cuproptosis in association with mild cognitive impairment in aged mice.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1816702},
pmid = {42212001},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI), a condition that falls somewhere between normal aging and severe cognitive dysfunction (e.g., Alzheimer's disease), is a common manifestation of the neurocognitive function decline that seniors encounter as they age. The fundamental processes causing its beginning are still not well understood yet.

METHODS: We employed aged (18-month-old) male C57BL/6J mice, including astrocyte-specific Pantothenate kinases 4 (PANK4) conditional knockout (Pank4 [f/f] ;Gfap-Cre, Pank4-CKO) mice. Cognitive function was assessed using the Barnes maze, Y-maze (spatial novelty preference, spontaneous alternation), novel object recognition (NOR) test, and open field test (OFT). Hippocampal PANK4 localization was analyzed via immunofluorescence (IF) and subcellular fractionation/western blotting (WB). Cuproptosis markers (FDX1, LIAS, DLAT), copper transporters (ATP7A, ATP7B, SLC31A1), and copper content (ICP-MS) were quantified in hippocampal tissue. In vitro studies used LPS-stimulated primary astrocytes for RNA-seq and qPCR validation.

RESULTS: Aged wild-type (18M+WT) mice exhibited specific deficits in Barnes maze retention and reversal learning, indicative of mild cognitive impairment, while Pank4-CKO mice showed significant rescue. We discovered a novel age-dependent nuclear accumulation of PANK4 in hippocampal cells, which was absent in Pank4-CKO mice. Aged hippocampi displayed upregulated pro-cuproptotic factors (FDX1, LIAS) and reduced DLAT, alongside decreased expression of the copper exporter ATP7A, ATP7B, SLC31A1 and increased copper accumulation. Astrocyte-specific Pank4 knockout reversed these changes: it suppressed FDX1/LIAS upregulation, restored ATP7B expression and DLAT levels, and normalized hippocampal copper content. In vitro, LPS-induced neuroinflammation triggered PANK4 nuclear translocation and selectively downregulated Atp7b expression in astrocytes. Small interfering RNA (siRNA)-mediated knockdown of Pank4 significantly upregulated Atp7b expression.

CONCLUSION: This study identifies a novel pathological mechanism in age-related MCI: the nuclear accumulation of PANK4 in hippocampal exacerbates cuproptosis susceptibility by specifically impairing ATP7B-dependent copper efflux, leading to copper overload. Astrocyte-specific PANK4 ablation mitigates these effects, highlighting PANK4 as a potential therapeutic target for preventing or treating age-associated cognitive decline.},
}

@article {pmid42212002,
year = {2026},
author = {Ma, X and Yao, L and Li, F and Cui, C and Wang, E and Wang, C and Zhao, P and Weng, X and Liu, C and Liu, S and Hu, H},
title = {From muscle to brain: the mediating effect of vitamin D in the relationship between muscle loss and cognitive function in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1630798},
pmid = {42212002},
issn = {1663-4365},
abstract = {OBJECTIVE: To investigate the association among Vitamin D (VD), muscle loss and cognitive function, and further analyze the possible role of VD in the association between muscle loss and cognitive function in patients with Alzheimer's disease (AD).

METHODS: This cross-sectional study included 58 patients with AD (30 mild and 28 moderate) and 30 neurotypical controls (NC). Demographic data, neuropsychological tests, and serum VD levels were collected. Muscle loss related indicators, including both clinical macroscopic and morphological microstructural indicators, were measured.

RESULTS: The differences among 3 groups in different cognitive domains, muscle loss related indicators and serum VD levels were statistically significant (P < 0.05). Adjusted for age, sex and BMI, correlations were observed among broad cognitive domains, muscle loss related indicators (especially muscle mass and upper limb muscle strength) and serum VD levels in patients with AD (P < 0.05). Mediation analyses revealed that muscle loss, particularly muscle mass reduction, significantly impacted cognitive function in patients with AD (P < 0.05). This effect remained statistically significant after accounting for VD levels (P < 0.05), and VD deficiency partially mediated the effect of muscle loss on cognitive function (P < 0.05).

CONCLUSION: VD level, muscle loss, and cognitive dysfunction are closely related, and VD partially mediated the association between muscle mass reduction and cognitive dysfunction in patients with AD. These preliminary findings highlight the importance of assessing muscle loss and VD deficiency, and suggest that targeted intervention may be a valuable management strategy for the AD population.},
}

@article {pmid42212061,
year = {2026},
author = {Bai, S and Chen, L and Zhang, W and Li, M and Liu, H and Huang, X and Zhou, L and Xin, W and Jiang, C and Li, CZ},
title = {Brain-Derived Extracellular Vesicle Subpopulations: from Bulk Measurements to Single-Entity Assays.},
journal = {JACS Au},
volume = {6},
number = {5},
pages = {2692-2708},
pmid = {42212061},
issn = {2691-3704},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD), pose a significant global health challenge, currently affecting over 40 million individuals and placing a heavy burden on healthcare systems. Existing diagnostic methods, such as neuroimaging and cognitive assessments, often lack sufficient sensitivity and specificity, especially in the early stages of disease. This underscores the need for novel biomarkers. Extracellular vesicles (EVs), particularly those derived from the brain, i.e., brain-derived extracellular vesicles (BDEVs), hold great potential as noninvasive diagnostic tools due to their ability to reflect the physiological and pathological states of their cells of origin. However, isolation and detection of such EV subpopulations from accessible body fluids such as blood remain a technical challenge due to their low abundance and overlapping physical properties compared to other EVs. This review discusses rationally designed isolation and detection technologies for EVs from major brain cell subpopulations and their integration with emerging fields like AI and big data analysis. We specifically contrast traditional ensemble-averaged bulk measurements with emerging single-entity assays, highlighting how the latter bypass biological noise to resolve rare BDEV subpopulations. It highlights the potential of these EV subpopulations as biomarkers, addresses EV isolation challenges and proposes standardized methodologies, and emphasizes the need for comprehensive profiling of EV markers at single-entity level, and point-of-care testing (POCT) development.},
}

@article {pmid42212095,
year = {2026},
author = {Piersson, C and Lublin, V and Duttine, M and Khemtemourian, L and Loquet, A and Mathelié-Guinlet, M and Fichou, Y},
title = {Local Organization of Biological Membranes Modulates Tau-Lipid Interactions and Fibril formation.},
journal = {JACS Au},
volume = {6},
number = {5},
pages = {3014-3026},
pmid = {42212095},
issn = {2691-3704},
abstract = {The formation of Tau amyloids is a hallmark of several neurodegenerative diseases, called Tauopathies, including Alzheimer's disease. In different Tauopathies, Tau amyloid filaments adopt a distinct structure, highlighting the existence of disease specific pathways. In this pathological context, lipid metabolism is heavily disrupted, leading to a perturbation of membrane composition. Lipid membranes have been shown to nucleate tau aggregation under some conditions. However, no general model has been established to explain how the organization of the lipid membrane modulates Tau aggregation. Here, we combined biochemistry and biophysical tools, including EPR spectroscopy, to investigate the mechanisms of membrane-induced Tau aggregation. After showing the importance of the electrostatic interaction between Tau and anionic lipids, we investigate how the amount and density of charges influence Tau aggregation. This work allows us to draw a general model where membrane-induced Tau aggregation is a two-step process. First, the binding to the membrane through electrostatic interactions is a necessary but not a sufficient step. Second, the nucleation of Tau amyloids at the membrane surface occurs only when specific conditions are fulfilled, i.e., high surface density altering Tau conformation and spatial proximity between aggregation-prone conformers. A direct implication of this model is that local membrane heterogeneities, such as phase separation or lipid rafting, are strong modulators of Tau aggregation. This work provides the molecular basis to predict how different membrane states regulate Tau aggregation.},
}

@article {pmid42212097,
year = {2026},
author = {Chang, H and Feng, Y and Zhang, B and Xue, Y and Jiao, J and Guo, Y},
title = {Decoding the Spatiotemporal Logic of Cellular Senescence through Multimodal Exosomal miRNA Integration.},
journal = {JACS Au},
volume = {6},
number = {5},
pages = {3027-3038},
pmid = {42212097},
issn = {2691-3704},
abstract = {We have developed a multimodal biosensing platform for the in situ monitoring of exosomal RNAs without cell lysis. This system employs a cascade of aptamer recognition, rolling circle amplification (RCA), and G-quadruplex/hemin signal transduction. Electrochemical and colorimetric outputs are seamlessly integrated using an inverse-variance-weighted data fusion algorithm, achieving ultrasensitive and precise detection. Applying this method to oxidative stress-induced cellular senescence, we successfully constructed a comprehensive RNA dynamic map. This analysis revealed time-resolved molecular logic: miRNA-21 displayed transient early upregulation as an adaptive response, while miRNA-29c and miRNA-34a accumulated progressively at later stages, driving irreversible senescence. Clinical validation further demonstrated the platform's efficacy in staging Alzheimer's disease (AD), where the integrated trimodal signals effectively distinguished between mild cognitive impairment (MCI) and progressive AD stages. Detailed statistical analysis identified exosomal miRNA-21 and miRNA-34a as significant independent risk factors, establishing a robust molecular signature for precision AD diagnostics. This work establishes an amplified, multimodal biosensing framework for profiling exosomal RNA communication during aging, offering a powerful tool for stage-resolved biomolecular mapping in precision geroscience.},
}

@article {pmid42212127,
year = {2026},
author = {Li, BF and Chen, XY and Xie, R and Mo, YF and Wu, YZ and Meng, Y and Han, XL and Chen, MH and Peng, YJ},
title = {Targeting microglia-mediated neuroinflammation in Alzheimer's disease: mechanisms and therapeutic approaches.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1818802},
pmid = {42212127},
issn = {1664-3224},
mesh = {Humans ; *Microglia/immunology/metabolism/drug effects/pathology ; *Alzheimer Disease/immunology/metabolism/pathology/drug therapy/therapy ; Animals ; *Neuroinflammatory Diseases/metabolism/immunology/therapy ; Amyloid beta-Peptides/metabolism ; Molecular Targeted Therapy ; Receptors, Immunologic/metabolism ; },
abstract = {While the recent approval of amyloid-beta (Aβ)-clearing monoclonal antibodies (mAbs) marks a milestone in treating Alzheimer's disease (AD), their modest clinical efficacy has catalyzed a paradigm shift, underscoring the necessity of targeting complementary pathological drivers. Neuroinflammation, once considered a secondary phenomenon, is now established as a third core pathological pillar of AD, with microglia at its epicenter. This review provides a comprehensive analysis of the multifaceted role of microglia in AD pathogenesis and evaluates the rapidly evolving landscape of microglia-targeted therapeutic strategies. We first delineate the dynamic and dichotomous function of microglia, which act as a "double-edged sword." Emerging evidence reveals a complex, three-stage functional arc: microglia are implicated in the initial seeding of Aβ plaques, then transition to a neuroprotective role by containing established plaques, and finally devolve into a chronic, pro-inflammatory state that drives neurodegeneration. We then delve into the core molecular mechanisms governing this plasticity, including the pivotal Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)-APOE signaling axis, the inhibitory receptor Cluster of Differentiation 33 (CD33), and key intracellular hubs like the NLRP3 inflammasome, which directly link genetic risk factors to microglial dysregulation. Based on this mechanistic understanding, we critically evaluate diverse therapeutic strategies, ranging from suppressing neurotoxic inflammation (e.g., TNF-α and NLRP3 inhibitors) to enhancing protective functions (e.g., TREM2 agonism and CD33 antagonism), eliminating senescent microglia (senolytics), and utilizing advanced nanoplatforms for brain-targeted delivery. Finally, we highlight the critical role of neuroinflammatory biomarkers within the emerging ATI(N) framework for enabling precision medicine. In conclusion, targeting microglia represents a vital therapeutic avenue that moves beyond amyloid-centric approaches, where a sophisticated understanding of their stage-dependent functions is paramount for developing effective immunomodulatory therapies to alter the devastating course of AD.},
}

Humans
*Microglia/immunology/metabolism/drug effects/pathology
*Alzheimer Disease/immunology/metabolism/pathology/drug therapy/therapy
Animals
*Neuroinflammatory Diseases/metabolism/immunology/therapy
Amyloid beta-Peptides/metabolism
Molecular Targeted Therapy
Receptors, Immunologic/metabolism

@article {pmid42212154,
year = {2026},
author = {Zhao, L and Xia, X and Wang, S and Liu, R and Liu, Z and Sun, D and Yu, X and Wu, H},
title = {The inhibition of the Aβ-ASC interaction site suppresses β-amyloid aggregation and cytotoxicity.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1748748},
pmid = {42212154},
issn = {1664-3224},
mesh = {Animals ; *Amyloid beta-Peptides/immunology/metabolism/chemistry ; Mice ; *Alzheimer Disease/immunology/metabolism ; Humans ; Mice, Inbred C57BL ; Protein Binding ; Binding Sites ; Nanovaccines ; Peptide Fragments/immunology ; Protein Subunit Vaccines ; },
abstract = {BACKGROUND AND AIMS: The deposition of β-amyloid (Aβ) in the cerebral cortex and hippocampus is a key pathological hallmark of Alzheimer's disease (AD). Previous studies have shown that ASC specks released by activated microglia can bind to Aβ and promote its aggregation, thereby accelerating AD progression. However, the specific mechanisms underlying this interaction remain poorly understood. This study aims to identify the interaction sites between ASC and Aβ, design a vaccine targeting these sites, and evaluate its immunogenicity and therapeutic efficacy.

METHODS: The interaction regions between ASC and Aβ were identified using pull-down and ELISA assays. Four types of nanoparticle carriers were purified using a prokaryotic expression system, and two peptides targeting the interaction sites were synthesized in vitro. These peptides were conjugated to the carriers via the SpyCatcher-SpyTag system. C57BL/6J mice were immunized with the constructed nanoparticles, and the immunogenicity of the vaccines was assessed by ELISA, while safety was evaluated by ELISpot. Serum antibodies were purified for further functional analysis.

RESULTS: Pull-down and ELISA results demonstrated that the C-terminal region of Aβ, particularly residues 29-42, and the pyrin domain (PYD) of ASC are key regions involved in binding. Eight nanoparticle vaccines carrying Aβ C-terminal epitopes were successfully prepared. Among them, the Ferritin-based Aβ vaccine induced a potent immune response targeting the Aβ-ASC interaction site without activating Aβ-specific T-cell responses. In vitro functional assays confirmed that the purified antibodies effectively disrupted Aβ-ASC binding, inhibited Aβ aggregation, and subsequently reduced its neurotoxicity.

DISCUSSION: Our findings indicate that the interaction site between ASC and Aβ is located within amino acids 29-42 of Aβ. Vaccines designed based on this site, Ferritin-Aβ29-35-3copy and Ferritin-Aβ36-42-3copy, effectively induced antibody production. The resulting antibodies suppressed Aβ aggregation and the neurotoxicity of Aβ oligomers. These data suggest that the Aβ-ASC interaction site may represent a potential target for AD therapy.},
}

Animals
*Amyloid beta-Peptides/immunology/metabolism/chemistry
Mice
*Alzheimer Disease/immunology/metabolism
Humans
Mice, Inbred C57BL
Protein Binding
Binding Sites
Nanovaccines
Peptide Fragments/immunology
Protein Subunit Vaccines

@article {pmid42212212,
year = {2026},
author = {Yarahmadi, S and Alidoust, L and Saberi, A and Khakpour-Taleghani, B and Rostampour, M and Jafari, A},
title = {Comparison of long non-coding RNA NEAT1 expression, P53, and anti-oxidant factors between Alzheimer's patients and healthy individuals.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {4},
pages = {598-604},
pmid = {42212212},
issn = {2008-3866},
abstract = {OBJECTIVES: Several studies have reported that the lncRNA Nuclear-enriched abundant transcript 1 (NEAT1) is associated with the progression of Alzheimer's disease (AD). Oxidative stress and apoptosis also play crucial roles in the development of AD. The present study compared the serum levels of NEAT1, superoxide dismutase (SOD), glutathione (GSH), and P53 between individuals with AD and healthy controls.

MATERIALS AND METHODS: Peripheral blood samples were collected from 30 AD patients and 33 healthy controls and then centrifuged to separate serum. Total RNAs were isolated, and real-time polymerase chain reaction (RT-qPCR) was applied to determine NEAT1 gene expression. Also, Enzyme-linked immunoassays (ELISA) were conducted to measure SOD and GSH as anti-oxidant factors, and p53 as an apoptosis marker.

RESULTS: NEAT1 expression was significantly higher in AD patients than in controls (P<0.001). In addition, ROC analysis revealed that serum NEAT1 levels distinguished AD patients from healthy controls with 90% sensitivity and 84.85% specificity. Moreover, the anti-oxidant levels of SOD (P<0.0001) and GSH (P<0.05) were significantly decreased in AD patients, while P53 levels were significantly increased (P<0.05). However, no significant association was found between NEAT1 expression and the measured blood factors.

CONCLUSION: The serum levels of NEAT1 effectively distinguished between AD patients and non-AD people, underscoring its potential as a blood-based biomarker for the development of Alzheimer's disease.},
}

@article {pmid42212223,
year = {2026},
author = {Grødem, EOS and Vidal-Pineiro, D and Sørensen, Ø and Bartrés-Faz, D and Brandmaier, AM and Cattaneo, G and Garrido, PF and Henson, RN and Kühn, S and Lindenberger, U and MacIntosh, BJ and Nyberg, L and Pascual-Leone, A and Smith, SM and Solé-Padullés, C and Solana-Sánchez, J and Watne, LO and Walhovd, KB and Bjørnerud, A and Fjell, AM},
title = {Stable individual differences dominate adult brain volume variation until later life.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42212223},
issn = {2837-6056},
abstract = {Individual differences in the volumes of brain structures are often linked to various conditions, including Alzheimer's disease, schizophrenia, and overall brain health. However, it remains unclear to what extent these differences reflect individual levels present from young adulthood or diverging aging trajectories from later ages. In this study, we analyze the aging dynamics of the volumes of six brain structures based on magnetic resonance imaging (MRI) scans from a large cross-cohort longitudinal sample of cognitively healthy adults (n = 8,311 with 18,520 MRIs, ages from 18 to 97 years). From general assumptions about structural brain dynamics and measurement noise, a stochastic dynamical model was fitted to the data to estimate both the variability and persistence of structural changes across adulthood. Using this model, we calculated how much of the variance of volumetric differences between individuals can be attributed to stable levels from young adulthood versus systematic changes at older ages, as well as the theoretical sensitivity of longitudinal studies to detect individual differences in change. The findings were as follows: (1) Before age 60 years, inter-individual differences in neuroanatomical volumes almost exclusively reflect stable differences between individuals, while the influence from systematic differences in rate-of-change increases thereafter: up to 50% of the variation being due to differences in change at 80 years. In contrast, ventricular volume reflects differences in change from early adulthood. (2) Current brain-age models are unlikely to be sensitive to detect differences in aging trajectories. (3) Imaging studies have low reliability in detecting inter-individual brain changes before age 60 years. After 60 years, the study reliability increases sharply with longer intervals between scans and more modestly with additional intermediate observations. In conclusion, our results reinforce the view that it is critical to distinguish stable early adulthood levels from systematic differences in change when studying adult brain aging.},
}

@article {pmid42212298,
year = {2026},
author = {Han, M and Li, Z and Sun, T and Xiao, B and Zhang, J and Liu, S and Yang, J and Ma, J and Wang, P},
title = {Targeting amyloid-β in Alzheimer's disease: A critical analysis of clinical trials and their implications for drug development.},
journal = {Iranian journal of basic medical sciences},
volume = {21},
number = {2},
pages = {531-543},
pmid = {42212298},
issn = {2008-3866},
abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative dementia, is characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles, with Aβ playing a central pathogenic role. Approved AD drugs, primarily acetylcholinesterase inhibitors, only alleviate symptoms without modifying disease progression. Aβ-targeting strategies aim to inhibit Aβ production or enhance its clearance, leveraging early deposition for proactive intervention. Preclinical studies show Aβ reduction mitigates neurodegeneration, but clinical trials reveal challenges: γ-secretase inhibitors face off-target toxicities and limited efficacy, while BACE1 inhibitors suffer from safety issues or failure to improve cognition. Despite setbacks, advancing understanding of AD pathogenesis and optimized drug design/ trial protocols sustain the potential of Aβ-targeted therapies. This review aims to advance Aβ-targeted therapies for AD by integrating lessons from prior clinical trials and outlining strategic directions for future research and development.},
}

@article {pmid42212363,
year = {2026},
author = {Xue, X and Lai, Y and Song, S and Wu, L and Wang, L},
title = {Elucidating the multitarget neuroprotective mechanisms of protocatechuic acid in neurological disorders (Review).},
journal = {Molecular medicine reports},
volume = {34},
number = {1},
pages = {},
doi = {10.3892/mmr.2026.13921},
pmid = {42212363},
issn = {1791-3004},
mesh = {Humans ; *Hydroxybenzoates/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; },
abstract = {Neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, anxiety and depression pose significant global public health challenges due to their high prevalence and complex pathological mechanisms. Current therapeutic strategies primarily offer symptomatic relief, with limited efficacy in mitigating disease progression. Neuroprotection involves interventions aimed at preserving neuronal structure and function through mechanisms such as reducing oxidative stress, modulating inflammation and inhibiting apoptosis, presenting a promising avenue for treating these conditions. Protocatechuic acid (PCA), a natural phenolic acid compound prevalent in a variety of foods and herbal medicines, has received considerable attention for its notable antioxidant, anti‑inflammatory and neuroprotective properties. The present study systematically reviews the neuroprotective effects and molecular mechanisms of PCA in various neurological disorders (including AD, PD and cerebral ischemia). The present review highlights the multi‑target mechanisms of PCA, which act by mitigating oxidative stress, neuroinflammation, mitochondrial dysfunction and apoptosis, while promoting neuronal regeneration. Furthermore, the present review integrates the body of evidence across neurological contexts to identify conserved protective pathways and discusses the translational potential of PCA, providing a foundation for its clinical application in treating neurological diseases.},
}

Humans
*Hydroxybenzoates/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
*Nervous System Diseases/drug therapy/metabolism
Oxidative Stress/drug effects
Apoptosis/drug effects
Antioxidants/pharmacology/therapeutic use

@article {pmid42212383,
year = {2026},
author = {Morcillo-Nieto, AO and Franquesa-Mullerat, M and Zsadanyi, SE and Arriola-Infante, JE and Vaqué-Alcázar, L and Rozalem-Aranha, M and Parra, JA and Zhao, Z and Arranz, J and Rodríguez-Baz, Í and Maure-Blesa, L and Videla, L and Barroeta, I and Del Hoyo Soriano, L and Benejam, B and Fernández, S and Sanjuan Hernandez, A and Pertierra, L and Giménez, S and Santos-Santos, M and Dols-Icardo, O and Illán-Gala, I and Alcolea, D and Belbin, O and Lleó, A and Carmona-Iragui, M and Fortea, J and Bejanin, A},
title = {Peak width of skeletonized mean diffusivity reveals early and multifactorial white matter injury across sporadic and Down syndrome-associated Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71507},
doi = {10.1002/alz.71507},
pmid = {42212383},
issn = {1552-5279},
support = {#1913cycle2019B//Fondation Jérôme Lejeune/ ; #2425cycle2024B//Fondation Jérôme Lejeune/ ; #1801Cycle2020//Fondation Jérôme Lejeune/ ; #51PDC-2023-51//Fondation Jérôme Lejeune/ ; 2326-GRT-2024A//Fondation Jérôme Lejeune/ ; IIBSP-DOW-2020-151//Fundación Tatiana Pérez de Guzmán el Bueno/ ; 1R01AG056850-01A1/NH/NIH HHS/United States ; R21AG056974/NH/NIH HHS/United States ; R01AG061566/NH/NIH HHS/United States ; 1R01AG081394-01/NH/NIH HHS/United States ; 1R61AG066543-01/NH/NIH HHS/United States ; R01AG080470/NH/NIH HHS/United States ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; INT21/00073//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI20/01473//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI23/01786//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI18/00435//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI22/00611//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; INT19/00016//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; INT23/00048//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; CP20/00038//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI22/00307//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; CP24/00112//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI18/00335//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI22/00758//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; ICI23/00032//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; CD23/00235//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI20/00836//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; CM23/00291//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; CM22/00052//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; CM22/00243//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI21/00791//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI24/00598//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; JR20/0018//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; JR18-00018//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI19/00882//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI21/01395//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI24/01087//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI21/00063//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; PI24/00968//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; DTS22/00111//Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. ERDF/ ; AARG-22-923680/ALZ/Alzheimer's Association/United States ; AARG-22-973966/ALZ/Alzheimer's Association/United States ; AARFD-21-852492/ALZ/Alzheimer's Association/United States ; AACSF-25-1486364/ALZ/Alzheimer's Association/United States ; AACSF-21-850193/ALZ/Alzheimer's Association/United States ; AACSF-22-972945/ALZ/Alzheimer's Association/United States ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; AARG-22-974373/ALZ/Alzheimer's Association/United States ; 2021SGR00979//Department of Research and Universities from the Generalitat de Catalunya/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; H2020-SC1-BHC-2018-2020//Horizon 2020 - Research and Innovation Framework Programme from the European Union/ ; SLT006/17/125//Department of Health Generalitat de Catalunya PERIS program/ ; 23S06157-001//Ajuntament de Barcelona, in collaboration with Fundació La Caixa/ ; GBHI_ALZ-18-543740//Global Brain Health Institute/ ; GBHI_ALZ-23-971107//Global Brain Health Institute/ ; GBHIALZUK-21-72097//Global Brain Health Institute/ ; //FUNDELA/ ; //Fundación Luzón/ ; },
mesh = {Humans ; *Down Syndrome/complications/diagnostic imaging/pathology ; *Alzheimer Disease/diagnostic imaging/pathology/complications/cerebrospinal fluid ; Female ; *White Matter/pathology/diagnostic imaging ; Male ; Cross-Sectional Studies ; Diffusion Tensor Imaging ; Middle Aged ; Aged ; Disease Progression ; Diffusion Magnetic Resonance Imaging ; Brain/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: This study investigates the evolution with disease progression and pathological correlates of peak width of skeletonized mean diffusivity (PSMD), a sensitive diffusion magnetic resonance imaging (MRI) marker of microvascular white matter (WM) injury, in sporadic Alzheimer's disease (sAD) and Down syndrome (DS)-associated AD (DSAD).

METHOD: This cross-sectional study included 150 euploid controls, 118 subjects with sAD, and 228 DS adults (34.65% with symptomatic AD). PSMD was derived from 3T-MRI diffusion tensor imaging. Associations with sociodemographic, clinical stage, cerebrospinal fluid (CSF), and small vessel disease markers were examined.

RESULTS: PSMD correlated with age in all groups, showing a stronger association in DS, with alterations apparent 15 years before the population's dementia age at onset. In euploid and DS, higher PSMD correlated with AD severity, CSF-neurofilament light chain (NfL), microbleeds, and WM hyperintensities (WMH). PSMD abnormalities were more frequent than WMH, especially in DS.

DISCUSSION: PSMD is a sensitive early biomarker of WM injury across sAD and DSAD, preceding symptom onset and capturing multifactorial disease processes.},
}

Humans
*Down Syndrome/complications/diagnostic imaging/pathology
*Alzheimer Disease/diagnostic imaging/pathology/complications/cerebrospinal fluid
Female
*White Matter/pathology/diagnostic imaging
Male
Cross-Sectional Studies
Diffusion Tensor Imaging
Middle Aged
Aged
Disease Progression
Diffusion Magnetic Resonance Imaging
Brain/pathology/diagnostic imaging

@article {pmid42212431,
year = {2026},
author = {Kim, JP and Lee, H and Kim, BH and Kang, H and Shin, D and Yim, S and Kim, S and Seo, SW and Kim, HN},
title = {Genetically prioritized druggable targets for amyloid-β pathology highlight ACE as a therapeutic candidate in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261454540},
doi = {10.1177/13872877261454540},
pmid = {42212431},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by a neuropathological cascade that begins with amyloid-β (Aβ) deposition. The recent success of disease-modifying drugs targeting Aβ has demonstrated that modulating amyloidopathy can yield clinical benefits, underscoring the need for additional drugs affecting amyloid pathology.ObjectiveTo identify novel drug targets associated with Aβ accumulation in AD using Mendelian randomization (MR) analysis of the druggable genome.MethodsWe performed MR analysis on expression quantitative trait loci (eQTLs) of the druggable genome in relation to Aβ accumulation using summary-data-based MR (SMR). Blood eQTL data were obtained from the eQTLGen consortium, and brain eQTL data from BrainMeta and PsychENCODE, while Aβ positron emission tomography (PET) genome-wide association study data were derived from 11,816 non-Hispanic White participants across 13 cohorts. Co-localization analysis was conducted to enhance the reliability of the MR results, and additional validation was performed using blood and brain protein quantitative trait loci (pQTLs) as instrumental variables.ResultsThe SMR and co-localization analyses revealed causal associations between the druggable genome and Aβ accumulation, with APH1B identified in blood eQTL data and ACE, APH1B, and CR1 identified in brain eQTL data. Further analysis using pQTL data confirmed causal associations for ACE and CR1, with ACE showing a negative association with Aβ PET uptake.ConclusionsThese findings highlight potential target genes for AD treatment, and the protective effect of ACE against amyloid pathology suggests that alternative medications to ACE inhibitors may be preferred for blood pressure management in the context of AD. Overall, our study demonstrates the potential of MR to facilitate drug repurposing for AD.},
}

@article {pmid42212437,
year = {2026},
author = {Perez-Rocha, Y and Calderon, LE and Kogut, K and Rojas, N and Eskenazi, B and Warner, M and Rojas-Saunero, LP and Gunier, RB and Ambriz, E and Torres, JM},
title = {Longitudinal food insecurity patterns and cognitive performance among midlife Latina women: Findings from the CHAMACOS Maternal Cognition Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453615},
doi = {10.1177/13872877261453615},
pmid = {42212437},
issn = {1875-8908},
abstract = {BackgroundAlthough food insecurity (FI) has been linked to cognitive aging, few studies have examined associations in midlife or socioeconomically disadvantaged populations or considered longitudinal FI patterns.ObjectiveTo examine cross-sectional and longitudinal associations between FI and cognitive performance in a prospective cohort of midlife women.MethodsWe analyzed data from 512 women in the CHAMACOS Maternal Cognition Study (2018-2024). FI was measured twice (approximately 3.2 years apart) with the six-item Short Form of the USDA Household Food Security Survey Module (range: 0-6). We categorized FI cross-sectionally (secure, scores of 0-1; insecure, scores 2-6) and longitudinally (persistent security, persistent FI, new FI). Cognitive performance was assessed across multiple domains with the SOL-INCA-AD assessment. We estimated associations using linear regression adjusted for sociodemographic confounders and, among a subset, APOE ɛ4 carrier status.ResultsCross-sectionally, FI was associated with lower global cognition z-scores (β = -0.11, 95% CI: -0.21, -0.01), with similar trends for executive function (β = -0.10, 95% CI: -0.19, 0.01) and memory domains (β = -0.13, 95% CI: -0.29, 0.03). Longitudinally, new FI (versus persistent security) was associated with lower scores across all domains (Global β = -0.19, 95% CI: -0.32, -0.06; Executive function β = -0.15, 95% CI: -0.27, -0.02; Memory β = -0.22, 95% CI: -0.43, -0.01; Verbal fluency β = -0.17, 95% CI: -0.36, 0.02). Persistent FI showed weaker associations.ConclusionsIn this cohort of midlife women, FI and particularly new onset FI were associated with worse cognitive performance after adjusting for sociodemographic and genetic confounders.},
}

@article {pmid42212439,
year = {2026},
author = {Kapoor, A and Nguyen, AD and Joyce, JL and Gaubert, A and Duke Han, S and Hughes, CCW and Nation, DA},
title = {Biomarkers of angiogenesis in Alzheimer's disease: Systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453391},
doi = {10.1177/13872877261453391},
pmid = {42212439},
issn = {1875-8908},
abstract = {BackgroundCerebrovascular dysfunction can contribute to the pathophysiology of Alzheimer's disease (AD) and trigger angiogenesis. To date, no prior systematic review and meta-analysis (SRMA) study has attempted to qualitatively and quantitatively review existing literature examining angiogenic factors in AD.ObjectiveIn this review, we aimed to identify markers of angiogenesis in biofluids that can differentiate between individuals with AD and healthy older adults, and inform the role of angiogenesis in AD.MethodsUsing Medline (1946 to August 4, 2021), the literature was systematically searched for articles according to PRISMA guidelines. Angiogenesis and AD terms were searched as keywords and mapped to MeSH headings. A total of 18 studies (including 28 dependent effect sizes) were included in the meta-analysis. Hedges' g was selected as the effect size of interest.ResultsA random-effects model including all eligible biofluid studies revealed a small and nonsignificant overall effect size (combined Hedges' g = -0.26, 95% CI [-1.45, 0.92], p = 0.647), with significant heterogeneity (I[2] = 98.6%, p < 0.0001). Moderator analysis revealed no significant difference based on which specific angiogenic biomarker was examined (i.e., vascular endothelial growth factor (VEGF) versus others).ConclusionsVEGF-related marker levels were not significantly different in AD and normal aging. Based on our findings, few studies have examined fibroblast growth factor and platelet-derived growth factor-related markers; however, we believe they warrant further investigation. Identifying novel angiogenic biomarkers could elucidate the role of vascular mechanisms in AD and reveal potential therapeutic targets.},
}

@article {pmid42212442,
year = {2026},
author = {He, X and Liu, W and Liu, R and Li, B and Xu, X and Cheng, Y and Li, Y and Jiang, H},
title = {Exploratory study on the synergistic use of plasma neurofilament light chain, phosphorylated Tau181, and retinal examination for assessing the risk of Alzheimer's disease and mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453611},
doi = {10.1177/13872877261453611},
pmid = {42212442},
issn = {1875-8908},
abstract = {BackgroundBiomarker detection is crucial for diagnosing Alzheimer's disease (AD). A highly promising approach combines non-invasive fundus imaging of the retinal nerve fiber layer (RNFL) with plasma biomarkers. Combining RNFL with plasma neurofilament light chain (pNFL) and phosphorylated Tau181 (P-tau181) may play a significant role in the diagnosis and monitoring of mild cognitive impairment (MCI) and AD.ObjectiveThis study aimed to evaluate the utility of combining RNFL thickness with plasma pNFL and P-tau181 levels for assessing the risk of clinically diagnosed AD.MethodsA total of 143 patients with AD and MCI underwent clinical and cognitive assessments as well as biomarker evaluations (plasma pNFL, P-tau181, RNFL), and receiver operating characteristic (ROC) analysis was finally employed to assess their diagnostic efficacy for clinically diagnosed AD.ResultsSignificant inverse correlations were found between Mini-Mental State Examination scores and pNFL (R[2] = 0.344, p < 0.001) and P-tau181 (R[2]=0.424, p < 0.001). Temporal RNFL thickness was significantly lower in the MCI group versus healthy control (HCs), while the AD group showed intermediate thickness not significantly different from HCs. For AD diagnosis, pNFL achieved the highest area under the curve (AUC=0.748). Combining pNFL with P-tau181 improved the AUC to 0.784, and models further incorporating Apolipoprotein E (APOE) ε4 or RNFL thickness similarly showed high accuracy (AUCs=0.785/0.782).ConclusionsElevated levels of pNFL and P-tau181 are independent risk factors for cognitive decline. Combination with fundus examination confers significant diagnostic utility for clinically diagnosed AD.},
}

@article {pmid42212443,
year = {2026},
author = {Xiang, C and Tang, L and Zhao, C and Zhao, Y and Xu, X and Zhang, Y},
title = {U-shaped relationship between hemoglobin glycation index and cognitive outcome in older population in China: A population-based prospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453337},
doi = {10.1177/13872877261453337},
pmid = {42212443},
issn = {1875-8908},
abstract = {BackgroundThe hemoglobin glycation index (HGI) effectively captures individual variations in glycation, its association with cognitive impairment remains unclear.ObjectiveThe purpose of this study was to investigate the relationship between HGI and cognitive impairment risk in the Chinese population.MethodsData from the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2015 were analyzed. Cognitive function was assessed using the American Health and Retirement Study's methodology, which included episodic memory and mental status. Multivariate Cox proportional hazards models and restricted cubic splines were used to examine the link between HGI and the likelihood of cognitive impairment, specific cognitive domains included. Moreover, the potential inflection points were investigated using saturation threshold effect analysis, with bootstrap resampling applied for internal validation.ResultsA U-shaped relationship was observed between HGI and the risk of cognitive impairment, as demonstrated by the restricted cubic spline analysis (p for non-linearity <0.001). The primary analysis identified an inflection point at approximately 0.085. Internal validation via bootstrapping yielded a 95% empirical confidence interval of 0.013 to 0.255 for this point. Conversely, HGI levels above 0.085 resulted in a 70.6% increase in the hazard ratio of cognitive impairment (all p < 0.05).ConclusionsIn the Chinese population, our results point to a U-shaped association between HGI and the risk of cognitive impairment, suggesting that both very low and very high HGI levels raise the risk of cognitive impairment, especially execution and memory.},
}

@article {pmid42212444,
year = {2026},
author = {Day, SM and Reitz, NL and Savage, LM},
title = {Adolescent intermittent ethanol exacerbates amyloid-β with age in the dorsal hippocampus of female TgF344-AD rats.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453081},
doi = {10.1177/13872877261453081},
pmid = {42212444},
issn = {1875-8908},
abstract = {BackgroundAlcohol misuse increases Alzheimer's disease (ΑD) risk; however, the mechanisms linking these conditions are unknown. In rodents, chronic and acute ethanol increases amyloid-β (Aβ); however, most of those studies have been limited to a single sex or brain region.ObjectiveThis study explored how adolescent intermittent ethanol (AIE), alters Aβ in multiple regions of the brain in female and male TgF344-AD rats as they age.MethodsFrom postnatal days 28-58, female and male TgF344-AD rats were administered either water (CON) or 5.0 g/kg ethanol (AIE; 20% ethanol w/v) via intragastric gavage on a 2-day on/off cycle. In Experiment 1, Aβ was measured in the medial prefrontal cortex, orbitofrontal cortex (OFC), piriform cortex (PC), entorhinal cortex (EC), ventral hippocampus (vHPC), and dorsal hippocampus (dHPC) in 6- and 10-month-old rats. In Experiment 2, in vivo microdialysis was used in 3-month-old female rats to measure how ethanol directly modulates Aβ levels in the dHPC.ResultsIn the OFC, PC, EC, vHPC, and dHPC, Aβ40 and Aβ42 was higher in 6-month-old female TgF344-AD rats compared to males. However, at 10 months Aβ40 and Aβ42 levels were only elevated in the dHPC of AIE-treated females, compared to all other groups. An acute ethanol challenge at 3 months selectively evoked a sustained increase in interstitial fluid Aβ40 levels in AIE-treated females.ConclusionsIn aged females, the dHPC is a region sensitive to ethanol-associated Aβ pathology. This may be due to disruptions in Aβ clearance in early life, which may have an additive effect on Aβ aggregation over the lifespan.},
}

@article {pmid42212445,
year = {2026},
author = {Knell, G and Meeker, KL and Zhou, Z and Petersen, ME and Hall, JR and O'Bryant, SE},
title = {Evaluation of physical functioning as a marker of brain imaging outcomes in a multiethnic community-based cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449514},
doi = {10.1177/13872877261449514},
pmid = {42212445},
issn = {1875-8908},
abstract = {BackgroundPhysical functioning (PF) tests are scalable screening tools for neurodegenerative risk that differ by race and ethnicity, reflecting upstream social inequities. Prior work shows that PF relates to Alzheimer's disease blood biomarkers differentially by race and ethnicity, yet it is unclear if similar associations exist with structural brain outcomes (hyperintensities and brain volumes).ObjectiveThis study evaluated associations between PF and white matter hyperintensity volume (WMH), total brain volume (TBV), and hippocampal volume (HV) and assessed heterogeneity by race and ethnicity.MethodsCognitively normal non-Hispanic Black (n = 420), non-Hispanic white (n = 917), and Hispanic (n = 828) older adults (mean [SD] age = 64.7 [8.4]) from the Healthy Aging Brain Study-Health Disparities cohort completed the Timed Up and Go (TUG) and Short Physical Performance Battery (SPPB). Brain imaging was collected via 3 T magnetic resonance imaging (MRI). Multivariable linear models related PF to brain imaging outcomes (normalized by intracranial volume) and assessed heterogeneity by race and ethnicity.ResultsBonferroni adjusted significant (p < 0.05) associations were observed between WMH and PF (TUG: β = 0.28, 95% CI = 0.17, 0.40; SPPB:β = -0.19, 95% CI = -0.32, -0.07), TBV and PF (TUG: β = -0.50, 95% CI = -0.61, -0.40; SPPB: β = 0.30, 95% CI = 0.18, 0.42), and HV and PF (TUG: β = -0.28, 95% CI = -0.38, -0.18). Associations were generally similar across race and ethnicity groups for TBV and HV.ConclusionsPoorer PF was associated with reduced TBV and HV and greater WMH. Results support PF tests as scalable, non-invasive indicators of brain health in community-based populations.},
}

@article {pmid42212447,
year = {2026},
author = {Miller, JB and Rhoads, T and Vintimilla, R and Petersen, M and Wong, CG and Zhang, F and Kind, AJ and O'Bryant, SE and , },
title = {Associations between Alzheimer's disease blood biomarkers and neighborhood disadvantage: A HABS-HD community cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452660},
doi = {10.1177/13872877261452660},
pmid = {42212447},
issn = {1875-8908},
abstract = {BackgroundNeighborhood disadvantage has been associated with reduced cognitive reserve, increased risk for cognitive impairment, and greater Alzheimer's disease (AD) neuropathology, with particularly pronounced effects among Black and Hispanic/Latino older adults. Blood-based AD biomarkers offer a scalable approach to population-level study of AD risk; however, whether neighborhood-level social determinants influence these biomarkers across diverse populations remains unknown.ObjectiveTo characterize associations between neighborhood disadvantage and AD blood biomarkers in a racially and ethnically diverse community sample of older adults with and without cognitive impairment, and to examine whether these associations differ by race, ethnicity, and cognitive status.MethodsRegression models predicting AD biomarkers (amyloid-β 42/40 ratio, phosphorylated tau-181, total tau, and neurofilament light chain) from demographics and the Area Deprivation Index (ADI) were fit for 1179 Non-Hispanic White, 1264 Hispanic/Latino, and 724 Black adults. Models were stratified by cognitive impairment status and fit separately by race and ethnicity.ResultsAmyloid markers were associated with ADI, but only in cognitively impaired individuals living in highly disadvantaged areas. Total tau was elevated in those from disadvantaged neighborhoods, regardless of cognitive status; however, pTau-181 was not associated with ADI for any group. Significant associations were primarily evident among Black and Hispanic/Latino older adults.ConclusionsThe social exposome is an important factor in AD research, and findings show associations between neighborhood disadvantage and AD blood biomarkers; however, associations are mainly evident among ethnic/racial minority older adults living in moderately to severely disadvantaged neighborhoods. More work is needed to understand these associations.},
}

@article {pmid42212579,
year = {2026},
author = {Tan, Y and Liu, Q and Wu, C and Zhang, C and Yao, Q and Li, J and Kang, Y and Huang, B and Gu, L and Lu, J and Zhu, D and Sun, M},
title = {Comparative long-term outcomes of home-based versus institutional care in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451155},
doi = {10.1177/13872877261451155},
pmid = {42212579},
issn = {1875-8908},
abstract = {BackgroundThe decision between home-based (HC) and institutional care (IC) for Alzheimer's disease (AD) is critical for patients, families, and healthcare systems, yet evidence on long-term trade-offs remains insufficient.ObjectiveThis study comprehensively compare the 5-year clinical, economic, and family-related outcomes between HC and IC for AD patients.MethodsWe conducted a prospective-retrospective cohort study involving 252 AD patients (HC = 124; IC = 128) and their families. Outcomes included cognitive and functional status (using Mini-Mental State Examination and Barthel index), neuropsychiatric symptoms (Neuropsychiatric Inventory), medication adherence (Medication Possession Ratio and Morisky Medication Adherence Scale), healthcare costs, and family impact (Depression, Anxiety and Stress Scales and General Health Questionnaire).ResultsAnalysis revealed a critical dichotomy: HC showed better early cognitive preservation but later accelerated decline, contrasting with IC's stable trajectory. IC demonstrated superior control of harmful behaviors and prevention of consequential events, while HC was associated with more significant medical complications. Medication adherence was sustainably higher in IC but progressively deteriorated in HC. Economically, HC's lower initial direct costs were offset by substantial indirect costs, while IC incurred higher but predictable direct expenditures. Crucially, the psychological and health impact on family progressed substantially in HC but remained low and stable in IC.ConclusionsNo single care model was universally superior. The HC versus IC decision involves strategic trade-offs across clinical, economic, and family domains. These findings advocate for personalized, dynamic care models that facilitate timely transitions, guided by patient needs and family capacity, to optimize long-term outcomes for both patients and their families.},
}

@article {pmid42213044,
year = {2026},
author = {Marquilly, C and Busto, GU and Pasquer, L and Zinzen, RP and Hassan, BA and Fradkin, LG and Preat, T and Boulanger, A and Dura, JM},
title = {Amyloid precursor protein ortholog Appl acts with Vnd during mushroom body axon growth in Drosophila.},
journal = {Genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/genetics/iyag112},
pmid = {42213044},
issn = {1943-2631},
support = {//Ministère de l'Enseignement Supérieur et de la Recherche/ ; //Fondation pour la Recherche Médicale/ ; //Centre National de la Recherche Scientifique/ ; PJA 20151203422//Association pour la Recherche sur le Cancer/ ; ANR-21-CE16-0033-ORIO//Agence Nationale de la Recherche/ ; ANR-24-CE16-5161-ExOrion//Agence Nationale de la Recherche/ ; MND202411019909)//Fondation Langlois and the Fondation pour la Recherche Médicale/ ; },
abstract = {The amyloid precursor protein (APP) is associated with Alzheimer's disease. Appl is the single Drosophila APP ortholog and is expressed in all neurons throughout development. Appl was previously shown to cell-autonomously modulate axon outgrowth in the mushroom bodies (MBs), the fly olfactory memory center. However, we found that Appld, the only reported null allele, affects the normal function of vnd, the gene just proximal to Appl. To decipher developmental and memory defects specifically due to a loss of only Appl function, we generated a precise Appl null allele (ApplC2.1) by CRISPR/Cas9 genomic engineering. With ApplC2.1, we confirmed the partial contribution for Appl in MB axon outgrowth. We also produced new CRISPR vnd alleles removing either vnd-B or vnd-A function. We report here that vnd is also required for MB β-branch axon outgrowth and to a much greater extent than Appl itself. Moreover, vnd is expressed in neurons close to, but not within, the MB during development and is required non-cell-autonomously for MB axon outgrowth. It was previously shown that Appl knockdown in the MBs results in loss of memory following the association of odorants with electric shocks. Differently from Appld flies we found no defects of electric shock avoidance in ApplC2.1 flies, allowing us to test for memory. ApplC2.1 flies showed a complete loss of long-term memory which was fully rescued by MB-restricted expression of Appl+ only during the adult stage. Therefore, we demonstrate that the complete lack of Appl affects memory independently from structural developmental defects.},
}

@article {pmid42213122,
year = {2026},
author = {Chen, J and Yu, C and Xiang, J},
title = {DNA nanocage-assisted multiplex fluorescence quantification of size-fractionated low-mass soluble amyloid-β oligomers.},
journal = {Analytical and bioanalytical chemistry},
volume = {},
number = {},
pages = {},
pmid = {42213122},
issn = {1618-2650},
support = {kq2202071//the Natural Science Foundation of Changsha/ ; No. 2019TP1001//the Hunan Provincial Science and Technology Plan Project, China/ ; KF1910//the State Key Laboratory of Fine Chemicals, Dalian University of Technology/ ; 21573290//the National Natural Science Foundation of China/ ; },
abstract = {Low-mass soluble amyloid-β oligomers (LSAβOs) are increasingly recognized as key neurotoxic species in Alzheimer's disease, yet their structural heterogeneity and low abundance hinder fraction-specific quantitative analysis. Herein, we report a DNA nanocage-assisted multiplex fluorescence analytical platform for size-fractionated detection of LSAβOs in cerebrospinal fluid (CSF). The platform integrates size-selective nanocage recognition with a coupled catalytic hairpin assembly (CHA)-DNAzyme signal amplification architecture. Three customizable DNA nanocages with distinct cavity dimensions act as molecular size sieves, enabling differential capture of LSAβO fractions enriched in <10 kD, 10-30 kD, and 30-50 kD species. The released trigger strands initiate CHA-DNAzyme amplification, generating fluorescence signals that are subsequently resolved via signal deconvolution to yield apparent fraction-specific concentrations. The method achieves detection limits of 5 and 10 pM (S/N = 3) and demonstrates satisfactory recovery in spiked diluted CSF samples. This work establishes an analytical strategy that advances DNA nanocage-based sensing from size-selective recognition toward multiplex amplified quantitative profiling of heterogeneous amyloid oligomers.},
}

@article {pmid42213199,
year = {2026},
author = {Dhiman, N and Patial, K and Sandhir, R},
title = {Differential expression of PPAR isoforms in streptozotocin induced model of sporadic alzheimer's disease in zebrafish.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42213199},
issn = {1573-4978},
support = {DST/INSPIRE Fellowship/2019/IF190499//Department of Science and Technology/ ; CRG/2022/008902//Anusandhan National Research Foundation/ ; },
mesh = {Animals ; Zebrafish/genetics/metabolism ; Streptozocin/pharmacology ; *Alzheimer Disease/metabolism/genetics/chemically induced ; *Peroxisome Proliferator-Activated Receptors/genetics/metabolism ; Protein Isoforms/genetics/metabolism ; Disease Models, Animal ; PPAR gamma/genetics/metabolism ; Brain/metabolism ; Gene Expression Regulation ; },
abstract = {BACKGROUND: Sporadic Alzheimer's Disease (sAD) is a multifactorial neurodegenerative disorder in which metabolic dysfunctions and central insulin resistance are recognized as key pathogenic drivers accompanied by amyloid and tau pathology. Effective disease-modifying therapies remain elusive, representing a major global public health concern. Peroxisome proliferator-activated receptors (PPARs) have emerged as promising therapeutic targets due to their roles in regulating neuroinflammation, lipid metabolism and insulin sensitivity. Despite extensive studies highlighting the distinct role of PPAR isoforms in neurodegeneration, their involvement in sAD pathology remains unexplored.

METHODS: The role of PPARs was evaluated in streptozotocin (STZ) model of sAD. STZ was administered intracerebroventricularly at a dose of 5 mg/kg for 7 days. The cognitive functions and expression of PPAR isoforms and its downstream targets were investigated in adult zebrafish.

RESULTS: STZ-treated zebrafish exhibited significant cognitive impairment with decreased preference for the novel object indicating working memory deficits. Molecular analysis revealed isoform-specific modulation of PPARs. PPARα was upregulated, whereas its downstream targets (acox1, cpt1, map3k8) were downregulated suggesting impaired transcriptional activation. PPARγ, PPARβ/δ and their targets were significantly downregulated at both transcript and protein levels suggesting suppression of their neuroprotective functions. Immunofluorescence revealed distinct spatial localization patterns; PPARα was prominent in telencephalon and optic tectum; PPARγ showed punctate nuclear expression in preoptic area; and PPARβ/δ displayed diffuse nuclear staining in diencephalon.

CONCLUSIONS: These findings demonstrate that STZ-induced cognitive deficits are accompanied by region-specific dysregulation in expression of PPAR isoforms suggesting that PPAR modulation may be a therapeutic strategy to prevent sAD pathogenesis.},
}

Animals
Zebrafish/genetics/metabolism
Streptozocin/pharmacology
*Alzheimer Disease/metabolism/genetics/chemically induced
*Peroxisome Proliferator-Activated Receptors/genetics/metabolism
Protein Isoforms/genetics/metabolism
Disease Models, Animal
PPAR gamma/genetics/metabolism
Brain/metabolism
Gene Expression Regulation

@article {pmid42213219,
year = {2026},
author = {Abbracchio, MP and Damiani, E},
title = {Turning failure into success: how artificial intelligence can help personalize therapies and re-use patient data.},
journal = {Purinergic signalling},
volume = {22},
number = {3},
pages = {},
pmid = {42213219},
issn = {1573-9546},
mesh = {Humans ; *Precision Medicine/methods ; *Artificial Intelligence ; *Alzheimer Disease/drug therapy ; Clinical Trials as Topic ; },
abstract = {Despite robust preclinical evidence, many clinical trials, including several that targeted the purinergic system, fail to demonstrate efficacy in humans. Failure may stem from inability to accurately identify patient subgroups responding similarly to treatments. Here, we explore the potential of artificial intelligence to revolutionize how we group and classify patients in clinical studies. We introduce a new framework using Large Language Models-generated embeddings of detailed patient data, to create a semantic-aware latent space, enabling us to identify truly meaningful patients' clusters. Large Language Models can provide explainable groupings, giving clear reasons why certain patients respond similarly to treatments. We present an example of successful application of this approach through the re-analysis of the AMARANTH clinical trial (NCT02245737, involving ~ 2200 patients and completed in 2018) testing Lanabecestat, a BACE1 inhibitor decreasing β-amyloid production in Alzheimer's disease, for which traditional analysis reported no efficacy. As in the original trial, our simulation showed no overall benefit. However, re-analysis per patients' clusters and subjects' re-stratification by semantic similarities (shared symptom profiles, progression patterns) identified a patients' subgroup in one of the clusters showing Lanabecestat-associated slower disease worsening, thus succeeding where the full trial had failed. By making a new therapy available to at least a subset of patients with a defined disease, this new approach may help maximize the return on drug development and reduce the burden on healthcare. Moreover, it will significantly improve the precision, efficiency and interpretability of clinical trials, paving the way for a new era of personalized medical treatments.},
}

Humans
*Precision Medicine/methods
*Artificial Intelligence
*Alzheimer Disease/drug therapy
Clinical Trials as Topic

@article {pmid42213235,
year = {2026},
author = {Golomski, C},
title = {Dementia Diagnosis in Postapartheid South Africa: Providers' Perspectives in Ethnographic Context.},
journal = {Culture, medicine and psychiatry},
volume = {50},
number = {2},
pages = {},
pmid = {42213235},
issn = {1573-076X},
mesh = {Humans ; South Africa/ethnology ; *Dementia/diagnosis/ethnology ; Anthropology, Cultural ; *Apartheid ; *Alzheimer Disease/diagnosis/ethnology ; *Healthcare Disparities/ethnology ; Aged ; *Attitude of Health Personnel/ethnology ; *Racism/ethnology ; },
abstract = {This article situates perspectives of South African social service and health care providers on older adults who live with dementia and Alzheimer's disease in ethnographic context. A review of findings from multi-year field research on long-term care and service provision for older adults in peri-urban Mpumalanga shows: racial disparities in accessing formal dementia diagnoses; aggression, forgetfulness, and wandering as the most reported symptoms of presumed dementia; and provider-reported ethno-racial differences in families' diagnostic- and care-seeking practices. Findings corroborate evaluative research showing structural barriers to diagnosis and care. Hansen's concept of diagnostic apartheid is expanded to explain how making sense of dementia is a sometimes partial, unequal, and racializing process; how older adulthood is reproduced as a structurally vulnerable position; and how historical consciousness of violence informs understandings and non-integration of neuropsychiatric and other models of dementia.},
}

Humans
South Africa/ethnology
*Dementia/diagnosis/ethnology
Anthropology, Cultural
*Apartheid
*Alzheimer Disease/diagnosis/ethnology
*Healthcare Disparities/ethnology
Aged
*Attitude of Health Personnel/ethnology
*Racism/ethnology

@article {pmid42213639,
year = {2026},
author = {Li, N and He, F and Xie, S and Wang, Z and Tan, J and Yuan, S},
title = {Exploring the Causality Between Mood Swings and Neurological Diseases: A Mendelian Randomization Study.},
journal = {Brain and behavior},
volume = {16},
number = {6},
pages = {e71506},
doi = {10.1002/brb3.71506},
pmid = {42213639},
issn = {2162-3279},
support = {82405591//Young Scientists Fund of the National Natural Science Foundation of China/ ; Z2023XJZD08//Key project of Hunan University of Chinese Medicine/ ; B2024011//General Project of Hunan Traditional Chinese Medicine Research Project/ ; S202410541039//Hunan University of Chinese Medicine Undergraduate Research Innovation Fund Project/ ; },
mesh = {Humans ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; *Nervous System Diseases/genetics ; Stroke/genetics ; *Mood Disorders/genetics ; Epilepsy/genetics ; Headache/genetics ; Alzheimer Disease/genetics ; Causality ; },
abstract = {BACKGROUND: Associations between genetically predicted mood swings and neurological diseases have been suggested. However, the causal relationships between these factors remain undefined.

METHOD: We used a Mendelian randomization (MR) study to examine the causal relationship of genetically predicted mood swings with the risk of neurological diseases, including stroke, Alzheimer's disease (AD), multiple sclerosis (MS), epilepsy (EP), and headache. The single-nucleotide polymorphisms (SNPs) that exhibited genetic associations with mood swings were utilized as instrumental variables (IV) in the study. We performed MR analyses using the inverse variance weighted (IVW) method as the main approach. Sensitivity analyses were further performed using MR-Egger and MR-PRESSO to assess the robustness.

RESULTS: The MR analysis revealed significant causal of mood swings on stroke (OR = 1.300, 95% CI = 1.060-1.600; p = 0.012), headache (OR = 1.020, 95% CI = 1.000-1.030; p = 0.005), excluding AD (p = 0.548), EP (p = 0.449), MS (p = 0.494).

CONCLUSION: The findings of this research indicate a possible causal link existing between mood swings and stroke and headache. Additional investigative efforts are requisite for elucidating the underlying biological mechanisms that drive these observed associations.},
}

Humans
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
*Nervous System Diseases/genetics
Stroke/genetics
*Mood Disorders/genetics
Epilepsy/genetics
Headache/genetics
Alzheimer Disease/genetics
Causality

@article {pmid42213773,
year = {2026},
author = {Maehara, N and Hattori, S and Nakamura, A and Nagatoishi, S and Hirota, A and Kudo, K and Yoshikawa, Y and Matsunaga, R and Tsumoto, K and Miyakawa, T and Arai, S and Miyazaki, T},
title = {CD5L promotes phagocytic removal of amyloid β oligomers and improves cognitive function in a mouse model of Alzheimer's disease.},
journal = {Cell reports},
volume = {45},
number = {6},
pages = {117468},
doi = {10.1016/j.celrep.2026.117468},
pmid = {42213773},
issn = {2211-1247},
abstract = {Alzheimer's disease (AD), a neurodegenerative disorder, is the leading cause of dementia. Amyloid-beta (Aβ) and tau are major contributors to AD onset and progression. Here, we investigate the therapeutic potential of CD5L, a macrophage-specific secretory protein, in reducing Aβ accumulation and improving AD pathology. CD5L directly binds to Aβ, particularly the neurotoxic Aβ42, and blocks their aggregation. Moreover, CD5L enhances microglial phagocytosis against several forms of Aβ40 and Aβ42. In 5xFAD mice, a well-established AD murine model, forced expression of CD5L reduces Aβ plaque size and number. RNA sequencing shows that CD5L promotes phagocytic activity in microglia within the 5xFAD mouse brain. Furthermore, adeno-associated virus (AAV)-mediated delivery of CD5L improves cognitive function, as demonstrated by enhanced performance in the T-maze test. These findings highlight the role of CD5L in inhibiting Aβ aggregation and facilitating Aβ clearance via enhanced phagocytosis, offering a promising therapeutic strategy for AD.},
}

@article {pmid42213912,
year = {2026},
author = {Wilson, S and Beswick, E and Popp, Z and Rahman, S and Bhogal, S and Whitfield, T and Low, S and Khan, R and Tolley, C and Walker, Z and Au, R and Slight, SP},
title = {Acceptability of Technologies to Support Early Dementia Detection: Qualitative Study With the Boston University Alzheimer's Disease Center Cohort.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e84004},
doi = {10.2196/84004},
pmid = {42213912},
issn = {1438-8871},
mesh = {Humans ; Aged ; Female ; *Dementia/diagnosis ; Male ; Boston ; *Alzheimer Disease/diagnosis ; Digital Health ; Cognitive Dysfunction/diagnosis ; Cohort Studies ; Aged, 80 and over ; Early Diagnosis ; Qualitative Research ; *Patient Acceptance of Health Care ; },
abstract = {BACKGROUND: Dementia is on the rise globally due to increasing life expectancies and population growth. Digital technologies may help detect early signs, enabling timely interventions to slow or reverse cognitive decline. However, to support the successful implementation of these digital technologies into health care settings, they must be acceptable to target users. Older adults and those with mild cognitive impairment (MCI) are at risk of developing dementia in later life and need to be able to use these technologies in order for this intervention to be approved and implemented in clinical practice.

OBJECTIVE: This study explored the perspectives of older adults and those living with a clinical diagnosis of MCI on the acceptability of using various digital technologies that have the potential to support early dementia detection.

METHODS: Participants were recruited from Boston University's Alzheimer's Disease Research Center. Participants selected at least 2 technologies from 9 different wearables and software to use for 2 weeks, at 3-month intervals, over a total duration of 2 years. A subgroup of self-selecting participants was interviewed after the first 2 weeks of use to gather initial perspectives regarding the acceptability of using the digital technologies. An inductive framework thematic analysis approach was used, assisted by NVivo (version 14.23.2; QSR International).

RESULTS: In total, 13 individuals living with a clinical diagnosis of MCI and 11 adults aged 65 years and older were interviewed. Our analysis identified five key themes: (1) gamification, (2) wearability, (3) user guidance, (4) burden of use, and (5) usefulness. Gamified apps were generally liked, although users with little experience of digital games needed time to adjust. Wearables resembling everyday accessories (eg, watches) were preferred, but complaints about tight or uncomfortable straps were frequently reported. Clear instructions were critical to support correct use, but many participants would have liked more troubleshooting support when technical issues arose. The use of 5 or more devices led to a high burden, especially when devices had practicality issues such as not being waterproof. Devices offering personal feedback were perceived as useful to satisfy personal interests, though some questioned their usefulness within health care. Participants raised concerns about losing valued personal interactions with health care professionals and questioned how their existing health conditions and treatment for such conditions may affect the validity of the data collected by the devices.

CONCLUSIONS: These findings can guide researchers in choosing appropriate devices and minimizing burden. Future work should explore the views of those experiencing digital exclusion to ensure equitable access to dementia-detection technologies.},
}

Humans
Aged
Female
*Dementia/diagnosis
Male
Boston
*Alzheimer Disease/diagnosis
Digital Health
Cognitive Dysfunction/diagnosis
Cohort Studies
Aged, 80 and over
Early Diagnosis
Qualitative Research
*Patient Acceptance of Health Care

@article {pmid42214129,
year = {2026},
author = {Saunders, DM and Kearns, NA and Ng, B and Sultan, F and Vyas, H and Vialle, RA and Clark, EM and Tissera, S and Xu, J and Bennett, DA and Wang, Y},
title = {Modeling stimulus-induced stress responses in microglia-like cells using a commercial iPSC-dCas9-KRAB line.},
journal = {Stem cell research},
volume = {94},
number = {},
pages = {104017},
doi = {10.1016/j.scr.2026.104017},
pmid = {42214129},
issn = {1876-7753},
abstract = {Commercially available human iPSC lines with inducible CRISPR interference (CRISPRi) systems offer scalable platforms for gene function studies. One widely available line, the AICS-0090 dCas9-KRAB iPSC line developed by the Allen Institute, has been extensively validated for genomic integrity and stem cell potency. However, its utility in modeling specialized immune cell types such as microglia - and in assessing their functional responses to disease-relevant stimuli - has not been fully established. Here, we evaluated the AICS-0090 line for its ability to differentiate into microglia-like cells, support efficient gene knockdown, and respond to environmental stressors. We assessed its differentiation capacity by qPCR, flow cytometry, and immunocytochemistry, confirming reproducible expression of microglial surface markers at early and late timepoints. Gene knockdown efficiency was validated both at the single-gene level and in pooled CRISPRi screens. Focusing on functional responsiveness, we exposed the microglia-like cells to two distinct stimuli: aggregated amyloid-β (Aβ), a disease-associated trigger in Alzheimer's disease, and lipopolysaccharide (LPS), a classical inflammatory signal. Transcriptomic and functional analyses revealed stimulus-specific responses: aggregated Aβ induced limited activation of stress and inflammation pathways, whereas LPS elicited broader transcriptional reprogramming and cytokine release. Signatures from both conditions partially overlapped with ex vivo human and mouse microglial states. Together, these findings support the use of the AICS-0090 dCas9-KRAB iPSC-derived microglia-like cells as a flexible and tractable model for gene function interrogation under defined inflammatory contexts, with potential for future applications in neuroimmune modeling and perturbation-based screening.},
}

@article {pmid42214165,
year = {2026},
author = {Łosińska, K and Maszczyk, A},
title = {Can table tennis protect the aging brain? A systematic review and meta-analysis in neurodegenerative diseases.},
journal = {Acta psychologica},
volume = {267},
number = {},
pages = {107135},
doi = {10.1016/j.actpsy.2026.107135},
pmid = {42214165},
issn = {1873-6297},
abstract = {BACKGROUND: Table tennis (TT) is an increasingly investigated intervention for supporting cognitive, motor, and psychosocial functions in older adults with neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. However, the available evidence remains limited, heterogeneous, and methodologically inconsistent.

MATERIALS AND METHODS: Following PRISMA 2020 guidelines, a systematic search of PubMed, Scopus, Web of Science, and SPORTDiscus was conducted through June 30, 2025. Out of 499 screened records, ten studies met the inclusion criteria, with five eligible for quantitative synthesis. Random-effects meta-analyses (DerSimonian-Laird) were performed for cognitive and motor outcomes. Risk of bias was assessed using the JBI checklist, and certainty of evidence was evaluated with the GRADE framework.

RESULTS: The meta-analysis demonstrated large pooled effects for cognitive outcomes (MMSE: d = 1.44; MoCA: d = 1.31), motor function (UPDRS-III: d = 1.27), and dual-task gait (TUG: d = 0.93). Heterogeneity was low to moderate (I[2] = 18-42%), although the small number of studies warrants cautious interpretation. Sensitivity analyses confirmed the robustness of the findings, and no serious adverse events were reported.

CONCLUSIONS: TT appears to be a safe, feasible, and potentially effective non-pharmacological intervention for improving cognitive and motor outcomes in individuals with AD, PD, and dementia. Nevertheless, the limited number of small-scale studies and methodological variability restrict definitive conclusions, highlighting the need for high-quality trials.},
}

@article {pmid42214342,
year = {2026},
author = {Chayama, Y and Rao, NR and Perla, D and Zhang, Z and Reid, M and Nelson, S and Wen, X and Ding, B and Blumenfeld, J and Apolonio, A and Doddipalli, S and Zhou, H and Turhan, SG and Shih, PY and Brendel, M and Fu, YH and Ertürk, A and Kolabas, ZI and Huang, Y and Yang, AC},
title = {Physiological brain clearance architecture revealed by neuronal protein tracing.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.04.048},
pmid = {42214342},
issn = {1097-4172},
abstract = {The brain must efficiently clear protein waste to maintain homeostasis, yet physiological drainage pathways remain poorly defined. Standard tracer injection approaches may not reflect endogenous efflux. Here, we develop a non-invasive genetic system to trace neuron-derived protein clearance from the brain to cerebrospinal fluid (CSF) and border tissues. We identify distinct drainage routes and border hotspots missed by tracer injection, confirmed by bioorthogonal labeling of endogenous neuronal proteins. Pulse-chase kinetics reveal slow skull outflow versus rapid dural and nasal clearance. Transcriptomic analyses uncover border cells sampling neuronal antigens, including tolerogenic skull-resident B cells. Region-restricted reporter expression demonstrates compartmentalized clearance following a "nearest exit" principle, where anatomical origin dictates drainage pathway. Disease disrupts clearance through distinct mechanisms: inflammation drives vascular leakage into blood, while amyloid pathology causes parenchymal retention and border exit obstruction. These findings define brain clearance as a compartmentalized system of organized pathways and immune niches whose dysfunction may underlie regional vulnerability in neurological disease.},
}

@article {pmid42214359,
year = {2026},
author = {Schnieder, M and von Arnim, C},
title = {[Advances in Anti-Dementia Therapies in Older Adults].},
journal = {Deutsche medizinische Wochenschrift (1946)},
volume = {151},
number = {12},
pages = {606-611},
doi = {10.1055/a-2676-7649},
pmid = {42214359},
issn = {1439-4413},
mesh = {Humans ; *Dementia/therapy/drug therapy ; Cholinesterase Inhibitors/therapeutic use ; Aged ; Alzheimer Disease ; },
abstract = {The rising prevalence of dementia, driven by demographic aging, underscores the urgent need for effective therapeutic strategies. This update reviews recent advances in anti-dementia treatments, focusing on pharmacological and non-pharmacological interventions. Acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor agonist memantine, traditionally used for Alzheimer's disease, are now recommended off-label for vascular dementia, offering modest cognitive benefits with manageable side effects. The approval of amyloid-targeting monoclonal antibodies - lecanemab and donanemab - marks a paradigm shift, as these agents demonstrate disease-modifying potential in mild cognitive impairment (MCI) and early Alzheimer's disease by reducing amyloid plaques and slowing cognitive decline. However, their use is complicated by amyloid-related imaging abnormalities (ARIA), necessitating careful patient selection and monitoring, particularly in APOE4 homozygotes. Non-pharmacological approaches, including cognitive and physical training, have gained prominence. Regular moderate exercise (150 minutes/week) improves cognitive function in MCI and dementia, while multimodal interventions (e.g., FINGER, POINTER) target risk reduction through lifestyle modifications. Digital health applications, such as "Neuronation" and "Memodio", offer promising adjuncts, though evidence remains limited. The failure of GLP-1 analogs (e.g., semaglutide) in recent trials highlights the challenges in repurposing metabolic agents for neurodegeneration. The introduction of disease-modifying therapies emphasizes the importance of early diagnosis and comprehensive geriatric assessment to balance efficacy, safety, and patient-centered outcomes. Ongoing research and real-world data will further clarify the long-term benefits and risks of these innovations, shaping future dementia care.},
}

Humans
*Dementia/therapy/drug therapy
Cholinesterase Inhibitors/therapeutic use
Aged
Alzheimer Disease

@article {pmid42214568,
year = {2026},
author = {Zhong, RF and Chen, ZQ and Li, SF and Jiang, JG},
title = {Neuroprotective effects of Uncaria rhynchophylla alkaloid extracts against amyloid-β toxicity via regulation of oxidative stress pathways.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121918},
doi = {10.1016/j.jep.2026.121918},
pmid = {42214568},
issn = {1872-7573},
abstract = {Uncaria rhynchophylla is a important medicinal plant in Chinese traditional medicine for the treatment of neurological disorders, its alkaloid-rich constituents are considered the primary bioactive components responsible for its effects on the central nervous system.

AIM OF THE STUDY: This study aimed to investigate the neuroprotective effects of U. rhynchophylla alkaloid extract (URAs) against amyloid-β (Aβ)-induced neurotoxicity and oxidative stress, and elucidate underlying molecular mechanisms.

MATERIALS AND METHODS: URAs was prepared and characterized by LC-MS/MS for chemical profiling. The neuroprotective effects were evaluated using transgenic C. elegans CL2006 and CL2355, and H2O2-induced PC12 cells. In C. elegans, paralysis assay, Aβ deposition, and chemotaxis behavior were assessed. Oxidative stress markers including reactive oxygen species (ROS), lipofuscin accumulation, lipid peroxidation (MDA), and antioxidant enzyme activities (SOD, CAT) were measured. Quantitative real-time PCR was performed to examine the expression of genes of related signaling pathways. In PC12 cells, cell viability, ATP levels, and oxidative stress were evaluated.

RESULTS: URAs treatment significantly delayed Aβ-induced paralysis, reduced Aβ deposition, and improved chemotaxis behavior in transgenic C. elegans, while decreasing ROS, lipofuscin, and MDA, and increasing SOD and CAT activities. Furthermore, URAs modulated the expression of genes involved in Aβ metabolism, proteasome function, and antioxidant defense, and significantly suppressed the expression of p38 MAPK signaling pathway components.

CONCLUSION: Our findings demonstrate that URAs exert neuroprotective effects against Aβ toxicity and oxidative stress through multi-target mechanisms involving enhanced antioxidant defense, regulated proteostasis, highlighting their therapeutic potential for AD intervention.},
}

@article {pmid42214573,
year = {2026},
author = {Huang, R and Ye, X and Liu, J and Yang, C and Meng, X and Dou, T and Zhuang, X and Yang, J and Zheng, N and Zhao, Y and Wang, Z and Wang, Q and Hu, J},
title = {Ext1-targeted gene therapy ameliorates tauopathy by inhibiting heparan sulfate-dependent tau propagation.},
journal = {Pharmacological research},
volume = {230},
number = {},
pages = {108265},
doi = {10.1016/j.phrs.2026.108265},
pmid = {42214573},
issn = {1096-1186},
abstract = {The propagation of pathological tau protein in neuronal cells is a critical driver of neurodegeneration in tauopathies, including Alzheimer's disease. Heparan sulfate (HS) critically regulates pathological tau seeding and cellular uptake processes closely linked to the development of tau pathology in tauopathies, identifying HS as a key potential therapeutic target. Here, we focused on targeting Exostosin-1 (Ext1), an essential enzyme for HS biosynthesis, in the tau[P301S] transgenic (PS19) tauopathy mouse model. Conditional knockdown of neuronal Ext1 in PS19 mice by delivering an adeno-associated viral vector expressing Ext1 shRNA decreased neuronal HS levels, resulting in reduced pathological tau phosphorylation, enhanced synaptic function, and restored cognitive performance. Notably, decreasing neuronal Ext1 impeded the intercellular spread of human tau in the mouse brain. Furthermore, treating disease-onset PS19 mice with an antisense oligonucleotide targeting Ext1 ameliorated tau aggregation, improved behavioral deficits, and attenuated neurodegeneration and neuroinflammation. These results suggest that inhibiting tau propagation by targeting Ext1-mediated HS production could be a promising gene therapy approach for tauopathies.},
}

@article {pmid42214609,
year = {2026},
author = {Yuan, S and Lin, L and Liu, J and Lin, Q and Wang, S and Wu, J and Xu, D and Liu, Y and Lee, JY and Qiu, L},
title = {Treadmill exercise attenuates neuroinflammation in APP/PS1 mice via gut microbiota remodeling: Evidence from fecal microbiota transplantation.},
journal = {Life sciences},
volume = {400},
number = {},
pages = {124500},
doi = {10.1016/j.lfs.2026.124500},
pmid = {42214609},
issn = {1879-0631},
abstract = {Alzheimer's disease is associated with gut microbiota dysbiosis, intestinal barrier dysfunction, lipopolysaccharide (LPS) translocation, and neuroinflammation. However, it is unclear whether exercise-induced gut microbiota remodeling causally contributes to the neuroprotective effects of exercise in AD. Herein, APP/PS1 mice underwent 12 weeks of treadmill exercise, and fecal microbiota transplantation (FMT) was used to determine whether exercise-related benefits could be transferred to the recipient mice. Behavioral performance was assessed using the Morris water maze and open-field test. Gut microbial profiles were analyzed by 16S rDNA sequencing. Intestinal barrier integrity was evaluated using histology, AB-PAS staining, and tight-junction protein expression, while plasma and brain LPS levels were measured by enzyme-linked immunosorbent assay. Neuroinflammation was examined with immunofluorescence and Western blotting. It was found that treadmill exercise improved spatial learning, memory, and anxiety-like behavior in APP/PS1 mice. These benefits were partly reproduced in recipients of microbiota from exercised donors. Exercise also restored gut microbial diversity and composition, increased the abundance of taxa including Dubosiella and UBA1819, alleviated colonic injury, enhanced mucus secretion, upregulated ZO-1, Occludin, and Claudin-1, and reduced plasma and brain LPS levels. In parallel, exercise and FMT from exercised donors decreased brain TLR4 expression, attenuated microglial and astrocytic activation, and suppressed TLR4/NF-κB signaling and downstream inflammatory cytokines. These findings indicate that treadmill exercise alleviates neuroinflammation in APP/PS1 mice, at least in part, through gut microbiota remodeling, improved intestinal barrier integrity, and reduced LPS-driven inflammatory signaling.},
}

@article {pmid42214647,
year = {2026},
author = {Nguyen, HTN and Hwang, YY and Park, RM and Kim, YH and Min, J and Choi, DW},
title = {Yeast-derived vacuoles as potential therapeutic agents for modulating neuroinflammation in Alzheimer's disease.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {102963},
doi = {10.1016/j.nano.2026.102963},
pmid = {42214647},
issn = {1549-9642},
abstract = {Neuroinflammation is a major contributor to Alzheimer's disease (AD) pathology, including amyloid precursor protein (APP)/amyloid-beta (Aβ)-associated protein expression and Tau phosphorylation. Here, we evaluated yeast-derived vacuoles as orally deliverable bio-derived vesicular structures for modulating AD-associated neuroinflammatory responses. In lipopolysaccharide (LPS)-stimulated C6 glioma cells, vacuoles were efficiently internalized, showed minimal cytotoxicity, reduced APP/Aβ-related protein and phosphorylated Tau levels, and suppressed p38 MAPK and NF-κB signaling, including downstream inducible nitric oxide synthase expression. In aged C57BL/6 mice, oral vacuole administration reduced brain APP/Aβ-related protein, Tau, and phosphorylated Tau levels and improved histological features in the hippocampus and cortex. Although direct brain biodistribution was not detected by IVIS imaging, the observed functional changes support further investigation of vacuole-mediated gut-to-brain bioactivity. These findings suggest yeast-derived vacuoles as a promising bio-derived platform for modulating neuroinflammation in AD.},
}

@article {pmid42214747,
year = {2026},
author = {Long, X and Shen, R and Yang, Y and Xu, Y and Wang, Y and He, Y and Xie, Y and Xie, X and Gao, D and Pang, X and Du, L},
title = {Isoquercetin-ligustrazine co-polymorph attenuates hypoxia-accelerated Alzheimer's disease by suppressing PERK-CHOP-mediated ER stress.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115856},
doi = {10.1016/j.expneurol.2026.115856},
pmid = {42214747},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD), a neurodegenerative disorder predominantly affecting the elderly population, is frequently associated with hypoxic conditions, including obstructive sleep apnea and other age-related comorbidities. Arising from various pathological conditions, chronic hypoxia may contribute to the acceleration of AD progression. However, the precise mechanisms underlying hypoxia-induced cellular stress responses, particularly those involving ER stress and the PERK pathway, remain insufficiently explored. In this study, the therapeutic effects of a co-polymorph combining Isoquercetin and Ligustrazine (ILCP) on AD-related pathologies aggravated by chronic hypoxia were investigated. ApoE3/4 transgenic mice were exposed to hypoxic conditions for four weeks; results on oxidative stress levels, β-amyloid (Aβ) deposition, and neuronal apoptosis were assessed. Chronic hypoxia was found to intensify PERK pathway activity, elevate neuronal damage, and further aggravate AD-associated cognitive deficits. ILCP administration was associated with reduced PERK pathway activation, resulting in reduced oxidative stress, alleviated neuronal damage, and preserved synaptic plasticity. These findings support a role for PERK-CHOP signaling in hypoxia-driven AD pathology and suggest a potential link between ILCP treatment and modulation of this pathway.},
}

@article {pmid42214748,
year = {2026},
author = {Fritz, N and Johannesson, M and Eriksson, F and Osswald, G and Lannfelt, L and Möller, C and Söderberg, L},
title = {Lecanemab promotes Fc receptor-dependent cell-mediated internalization and degradation of aggregated amyloid-beta in vitro and ex vivo.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138645},
doi = {10.1016/j.neulet.2026.138645},
pmid = {42214748},
issn = {1872-7972},
abstract = {Plaque deposits containing aggregated amyloid beta peptide (Aβ) fibrils are present in brain regions affected by Alzheimer's disease (AD). Lecanemab is a therapeutic monoclonal antibody that binds preferentially to soluble Aβ assemblies known as protofibrils, as well as to aggregated Aβ in amyloid plaques. Administration of lecanemab to individuals with early-stage AD reduces plaque burden and slows cognitive decline. The present study explored the role of immune cells in the mechanism of action of lecanemab using confocal microscopy, flow cytometry, and immunoassays. We show that lecanemab increases the internalization of synthetic Aβ42 protofibrils by human monocytic and mouse microglial cells, and that this effect is Fc gamma receptor-dependent. The Aβ42 protofibrils taken up by these cells were subsequently degraded within lysosomes. To investigate immune cell involvement in a system that resembled the clinical situation more closely, we evaluated the involvement of lecanemab in the removal of plaque pathology from sections of postmortem AD brain by primary human macrophages. Our results confirm that the lecanemab-mediated decrease in plaque pathology requires the presence of immune cells and is Fc gamma receptor-dependent. These data support the hypothesis that lecanemab's clinical effects involve Fc gamma receptor-dependent immune cell-mediated internalization and lysosomal degradation of Aβ protofibrils and plaques.},
}

@article {pmid42214759,
year = {2026},
author = {Liu, Y and Luo, S and Liu, J and Xu, B},
title = {The association between exposure to flame retardants and cognitive function in the elderly: Unveiling potential intervention strategies.},
journal = {Neurotoxicology},
volume = {114},
number = {},
pages = {103478},
doi = {10.1016/j.neuro.2026.103478},
pmid = {42214759},
issn = {1872-9711},
abstract = {BACKGROUND: Human beings have been widely exposed to various types of flame retardants, but little is known about their effects on cognitive function in the elderly.

OBJECTIVE: To investigate the individual and combined effects of four common flame retardants on cognitive function and the gender differences in the relationship between the four flame retardants and cognitive function.

RESULTS: Results revealed that BDCPP and BCEP are both negatively correlated to cognitive function scores (β = -0.06; 95% CI: -0.23, 0.36; β = -0.01; 95% CI: -0.26, 0.28). Notably, two flame retardants, BDCPP and BCEP showed higher relative contribution weights in the WQS model, suggesting they may play a more important role in the mixture effect, pending further validation. Furthermore, Serum Klotho levels were statistically associated with exposure to flame retardants and cognitive outcomes, supporting the exploratory hypothesis that Klotho acts as a potential mediating factor. In the bioinformatics analysis, we identified 622 target genes associated with cognitive decline observed in relation to flame retardant exposure. In addition, enrichment analysis showed that flame retardant-related cognitive decline was associated with pathways such as Apoptosis, Gene expression, Cell proliferation, Metabolic pathways, Pathways of neurodegeneration, PI3K-Akt signaling pathway, MAPK signaling and Alzheimer disease. Cytoscape was used to identify key genes, including MDM2, CASP3, ACTB, TP53, SQSTM1, and PCNA.

CONCLUSIONS: Our results showed a negative correlation between the four flame retardants and cognitive function. Potential biological pathways of the association between mixed flame retardants exposure and cognitive function may involve Apoptosis, Metabolic pathways, PI3K-Akt signaling pathway, MAPK signaling, and Alzheimer disease. The causality and mechanisms underlying this association require further validation through longitudinal studies or interventional research.},
}

@article {pmid42214901,
year = {2026},
author = {Zhou, Y and Peng, G and Liao, Z and Liu, H and Liu, J and Liao, W and Qu, Q and Shi, J and Geng, J and Zhi, N and Cao, W and Song, Y and Zhang, Y and Wang, X and Wang, L and Zhu, Y and Zhou, Y and Wang, H and Sun, Y and Ren, R and Xie, H and Wang, G and , },
title = {Mapping the nature, type, and association network of safety incidents among individuals with cognitive impairment in China: a large-scale multicenter cross-sectional study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100606},
doi = {10.1016/j.tjpad.2026.100606},
pmid = {42214901},
issn = {2426-0266},
abstract = {BACKGROUND: Patient safety critically influences both quality of life and disease progression in older adults with cognitive impairment, yet large-scale multicenter data remain scarce. This study aims to systematically analyze the types of safety incidents experienced by patients with Alzheimer's disease and related cognitive impairments, and explore the network associations of different safety incidents.

METHODS: Initiated by the Alzheimer's Disease China (ADC), this survey recruited 1057 older individuals with Alzheimer's and related cognitive impairments, along with their families, across 31 provinces, autonomous regions, and municipalities. The safety incidents evaluated in this study included falls, getting lost, medication errors, verbal aggression, physical aggression, household fire, aspiration, and choking. Incidence rates for overall and specific safety incidents were calculated. Correlation analyses and network analysis were performed to examine relationships between safety incidents.

RESULTS: A high proportion (73.5%) of participants reported at least one safety incident in the past year, with over one-third (36.0%) experiencing three or more concurrent incidents. Medication errors (55.9%) and verbal aggression (39.6%) were most frequent, followed by falls (32.5%) and physical aggression (22.7%). Incidence rates varied significantly by cognitive impairment stage, care setting, and geographic region. Network analysis highlighted medication errors and getting lost as central nodes bridging other incidents.

CONCLUSIONS: This study reveals an alarmingly high incidence of safety incidents among cognitively impaired patients, affecting their physical, psychological, and familial well-being. A collaborative, multidisciplinary effort involving healthcare professionals, family caregivers, fire and police emergency responders, and public health policymakers is essential to develop individualized safety strategies aligned with patient needs and contextual considerations.},
}

@article {pmid42214902,
year = {2026},
author = {Kuhn, E and Kleineidam, L and Stark, M and Peters, O and Hellmann-Regen, J and Preis, L and Gref, D and Priller, J and Spruth, EJ and Gemenetzi, M and Schneider, A and Fliessbach, K and Wiltfang, J and Bartels, C and Hansen, N and Rostamzadeh, A and Düzel, E and Glanz, W and Incesoy, E and Buerger, K and Janowitz, D and Stöcklein, S and Perneczky, R and Rauchmann, BS and Teipel, SJ and Kilimann, I and Laske, C and Sodenkamp, S and Spottke, A and Kronmüller, M and Roeske, S and Brosseron, F and Ramirez, A and Synofzik, M and Schmid, MC and Jessen, F and Wagner, M and , and , },
title = {Subjective cognition trajectories, Alzheimer biomarkers, and incident mild cognitive impairment.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100609},
doi = {10.1016/j.tjpad.2026.100609},
pmid = {42214902},
issn = {2426-0266},
abstract = {BACKGROUND: Subjective cognitive decline is common in older adults and may represent an early clinical signal along the Alzheimer's disease continuum. The clinical relevance of longitudinal changes in subjective cognitive decline remains unclear.

OBJECTIVES: To determine whether trajectories of self- or study partner-reported cognitive decline predict progression to mild cognitive impairment and reflect Alzheimer's disease-specific biological patterns.

DESIGN, SETTING, PARTICIPANTS: Data were pooled from two observational cohorts. Cognitively unimpaired participants with baseline amyloid status, repeated assessments of subjective cognitive decline, and clinical follow-up were included. The study included 770 participants with a median follow-up of 5.0 years (interquartile range 4.0-7.0).

MEASUREMENTS: Subjective cognitive decline was assessed using the Everyday Cognition questionnaire completed by participants and study partners. Linear mixed-effects models examined associations with amyloid status and progression to mild cognitive impairment. Cox proportional hazards models tested whether one-year changes predicted progression.

RESULTS: Amyloid-positive participants and those who progressed to mild cognitive impairment showed steeper increases in self- and study partner-reported cognitive difficulties over time. Among amyloid-positive participants, only increases in study partner-report differentiated progressors from non-progressors. One-year increases in study partner-report predicted a higher risk of mild cognitive impairment compared with unchanged scores (hazard ratio 3.24; 95% confidence interval 1.73-6.07]), with effects confined to amyloid-positive participants.

CONCLUSIONS: Short-term increases in study partner-reported cognitive difficulties identify amyloid-positive cognitively unimpaired older adults at increased risk of near-term progression to mild cognitive impairment. Longitudinal monitoring using study partner reports may provide a low-burden and clinically relevant approach for early risk stratification and surveillance in aging populations.},
}

@article {pmid42215016,
year = {2026},
author = {Kandoi, S and Hiya, S and Maldonado-Díaz, C and Rohde, SK and Bernardes, C and Almeida, FC and Samanamud, J and Clare, K and Virata, MC and Slocum, CC and Mir, E and White, CL and Daoud, EV and Farrell, K and Crary, JF and Oliveira, TG and Gonzales, MM and Walker, JM and Richardson, TE},
title = {Comorbid neuropathologies but not Braak stage influence cognitive impairment in primary age-related tauopathy.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag053},
pmid = {42215016},
issn = {1554-6578},
support = {R21 AG078505/AG/NIA NIH HHS/United States ; 957581 and 957607//Texas Alzheimer's Research and Care Consortium (TARCC)/ ; },
abstract = {Primary age-related tauopathy (PART) is a β-amyloid-independent tauopathy, thought by some to be a distinct process from Alzheimer disease neuropathologic change (ADNC). Two categories of PART have been defined: definite PART (those with complete absence of β-amyloid deposition) and possible PART (those with minimal and restricted β-amyloid distribution). It is unclear whether there is any significant cognitive effect of "isolated" or "pure" PART, as opposed to ADNC, in which cognitive decline mirrors pathologic progression. We evaluated the effects of neurodegenerative pathologies on longitudinal cognitive decline using a combination of univariate analysis, multivariable logistic regression analysis, and variance decomposition in patient cohorts with neuropathologically confirmed definite PART (n = 174) and possible PART (n = 182). ADNC-related pathologies did not significantly contribute to cognitive impairment in either cohort. Cognitive decline in definite PART was instead dependent on the presence and severity of TDP-43 pathology/limbic-predominant age-related TDP-43 encephalopathy (LATE) stage, Lewy body pathology, and arteriolosclerosis, while cognitive impairment in possible PART was primarily affected by hippocampal sclerosis and infarcts. Additionally, 67.8%-75.7% of variance in cognitive decline was unaccounted for by these neurodegenerative pathologies. These results indicate that PART pathology in isolation does not significantly impair cognition, which is instead primarily influenced by comorbid neuropathologic features.},
}