@article {pmid42492030,
year = {2026},
author = {Turner, RS},
title = {Clinical Trial Outcomes in the Alzheimer's Disease Spectrum: What Should We Measure?.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218468},
doi = {10.1212/WNL.0000000000218468},
pmid = {42492030},
issn = {1526-632X},
}

@article {pmid42492033,
year = {2026},
author = {Li, C and Fu, M and Berg, K and Wallach, J and Ling, K and Wei, R and Shi, L and Ross, J and Guan, X},
title = {Efficacy Measures Used in Alzheimer Disease Clinical Trials Between 2015 and 2025: A Systematic Review.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218373},
doi = {10.1212/WNL.0000000000218373},
pmid = {42492033},
issn = {1526-632X},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Clinical Trials as Topic ; *Outcome Assessment, Health Care ; Cognitive Dysfunction/drug therapy ; Treatment Outcome ; Biomarkers ; },
abstract = {BACKGROUND AND OBJECTIVES: Regulatory guidance has long emphasized clinically meaningful outcomes in Alzheimer disease (AD) drug trials. No contemporary review has examined the efficacy measures used for clinical trials of AD therapies. The objective of this study was to evaluate the clinical relevance and heterogeneity of efficacy measures used in phase II-IV AD drug trials over the past decade.

METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. All phase II-IV clinical trials of pharmacologic therapies in individuals with mild cognitive impairment due to AD or mild-to-moderate AD that were published, completed, or terminated between January 1, 2015, and November 15, 2025, or still ongoing as of November 15, 2025, were eligible for inclusion. We summarized the proportion of trials using clinical outcomes or biomarkers as primary or secondary efficacy measures, key clinical domains addressed, and the number of distinct measures using descriptive statistics. This study is registered with PROSPERO (CRD420251032087).

RESULTS: Among 238 included trials, 95.4% (227/238) used at least one clinical outcome and 73.5% (175/238) used at least one biomarker as efficacy measures. Cognitive abilities (87.0%, 207/238), global status (76.9%, 183/238), and functional ability (71.4%, 170/238) were the most frequently measured clinical domains, whereas patient (16.0%, 38/238) and caregiver (8.8%, 21/238) quality of life and significant disease-related life events (2.5%, 6/238) were less frequent. Only 21.8% (52/238) of trials adopted regulatory-recommended co-primary measures of cognition with either function or global status, whereas 8.4% (20/238) used biomarkers as the sole primary efficacy measure. We identified 318 distinct clinical outcome measures and 219 distinct biomarkers used across all trials, 6.9% (22/318) and 6.8% (15/219) of which were used in more than 5% of trials.

DISCUSSION: Efficacy measures in AD drug trials primarily focused on cognition, global status, and functional outcomes, which are important indicators of AD progression. However, other clinical domains that may also be meaningful to patients and caregivers were far less frequently assessed, while biomarker use is widespread. Substantial heterogeneity in efficacy measure use limits comparability across trials and highlights the need for standardized, consensus-based, clinically meaningful core measure sets for AD drug trials.},
}

*Alzheimer Disease/drug therapy
Humans
*Clinical Trials as Topic
*Outcome Assessment, Health Care
Cognitive Dysfunction/drug therapy
Treatment Outcome
Biomarkers

@article {pmid42492268,
year = {2026},
author = {Luo, S and Guo, J and Xu, J and Song, J and Dai, Y and Xu, S},
title = {Natural polysaccharides as multi-target therapeutic candidates for Alzheimer's disease: Mechanisms, structure-activity relationships, and translational perspectives.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {159},
number = {},
pages = {158585},
doi = {10.1016/j.phymed.2026.158585},
pmid = {42492268},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a systems-level disorder involving amyloid-β (Aβ) deposition, tau pathology, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and microbiota-gut-brain axis dysregulation. Although previous reviews have summarized the anti-AD effects of natural polysaccharides according to individual pathological pathways, an integrated framework linking polysaccharide structure, gut microbial metabolism, peripheral immune regulation, and central AD pathology remains insufficiently developed.

PURPOSE: This review aims to provide an updated and integrative synthesis of natural polysaccharides as multi-target therapeutic candidates for AD, with particular emphasis on their mechanistic networks, structure-activity relationships, and translational potential.

METHODS: A systematic PubMed search was performed for studies published from January 1, 2016, to June 7, 2026. Eligible studies investigated natural polysaccharides as primary therapeutic interventions in in vivo AD models. Reviews, editorials, purely in vitro studies, studies using polysaccharides solely as drug-delivery carriers, synthetic derivatives, and inseparable compound formulations were excluded. Seventy-four original studies were included for mechanistic and structure-activity analyses.

RESULTS: Natural polysaccharides were found to regulate multiple interconnected AD-related processes, including Aβ production, aggregation, and clearance, tau phosphorylation, redox homeostasis, glial activation, inflammasome signaling, synaptic plasticity, cholinergic function, intestinal barrier integrity, gut microbiota composition, and short-chain fatty acid production. Unlike earlier pathway-based summaries, this review proposes a structure-microbiota-metabolite-barrier-inflammation-redox-brain pathology framework to explain how polysaccharide structural features may determine microbial utilization, metabolite generation, immune modulation, and downstream neuroprotective effects.

CONCLUSION: Natural polysaccharides represent promising multi-target candidates for AD prevention and treatment. Future studies should prioritize structurally defined polysaccharide fractions, causal microbiota validation, pharmacokinetic/pharmacodynamic profiling, biomarker-guided assessment, and rigorously designed clinical trials.},
}

@article {pmid42492404,
year = {2026},
author = {Yang, G and Du, Y and Hu, X and Shi, W and Yang, M and Wang, S and , },
title = {Taming arbitrary modality missingness and imbalance: A unified graph-MoE framework for Alzheimer's disease diagnosis.},
journal = {Medical image analysis},
volume = {113},
number = {},
pages = {104222},
doi = {10.1016/j.media.2026.104222},
pmid = {42492404},
issn = {1361-8423},
abstract = {Multimodal biomarkers hold significant potential for improving Alzheimer's disease (AD) diagnosis. However, existing multimodal learning methods typically rely on idealized assumptions of complete and balanced modality availability, which rarely hold in clinical practice. Real-world datasets are plagued by arbitrary modality missingness and, more critically, a long-tailed modality-combination imbalance stemming from hierarchical clinical protocols. These issues cause conventional models to be biased toward frequent combinations while failing on rare but diagnostically critical ones for early AD diagnosis. To address these challenges, we propose UniMIX-AD, a unified framework tailored for robust AD diagnosis under realistic, imperfect multimodal settings. UniMIX-AD integrates two core innovations: (i) a Unified Missing-modality Imputation (UMI) module that dynamically reconstructs representations of missing modalities by capturing cross-modal dependencies from any observed modality combination, ensuring comprehensive patient representations; and (ii) a Graph-coordinated Sparse Mixture-of-Experts (G-Sparse-MoE) that adaptively routes patients to specialized experts and facilitates structured knowledge transfer from frequent (head) to rare (tail) combinations, effectively alleviating the long-tailed modality-combination imbalance. Extensive experiments on the ADNI and OASIS-3 datasets demonstrate that UniMIX-AD consistently outperforms state-of-the-art methods, achieving a relative average accuracy improvement of 7.1% and a significant boost of up to 14.3% on tail modality combinations in ADNI.},
}

@article {pmid42492417,
year = {2026},
author = {Pilat, D and Baranger, K and Rivera, S},
title = {The multifaceted roles of IL-1β in Alzheimer's disease: From pathogenic amplifier to neuroimmune modulator.},
journal = {Cytokine & growth factor reviews},
volume = {91},
number = {},
pages = {82-98},
doi = {10.1016/j.cytogfr.2026.07.004},
pmid = {42492417},
issn = {1879-0305},
abstract = {Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder and the most common form of dementia worldwide. Traditionally, its pathology has been defined by the presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), primarily composed of hyperphosphorylated tau (pTau), alongside widespread synaptic and neuronal loss. Despite decades of research, AD etiology remains only partially understood. While recent advances in amyloid-targeted therapies mark significant progress, most current approaches have fallen short of expectations. This gap has spurred the re-evaluation of the central mechanisms driving AD, with neuroinflammation emerging as a critical contributor rather than a mere bystander. Among the numerous inflammatory mediators implicated in AD, interleukin-1β (IL-1β) stands out for its dual role, associated with the exacerbation of pathological features but also with neuroprotective effects, including Aβ clearance and neuronal support. This apparent duality highlights the complexity of neuroinflammation in AD, suggesting that IL-1β can act as a context-dependent modulator, its effects shaped by factors such as timing, cellular origin, and disease stage. The purpose of this review is to summarize the evidence on IL-1β's role in AD pathophysiology and clarify its contribution to disease mechanisms and progression.},
}

@article {pmid42492469,
year = {2026},
author = {Hu, J and Wang, WX},
title = {Chronic lead exposure disrupts copper redox homeostasis and aggravates neurodegeneration.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {407},
number = {},
pages = {128818},
doi = {10.1016/j.envpol.2026.128818},
pmid = {42492469},
issn = {1873-6424},
abstract = {Lead (Pb) represents a critical environmental health concern due to its profound impact on neurodegenerative processes. However, its specific influence on copper (Cu) redox states and the associated neurotoxic mechanisms remain inadequately understood. In this study, male wild-type C57BL/6 and 5xFAD Alzheimer's disease (AD) model mice were used to investigate how chronic low-dose Pb exposure (200 μg/L via drinking water) exacerbated AD-related pathology through perturbation of Cu homeostasis. Elemental analysis revealed that Pb exposure depleted essential cerebral metals, including Ca, Mg, Fe, and Zn. In contrast to these metals, Cu showed concurrent accumulation in both the brain and bloodstream, particularly in the ADPb group, consistent with disturbed Cu homeostasis in the AD background. In situ fluorescent imaging demonstrated that Pb exposure significantly disrupted the Cu(I)/Cu(II) valence balance within the hippocampus. While the unexposed AD brain showed relatively higher Cu(I) signals, Pb exposure shifted the fluorescence pattern toward Cu(II). Behavioral assessments further indicated that Pb exposure was associated with reduced locomotor activity, anxiety-like responses, and accelerated spatial memory decay in AD mice. Histopathological and immunofluorescence evaluations structurally confirmed these functional deficits, revealing disorganized hippocampal cytoarchitecture, myelin loss, and accelerated Aβ plaque deposition in the ADPb group. Ultimately, these findings demonstrated that environmental Pb exacerbated AD progression not solely through direct physical toxicity, but fundamentally by disrupting the in situ Cu(II)/Cu(I) redox equilibrium. This study highlights Cu redox imbalance as a potential mediator linking Pb exposure with AD progression and warrants further biochemical validation.},
}

@article {pmid42492536,
year = {2026},
author = {Weber, MC and Goedecke, J and Fink, GR and Onur, OA},
title = {[Predicting and Preventing Alzheimer's Disease].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2906-0084},
pmid = {42492536},
issn = {1439-3522},
abstract = {Alzheimer's disease is a long-term biological process whose neuropathological changes begin decades before clinical symptoms appear. Advances in biomarker diagnostics enable the early identification of pathological changes and a more precise classification of different disease stages. Since therapeutic options have shown only limited effects so far, modifiable risk factors and preventive lifestyle interventions are increasingly coming into focus.},
}

@article {pmid42492708,
year = {2026},
author = {Luo, C and Wu, G and Xiao, Z and Hu, R and Qiao, M and Li, W and Liu, C and Li, Z and Lan, C and Huang, Z},
title = {Retraction notice to "Role of miRNA regulation in IGFBP-2 overexpression and neuronal ferroptosis: Insights into the Nrf2/SLC7A11/GPX4 pathway in Alzheimer's disease" [International Journal of Biological Macromolecules 287 (2025) 138537].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153649},
doi = {10.1016/j.ijbiomac.2026.153649},
pmid = {42492708},
issn = {1879-0003},
}

@article {pmid42492887,
year = {2026},
author = {Xie, M and Niu, X and Shi, L},
title = {Integrated identification and validation of HSP90AA1 as a therapeutic target of Astragalus membranaceus in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.044},
pmid = {42492887},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder lacking effective disease-modifying therapies. Astragalus membranaceus (AM) has shown potential neuroprotective effects, but its underlying mechanisms remain incompletely understood. In this study, a meta-analysis, network pharmacology, molecular simulation, and experimental validation were integrated to investigate the therapeutic potential of AM in AD. Meta-analysis of three randomized controlled trials showed that AM significantly improved Clinical Dementia Rating-Sum of Boxes scores, whereas no significant differences were observed for MMSE, memory-related outcomes, or SNSB-D. Network pharmacology identified 350 overlapping targets between AM and AD, with enrichment in pathways related to PI3K-Akt signaling and neural ligand-receptor interactions. HSP90AA1, PIK3CA, and ESR1 were identified as hub targets. Molecular docking predicted stable binding of astragaloside VII to the ATP-binding pocket of HSP90AA1 (-8.9 kcal/mol), which was further supported by molecular dynamics simulation and MM/PBSA analysis (-63.13 ± 4.82 kcal/mol). In Aβ-induced SH-SY5Y cells, astragaloside VII improved cell viability, reduced inflammatory cytokine production and the Aβ42/Aβ40 ratio, restored mitochondrial membrane potential, decreased reactive oxygen species accumulation, alleviated Tau hyperphosphorylation, and increased PSD95 expression. These effects were markedly attenuated following HSP90AA1 knockdown. Collectively, these findings suggest that AM may exert neuroprotective effects through HSP90AA1-associated regulation of multiple AD-related pathological processes and provide preliminary evidence supporting further mechanistic and translational studies.},
}

@article {pmid42493106,
year = {2026},
author = {Wu, L and Jiang, W and Zhao, N and Wang, F},
title = {Corrigendum to "Heparan sulfate from porcine mucosa promotes amyloid-beta clearance in APP/PS1 mice and alleviates Alzheimer's pathology" [Carbohydrate Polymers 285 (2022) 119205].},
journal = {Carbohydrate polymers},
volume = {388},
number = {},
pages = {125541},
doi = {10.1016/j.carbpol.2026.125541},
pmid = {42493106},
issn = {1879-1344},
}

@article {pmid42493137,
year = {2026},
author = {Cardoso, E and Serra, AC and Coelho, JFJ and Pereira, P},
title = {Glycopolymers as emerging modulators of Amyloid-β aggregation: structure-activity relationships and therapeutic potential.},
journal = {Carbohydrate polymers},
volume = {388},
number = {},
pages = {125572},
doi = {10.1016/j.carbpol.2026.125572},
pmid = {42493137},
issn = {1879-1344},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Structure-Activity Relationship ; Animals ; Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Despite ongoing debate about the "amyloid hypothesis", the imbalance between the production and clearance of β-amyloid (Aβ) peptides in the brain remains one of the most compelling explanations for the progression of Alzheimer's disease. Current strategies therefore focus on discovering clinically relevant therapeutic agents that target Aβ peptides and amyloid structures. Because of their unique and attractive properties - biocompatibility, non-immunogenicity, non-toxicity, and ease of functionalization and production - the use of glycopolymers as amyloid inhibitors has generated interest in therapeutic research for Alzheimer's disease. This review provides a comprehensive and critical overview of the literature on glycopolymers in the treatment of Alzheimer's disease. It begins with a description of the disease's neuropathological mechanisms and the formulations approved by the FDA or currently in clinical trials. The second part discusses the use of glycopolymers as amyloid inhibitors, which prevent the formation of neurotoxic soluble oligomers and subsequent plaques observed in Alzheimer's disease. This is achieved by binding to monomers, blocking self-aggregation, and interrupting toxic interactions, offering a therapeutic strategy to halt disease progression. Finally, the main conclusions and perspectives on the use of glycopolymers as amyloid inhibitors are presented.},
}

Humans
*Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors
*Alzheimer Disease/drug therapy/metabolism/pathology
Structure-Activity Relationship
Animals
Protein Aggregates/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism

@article {pmid42493280,
year = {2026},
author = {Faheem, MSB and Hassan, ST and Najmi, OEM and Waheed, A and Ullah, ZB and Sattar, Y and Alraies, MC},
title = {Rising burden of Alzheimer's mortality linked to hypertension: A U.S. population-based study, 1999-2023.},
journal = {Journal of the National Medical Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jnma.2026.06.020},
pmid = {42493280},
issn = {1943-4693},
abstract = {BACKGROUND: Hypertension (HTN) remains a key contributor to adverse outcomes in older adults with Alzheimer's disease (AD), which itself is the seventh leading cause of death in the U.S., affecting over 120,000 Americans annually. The co-existence of these conditions significantly increases the risk of morbidity and mortality, and despite their strong relationship, long-term mortality trends accounting for both conditions have not been assessed. This study examines trends and disparities in AD mortality among older patients (aged ≥ 65 years) with HTN in the U.S. from 1999 to 2023.

METHODS: Mortality records of older patients listing AD as the primary cause of death and HTN as a contributing cause were evaluated from 1999 to 2023 using the CDC WONDER database. Age-adjusted mortality rates (AAMRs) were computed per 100,000 population, and annual percent changes (APCs) were derived to assess temporal trends across different demographics and geographies.

RESULTS: Overall, 314,914 mortalities were attributed to AD in patients with HTN, with overall AAMRs increasing from 1999 (7.1) to 2023 (41.1). Females (AAMR: 31.6) experienced higher rates than males (AAMR: 20.7). Rates peaked among NH African Americans (AAMR: 31.8), followed by NH Whites (AAMR: 28.3) and Hispanics (AAMR: 22.3). Adults aged 85+ years (AAMR: 142.3) had higher rates compared with those aged 75-84 (AAMR: 25.1) and 65-74 years (AAMR: 2.5). Geographically, AAMRs were highest in the West region (AAMR: 31.5) and among non-metropolitan residents (AAMR: 27.9) compared to metropolitan residents (AAMR: 25.03). Trend analysis revealed statistically significant APCs (p < 0.05) across all evaluated demographic and geographic subgroups.

CONCLUSION: This sharp, six-fold rise in AD and HTN-related mortality highlights a compounding public health challenge. The significant disparities observed in the disproportionate burden on females, NH African Americans, and non-metropolitan residents likely reflect intersecting biological vulnerabilities and structural inequities in healthcare access. These findings stress the urgent need for targeted health policy strategies and the proactive clinical management of comorbid conditions to protect these high-risk populations.},
}

@article {pmid42493523,
year = {2026},
author = {Elkotamy, MS and Elgohary, MK and Alkotami, AS and Eldesouki, MM and Elsayed, ZM and Mattar, AA and Abo-Ashour, MF and Tawfik, HO and Eldehna, WM and Abdel-Aziz, HA},
title = {In silico pipeline for GSK 3β inhibitor discovery in Alzheimer's disease using pharmacophore screening, docking, ADME filtering, and MD validation.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42493523},
issn = {2045-2322},
mesh = {*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; Pharmacophore ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; *Drug Discovery/methods ; Ligands ; Blood-Brain Barrier/metabolism ; Drug Evaluation, Preclinical ; *Protein Kinase Inhibitors/chemistry/pharmacology ; },
abstract = {Glycogen synthase kinase-3β (GSK-3β) is a key therapeutic target for Alzheimer's disease, but identifying safe, brain-penetrant inhibitors remains difficult. This study aimed to discover novel CNS-active GSK-3β inhibitors using a rigorous multi-tier computational pipeline. The workflow combined ligand-based and structure-based pharmacophore modeling, virtual screening of the ZINCPharmer database, AutoDock Vina docking, ADME and blood-brain barrier (BBB) filtering with SwissADME, toxicity prediction using ProTox-3.0, and validation by 100-ns molecular dynamics simulations with MM/GBSA and MM/PBSA free energy calculations. Pharmacophore screening with a ≤ 1.0 Å RMSD cutoff identified 1,085 ligand-based and 36 structure-based hits. After docking and developability filtering, two BBB-permeant candidates were prioritized: SB1, a structure-based hit (predicted LD50 = 2500 mg/kg, toxicity class 5), and LB1, a ligand-based hit (predicted LD50 = 521 mg/kg, toxicity class 4). Molecular dynamics confirmed stable binding for both compounds. MM/GBSA analysis showed favorable binding free energies for SB1 (-27.68 kcal/mol) and LB1 (-25.74 kcal/mol), both surpassing the co-crystallized reference (-8.75 kcal/mol). These findings identify SB1 and LB1 as promising, safe, and brain-penetrant GSK-3β lead compounds for experimental validation in Alzheimer's disease.},
}

*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/chemistry/metabolism
*Alzheimer Disease/drug therapy
Pharmacophore
Molecular Dynamics Simulation
Molecular Docking Simulation
Humans
*Drug Discovery/methods
Ligands
Blood-Brain Barrier/metabolism
Drug Evaluation, Preclinical
*Protein Kinase Inhibitors/chemistry/pharmacology

@article {pmid42493572,
year = {2026},
author = {},
title = {Early detection of Alzheimer's disease with circular RNA from blood.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42493572},
issn = {1546-170X},
}

@article {pmid42493706,
year = {2026},
author = {Hoffman, I and Ross, JA and Tumasz, M and Thomas, SA and Van Bockstaele, EJ},
title = {Norepinephrine-mediated regulation of endogenous Aβ42 peptide levels: effects of noradrenergic depletion and restoration.},
journal = {MedScience},
volume = {},
number = {},
pages = {},
pmid = {42493706},
issn = {3091-4981},
abstract = {The locus coeruleus (LC), a cluster of noradrenergic neurons in the dorsal pons, is the brain's main source of norepinephrine (NE), crucial for memory, cognition, and stress response. NE dysregulation has been linked to mood disorders, chronic stress, and neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid-β42 (Aβ42) is a key protein in AD pathology, and forms plaques that trigger neurodegeneration. Studies show elevated Aβ42 levels are associated with anxiety symptoms, even in cognitively normal individuals. Previous research suggests a positive correlation between NE and Aβ42, with Aβ42 present in NE-producing LC neurons. NE may affect Aβ42 levels through adrenergic receptors on neurons or microglia. However, the exact role of NE in modulating Aβ42 remains unclear. Using the NE depletion models, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) lesions and dopamine β-hydroxylase (DBH) knockout (KO) mice, researchers found reduced Aβ42 levels without changes in amyloid precursor protein processing. A newer model, DBH internal ribosome entry site-Cre × floxed tyrosine hydroxylase (DBH-IRES-Cre × floxed-TH) preserved dopamine (DA) but eliminated NE in adrenergic neurons, further supporting the specific influence of NE on Aβ42. Findings indicate that decreased Aβ42 in NE-depleted mice stems not from altered DA but from NE loss. This highlights the NE-mediated regulation of endogenous Aβ42 and the role of NE in AD-related pathology.},
}

@article {pmid42493790,
year = {2026},
author = {Xiao, Y and Wang, S and Hou, Y and Shang, H},
title = {Application of the Allen Human Brain Atlas in Alzheimer's disease and Parkinson's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42493790},
issn = {2047-9158},
support = {2023NSFSC1576//National Science Fund of Sichuan Province/ ; 82301427//National Science Fund of China/ ; TJCZ202506//Rongcheng Talent Program/ ; 2021YFC2501200//National Key Research and Development Program of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism ; *Parkinson Disease/genetics/diagnostic imaging/pathology ; *Brain/diagnostic imaging/metabolism/pathology ; *Atlases as Topic ; Transcriptome ; Gene Expression Profiling/methods ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common age-related neurodegenerative disorders. Allen Human Brain Atlas (AHBA) provides high-resolution transcriptomic data across 102 brain regions with multi-site sampling from healthy controls, promoting the use of brain-wide transcriptomic data for imaging transcriptomics and cross-modal model construction. Increasingly, researchers are utilizing brain-wide transcriptomic datasets to investigate the transcriptome correlates of the neuroimage phenotypes in AD and PD. Leveraging the AHBA, researchers have analyzed the transcriptomic correlations of regional susceptibility to Aβ deposition, tau deposition, α-synuclein propagation, and disease-related multiple-dominal neuroimage phenotypes. These studies revealed that transcriptomic pathways related to metabolism, immunity, neurotransmission, and synaptic function play critical roles in the neuroimage phenotype of AD and PD. By incorporating transcriptomic data modeling, subsequent analyses further confirmed that transcriptomic differences provide the molecular basis for the varying susceptibility observed across brain regions. The analytical approaches of imaging transcriptomics, multimodal data integration strategies, and model construction methods used in AD and PD provide a novel perspective for exploration and can be extended to other neurodegenerative diseases. Future research is expected to utilize brain-wide transcriptomic data to uncover the gene expression mechanisms driving neurodegenerative disease phenotypes.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism
*Parkinson Disease/genetics/diagnostic imaging/pathology
*Brain/diagnostic imaging/metabolism/pathology
*Atlases as Topic
Transcriptome
Gene Expression Profiling/methods

@article {pmid42493810,
year = {2026},
author = {Piras, IS and Capuano, AW and Maher, AC and Schafer, R and Bonfitto, A and Song, S and Taguinod, F and Goldstein, F and Roberts, A and Okonkwo, O and Martersteck, A and , and Huentelman, MJ and Rogalski, E},
title = {SuperAging is not the inverse of common-variant Alzheimer's risk: evidence across genetic ancestries.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42493810},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/genetics ; Female ; Genetic Risk Score ; Male ; Aged, 80 and over ; *Apolipoproteins E/genetics ; Genome-Wide Association Study ; *Genetic Predisposition to Disease/genetics ; *Aging/genetics ; Memory, Episodic ; *Longevity/genetics ; Aged ; Genotype ; },
abstract = {BACKGROUND: As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer's disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative.

METHODS: We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRSLambert, PRSWightman, PRSBellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions.

RESULTS: APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status.

CONCLUSIONS: These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.},
}

Humans
*Alzheimer Disease/genetics
Female
Genetic Risk Score
Male
Aged, 80 and over
*Apolipoproteins E/genetics
Genome-Wide Association Study
*Genetic Predisposition to Disease/genetics
*Aging/genetics
Memory, Episodic
*Longevity/genetics
Aged
Genotype

@article {pmid42494057,
year = {2026},
author = {Li, Y and Leng, Q and Wang, Y},
title = {The impact of supplements on cognitive function for Alzheimer's disease or mild cognitive impairment: a systematic review and network meta-analysis.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1028415X.2026.2703619},
pmid = {42494057},
issn = {1476-8305},
abstract = {OBJECTIVE: Global aging is increasing the incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This network meta-analysis evaluates the effects of dietary supplements on cognitive function in AD/MCI patients.

METHODS: We systematically searched PubMed, Embase, Cochrane Library, and Web of Science for randomized controlled trials up to July 2024. Study quality was assessed using risk-of-bias tools, and a network meta-analysis was performed using R and STATA.

RESULTS: Analysis of 29 trials (n = 2000) demonstrated that several supplements significantly improved Mini-Mental State Examination (MMSE) scores compared to placebo. Cosmos caudatus increased MMSE scores (MD = 1.02, 95% CI 0.41-1.63, intervention vs placebo). In comparisons where placebo was the reference group, the following supplements were superior: plant extraction (MD = -1.54, 95% CI -1.88 to -1.19), probiotics with selenium (MD = -1.7, 95% CI -2.34 to -1.05), phosphatidylserine-100 mg (MD = -1.14, 95% CI -1.86 to -0.41), spirulina (MD = -0.68, 95% CI -1.23 to -0.13), and vitamin B (MD = -0.88, 95% CI -1.67 to -0.09). Probiotics with selenium showed the strongest effect. No supplement produced significant improvements on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

CONCLUSION: Specific supplements, including Cosmos caudatus, probiotic-selenium combinations, and plant extracts, are associated with improvements in MMSE scores among AD/MCI patients. The absence of effects on ADAS-Cog scores underscores the importance of assessment tool selection. This study provides evidence for considering nutritional interventions in cognitive support strategies.},
}

@article {pmid42494118,
year = {2026},
author = {Paul, S and Dubey, S and Tiwari, P},
title = {Integrative Insights Into DYRK1A From Molecular Function to Therapeutic Advancement.},
journal = {Chemical biology & drug design},
volume = {108},
number = {1},
pages = {e70366},
doi = {10.1111/cbdd.70366},
pmid = {42494118},
issn = {1747-0285},
mesh = {Dyrk Kinases ; *Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors/chemistry ; Protein-Tyrosine Kinases/metabolism/chemistry ; Humans ; *Protein Kinase Inhibitors/chemistry/pharmacology/metabolism/therapeutic use ; Structure-Activity Relationship ; Binding Sites ; Drug Design ; Adenosine Triphosphate/metabolism ; Proteolysis Targeting Chimera ; Tyrosine Kinase Inhibitors ; Animals ; },
abstract = {Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), located within the Down syndrome critical region and implicated in Alzheimer's disease (AD), Parkinson's disease (PD), and context-dependent cancer biology, represents a high-value yet challenging therapeutic target. This review compiles comprehensive structure-activity relationship (SAR) insights essential for medicinal chemists designing selective DYRK1A inhibitors. We detail the molecular architecture of the ATP-binding pocket of DYRK1A, key regulatory residues (Lys188, Phe238, Glu239, Leu241), and structure-function relationships governing inhibitor classes: ATP-competitive agents, ATP-non-competitive inhibitors, and Proteolysis-Targeting Chimeras (PROTAC) degraders with emphasis on functional group modifications and scaffold optimization strategies. Readers will gain actionable insights on binding mode predictions, potency-selectivity trade-offs, and prioritization of lead compounds for preclinical validation. The framework addresses pharmacokinetic property optimization and selectivity profiling across kinase families, enabling researchers to accelerate rational inhibitor design and facilitate translation of DYRK1A therapeutics into clinical trials for neurodegenerative and developmental disorders.},
}

Dyrk Kinases
*Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors/chemistry
Protein-Tyrosine Kinases/metabolism/chemistry
Humans
*Protein Kinase Inhibitors/chemistry/pharmacology/metabolism/therapeutic use
Structure-Activity Relationship
Binding Sites
Drug Design
Adenosine Triphosphate/metabolism
Proteolysis Targeting Chimera
Tyrosine Kinase Inhibitors
Animals

@article {pmid42494202,
year = {2026},
author = {Ali, A and Maqsood, A and Mustafa, A and Hussain, Z and Ashraf, A and Sarfaraz, S and Butt, A and Shamoon, M and Ghafoor, LA and Azam, H and Abdullah, M and Pannun, AA and Shabbir, MA and Abdullah, A and Sharma, MK},
title = {Burden of Diabetes as a Contributing Cause in Dementia Mortality Among Older Adults in the United States, 1999-2020.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71616},
doi = {10.1002/brb3.71616},
pmid = {42494202},
issn = {2162-3279},
mesh = {Humans ; *Dementia/mortality/epidemiology ; United States/epidemiology ; Female ; Aged ; Cause of Death/trends ; *Diabetes Mellitus/epidemiology/mortality ; Male ; Aged, 80 and over ; Risk Factors ; },
abstract = {BACKGROUND: Diabetes is a well-established risk factor for cognitive decline and dementia; however, the extent to which diabetes is documented as a contributing cause on death certificates among decedents with dementia remains poorly characterized. This study aimed to evaluate temporal trends and demographic disparities in diabetes as a contributing condition among dementia-related deaths in older adults in the United States.

METHODS: We analyzed multiple-cause-of-death data from the CDC WONDER database for adults aged ≥ 65 years with dementia listed as an underlying or contributing cause of death between 1999 and 2020. Diabetes was identified using ICD-10 codes E10-E14. We calculated age-adjusted mortality rates (AAMR), crude death rates (CDR), annual percentage changes (APC) using Joinpoint regression, and the proportion of dementia deaths with coexisting diabetes. Analyses were stratified by age, sex, race, and state.

RESULTS: Among 3,818,272 dementia-related deaths, 234,793 (6.2%) had diabetes documented as a contributing condition. The AAMR for dementia with diabetes increased from 8.7 per 100,000 in 1999 to 36.1 per 100,000 in 2020. Joinpoint regression identified a sharp increase from 1999 to 2009 (APC: +13.09%, 95% CI: 11.47-14.94, p < 0.001), followed by a stable trend from 2009 to 2020 (APC: +0.84%, 95% CI: -0.55-2.11, p = 0.187). Both dementia alone and dementia with diabetes demonstrated a sharp spike in 2020. The proportion of dementia deaths with coexisting diabetes was highest among decedents aged 65-74 years (8.5%) and decreased with age (85+ years: 5.3%). By race, American Indian/Alaska Native decedents had the highest proportion (10.4%), followed by Asian/Pacific Islander (9.2%), Black/African American (9.0%), and White (5.8%). Substantial state-level variation was observed across the United States.

CONCLUSIONS: The burden of diabetes, documented as a contributing condition among dementia-related deaths, increased substantially from 1999 to 2009 and remained relatively stable thereafter. Significant racial, age, and geographic disparities exist, with American Indian/Alaska Native decedents showing the highest proportion of coexisting diabetes. These findings highlight the burden of metabolic comorbidity among older adults with dementia and underscore the importance of continued surveillance and targeted public health strategies.},
}

Humans
*Dementia/mortality/epidemiology
United States/epidemiology
Female
Aged
Cause of Death/trends
*Diabetes Mellitus/epidemiology/mortality
Male
Aged, 80 and over
Risk Factors

@article {pmid42494763,
year = {2026},
author = {Zhou, M and Wang, X},
title = {Curcumin and piperine in neurodegenerative disorders: a systematic review of preclinical neuroprotective evidence.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1855377},
pmid = {42494763},
issn = {2296-861X},
abstract = {BACKGROUND: Curcumin and piperine are phytochemicals with neuroprotective potential; however, curcumin's limited bioavailability restricts its therapeutic efficacy. Increasing evidence suggests that their co-administration may provide synergistic neuroprotective benefits. This systematic review evaluates the current preclinical evidence for curcumin-piperine (CUR-PP) combinations in neurodegenerative disorder models.

METHODS: We searched electronic databases for studies published between 2010 and 2026. Twenty unique preclinical studies, involving rodent models and neuronal cell cultures, met the eligibility criteria. Due to substantial methodological heterogeneity in study designs, dosing regimens, and outcome measures, a quantitative meta-analysis was not feasible. Findings were synthesized qualitatively, focusing on behavioral, biochemical, and molecular outcomes.

RESULTS: CUR-PP co-administration consistently demonstrated superior neuroprotective efficacy compared to monotherapy. The combination significantly improved cognitive and locomotor performance, mitigated oxidative stress, and modulated neuroinflammatory pathways. Nanoformulations, such as PLGA nanoparticles, further enhanced bioavailability and therapeutic impact across the included studies.

CONCLUSION: Preclinical data indicate that CUR-PP combinations exert synergistic neuroprotective effects, suggesting they are promising multi-target candidates for neurodegeneration. However, the therapeutic potential is currently limited by a reliance on preclinical models, substantial inter-study heterogeneity, and a total lack of clinical trial data, which prevents the establishment of validated human dosing protocols.},
}

@article {pmid42494770,
year = {2026},
author = {Woolsey, B and Sen, K},
title = {Dietary approaches to support cognition in older adults: a systematic review.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1869091},
pmid = {42494770},
issn = {2296-861X},
abstract = {BACKGROUND: Older adults, particularly those residing in long-term care, experience disproportionate rates of cognitive decline and Alzheimer's disease (AD). While isolated nutrient supplementation has demonstrated limited clinical efficacy, comprehensive whole-food dietary patterns may offer significant neuroprotective benefits through complex nutrient synergy. This systematic review evaluates the efficacy of the Mediterranean, Nordic, Okinawan, and plant-based dietary approaches in mitigating cognitive decline and reducing dementia risk in older populations.

METHODS: The study protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration ID CRD420261349593. Conducted in accordance with PRISMA 2020 guidelines, a systematic search of PubMed, Web of Science, CINAHL, and ScienceDirect was performed to identify peer-reviewed articles published between January 2021 and the present. Eligible studies included randomized controlled trials (RCT), prospective cohort studies, and longitudinal studies evaluating the impact of whole-food dietary patterns on cognitive outcomes in adults aged 60 and older.

RESULTS: Out of 622 initial records, 16 articles met all inclusion criteria. The synthesized evidence demonstrates that high adherence to these comprehensive dietary patterns is consistently associated with improved memory, enhanced executive function, and a reduced incidence of AD. These cognitive improvements are driven by interconnected physiological mechanisms, including reduced systemic inflammation, improved vascular integrity, favorable shifts in the gut microbiome, and optimized circulating endocannabinoid profiles. Additionally, the magnitude of these benefits is frequently modulated by individual biological factors, such as sex and APOE genotype.

CONCLUSION: Whole-food dietary patterns provide an effective, evidence-based framework for preserving cognitive resilience compared to single-nutrient interventions. Integrating these nutrient-dense diets into public health initiatives and long-term care settings offers a powerful strategy for neuroprotection, highlighting the need to advance personalized nutrition strategies in future clinical trials.},
}

@article {pmid42494775,
year = {2026},
author = {Lavigne, SB and Hromas, G and LaRoche, A and Parker, AS and Abdullah, MS and Fernandez, RA and Wang, CP and de Erausquin, G and Salardini, A and Tanner, J and Kautz, TF and Castro, J and Mendoza, C and Seshadri, S and Sullivan, AC},
title = {Frontotemporal dementia in Hispanic populations: Regional and national comparisons.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70396},
pmid = {42494775},
issn = {2352-8729},
abstract = {INTRODUCTION: Although Hispanic/Latine populations experience higher dementia rates, they remain underrepresented in frontotemporal dementia (FTD) research. This study examines clinical manifestations of FTD within a South Texas Hispanic/Latine cohort compared to national data.

METHODS: Participants diagnosed with FTD were included from (1) our FTD clinic, the South Texas Alzheimer's Disease Research Center, and local Advancing Research and Treatment in Frontotemporal Lobar Degeneration-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Longitudinal Frontotemporal Lobar Degeneration cohort (Hispanic: n = 17; White non-Hispanic: n = 22), and (2) the National Alzheimer's Coordinating Center dataset (Hispanic: n = 24; White non-Hispanic: n = 407; National Institute on Aging/National Institutes of Health Grant U24 AG072122). Clinical, neuroimaging, and neuropsychological data were harmonized for cross-cohort comparisons.

RESULTS: Hispanic participants presented with more movement-related symptoms and advanced cognitive impairment at diagnosis than non-Hispanic Whites. Diagnostic delays averaged 4 years from symptom onset. Educational disparities significantly contributed to health-care access differences.

DISCUSSION: Findings underscore diagnostic severity and systemic barriers faced by Hispanic populations with FTD, emphasizing the need for culturally sensitive diagnostic tools and interventions for equitable dementia care.},
}

@article {pmid42495050,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Streamlining eligibility assessment for Alzheimer's disease-modifying therapies: Prediction of MMSE scores using the digital clock and recall.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1799372},
pmid = {42495050},
issn = {2673-253X},
abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks of perpetuating health disparities, given the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR™)-a rapid, FDA-listed digital cognitive assessment-to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.

METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 (BH) study (NCT04733989, N = 945). Participants were clinically classified as cognitively unimpaired, mild cognitive impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model on 70% of the sample, using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was validated using the remaining 30% of Bio-Hermes-001 and an independent external validation cohort from the Apheleia study (NCT05364307, N = 238).

RESULTS: The machine learning model predicted MMSE scores with a root-mean-squared error (RMSE) of 2.43 in the BH test set. This error margin falls within the established test-retest reliability range of the manual MMSE itself (∼4.0-4.2 points at short inter-test intervals), providing evidence that the predicted score is of comparable precision to a repeat human administration of the MMSE. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). In the BH held-out test set, the model showed comparable performance across Race (White RMSE = 2.46; Non-White RMSE = 2.25) and Ethnicity (Hispanic RMSE = 2.19; Non-Hispanic RMSE = 2.45), a balanced pattern also observed in the Apheleia-001 external cohort. Exploratory demographic analyses on prediction errors, including Age, Sex, Race, and Ethnicity, yielded significant differences only for Sex and Age in Apheleia, with signed errors becoming progressively more negative (i.e., increasing under-prediction) at older ages for the latter. This scarcity of statistical differences across cohorts suggested that our predictions were fair.

DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.},
}

@article {pmid42495266,
year = {2026},
author = {Martinez, R and Thakur, KT and Alviz, LF and Gardner, WM and Varela, FJ and Hennis, AJM and Oliveira E Souza, R},
title = {The burden of noncommunicable and injury-related nervous system disorders in the Americas, 1990-2023: an analysis of the Global Burden of Disease Study 2023.},
journal = {Lancet regional health. Americas},
volume = {62},
number = {},
pages = {101581},
pmid = {42495266},
issn = {2667-193X},
abstract = {BACKGROUND: Noncommunicable and injury-related nervous system disorders (NINSDs)-including cerebrovascular and neurodegenerative diseases, neurodevelopmental disorders, neuromuscular conditions, brain cancers, and traumatic brain injuries-are major contributors to morbidity, disability, and premature mortality in the Americas. However, comprehensive regional and national assessments remain limited. We assessed the burden of NINSDs and their attributable risk factors in the Americas from 1990 to 2023.

METHODS: We analysed prevalence, mortality, and disability-adjusted life years (DALYs), with 95% uncertainty intervals (UIs), for 19 NINSDs by age and sex across 38 countries and territories, using estimates from the Global Burden of Disease Study 2023. Temporal trends were assessed using annual percentage change (APC) estimated through log-linear regression. Burden attributable to modifiable risk factors was also examined.

FINDINGS: In 2023, an estimated 470 million (95% UI 418-523) people in the Americas were living with at least one NINSD. These conditions caused 1·1 million (0·8-1·7) deaths and 37·5 million (27·9-51·8) DALYs, representing 12% of the total burden from noncommunicable diseases in the region. Migraine, Alzheimer's disease and other dementias, ischaemic stroke, and intracerebral haemorrhage were the leading contributors to DALYs. From 1990 to 2023, age-standardised DALY rates declined for ischaemic stroke, haemorrhagic stroke, and neural tube defects, but increased for neurodegenerative disorders, including multiple sclerosis and motor neuron diseases. High systolic blood pressure was the leading risk factor for stroke subtypes, high fasting plasma glucose for dementias, and lead exposure accounted for nearly 60% of DALYs from idiopathic intellectual disability.

INTERPRETATION: NINSDs impose a substantial and persistent burden in the Americas, with disability increasingly outweighing premature mortality. Strengthening prevention of modifiable risk factors, integrating neurological health into noncommunicable disease strategies, and expanding long-term care, rehabilitation, and disability support are essential to address this growing challenge.

FUNDING: No funding to declare.},
}

@article {pmid42495541,
year = {2026},
author = {Li, Y and Xu, X and Meng, Z and Chen, L and Yu, Q and Wang, R and Ren, Y and Chen, F and Liang, G and Zhao, X and Yu, H and Wei, J},
title = {Tuberostemonine ameliorates Alzheimer's disease pathology by suppression of the p38 MAPK signaling pathway.},
journal = {iScience},
volume = {29},
number = {8},
pages = {116887},
pmid = {42495541},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with limited therapeutic options. Here, we report that tuberostemonine (Tub), an alkaloid from Stemona tuberosa, exerts neuroprotective effects in AD models. In Aβ1-42-treated PC12 cells, Tub reduced cytotoxicity, apoptosis, and oxidative stress while restoring mitochondrial function. In APP/PS1 transgenic mice, Tub administration improved cognitive performance, reduced amyloid-β plaque deposition, attenuated microglial activation, and attenuated neuronal loss, with efficacy superior to donepezil. Mechanistically, Tub selectively inhibited p38 MAPK phosphorylation without affecting ERK or JNK pathways, as confirmed by pharmacological inhibition and activation experiments. These findings identify Tub as a promising multi-target natural compound for AD intervention through p38 MAPK pathway modulation.},
}

@article {pmid42495562,
year = {2026},
author = {Pujar, KG and Purohit, D and Shetty, RP and S, P and Kolachi, KY and Bharathi H M, A and Achar, PG and P, P},
title = {Pharmacophore-driven design and biological evaluation of heterocyclic PDE4B inhibitors for Alzheimer's disease.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42495562},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition marked by a gradual loss of cognitive function, impaired synaptic signalling, and sustained neuroinflammatory responses. Among the molecular pathways associated with disease progression, cyclic adenosine monophosphate (cAMP) signalling, plays a crucial factor in disruption of cellular homeostasis. Phosphodiesterase-4 (PDE4), especially the PDE4B isoform, controls intracellular cAMP levels in neuronal and glial cells, which affects inflammatory signalling and synaptic plasticity in the brain. Therefore, selectively targeting PDE4B is a novel approach to identify the small molecule's therapeutic activity to restore the cAMP signalling, with parallel regulation of the dose-limiting side effects. GSK356278 and Rolipram are the known PDE4B modulators, which have been considered for the current study to generate significant pharmacophoric features and execute drug design as CNS-active PDE4B inhibitors. Six heterocyclic derivatives were designed and synthesised by altering the core scaffold in order to maximise hydrophobicity, CNS permeability, and Q-pocket engagement without depending on direct Zn[2+] or Mg[2+] coordination. Among these, molecule VCHH-19 and VCPH-19 demonstrated significant CNS compatibility and good binding stability. PC12 cell lines were chosen to verify the in vitro neuroprotective response, and the Drosophila model for in vivo for AD assessment. All of these results indicated the significance of pyridine-based heterocycles molecules as potential candidates for PDE4B-targeted AD treatment.},
}

@article {pmid42496006,
year = {2026},
author = {Jauregui, GV and Coomes, S and Emmett, E and Thatcher, A and Oyelakin, N and Čarna, M and Zelinkova, J and Novotny, JS and Polakova, N and Kuruvilla, T and Zorec, R and Verkhratsky, A and Parpura, V and Morgan, D and Moya, KL and Limback-Stokin, C and Stokin, GB},
title = {APP/Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70526},
doi = {10.1111/jnc.70526},
pmid = {42496006},
issn = {1471-4159},
support = {LX22NPO5107//European Union Project Next Generation EU - Project National Institute for Neurological Research/ ; //National Natural Science Foundation of China/ ; //Zhejiang Province People's Government Awards/ ; P3-310//Slovenian Research and Innovation Agency grants/ ; J3-50104//Slovenian Research and Innovation Agency grants/ ; J7-3153//Slovenian Research and Innovation Agency grants/ ; J3-2523//Slovenian Research and Innovation Agency grants/ ; J4-60077//Slovenian Research and Innovation Agency grants/ ; I0-0034 Celica//Slovenian Research and Innovation Agency grants/ ; I0-0048 Cipkebip//Slovenian Research and Innovation Agency grants/ ; I0-0022 UL//Slovenian Research and Innovation Agency grants/ ; //EU Interreg Italia-Slovenia Immunocluster-2/ ; //Coherence/ ; },
mesh = {*Astrocytes/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Humans ; *Amyloid beta-Protein Precursor/metabolism ; Animals ; *Signal Transduction/physiology ; *Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neurofibrillary pathology, synaptic dysfunction, and chronic neuroinflammation, yet the mechanisms driving early, localized pathology remain elusive. While traditionally viewed through a neuron-centric lens, astrocytes express abundant amyloid precursor protein (APP)-predominantly Kunitz-type protease inhibitor (KPI)-containing isoforms-and possess the complete enzymatic machinery for APP processing and Aβ clearance. Astrocytic APP is a stress-responsive signaling molecule regulated by inflammatory, metabolic, excitotoxic, and mechanical insults. Under local tissue stress, reactive astrocytes upregulate APP and shift toward amyloidogenic processing. The resulting bioactive fragments, including Aβ, promote astrocyte activation, disrupt homeostatic functions, and trigger feed-forward upregulation of endogenous APP. We propose that this reciprocal coupling establishes a self-reinforcing network where APP integrates local stress and diffusible Aβ propagates reactive states across the astroglial syncytium. This framework positions astrocytic APP signaling as an upstream driver of localized amyloid accumulation, neuroinflammation, and sporadic AD progression.},
}

*Astrocytes/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
Humans
*Amyloid beta-Protein Precursor/metabolism
Animals
*Signal Transduction/physiology
*Amyloid beta-Peptides/metabolism

@article {pmid42496210,
year = {2026},
author = {Dunckley, N and Driver-Dunckley, ED and Zhang, N and Serrano, GE and Shill, HA and Mehta, SH and Belden, C and Tremblay, C and Atri, A and Adler, CH and Beach, TG},
title = {Greater burden of Alzheimer's Co-pathology in women with Parkinson's disease dementia.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261470295},
doi = {10.1177/1877718X261470295},
pmid = {42496210},
issn = {1877-718X},
abstract = {ObjectiveTo investigate sex differences in Alzheimer's disease (AD) related pathology among autopsy-confirmed Parkinson's disease (PD) cases.BackgroundAD and PD frequently co-occur in older adults, yet the influence of sex on AD pathology in the context of PD remains unexplored.MethodsAll subjects were enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and Brain and Body Donation Program (BBDP) and had annual standardized research clinical assessments by neuropsychologists, subspecialty behavioral and movement disorders neurologists, as well as comprehensive neuropathological examinations after death.ResultsAmong 230 autopsy-confirmed PD cases, females exhibited greater amyloid plaque pathology burden than males, regardless of a co-occurring AD diagnosis. Specifically, females with PD had significantly higher mean cortical total plaque scores (mean 6.5/15 vs. 4.9/15, p = 0.045) and greater CERAD neuritic plaque density (mean 1.7/3 vs. 1.3/3, p = 0.035). Females were also more likely to have a higher cortical plaque burden (plaque total ≥ 5: 56.8% vs. 39.7%, p = 0.015). In multivariable logistic regression models, female subjects showed greater than twice the odds of having an amyloid plaque burden ≥5 compared to males (OR = 2.18; 95% CI = 1.17-4.06; p = 0.014), when controlling for ApoE ε4 status, Lewy body density score, and age at death.ConclusionsFemale sex is associated with increased amyloid plaque pathology in PD, independent of ApoE ε4 status. These findings highlight a sex-specific vulnerability to AD pathology in PD patients and support the need for sex-informed approaches to reseach in mixed neurodegenerative disease.},
}

@article {pmid42496263,
year = {2026},
author = {Powell, DS and Nieman, CL and Thorsell, P and Phillips, NA and Ekström, I},
title = {Hearing Loss, Cognitive Decline, and Dementia: Clinical Intersections.},
journal = {Audiology research},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/audiolres16040097},
pmid = {42496263},
issn = {2039-4330},
support = {P22-0785, 2023//Stiftelsen Riksbankens Jubileumsfond/ ; P30AG097158/AG/NIA NIH HHS/United States ; n/a//Swedish Dementia Foundation/ ; },
abstract = {Background/Objectives: Age-related hearing loss is one of the most prevalent chronic conditions in older adults and has emerged as a potentially modifiable risk factor for cognitive decline and dementia. Increasing evidence from epidemiological, neurobiological, and interventional studies has improved our understanding of the complex relationships between auditory dysfunction and cognitive aging. By highlighting findings in these areas, this review aims to aid clinicians and researchers gain a better understanding of the association between hearing loss, cognitive decline and dementia, and the importance of considering sensory decline during cognitive screening. Methods: This narrative review summarizes and integrates findings from epidemiological, neurobiological, and clinical studies examining relationships between hearing loss, cognitive decline, and dementia. Particular focus was placed on epidemiological associations, proposed mechanistic pathways, implications for screening and diagnostic assessment, and evidence regarding hearing rehabilitation interventions. Results: Accumulating evidence indicates that hearing loss is associated with accelerated cognitive decline and increased dementia risk. Proposed mechanisms include increased cognitive load, reduced sensory input, social isolation, depression, and shared neurodegenerative or vascular pathology, although causal pathways remain incompletely understood. Emerging evidence suggests that hearing rehabilitation may help preserve cognitive function in some groups, but findings remain heterogeneous. Clinical studies further support the importance of considering auditory function during cognitive assessment, as unrecognized hearing impairment may influence test performance, communication, and diagnostic accuracy. Conclusions: Current evidence supports hearing loss as an important factor in cognitive aging and dementia research and highlights the potential value of integrating hearing assessment and management into clinical and research settings.},
}

@article {pmid42496665,
year = {2026},
author = {Pinheiro, NR and Carneiro, CFD and Cancelliero, GS and Nogueira, GO and Almeida, GM and Fernandes, N and Wasilewska-Sampaio, AP and Martins, SM and Felix, A and Amaral, OB and Sebollela, A},
title = {Limitations and Strengths of the SH-SY5Y Neuroblastoma Cell Line as a Model of β-Amyloid Neurotoxicity: Lessons From a Systematic Review and Meta-Analysis.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70523},
doi = {10.1111/jnc.70523},
pmid = {42496665},
issn = {1471-4159},
support = {18/10721-0//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 22/12904-0//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 21/12263-2//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 21/10925-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; E-26/200.824/2021//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; E-26/204.061/2024//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 310813/2021-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Instituto Serrapilheira/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neuroblastoma/pathology/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; },
abstract = {The SH-SY5Y human neuroblastoma cell line is widely used as an in vitro model of β-amyloid (Aβ) neurotoxicity in Alzheimer's disease (AD). However, the lack of standardized protocols for assessing Aβ toxicity-including differentiation strategies for SH-SY5Y cells-limits the comparability of results across studies. To address these issues, we conducted a systematic review and meta-analysis to evaluate how methodological factors influence Aβ-induced toxicity in SH-SY5Y cells. We included 359 eligible studies encompassing 1192 MTT-based comparisons of cell viability between Aβ-treated and control SH-SY5Y cells. A three-level meta-analysis estimated mean cell viability after Aβ exposure at 63% of control levels (95% CI [61.6; 64.3]), with very high heterogeneity (I[2] = 99.6%). Meta-regression identified significant associations between increased toxicity and higher Aβ concentrations, longer exposure durations, and the use of peptide preparations described as fibrils. Conversely, differentiation protocols, duration, and cell density did not significantly influence toxicity outcomes. Reporting quality was often poor, with frequent omissions regarding cell line origin, authentication, contamination testing, Aβ preparation details, and nature of the experimental unit. Overall, our findings show robust Aβ toxicity in SH-SY5Y cells, primarily driven by dose, exposure time, and Aβ aggregation state, but not cell differentiation status. Our conclusions highlight the critical need for better reporting of Aβ exposure parameters to enhance reproducibility and translational potential in AD research.},
}

Humans
*Amyloid beta-Peptides/toxicity/metabolism
*Neuroblastoma/pathology/metabolism
Cell Line, Tumor
Cell Survival/drug effects/physiology

@article {pmid42496712,
year = {2026},
author = {Wittmann, FG and Zülke, AE and Vajnberger, M and Luppa, M and Riedel-Heller, SG},
title = {[Modifiable risk and protective factors for dementia: an overview of established and emerging evidence].},
journal = {Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00103-026-04279-7},
pmid = {42496712},
issn = {1437-1588},
abstract = {Alzheimer's disease and other dementias are among the most serious widespread diseases, with societal and healthcare-system relevance expected to increase further in the coming years. Projections of the future disease burden are correspondingly concerning. At the same time, considerable progress has been made in research, particularly in the field of risk reduction. A broad range of established protective and risk factors at the individual level has been identified, alongside a growing number of related intervention studies. Increasingly, however, attention is shifting toward population-based measures aimed at reducing dementia cases in the long term.This article provides an overview of the current state of research. First, drawing on recent data on disease burden, established risk factors are summarized. Building on this, more recent and previously less considered potential determinants are discussed. The review further outlines existing intervention approaches and examines the relevance of population-based prevention strategies for public health and health policy.},
}

@article {pmid42496756,
year = {2026},
author = {Sahu, SK and Nayak, M and Samal, A and Jena, S and Pradhan, J and Dandapat, J and Samanta, L and Jena, S},
title = {T3 and curcumin regulates collagen-IV and collagen-VI expression: role in suppression of amyloid-β via TGFβ1-Sp1 signaling in hypothyroid mice brain.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42496756},
issn = {1573-7365},
support = {26913/HED/HE-PTC-WB-02-17//OHEPEE and S&T Department, Government of Odisha/ ; 584/83/OSHEC//OURIIP, OSHEC, Government of Odisha/ ; },
mesh = {Animals ; *Curcumin/pharmacology/therapeutic use ; *Hypothyroidism/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Triiodothyronine/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Mice ; *Transforming Growth Factor beta1/metabolism ; *Collagen Type IV/metabolism/biosynthesis ; Male ; *Brain/metabolism/drug effects ; Mice, Inbred BALB C ; Sp1 Transcription Factor/metabolism ; },
abstract = {Hypothyroidism has been associated with cognitive disorders and high risk of neurodegenerative disorders like Alzheimer's disease (AD), which is caused by amyloid-β (Aβ) accumulation in brain. The aim of the study is to examine the therapeutic ability of triiodothyronine (T3) and curcumin in regulating two key extracellular matrix proteins (ECM), collagen IV and collagen VI in brain since both drugs have neuroprotective and anti-fibrotic effects. The study further explored the possible role of signaling molecules such as transforming growth factor β1 (TGFβ1) and specificity protein 1 (Sp1) in regulating the effects of T3 and curcumin on Aβ accumulation and ECM protein expression. Experiment was carried on Balb/c mouse model by inducing hypothyroidism with 0.05% PTU followed by treatment of T3, curcumin and a combination of both. The study revealed a significant increase in the expression of collagen IV and VI, along with elevated levels of TGFβ1 and Sp1 signalling proteins, in hypothyroid conditions in response to increased Aβ expression in both the cortex and hippocampus. Western blot and RT-PCR analysis showed that T3 and curcumin treatment downregulate the levels of ECM proteins, the APP gene, Aβ protein, and the signaling factors. The study found that T3 and curcumin treatment downregulates the collagen IV and VI expression by negatively regulating TGFβ1 and Sp1 when expression of APP and Aβ are low. T3 and coadministration of T3 with curcumin more effectively regulate thyroid function and ECM protein expression in both the cortex and hippocampus. Whereas curcumin alone exhibits limited impacts under the experimental conditions in our study, this may due to bioavailability, dosage or treatment duration which need to further investigation. Our results indicate a novel therapeutic approach for understanding Aβ pathology associated with hypothyroidism, emphasizing the potential association between thyroid hormone and nature-based compounds, such as curcumin, in modulating ECM dynamics and neuroprotection.},
}

Animals
*Curcumin/pharmacology/therapeutic use
*Hypothyroidism/metabolism/drug therapy
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Triiodothyronine/pharmacology/therapeutic use
Signal Transduction/drug effects
Mice
*Transforming Growth Factor beta1/metabolism
*Collagen Type IV/metabolism/biosynthesis
Male
*Brain/metabolism/drug effects
Mice, Inbred BALB C
Sp1 Transcription Factor/metabolism

@article {pmid42496783,
year = {2026},
author = {Roeder, HJ and Leira, EC},
title = {The Neurology of Menopause.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42496783},
issn = {1534-6293},
mesh = {Humans ; Female ; *Menopause/physiology ; *Nervous System Diseases/physiopathology ; },
abstract = {PURPOSE OF REVIEW: Menopause is a neuroendocrine process with important implications for neurological health. This review examines the complex, multidirectional relationships between menopause and major central nervous system conditions, including stroke, migraine, epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

RECENT FINDINGS: Menopause may mark an inflection point for vascular injury, neurodegeneration, and disability accumulation in several neurological conditions. Perimenopausal hormonal fluctuations may exacerbate migraines and seizures in susceptible women. Research increasingly supports the critical window hypothesis for estrogen therapy and highlights the importance of distinguishing reproductive and chronological aging when interpreting neurologic trajectories. Menopause represents an important transition for many conditions. Hormone therapy has heterogenous effects with cognitive benefit in premature ovarian insufficiency, harm related to stroke risk in older women, and greater uncertainty in other conditions. Therefore, individualized risk-benefit assessment is essential. Research gaps remain significant, and menopause should be a priority area for neurologic research.},
}

Humans
Female
*Menopause/physiology
*Nervous System Diseases/physiopathology

@article {pmid42496794,
year = {2026},
author = {Chen, K and Zhang, X and Sun, H and Xu, Y and Yang, C},
title = {N[6]-Methyladenosine-Driven Nuclear Export of circKCNN2 Impairs GRP75 Function to Promote Neuronal Apoptosis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42496794},
issn = {1559-1182},
mesh = {*Apoptosis/physiology/drug effects ; Humans ; *Adenosine/analogs & derivatives/metabolism ; *Neurons/metabolism/pathology ; Active Transport, Cell Nucleus ; Cell Line, Tumor ; *Cell Nucleus/metabolism ; *Membrane Proteins/metabolism ; *HSP70 Heat-Shock Proteins/metabolism ; RNA Methylation ; Epitranscriptome ; },
abstract = {Emerging evidence implicates circular RNAs (circRNAs) in Alzheimer's disease (AD) pathogenesis. Notably, circKCNN2 correlates with clinical dementia severity in AD patients; however, its biological functions and regulatory mechanisms in neuronal systems remain poorly understood. Here, we elucidated the molecular mechanism by which circKCNN2 regulated neuronal apoptosis and delineated the underlying post-transcriptional regulatory axis. Using SH-SY5Y cells as an in vitro neuronal model, we manipulated circKCNN2 expression through overexpression and siRNA-mediated knockdown. Apoptosis was assessed by flow cytometry and TUNEL assays. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), MS2-based RNA pull-down coupled with mass spectrometry, fluorescence in situ hybridization, and nuclear/cytoplasmic fractionation were employed to characterize the underlying mechanism. circKCNN2 overexpression significantly induced apoptosis, whereas its knockdown attenuated apoptosis. circKCNN2 underwent N6-methyladenosine (m[6]A) modification. Mechanistically, METTL3-catalyzed m[6]A modification enabled YTHDC2 binding and facilitated the nuclear export of circKCNN2. Both METTL3 depletion and YTHDC2 overexpression caused nuclear retention and attenuated apoptosis. Furthermore, MS2-based RNA pull-down coupled with mass spectrometry identified GRP75 as a cytoplasmic interactor of circKCNN2. Functionally, GRP75 overexpression rescued circKCNN2-induced apoptosis. Our findings revealed a novel "modification-localization-function" cascade wherein the METTL3-YTHDC2-m[6]A axis dictates circKCNN2 nuclear-cytoplasmic trafficking and the subsequent inhibition of GRP75, thereby driving neuronal apoptosis. This mechanism established circKCNN2 as a pathogenic driver in AD and highlighted the m[6]A regulatory machinery as a potential target for further investigation.},
}

*Apoptosis/physiology/drug effects
Humans
*Adenosine/analogs & derivatives/metabolism
*Neurons/metabolism/pathology
Active Transport, Cell Nucleus
Cell Line, Tumor
*Cell Nucleus/metabolism
*Membrane Proteins/metabolism
*HSP70 Heat-Shock Proteins/metabolism
RNA Methylation
Epitranscriptome

@article {pmid42496823,
year = {2026},
author = {Awwad, ZM},
title = {Dapagliflozin ameliorates Alzheimer's disease in rats via stimulating the protective arm of renin angiotensin system and suppressing neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42496823},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is associated with renin angiotensin system (RAS) overactivation that stimulates amyloid β-induced neurodegeneration. Activation of angiotensin II type 1 (AT1) receptor impairs the protective phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway. The combination between angiotensin converting enzyme 2 (ACE2)/ angiotensin 1-7 (Ang 1-7) /Mas receptor (MAS1) axis activation and PI3K/Akt stimulation counteracts AT1-induced apoptosis. Dapagliflozin (DAPA) alters the imbalance between the two RAS arms favoring the protective arm. Accordingly, the aim of the current study was to evaluate the possible neuroprotective effects of DAPA in guarding against scopolamine (SCO)-induced AD in rats via inhibiting RAS classical arm, and activating RAS protective arm, as well as PI3K/Akt pathway. DAPA administration suppressed ACE expression and reduced the levels of Ang II and AT1 in the hippocampi, while elevated the hippocampal levels of ACE2 and Ang 1-7 in addition to boosting MAS1 hippocampal expression. Of note, DAPA prominently augmented the level of PI3K. Also it enhanced the activity of protein kinase A. Furthermore, the hippocampal levels of caspase-3, cytochrome-c, interleukin-6 and nuclear factor kappa B were suppressed, while guanine nucleotide-binding protein alpha-3 level was elevated by DAPA administration. DAPA also attenuated the histopathological SCO-induced damage in rats and enhanced their recognition memory and learning in novel object recognition test and Y-maze spontaneous alternation test. Hence, the current results represent the first evidence for proving that DAPA-induced activation of the protective RAS arm suppressed the cognitive deficits in SCO-induced AD in rats.},
}

@article {pmid42496889,
year = {2026},
author = {Altves, S and Guclu, E and Yetisgin, E and Bilecen, K and Vural, H},
title = {Systems pharmacology and targeted transcriptional profiling suggest the putative neuroprotective role of Leuconostoc mesenteroides in an in vitro Alzheimer's disease model.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42496889},
issn = {1573-4978},
mesh = {*Alzheimer Disease/metabolism/genetics/drug therapy ; Humans ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/pharmacology ; *Leuconostoc mesenteroides/metabolism ; Cell Line, Tumor ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Gene Expression Profiling/methods ; Mitochondrial Dynamics/drug effects ; Network Pharmacology/methods ; Molecular Docking Simulation ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-beta (Aβ) accumulation, mitochondrial failure, and neuroinflammation. While probiotics show therapeutic potential via the gut brain axis, the molecular mechanisms remain poorly understood. This study investigated the neuroprotective potential of Leuconostoc mesenteroides lysate and its bioactive metabolites in an Aβ-induced SH-SY5Y neuroblastoma model.

METHODS: SH-SY5Y cells were challenged with Aβ and treated with L. mesenteroides lysate. Neuroprotective effects were evaluated via ROS accumulation, SOD1, APOE, NOS2, and mitochondrial dynamics (MFF, OPA1) using qPCR and WB. Potential mechanisms of action were explored computationally through integrated genome mining (antiSMASH 7.0), molecular docking (CB-Dock2), and systems pharmacology analysis (STRING/KEGG/R-studio) to identify candidate metabolites and host targets.

RESULTS: L. mesenteroides lysate significantly attenuated Aβ-induced ROS levels and upregulated SOD1, enhancing antioxidant capacity. The lysate effectively downregulated APOE expression and restored mitochondrial homeostasis by reducing mitochondrial fission (MFF) and promoting fusion (OPA1). In silico analysis predected phytoene as a primary bioactive metabolite with significant theoretical binding affinity for APOE. Systems biology mapping revealed highly significant enrichment in PPAR signaling and cholesterol metabolism pathways (FDR < 10⁻⁵). Specifically, Cellular Component analysis highlighted robust interactions within protein-lipid complexes (FDR = 1.98e-16).

CONCLUSION: L. mesenteroides lysate counteracts Aβ-induced neurotoxicity by modulating oxidative stress and restoring mitochondrial bioenergetics. Collectively, our findings suggest a theoretical Phytoene-PPAR-APOE signaling axis as a predictive framework for the observed cellular effects. We emphasize that phytoene represents a predicted candidate metabolite requiring future chemical characterization and biological validation.},
}

*Alzheimer Disease/metabolism/genetics/drug therapy
Humans
Amyloid beta-Peptides/metabolism
*Neuroprotective Agents/pharmacology
*Leuconostoc mesenteroides/metabolism
Cell Line, Tumor
Mitochondria/metabolism/drug effects
Oxidative Stress/drug effects
Reactive Oxygen Species/metabolism
Gene Expression Profiling/methods
Mitochondrial Dynamics/drug effects
Network Pharmacology/methods
Molecular Docking Simulation

@article {pmid42497020,
year = {2026},
author = {Li, C and Jiang, W and Lu, M},
title = {Metabolic endotoxemia in metabolic and neurodegenerative diseases.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026130},
pmid = {42497020},
issn = {1745-7270},
abstract = {Metabolic diseases, which include obesity, type 2 diabetes, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease (MASLD), are significant global health challenges. Patients with these conditions frequently exhibit gut dysbiosis and compromised gut barrier integrity, which lead to excessive translocation of Gram-negative bacterial lipopolysaccharide (LPS or endotoxin) from the gut lumen into the systemic circulation. This results in chronically elevated systemic LPS levels, a condition termed "metabolic endotoxemia". Gut-derived LPS may stimulate inflammatory responses and oxidative stress when it translocates and is recognized by host Toll-like receptor 4 (TLR4) and caspase-4/-5/-11. Metabolic endotoxemia is a primary trigger for the low-grade inflammation that promotes the development of metabolic diseases. Emerging evidence also indicates that metabolic endotoxemia acts as a key driver in the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease, by promoting chronic neuroinflammation. In this review, we discuss: (1) the molecular structure of LPS that determines its bioactivity and its recognition by host cells, (2) host regulation of its bioactivity, (3) its translocation from the gut lumen into the systemic circulation, and (4) how metabolic endotoxemia contributes to obesity, type 2 diabetes, atherosclerosis, MASLD, and Alzheimer's disease. We conclude by exploring potential interventions aimed at preventing or mitigating metabolic endotoxemia by promoting LPS degradation and inactivation.},
}

@article {pmid42497412,
year = {2026},
author = {Ghani, Z and Thant, PE and Saha, S and Anderberg, P and Aparicio, MQ and Barnestein-Fonseca, P and Cellek, S and Cleries, FM and Garolera, M and Guerrero-Pertiñez, G and Hayden, K and Moore, C and Zhang, J and Berglund, JS and Jarl, J},
title = {Effects of the Digital App "Support, Monitoring and Reminder Technology for Mild Dementia" (SMART4MD) on People With Mild Cognitive Impairment and Their Informal Caregivers: 18-Month Multicenter Pragmatic Randomized Controlled Trial.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e83123},
doi = {10.2196/83123},
pmid = {42497412},
issn = {1438-8871},
mesh = {Humans ; *Caregivers/psychology ; *Cognitive Dysfunction/therapy ; *Mobile Applications ; *Reminder Systems ; Aged ; Quality of Life ; Male ; Female ; Telemedicine ; Aged, 80 and over ; *Dementia ; Digital Health ; Sweden ; Adherence Interventions ; Spain ; },
abstract = {BACKGROUND: Previous research has shown that mobile health (mHealth) interventions are effective in reminding older adults with chronic conditions about health care appointments and promoting adherence to medication schedules. However, the evidence is limited by the short duration and poor quality of the interventions.

OBJECTIVE: We evaluated the effectiveness of the Support, Monitoring and Reminder Technology for Mild Dementia (SMART4MD) tablet app in improving the quality of life (QoL) of people with mild cognitive impairment (PwMCI) and their caregivers through medication reminders and health care appointment alerts.

METHODS: An 18-month pragmatic randomized controlled trial was conducted in Spain and Sweden from December 2017 to September 2020 and included 1078 PwMCI and their informal caregivers.

RESULTS: For PwMCI, the intervention improved the primary outcome, composite Quality of Life in Alzheimer's Disease (QoL-AD) scale, at 18 months (mean difference 0.75, 95% CI 0.07-1.42; P=.03), and a similar effect was observed at 6 months (mean difference 0.73, 95% CI 0.09-1.36; P=.02). Confirmatory secondary outcomes for PwMCI, including medication adherence (P=.12) and Mini-Mental State Examination (MMSE) score (P=.45), did not differ significantly between groups at the 18-month follow-up. Exploratory analyses showed higher total accumulated quality-adjusted life years (QALYs) at 6 months for PwMCI (mean difference 0.035, 95% CI 0.02-0.05; nominal P<.001), informal caregivers (mean difference 0.050, 95% CI 0.04-0.07; nominal P<.001), and dyads (mean difference 0.085, 95% CI 0.06-0.11; nominal P<.001). A dropout rate of approximately 40% (429/1083, 39.61%) was observed in both the intervention and control groups.

CONCLUSIONS: The SMART4MD intervention was associated with a modest improvement in PwMCI's QoL as measured by the composite QoL-AD score. Evidence for benefits among informal caregivers and dyads was less consistent and should be interpreted as exploratory. Nominally significant findings for exploratory outcomes should be interpreted with caution, as they were not adjusted for multiplicity.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03325699; https://clinicaltrials.gov/ct2/show/NCT03325699.

RR2-10.2196/13711.},
}

Humans
*Caregivers/psychology
*Cognitive Dysfunction/therapy
*Mobile Applications
*Reminder Systems
Aged
Quality of Life
Male
Female
Telemedicine
Aged, 80 and over
*Dementia
Digital Health
Sweden
Adherence Interventions
Spain

@article {pmid42497445,
year = {2026},
author = {Tatekawa, H and Oura, T and Takeda, A and Omori, A and Atsukawa, N and Matsushita, S and Horiuchi, D and Takita, H and Mitsuyama, Y and Ban, Y and Shimono, T and Pfeuffer, J and Ueda, D and Itoh, Y and Miki, Y},
title = {Amyloid-β-Related Cortical Susceptibility Alterations in Individuals Under Assessment for Alzheimer's Disease: A χ-Separation Study.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70458},
pmid = {42497445},
issn = {1522-2586},
support = {25K19115//JSPS KAKENHI/ ; //Takeda Science Foundation/ ; },
abstract = {BACKGROUND: Assessment of amyloid-β (Aβ) burden and associated iron deposition and neurodegeneration is important for Alzheimer's disease (AD) management. Although quantitative susceptibility mapping (QSM) detects iron and myelin changes, conventional metrics suffer from signal cancelation between paramagnetic and diamagnetic components. Consequently, spatial interactions between these independent susceptibility sources and Aβ burden remain unestablished.

PURPOSE: To investigate spatial associations between regional Aβ burden and independent paramagnetic and diamagnetic susceptibility sources using χ-separation.

STUDY TYPE: Prospective.

POPULATION: A total of 77 participants with mild cognitive impairment or dementia (mean age, 74 years; women, 50) examined using QSM and amyloid positron emission tomography (PET) ([18]F-flutemetamol or [18]F-florbetapir).

FIELD STRENGTH/SEQUENCE: 3 T/QSM (3-dimensional multi-echo gradient-echo sequence).

ASSESSMENT: χ-separation decomposed QSM data into paramagnetic (χ-para) and diamagnetic (χ-dia) components. Centiloid-scale maps standardized PET quantification for voxel-wise analysis. The spatial relationship between Aβ load and susceptibility metrics was analyzed using voxel-wise correlations within AD-signature cortical regions.

STATISTICAL TESTS: Voxel-wise spatial associations between Centiloid values and QSM metrics were evaluated using Pearson's coefficients. Spatial association was considered statistically significant if the 99% confidence interval (CI) did not cross zero.

RESULTS: Conventional QSM showed near-zero cortical susceptibility and obscured pathological details owing to physiological cancelation. χ-separation unmasked susceptibility sources. Local Aβ deposition was consistently associated with reduced absolute χ-dia across cortical regions (mean r range: -0.267 to -0.098; all 99% CIs did not cross zero), consistent with alterations in net diamagnetic susceptibility sources, potentially involving myelin-related components. χ-para showed weaker and regionally heterogeneous associations with Aβ burden, with a positive association most evident in the precuneus (mean r = 0.072, 99% CI: 0.052-0.092).

DATA CONCLUSION: χ-separation reveals region-specific cortical alteration associated with regional Aβ pathology. By separating these susceptibility sources, this method may provide complementary information to conventional QSM, offering a refined, noninvasive approach for characterizing amyloid-associated tissue changes in AD.

EVIDENCE LEVEL: 2.

TECHNICAL EFFICACY: Stage 2.},
}

@article {pmid42497446,
year = {2026},
author = {Kuo, YF and Tzeng, HM and Shan, Y and Jang, JH and Cram, P and Raji, MA},
title = {Association Between Annual Wellness Visits and Early Dementia Diagnoses: Roles of Post-Visit Healthcare Decisions.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70599},
pmid = {42497446},
issn = {1532-5415},
support = {5R01AG083102-03//National Institute on Aging of the National Institutes of Health/ ; P30-AG024832//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {BACKGROUND AND OBJECTIVES: Early recognition of cognitive impairment (CI) and timely diagnoses of mild CI (MCI) and Alzheimer's Disease and Related Dementias (ADRD) are key to optimal dementia care. No previous research has examined the extent to which healthcare interventions/services (specific blood tests, specialist referrals, and brain imaging) conducted after annual wellness visits (AWVs) contribute to subsequent MCI/ADRD diagnosis. We assessed the role of post-AWV healthcare services on the association of incident AWVs with the first ADRD or MCI diagnosis in Medicare enrollees.

METHODS: Propensity score matching of AWVs generated an active comparator cohort of Texas fee-for-service Medicare enrollees who received a Primary Care Provider visit, but without AWVs in 2018 (n = 66,443 in each group). Healthcare services (laboratory testing for CI: vitamin B12, thyroid stimulating hormone; specialist referrals: neurology, psychiatry; and brain images: CT, MRI) occurring after AWV and before the first MCI/ADRD diagnosis were examined.

RESULTS: Both groups had similar proportions of patients receiving specific blood tests, specialist referrals, and brain images in the 12 months before AWV/index date. Among those with no previous specialist visits, 39.2% in the AWV group and 31.1% in the non-AWV group received laboratory testing in the follow-up period. Similarly, among those with no previous brain images, 12.4% in the AWV group and 13.1% in the non-AWV group received brain images in the follow-up period. AWV receipt was associated with a 28% increase in MCI diagnosis; mediation analyses indicated that 14% of this increase was explained through post-AWV laboratory testing. AWV receipt was not associated with an increase in ADRD diagnosis.

DISCUSSION: Medicare AWV had a large direct effect on MCI diagnosis, but not on dementia diagnosis, suggesting that cognitive assessment and clinical evaluations during AWV directly contributed to the early recognition of MCI.},
}

@article {pmid42497465,
year = {2026},
author = {Seijo, MA and Yohannes, PA and Rogers, AL and Gonzalez, JC and Banerjee, A and Kelley, H and Pierce, M and McQuail, JA and Hernandez, CM},
title = {Posttraumatic stress disorder is associated with Alzheimer's disease-relevant molecular alterations in the basolateral amygdala of older Veterans.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {44-62},
doi = {10.1016/j.neurobiolaging.2026.07.006},
pmid = {42497465},
issn = {1558-1497},
abstract = {Posttraumatic stress disorder (PTSD) is associated with accelerated cognitive aging and increased risk for Alzheimer's disease (AD) and related dementias (ADRD), yet the biological substrates linking trauma-related psychiatric illness to altered brain aging trajectories remain poorly defined. The basolateral amygdala plays a central role in threat processing and emotional memory and exhibits persistent hyperactivity in PTSD, but its molecular and pathological state in aging individuals with PTSD has not been examined. Postmortem basolateral amygdala tissue from older adult donors (≥70 years) with lifetime PTSD (n = 5) and age-matched controls (n = 5) was obtained from the National PTSD Brain Bank. A multimodal analysis integrated immunohistochemical quantification of β-amyloid and phosphorylated tau pathology, targeted transcriptional profiling of AD-related genes, gene network analysis, and protein quantification of pathological, inflammatory, and synaptic markers. PTSD cases showed enrichment of combined tau-amyloid pathology within the basolateral amygdala and greater β-amyloid burden. Targeted transcriptomic profiling identified coordinated upregulation of genes involved in amyloid processing, lipid metabolism, proteostasis, and inflammatory signaling. Network analysis revealed an APP-centered molecular architecture with APOE, and MAPT as hubs. Protein analyses demonstrated increased amyloid-β and pTau231 abundance, markers of gliosis, and synaptic alterations characterized by elevated excitatory receptor expression and reduced inhibitory signaling. Collectively, these findings provide convergent human evidence that PTSD is associated with region-specific molecular alterations engaging pathways implicated in brain aging and neurodegenerative vulnerability. These data suggest that chronic trauma-related circuit dysregulation may intersect with aging-associated inflammatory and synaptic processes, promoting vulnerability to neurodegenerative change within emotionally salient brain circuits.},
}

@article {pmid42483925,
year = {2026},
author = {Li, W and Guo, C and Jin, Y and Ji, H and Zhang, L and Li, W and Zhang, W and Fu, L},
title = {Ganoderma sinense Polysaccharides Improve Cognition in a Mouse Model of Alzheimer's Disease by Modulating Gut Microbiota and Short-Chain Fatty Acid Metabolism.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050473800260622054102},
pmid = {42483925},
issn = {1875-5828},
abstract = {INTRODUCTION: The number of patients with Alzheimer's Disease (AD) worldwide is expected to reach 152 million by 2050, but developing an effective AD treatment remains challenging. This study purified two polysaccharides (GSP1 and GSP2) from Ganoderma sinense, a traditional Chinese medicine, and investigated their potential therapeutic effects against AD.

MATERIALS AND METHODS: GSP1 and GSP2 were purified and characterized for key physicochemical properties, including monosaccharide composition and molecular weight. In vitro neuroprotective efficacy was evaluated using glutamate-challenged SH-SY5Y cells. For in vivo assessment, an AlCl₃/D-galactose induced AD mouse model was established to quantify cognitive/memory enhancement. Multiomic analysis of the gut microbiota, Short-Chain Fatty Acid (SCFAs) metabolomics, and behavioural tests were conducted to elucidate the therapeutic mechanisms of GSP1.

RESULTS: Both GSP1 and GSP2 conferred neuroprotection against toxin-induced damage. Notably, GSP1 demonstrated superior efficacy compared with GSP2, significantly enhancing cognitive/ memory performance and reducing amyloid-β plaque deposition. Furthermore, GSP1 changed gut microbial diversity and SCFA metabolic profiles. Critical genus-level correlations emerged: Turicibacter, Jeotgalicoccus, and Staphylococcus were positively associated with therapeutic outcomes, whereas Odoribacter was negatively associated.

DISCUSSION: Natural polysaccharides, particularly GSP1, demonstrate therapeutic potential against AD by modulating gut microbiota. Mechanistically, this effect is linked to reshaping microbial communities and affecting the production of neuroprotective SCFAs. Although these findings position GSP1 as a promising AD therapeutic candidate, deeper exploration of gut-brain axis mechanisms remains essential for clinical translation.

CONCLUSION: GSP1 emerges as a promising therapeutic candidate for AD, offering a new approach to developing AD-targeted pharmaceuticals and nutraceuticals.},
}

@article {pmid42483984,
year = {2026},
author = {Silva-Rodríguez, J and Zhang, L and Kleineidam, L and López-González, FJ and Wagner-Reguero, S and Martínez-Castillo, M and Sogorb-Esteve, A and Guamán-Chulunchana, ME and Pastor, AB and Moreno, N and Ruiz-Calvo, A and Sánchez-Martín, C and Alfayate, E and Molero-Cartón, M and Valeriano-Lorenzo, EL and Frades-Payo, B and Valentí, M and Zea-Sevilla, MA and Moscoso, A and Ramírez, A and Martino-Adami, P and Riedel-Heller, SG and Scherer, M and Jeromin, A and Calero, M and Del Ser, T and Schneider, A and Grothe, MJ and Sánchez-Juan, P},
title = {Prognostic value of plasma %p-tau217 in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71599},
pmid = {42483984},
issn = {1552-5279},
support = {//CIEN Foundation/ ; //Reina Sofía Foundation/ ; PI24/00089//Instituto de Salud Carlos III/ ; PI23/01314//Instituto de Salud Carlos III/ ; PMP22/00022//Instituto de Salud Carlos III/ ; RYC2023-043746-Y//Ministerio de Ciencia e Innovación/ ; CNS2024-154295//Ministerio de Ciencia e Innovación/ ; //Hertie Network of Excellence in Clinical Neuroscience/ ; 101155955//European Union's Horizon Europe research and innovation programme/ ; //Cure Alzheimer Foundation/ ; //the Alzheimer Forschung Initiative/ ; NW21-049A-F//Ministry of Culture and Science of the State of North Rhine-Westphalia/ ; //German Ministry of Education and Research/ ; //Verum Foundation/ ; //the Network of University Medicine/ ; //Target ALS/ ; FZK01EK2102A//German Federal Ministry of Education and Research/ ; FZK01GP2213A//German Federal Ministry of Education and Research/ ; FZK 01GP2213A//Bundesministerium für Forschung und Technologie/ ; NW21-049 A-F//Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen/ ; N/A//Cure Alzheimer's Fund/ ; EXC2151-39087304//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *tau Proteins/blood ; Prognosis ; Female ; Disease Progression ; Aged ; Male ; Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnosis ; Dementia/blood/diagnosis ; Phosphorylation ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We evaluated the prognostic value of baseline plasma phosphorylated tau 217 ratio (%p-tau217) for predicting long-term progression in cognitively unimpaired (CU) older adults.

METHODS: We analyzed 982 community-dwelling individuals followed annually for up to 12 years. Baseline %p-tau217 levels were quantified by mass spectrometry and stratified into four strata using previously defined cut-offs. Outcomes included longitudinal changes in cognition, neurodegeneration, and progression to mild cognitive impairment (MCI)/dementia. Results were replicated with immunoassays in the same and an independent primary care cohort (n = 1204).

RESULTS: Participants with Elevated/High %p-tau217 exhibited accelerated cognitive decline, hippocampal atrophy, and significantly higher risks of progression to MCI (hazard ratio [HR] > 6.0) and dementia (HR > 9.9). The Low group demonstrated a 92.2% 10-year negative predictive value for any progression.

DISCUSSION: Our results suggest that %p-tau217 is a robust prognostic biomarker, accurately distinguishing CU individuals at minimal risk from those at high risk of future AD-related clinical and neurodegenerative decline. Similar performance was achieved by immunoassays.},
}

Humans
*tau Proteins/blood
Prognosis
Female
Disease Progression
Aged
Male
Biomarkers/blood
*Cognitive Dysfunction/blood/diagnosis
Dementia/blood/diagnosis
Phosphorylation
Longitudinal Studies
Aged, 80 and over

@article {pmid42484400,
year = {2026},
author = {Zawadzki, S and Okła, E and Ortega López, P and de la Mata, FJ and Ionov, M and Kreišmane, M and Skrastiņa, D and Jansons, J and Bryszewska, M and Miłowska, K},
title = {Multilevel Assessment of a Carbosilane Dendrimer-siRNA Nanoplatform: Cellular Compatibility, Blood-Brain Barrier Model Integrity, and Murine Model Biodistribution.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c06027},
pmid = {42484400},
issn = {1944-8252},
abstract = {The tight regulation of bidirectional solute flux between the systemic circulation and neural tissue by the blood-brain barrier (BBB) remains a principal obstacle to effective pharmacotherapy of the central nervous system. In this study, we evaluate the biocompatibility and biodistribution of a novel third-generation PEGylated carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex with an APOE4-directed siRNA relevant to late-onset Alzheimer's disease using a tiered, upstream strategy that progresses from BBB-relevant monocultures to a capillary-weighted BBB model and in vivo/ex vivo biodistribution in mice, in accordance with current recommendations for nanomaterial testing. In endothelial cells, pericytes, and astrocytes, mitochondrial/redox profiling (MTT, DCF-ROS, and JC-1 ΔΨm) defined tolerated exposure ranges. Complexation with siRNA consistently attenuated apparent cytotoxicity across cell types, yet both free and complexed formulations elicited modest ROS and dose-dependent ΔΨm depolarization, indicating persistent mitochondrial stress. In the BBB model, responses were concentration- and formulation-dependent: 10 µM free dendrimers produced sustained impedance and nuclear confluence loss with sheet-like detachment, whereas the 0.1-2.5 µM free dendrimer and the dendriplex induced transient, recoverable perturbations or increases in impedance and proliferation. In vivo, whole-body IVIS imaging demonstrated prolonged systemic exposure for the dendriplex and an ex vivo kidney-dominant, liver-secondary distribution; no robust dendriplex signal was detected in brain fluorescence by planar NIR-I IVIS under the applied acquisition conditions. Collectively, these data indicate that siRNA complexation broadens the functional window at the BBB model with partially recoverable barrier effects and improved systemic exposure, while not substantially reducing mitochondrial or oxidative stress responses. The results provide a mechanistically informed basis for dose optimization and efficacy testing of this dendrimer-siRNA platform in CNS indications and for advancing this platform in further investigations targeting Alzheimer's disease.},
}

@article {pmid42484409,
year = {2026},
author = {Tulloch, R and Gaffiero, D},
title = {Menopause, brain health and hormone replacement therapy: gaps in knowledge and policy solutions from a Scottish perspective.},
journal = {Post reproductive health},
volume = {32},
number = {1},
pages = {77-81},
doi = {10.1080/20533691.2026.2631221},
pmid = {42484409},
issn = {2053-3705},
mesh = {Humans ; Female ; Scotland ; *Menopause/physiology/psychology ; Women's Health ; *Health Policy ; *Brain/physiology ; *Hormone Replacement Therapy ; Health Knowledge, Attitudes, Practice ; Alzheimer Disease/prevention & control ; Primary Health Care ; Quality of Life ; },
abstract = {PURPOSE: This commentary argues for the systematic integration of brain health into menopause care and policy in the United Kingdom (UK). Using Scotland as a strategically bounded case study, it examines persistent knowledge gaps among women and primary care professionals and their implications for equitable menopause care.

KEY ISSUES: Menopause involves significant neuroendocrine changes that affect brain metabolism, structure, and cognition, contributing to women's disproportionate Alzheimer's disease risk. Although hormone replacement therapy may alleviate neurological and cognitive symptoms - and may offer neuroprotective benefits when initiated early - clinical uncertainty, stigma, and inconsistent guidance continue to delay recognition, support, and treatment. These gaps translate into avoidable cognitive decline, reduced quality of life, and marked inequities in access to menopause care.

IMPLICATIONS: Targeted primary care training, coherent public communication, and UK-specific investment in evidence-based menopause services are urgently required. This programme of research is situated within Scotland as a strategically bounded, devolved health system, allowing for a focused examination of how brain health is addressed within menopause policy and practice. By embedding brain health within Scotland's Women's Health Plan, the findings will inform future comparative and UK-wide research and contribute to the development of equitable, person-centred, and brain-health informed menopause care across the lifespan.},
}

Humans
Female
Scotland
*Menopause/physiology/psychology
Women's Health
*Health Policy
*Brain/physiology
*Hormone Replacement Therapy
Health Knowledge, Attitudes, Practice
Alzheimer Disease/prevention & control
Primary Health Care
Quality of Life

@article {pmid42484463,
year = {2026},
author = {Chen, Y and Kwapong, WR and Chen, X and Gao, Y and Chu, M and Zhang, X and Wu, L},
title = {Retinal structural and microvascular alterations as biomarkers of cerebral pathology and cognitive decline in Alzheimer's disease: An OCT/OCTA study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470439},
doi = {10.1177/13872877261470439},
pmid = {42484463},
issn = {1875-8908},
abstract = {BackgroundRetinal structural and microvascular alterations detected by optical coherence tomography (OCT) and OCT angiography (OCTA) have emerged as promising biomarkers of Alzheimer's disease (AD). However, the extent to which retinal changes reflect cerebral neurodegenerative and vascular pathology and contribute to cognitive impairment remains incompletely characterized.ObjectiveTo investigate the relationships among retinal OCT/OCTA metrics, cerebral neuroimaging markers, and global cognitive performance in patients with AD.Methods115 AD and 101 cognitively unimpaired controls underwent OCT/OCTA imaging, 3.0T brain magnetic resonance imaging, and neuropsychological assessment. Retinal structural measures, including peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses, and retinal microvascular densities of the superficial vascular complex (SVC) and deep vascular complex were analyzed alongside white matter hyperintensity (WMH) volume, hippocampal volume, and cerebral small vessel disease (SVD) burden.ResultsCompared with controls, patients with AD exhibited significantly thinner pRNFL and GCIPL and lower SVC density (all p < 0.01). Retinal structural and microvascular alterations were associated with greater WMH burden, hippocampal atrophy, increased SVD burden, and lower Mini-Mental State Examination and Montreal Cognitive Assessment scores (all p < 0.05). Significant interactions were observed between GCIPL thickness and periventricular WMH volume in relation to cognitive performance. Mediation analyses demonstrated that WMH volume and SVD burden partially mediated the association between reduced SVC density and cognitive impairment.ConclusionsRetinal OCT/OCTA metrics are associated with cerebral neurodegenerative and vascular abnormalities and reflect cognitive dysfunction in AD, supporting their potential utility as accessible, noninvasive biomarkers for disease assessment and monitoring.},
}

@article {pmid42484467,
year = {2026},
author = {Ramos-Henderson, M and Aliaga-Gallardo, P and Aguilar-Riveros, C and Fuentes, L and Calderón, C and Domic-Siede, M},
title = {Associations between higher-order executive planning and subjective cognitive decline in middle-aged individuals.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470712},
doi = {10.1177/13872877261470712},
pmid = {42484467},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is a recognized risk factor for future objective cognitive impairment and dementia. Although widely studied in older adults, SCD during midlife remains underexplored, despite this period representing a critical window for early detection. Higher-order executive functions, particularly cognitive planning, may be especially sensitive to subtle cognitive changes at this stage.ObjectiveTo examine the association between higher-order executive function performance and subjective cognitive decline in middle-aged individuals.MethodsThis cross-sectional study included 167 community-dwelling middle-aged adults (45-60 years) with SCD and normal global cognition. Participants completed the Subjective Cognitive Decline Questionnaire (SCDq), mood and sleepiness measures, structured executive function tests, and the Zoo Map Test (ZMT) to assess higher-order executive planning. Group comparisons, correlation analyses, and hierarchical linear regressions were performed.ResultsHigher SCD levels were associated with longer planning times and more planning errors on the ZMT. No associations were observed between SCD and global cognitive performance or structured executive function measures. In the hierarchical regression model, mood symptoms and daytime sleepiness explained 23% of SCD variance, while higher-order executive planning measures accounted for an additional 8.4%, yielding a final hierarchical model explaining 33.6% of the variance. Fully adjusted simultaneous model showed the same pattern.ConclusionsSCD in midlife is associated with subtle differences in higher-order executive functioning that emerge under high cognitive demand. Ecologically valid executive tasks may improve early detection of individuals at risk for future objective cognitive decline beyond traditional neuropsychological measures.},
}

@article {pmid42484558,
year = {2026},
author = {Arnold, MR and Westaway, SK and Woltjer, RL and Gray, NE and Quinn, JF},
title = {E326K GBA polymorphism is associated with clinical and pathological features of synucleinopathy in the absence of overt Parkinson's disease or Lewy body dementia.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261468542},
doi = {10.1177/1877718X261468542},
pmid = {42484558},
issn = {1877-718X},
abstract = {Heterozygote carriers of Gaucher's disease mutations and other polymorphisms in the glucocerebrosidase (GBA) gene show an increased incidence of Parkinson's disease. We hypothesized that common GBA polymorphisms would be associated with subtle parkinsonian features, mild cognitive impairment, and "silent" Lewy body (LB) pathology in aging individuals without a clinical diagnosis of parkinsonism. The most prevalent GBA variants, T369M and E326K, appear in the general population at rates of approximately 0.6% and 1%, respectively. We evaluated 845 participants from the Oregon Alzheimer's Disease Research Center (OADRC) with SNP data generated by the National Centralized Repository of Alzheimer's Disease (NCRAD). Twenty-one subjects were E326K carriers and eighteen were T369M carriers. Clinical measures and postmortem neuropathology were compared between each SNP group and non-carriers. Although there were no statistically significant clinical differences related to synucleinopathy across groups, neuropathological analyses revealed a significantly higher prevalence of LB pathology in E326K carriers compared to T369M carriers. When stratifying each genetic group by LB status (LB+ or LB-), LB+ E326K carriers demonstrated a significant reduction in Mini-Mental State Examination (MMSE) scores compared with LB- non-carriers and a modest decrease compared with T369M carriers. These preliminary findings from a small, uni-center cohort suggest that the E326K GBA polymorphism may predict LB pathology and subtle cognitive decline in aging individuals who lack overt parkinsonian symptoms. Further validation in a larger cohort is warranted. Identifying at-risk individuals through targeted genetic screening may ultimately support earlier intervention and preventative care strategies.},
}

@article {pmid42484559,
year = {2026},
author = {Ashar, MS and Anwar, M and Singh, AK and Pradhan, R and Gupta, A and Chakrawarty, A and Haldar, P and Tripathi, M and Dey, S},
title = {Quantitative correlation between extracellular matrix protein degradation and the progression of neurodegeneration in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470815},
doi = {10.1177/13872877261470815},
pmid = {42484559},
issn = {1875-8908},
abstract = {BackgroundThe extracellular matrix (ECM) supports synaptic connections. Breakdown of ECM net component perineuronal nets (PNN) loses synaptic plasticity and causes the symptoms of neurological disorder like Alzheimer's diseases (AD).ObjectiveThis study analyzed PNN proteins and Tenascin-C (TNC), in the blood of AD, mild cognitive impairment (MCI) patients, and geriatric controls (GC), with correlation with tau and p-tau levels.MethodsThis case control study included 77 AD, 53 MCI patients, and 51 GC. Serum PNN and TNC levels were measured by surface plasmon resonance (SPR) method and validated by western blot. Statistical analyses included Kruskal-Wallis, logistic regression, Spearman correlation and receiver operating curve.ResultsPNN proteins and TNC were significantly elevated in AD compared to MCI and GC. Aggrecan and versican showed strong discriminatory power for AD from MCI, while TNC distinguished MCI from GC, indicating its potential for early detection of cognitive decline. Higher protein levels correlated with lower cognitive scores. Western blot result was consistent with SPR findings.ConclusionsThese results emphasize the significance of ECM proteins as biomarkers for cognitive impairments, showcasing their diverse diagnostic capabilities for AD. These findings provide further support for the involvement of PNN proteins in the pathophysiology of AD during early stage.},
}

@article {pmid42484690,
year = {2026},
author = {Yao, Q and Han, X and Cui, T and Li, D and Shan, A and Wang, X and Li, S and Luan, H and Zhu, Y and Wen, B and Sun, Y and Li, C and Sun, Q and Wei, C},
title = {Serial failure of the brain clearance continuum in Alzheimer's disease: mechanisms and therapeutic perspectives.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42484690},
issn = {1432-1459},
support = {2021ZD0201802//Innovation of Science and Technology 2030 - Major Project on Brain Science and Brain-Inspired Intelligence Research/ ; 82471450//National Nature Science Foundation of China/ ; XCSTS-SD2024-02//Xicheng District Science and Technology Special Project/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/therapy ; Animals ; *Brain/metabolism/physiopathology ; *Glymphatic System/metabolism/physiopathology ; *Choroid Plexus/metabolism/physiopathology ; Amyloid beta-Peptides/metabolism ; Meninges/metabolism ; *Cerebrospinal Fluid/metabolism ; },
abstract = {Alzheimer's disease (AD) is usually regarded as a neurodegenerative disorder defined by amyloid-β (Aβ) deposition and abnormal tau accumulation. Increasing evidence suggests that reduced clearance of metabolic waste and pathological proteins from the brain also contributes to disease onset and progression. Previous studies have often considered choroid plexus (CP) function, glymphatic exchange, and meningeal lymphatic drainage as separate clearance processes. A continuous framework linking these structures and functions is still lacking. This review integrates recent clinical and experimental evidence and proposes the brain clearance continuum as an interpretative framework. It describes three interlinked functional interfaces: the upstream choroid plexus-cerebrospinal fluid (CP-CSF) inflow interface, the midstream parenchymal perivascular exchange interface, and the downstream meningeal lymphatic outflow interface. Under physiological conditions, these interfaces support CSF movement, parenchymal solute exchange, and the outward removal of metabolic waste. In AD, disrupted CSF homeostasis, impaired perivascular exchange, and obstructed meningeal lymphatic outflow may interact, leading to serial failure of the brain clearance continuum. This process is closely associated with Aβ/tau accumulation, vascular dysfunction, neuroinflammation, and cognitive decline. We also summarise potential therapeutic strategies directed at different clearance interfaces, whilst emphasising that most evidence remains preclinical or exploratory. The brain clearance continuum provides a systematic framework for understanding clearance failure in AD. It may also offer a theoretical basis for future mechanistic studies and therapeutic development that are stratified by clearance interface and disease stage.},
}

Humans
*Alzheimer Disease/metabolism/physiopathology/therapy
Animals
*Brain/metabolism/physiopathology
*Glymphatic System/metabolism/physiopathology
*Choroid Plexus/metabolism/physiopathology
Amyloid beta-Peptides/metabolism
Meninges/metabolism
*Cerebrospinal Fluid/metabolism

@article {pmid42484748,
year = {2026},
author = {Abroumand Gholami, A and Ghadiminia, N and Akhrorova, S and Kubaev, A and Agamurodov, S and Salomova, F},
title = {Correspondence: Erythrina caffra in cadmium-induced Alzheimer's-like pathology: A new candidate or a familiar pattern?.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42484748},
issn = {1573-4978},
mesh = {*Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; Animals ; *Cadmium/toxicity ; *Plant Extracts/pharmacology/therapeutic use ; *Erythrina/chemistry/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Rats ; Oxidative Stress/drug effects ; Disease Models, Animal ; },
abstract = {Cadmium neurotoxicity has been increasingly linked to neurodegenerative processes, and plant-derived compounds are being explored for their protective potential. The recent study by Ed-Day and colleagues investigated the neuroprotective effects of Erythrina caffra seed extract in a cadmium-induced Alzheimer's-like model in rats, reporting improvements in memory, cholinergic function, oxidative stress, and neuroinflammation. Four principal concerns are identified: (1) treatment protocol ambiguity, use of young rats to model an age-related disease, and unclear prevention-versus-therapy distinction; (2) memantine as positive control, mechanistically mismatched with cadmium toxicity pathways; (3) claim of Alzheimer's-like pathology without measuring Aβ plaques and tau tangles; and (4) no cadmium quantification in tissues or biofluids, leaving the mechanism, direct neuroprotection versus reduced bioavailability, unresolved. While the study offers promising preliminary evidence for the neuroprotective potential of E. caffra, its translational significance is constrained by these methodological and interpretative limitations. Addressing these concerns in future investigations would strengthen the evidence base for this medicinal plant's therapeutic potential.},
}

*Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism
Animals
*Cadmium/toxicity
*Plant Extracts/pharmacology/therapeutic use
*Erythrina/chemistry/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Humans
Rats
Oxidative Stress/drug effects
Disease Models, Animal

@article {pmid42484778,
year = {2026},
author = {Lill, CM and Homann, J and Ohlei, O and Smith-Byrne, K and Viallon, V and Huerta, JM and Artaud, F and Zhao, Y and Britten, A and Deecke, L and Dobricic, V and Mokoroa, O and Guevara, M and Petrova, D and Trupp, M and Sabin, J and Gröninger, M and Colorado-Yohar, SM and Alonso-Martin, S and Cabrera-Castro, N and Groppa, S and Robinson, O and Hansen, J and Eriksson, S and Sieri, S and Jimenez, A and Tong, TYN and Kaaks, R and Severi, G and Travis, R and Wareham, N and Benedet, AL and Zetterberg, H and Franke, A and Elbaz, A and Bertram, L and Vermeulen, R and Middleton, L and Masala, G and Sacerdote, C and Peters, S and Katzke, V and Ferrari, P and Gunter, MJ and Riboli, E},
title = {EPIC4ND-European Prospective Investigation into Cancer and Nutrition follow-up for neurodegenerative diseases.},
journal = {European journal of epidemiology},
volume = {},
number = {},
pages = {},
pmid = {42484778},
issn = {1573-7284},
support = {#008994//Michael J Fox Foundation/ ; JPND2021-650-289//EU Joint Programme - Neurodegenerative Disease Research/ ; LI 2654/3-1//Deutsche Forschungsgemeinschaft/ ; LI 2654/4-1 (Heisenberg)//Deutsche Forschungsgemeinschaft/ ; INTRAIBS-2020-06//Instituto de Investigación Biosanitaria ibs.GRANADA/ ; },
abstract = {The 'European Prospective Investigation into Cancer and Nutrition' cohort (EPIC) is a prospective study including ~ 520,000 participants recruited across Europe (1991-2000) with in-depth baseline data on nutritional, lifestyle, medical, and anthropometric variables, and baseline blood samples. Here we introduce EPIC4ND, a case-cohort study within EPIC designed to identify biomarkers predicting a future onset of dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). EPIC4ND comprises 6415 initially non-diseased participants (aged 35-80 years, mean age at baseline: 54 ± 9, 64% women) including 1899 incident cases with up to 30 years of follow-up and data on at least one omics domain available from pre-disease blood samples. EPIC4ND includes 4604 subcohort members (4441 non-cases and 163 incident cases) and 1811 additional incident cases ascertained from the broader EPIC cohort. Among the incident cases, there are 1190 dementia cases (818 AD), 610 PD cases, and 199 ALS cases. Additionally, 72 prevalent PD cases and 118 incident Parkinsonism cases are available for comparison. Molecular data generated encompass proteomics, genome-wide DNA methylation, and SNP genotyping with 4127 EPIC4ND participants (including 1635 incident cases) having data on all three domains. Smaller studies include data on metals, metabolites, and environmental chemicals, while ongoing efforts focus on ultrasensitive targeted biomarker measurements and small RNA sequencing. Genome-wide association studies and analyses of epidemiological risk factors validate the dataset by confirming many known risk factors. Leveraging these extensive pre-disease multi-layered omics data offers a unique opportunity to identify biomarker signatures predicting neurodegenerative diseases and to explore their interplay with epidemiological risk factors.},
}

@article {pmid42484938,
year = {2026},
author = {Wu, P and Liao, Y and Liu, C and Liu, X and Feng, Q and Cheng, X},
title = {The Clearance-Centered Bottleneck in Alzheimer's Disease: From Coupled Glymphatic-Lymphatic Circuits to Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42484938},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism/physiopathology/immunology ; *Glymphatic System/pathology/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; *Lymphatic System ; },
abstract = {While anti-amyloid-beta (Aβ) monoclonal antibodies have achieved substantial success in reducing plaque burden, their modest clinical impact highlights an "efficacy ceiling" that necessitates a re-evaluation of Alzheimer's disease (AD) pathogenesis. This review proposes a shift from an amyloid-centered paradigm to a "clearance-centered bottleneck" framework, conceptualizing brain homeostasis as a coupled glymphatic-lymphatic circuit. We identify three critical rate-limiting nodes-entry, transit, and exit-that govern this circuit. These nodes fail through distinct mechanisms: arterial stiffening (entry), aquaporin-4 (AQP4) depolarization (transit), and cerebral amyloid angiopathy with impaired meningeal lymphatic drainage (exit). This multilevel failure creates a self-sustaining "neuroimmune stalemate"-a state in which trapped antigens and inflammatory mediators perpetuate glial reactivity that further degrades the very clearance infrastructure needed to resolve it. Distinct from prior reviews of glymphatic dysfunction in isolation, this review contributes four interlinked advances: an integrated glymphatic-lymphatic coupled-circuit framework; a bidirectional immune-clearance crosstalk model; a critical appraisal of imaging endpoints graded by trial-readiness; and a combination therapy roadmap. To overcome the current therapeutic plateau, we advocate for multinode interventions that combine amyloid-targeting therapies with clearance-enhancing agents, supported by a readiness-tiered imaging strategy-standardized proxies such as DTI-ALPS and PVS burden as enrichment/secondary endpoints and dynamic contrast-enhanced MRI for mechanistic proof-of-concept.},
}

Humans
*Alzheimer Disease/therapy/pathology/metabolism/physiopathology/immunology
*Glymphatic System/pathology/metabolism
Animals
Amyloid beta-Peptides/metabolism
*Lymphatic System

@article {pmid42484959,
year = {2026},
author = {Lin, Q and Qiu, N and Wang, X and Wei, YB and Liu, JJ},
title = {Chronic Pain and the Risk of Dementia: A Systematic Review and Meta-Analysis.},
journal = {Current pain and headache reports},
volume = {30},
number = {1},
pages = {},
pmid = {42484959},
issn = {1534-3081},
mesh = {Humans ; *Dementia/epidemiology/etiology ; *Chronic Pain/epidemiology/complications ; Risk Factors ; },
abstract = {BACKGROUND: The relationship between chronic pain and dementia risk has been extensively studied, but findings remain inconclusive. We conducted an updated meta-analysis to synthesize evidence from recent large-scale cohort studies.

METHODS: Two authors independently and systematically searched PubMed, Web of Science, Embase, Cochrane Library, and Chinese National Knowledge Infrastructure for cohort studies published through April 2025, with a minimum follow-up of one year. Hazard ratios (HRs) were considered equivalent to risk ratios (RRs) assuming low event rates. Random-effect models pooled risk ratios (RR) with 95% confidence intervals (CI). Subgroup analyses and meta-regression explored heterogeneity.

RESULTS: Of 3,823 publications, 30 studies met the inclusion criteria. After excluding five studies with overlapping populations, 25 studies involving 2,091,835 participants were pooled in the primary analysis. Individuals with chronic pain had a 28% higher dementia risk (RR = 1.28, 95% CI = 1.18-1.38). Heterogeneity was high (I²=91%). Subgroup analyses showed migraine, headaches, arthritis-related pain, and widespread pain were associated with increased risk. The association was significant in Asia but not in America or Europe, and when using ICD (but not DSM) criteria. Chronic pain increased the risk of Alzheimer's disease and non-vascular dementia, but not vascular dementia. Study quality, region, measurement methods, and pain types influenced the relationship. Pain type was a source of heterogeneity.

CONCLUSIONS: In this meta-analysis of cohort studies, chronic pain was associated with an increased risk of dementia. Due to the observational nature of the included studies and high heterogeneity, this association should not be interpreted as causal. Further research is needed to determine whether pain management can mitigate dementia risk.},
}

Humans
*Dementia/epidemiology/etiology
*Chronic Pain/epidemiology/complications
Risk Factors

@article {pmid42485421,
year = {2026},
author = {Yang, S and Cui, L and Zhang, J and Yang, Y and Huo, J and Ding, Y and Zhang, J and He, S and Li, J},
title = {Association of triglyceride-glucose index (TyG) and a body shape index (ABSI) with cognitive decline and dementia risk.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354418},
doi = {10.1371/journal.pone.0354418},
pmid = {42485421},
issn = {1932-6203},
mesh = {Humans ; *Triglycerides/blood ; *Dementia/blood/epidemiology ; *Cognitive Dysfunction/blood/epidemiology ; Female ; Male ; *Blood Glucose/analysis/metabolism ; Aged ; Risk Factors ; },
abstract = {BACKGROUND: Longitudinal evidence linking the body shape index (ABSI) to dementia and its subtypes remains scarce. Furthermore, the use of ABSI and TyG-ABSI as predictors of cognitive decline and dementia is infrequent. Therefore, this study aimed to examine the relationships between the triglyceride-glucose (TyG) index, ABSI, and TyG-ABSI indices and their predictive value for cognitive decline and dementia risk.

METHODS: This study included 370,744 participants from the UK Biobank. The TyG and ABSI indices were calculated using their respective formulas, while the TyG-ABSI index was derived by multiplying TyG and ABSI. Cognitive decline was defined as scoring in the bottom 25% on cognitive tests, while dementia was diagnosed from first-recorded incidents and algorithmically-defined outcomes. Logistic regressions were employed to assess the associations of TyG, ABSI and TyG-ABSI indices with cognitive decline; Cox regressions were used to analyze the associations of these indices with the risk of all-cause dementia (ACD) and its subtypes.

RESULT: The TyG, ABSI, and TyG-ABSI indices were all significantly associated with cognitive decline. Additionally, compared with the lowest quartiles, the highest quartiles of TyG, ABSI and TyG-ABSI indices were associated with a significantly increased risk of ACD by 33% (HR = 1.33, 95% CI: 1.13-1.57), 79% (HR = 1.79, 95% CI: 1.65-1.94) and 67% (HR = 1.67, 95% CI: 1.54-1.82), respectively. These indices were also significantly associated with the risk of Alzheimer's disease (AD) and vascular dementia (VD) (all P < 0.05).

CONCLUSION: The TyG, ABSI, and TyG-ABSI indices are significantly and positively linked to the risk of cognitive decline and dementia.},
}

Humans
*Triglycerides/blood
*Dementia/blood/epidemiology
*Cognitive Dysfunction/blood/epidemiology
Female
Male
*Blood Glucose/analysis/metabolism
Aged
Risk Factors

@article {pmid42485548,
year = {2026},
author = {Moradi Sarcheshmeh, MS and Shahedi, A and Zabihirad, J and Taghipour, M and Kargar Jahromi, H and Delam, H},
title = {Global Prevalence of Urinary Incontinence in Individuals With Dementia: A Systematic Review and Meta-Analysis.},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70390},
pmid = {42485548},
issn = {1520-6777},
abstract = {BACKGROUND: Urinary incontinence (UI) is a common and debilitating complication in patients with dementia, significantly impacting quality of life, increasing caregiver burden, and accelerating institutionalization.

OBJECTIVE: Despite numerous studies, reported prevalence estimates vary widely, and a precise global pooled prevalence has not been established.

METHODS: This systematic review and meta-analysis followed PRISMA guidelines. A comprehensive search of PubMed/MEDLINE, Scopus, and Web of Science was conducted from November to December 2025, without publication year restrictions. Observational studies reporting the point prevalence of UI in dementia patients were included. Two independent reviewers screened studies, extracted data, and assessed methodological quality using the Newcastle-Ottawa Scale. A random-effects meta-analysis (restricted maximum likelihood method) was used to pool prevalence estimates. Heterogeneity was assessed using the I[2] statistic. Subgroup analyses were performed by setting and UI assessment method, and meta-regression examined associations with Human Development Index (HDI) and temporal trends.

RESULTS: Ten studies comprising 286,544 participants were included. The pooled global prevalence of UI in dementia patients was 39.7% (95% CI: 23.9%-58.1%), with substantial heterogeneity (I[2] > 95%). Prevalence ranged from 4% in Taiwan to 88% in Japan. Subgroup analyses revealed significantly higher prevalence in clinic/hospital settings compared to community settings (47.5% vs. 28.7%, p = 0.023), and in studies using single-question interviews versus medical record extraction (59.2% vs. 23.2%, p = 0.016). Meta-regression showed a significant positive association with HDI (coefficient: 5.69, p < 0.001). Sensitivity analysis confirmed the robustness of the pooled estimate.

CONCLUSION: Approximately 40% of dementia patients experience UI, with substantial variation by setting and assessment method. Standardized assessment protocols are needed to inform targeted interventions and reduce disease burden.},
}

@article {pmid42485607,
year = {2026},
author = {Chen, Y and Chen, A and Power, MC and Grodstein, F and Kapasi, A and Capuano, AW and Lange-Maia, BS and Moghtaderi, A and Stapp, EK and Bhattacharyya, J and Shah, RC and Barnes, LL and Bennett, DA and James, BD},
title = {Associations of Alzheimer Disease and Related Dementia Neuropathologies With Timely Diagnosis of Dementia in Healthcare Settings.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218352},
doi = {10.1212/WNL.0000000000218352},
pmid = {42485607},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/pathology/diagnosis ; Aged, 80 and over ; Retrospective Studies ; *Dementia/diagnosis/pathology ; Aged ; *Brain/pathology ; United States ; Cohort Studies ; Medicare ; },
abstract = {BACKGROUND AND OBJECTIVES: A timely diagnosis of dementia may provide valuable time for treatment and planning, yet underdiagnosis is common. This study investigated the relationship between presence of dementia pathologies and timeliness of dementia diagnosis by healthcare providers.

METHODS: This was a retrospective study using 5 cohorts at Rush Alzheimer's Disease Center. We included participants who met all of the following criteria: (1) incident dementia based on annual cohort assessments, (2) linkage to Medicare records, and (3) a completed postmortem brain autopsy. Postmortem neuropathologic examinations identified the presence of AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), vascular pathologies, and neocortical Lewy bodies (LBs). In linked Medicare data, we defined timely diagnosis as the presence of claims with dementia diagnoses within 3 years before or 1 year after the cohort-based dementia onset. We used logistic regressions to quantify associations of neuropathology markers with timely diagnosis vs underdiagnosis.

RESULTS: Of the 500 eligible participants (71% female, 95% non-Latino White, mean [SD] age at cohort dementia onset = 88 [7] years, mean [SD] years from onset to death = 4 [3]), only 54% received a timely diagnosis. After controlling for demographics, time to death, and other neuropathologies, a pathologic diagnosis of AD (OR = 1.91, 95% CI 1.21-3.00) and moderate/severe LATE-NC pathologies (OR = 1.83, 95% CI 1.25-2.68) were independently associated with higher odds of timely diagnosis. Moderate/severe vascular pathologies (OR = 0.94, 95% CI 0.55-1.59) and neocortical LB pathologies (OR = 1.00, 95% CI 0.64-1.55) were not significantly associated with receipt of a timely diagnosis. In a separate multivariable logistic regression, we found that participants with 3 or 4 neuropathologies present had an over 2-fold increase in odds of timely diagnosis (OR = 2.24, 95% CI 1.32-3.82), compared with those with 1 or no neuropathology.

DISCUSSION: In deceased older adults with cohort-determined incident dementia, the healthcare system was twice as likely to capture those with pathologic diagnosis of AD, moderate/severe LATE-NC, and more than 3 copathologies in a timely manner. While findings from this predominantly White and highly educated sample warrant replication in broader population, this study is an important initial step toward understanding biological correlates of timely diagnosis of dementia.},
}

Humans
Female
Male
*Alzheimer Disease/pathology/diagnosis
Aged, 80 and over
Retrospective Studies
*Dementia/diagnosis/pathology
Aged
*Brain/pathology
United States
Cohort Studies
Medicare

@article {pmid42485616,
year = {2026},
author = {Silva, JAFD and Nagra, A and Wadhwa, A and Mar, S and Tjoa, A and Flibotte, S and Barvalia, M and Matos, I and Priatel, J and Krebs, D and Harder, KW},
title = {A DLL1-culture system to propagate murine patrolling monocytes from bone marrow progenitors.},
journal = {Journal of leukocyte biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jleuko/qiag103},
pmid = {42485616},
issn = {1938-3673},
abstract = {Patrolling monocytes (pMos) scavenge debris from vessel walls and mediate antibody-dependent cellular phagocytosis, making them attractive cell therapy candidates for cancer, atherosclerosis, and Alzheimer's disease. However, methods to generate enhanced numbers of pMos are not available. To address this, we developed a two-step procedure to produce pMos in vitro from murine bone-marrow (BM). First, myeloid progenitors were expanded and enriched from BM using cytokines for four days. Second, expanded progenitors were differentiated into pMos on DLL1-expressing monolayers for eight days. We confirmed that in vitro grown pMos expressed the transcription factor Nr4a1 (Nur77) and other canonical pMos surface proteins, and depended on Notch signalling for their development. RNA sequencing revealed that in vitro pMos expressed hallmark pMos genes, including Cx3cr1, Itgax (CD11c), CD43, Fcγr4, and Cd274 (PD-L1), and their gene signatures clustered closely with in vivo blood and BM pMos. Transcriptomic and phenotypic analyses further demonstrated that in vitro pMos were distinct from classical BM macrophages. Phagocytosis assays demonstrated the function of in vitro pMos in cancer cell uptake. Adoptive transfer studies demonstrated that in vitro pMos persisted within the circulation and lung vasculature during the early post-transfer period compared with BM-derived macrophages, consistent with the vascular-patrolling properties of pMos. Adoptive transfer of pMos reduced lung tumour burden in a metastatic model, supporting an anti-tumoural role for pMos and their ability to mediate immune surveillance in vivo. These findings demonstrate that the DLL1 culture system allows for propagation of functional pMos, enabling studies of pMos biology and their therapeutic potential.},
}

@article {pmid42485924,
year = {2026},
author = {Xing, Z and Liu, Z and Zhang, DF and Xie, K and Fang, J and Bi, XA and Liu, T},
title = {Alzheimer's disease risk prediction via perceptual deformable attention generative adversarial network with large foundation models.},
journal = {Medical image analysis},
volume = {113},
number = {},
pages = {104225},
doi = {10.1016/j.media.2026.104225},
pmid = {42485924},
issn = {1361-8423},
abstract = {Predicting the risk of Alzheimer's disease (AD) is fundamental for early-stage intervention. Nevertheless, most methods struggle to extract multi-omics associative patterns due to the limited feature perception and inflexible disease modeling. This paper proposes a novel evolutionary pattern mining framework for precise disease risk prediction. Firstly, large foundational models are employed to automatically construct high-quality features. Second, a perceptual deformable attention mathematical model is proposed, which combines multi-scale sparse attention and deformable attention mechanisms to capture evolutionary patterns of fused multi-omics features. Finally, a Perceptual Deformable Attention Generative Adversarial Network (PDAT-GAN) is developed. PDAT-GAN can precisely simulate the evolutionary procedure of AD using multi-omics data, thereby achieving robust risk prediction and pathogeny extraction for AD. We validate the advanced performance and interpretability of PDAT-GAN on public datasets, underscoring significance of PDAT-GAN in supporting clinical intervention and pathogenetic research. The code of PDAT-GAN can be accessed at: .},
}

@article {pmid42486010,
year = {2026},
author = {Li, X and Li, S and Su, J and Zheng, F and Li, S and Zhao, X and Chen, D and Yan, J and Xia, C},
title = {Merocyanine derivatives as theranostic agents for cognitive improvement and real-time imaging of amyloid-β in APP/PS1 transgenic mice.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {363},
number = {Pt 1},
pages = {128458},
doi = {10.1016/j.saa.2026.128458},
pmid = {42486010},
issn = {1873-3557},
abstract = {Amyloid-β (Aβ) is widely recognized as a biomarker for the diagnosis and treatment of Alzheimer's Disease (AD). In our previous work, a series of merocyanine fluorescent probes were designed, synthesized and evaluated for the imaging of Aβ plaques. Here, we further identified the representative probe D4, which not only demonstrates the characteristics of a highly sensitive fluorescent probe for real-time imaging of Aβ content in the brain of APP/PS1 mice, but also exhibited the ability to treat AD, including inhibition of Aβ aggregation (inhibition rate: 89.5%), antioxidant activity (3.4 times that of Trolox); AChE inhibitory activity (IC50 = 0.5 ± 0.0 μM) and the capacity to cross the BBB (Pe = 8.6 ± 0.7). Additionally, D4 dramatically attenuates Aβ-induced SH-SY5Y cell death by preventing the generation of ROS, and intravenous administration of 0.5 mg/kg D4 for 15 days significantly improved the cognitive ability of 7-month-old APP/PS1 mice by protecting hippocampal and cortex neurons from necrosis, attenuating oxidative stress in the hippocampus and cortex, and reducing Aβ burden deposition. These findings strongly suggest that D4 owns a high theranostic potential for treating AD.},
}

@article {pmid42486312,
year = {2026},
author = {Jafar, T and Chowdhury, NF and Irimia, A},
title = {Spatial Transcriptomic Decoupling and Magnetic Resonance Imaging Identify the Genetic and Cytoarchitectonic Correlates of Regional Vulnerability in Alzheimer's Disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122144},
doi = {10.1016/j.neuroimage.2026.122144},
pmid = {42486312},
issn = {1095-9572},
abstract = {The genetic and cytoarchitectonic factors associated with neurodegeneration in Alzheimer's disease (AD) remain poorly understood due to challenges linking gene expression to macroscale neuroanatomic features. Gray-white matter contrast C, an MRI-derived measure sensitive to relative cortical tissue contrast and myelin-related lipid content, declines with aging and AD. By relating C to spatial transcriptomics, we identify AD-related alterations in gene-C coupling. Spatial gene expressions facilitate comparing C between cognitively normal adults (CN, N = 1,447) and adults with AD (N = 1,447) from the National Alzheimer's Coordinating Center (NACC, N = 2,286) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 608). For 25 genes, expression significantly correlates with mean C in AD, but not CN, participants. Cell-type enrichment links AD-correlated genes to astrocytic, endothelial, neuronal markers, in cortical regions with age-related C decline. NACC findings are reproduced in ADNI. Amyloid and tau PET corroborate that regions with AD-related alterations in gene-C coupling also exhibit molecular AD signatures. This multimodal convergence supports spatial transcriptomic associations with cytoarchitectonic changes and AD pathology. We integrate transcriptomics with neuroimaging to identify how genes involved in AD are associated with cortical lipid content, providing novel insights into the genetics of neurodegeneration.},
}

@article {pmid42486320,
year = {2026},
author = {Dilip, PI and Daksh, R and Sharma, P and Khanna, S and Bojja, SL and Singh, AK and Nampoothiri, M},
title = {Repressor Element 1 Silencing Transcription Factor as a central regulator of autophagy and neuroinflammation in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179168},
doi = {10.1016/j.ejphar.2026.179168},
pmid = {42486320},
issn = {1879-0712},
abstract = {Repressor element-1 silencing transcription factor (REST) is a critical epigenetic regulator involved in multiple cellular processes, including apoptosis, autophagy, and neuronal survival. By modulating the expression of neuronal and stress-response genes, REST contributes significantly to neuroprotection. REST is predominantly localised in the nucleus; however, in Alzheimer's Disease (AD), nuclear REST is reduced, leading to transcriptional dysregulation and contributing to AD pathology. The low levels of REST are associated with defective autophagy flux, including mitochondrial dysfunction and enhanced vulnerability to toxic protein aggregates, causing AD and other neurodegenerative disorders. Recent research shows that REST suppresses several apoptotic genes, modulating neuroinflammatory signalling and regulates autophagy. The specific regulatory mechanism of REST suggests new strategies for the prevention and treatment of AD and ageing. Despite REST's unique functions and importance in AD, its precise role and the molecular mechanisms underlying REST-mediated signalling pathways have not been comprehensively reviewed. The purpose of this review is to provide an overview of the structural and functional characteristics of REST, explore the mechanisms underlying REST-mediated autophagy, neuroinflammation and apoptosis in AD and discuss the emerging therapeutic implications of targeting REST.},
}

@article {pmid42486330,
year = {2026},
author = {Arriagada, J and Ardiles, Á and Mery, E and Garay, C and Conejera, F and Herrera, EA and Paula-Lima, A and Muñoz, P},
title = {Metformin enhances hippocampal excitatory synaptic transmission and preserves synaptic plasticity under amyloid-β oligomer-induced dysfunction.},
journal = {Neuropharmacology},
volume = {299},
number = {},
pages = {111116},
doi = {10.1016/j.neuropharm.2026.111116},
pmid = {42486330},
issn = {1873-7064},
abstract = {Early stages of Alzheimer's disease (AD) are characterized by synaptic dysfunction and alterations in synaptic plasticity that precede neuronal loss. Soluble amyloid-β oligomers (AβOs) are important contributors to these early synaptic alterations by disrupting excitatory neurotransmission and impairing hippocampal function. Metformin (Met), a widely used antidiabetic drug, has recently gained attention for its potential neuroprotective properties; however, its effects on hippocampal synaptic transmission and plasticity under amyloid-induced stress remain incompletely understood. In the present study, we investigated the effects of orally administered Met (200 mg/kg/day) on basal excitatory synaptic transmission, presynaptic release probability, and long-term synaptic plasticity in hippocampal slices from rats subjected to stereotaxic injection of AβOs into the CA1 region. Using field electrophysiological recordings, we show that Met significantly enhances basal excitatory synaptic transmission, increases presynaptic release probability, potentiates long-term potentiation (LTP), and attenuates long-term depression (LTD). Notably, Met prevented the impairments in synaptic transmission and plasticity induced by AβOs, maintaining synaptic responses at levels comparable to those observed in control animals. Together, these findings indicate that Met modulates hippocampal synaptic function and preserves physiological forms of synaptic plasticity under amyloid-induced stress conditions. Our results identify synaptic transmission and plasticity as functionally relevant targets of Met action and support further investigation of Met as a potential strategy for preserving synaptic function during the early stages of AD.},
}

@article {pmid42486339,
year = {2026},
author = {Yin, N and Ding, H and Su, R and Chen, Y and Zhou, L and Tao, Y and Chen, H and Sun, Z and Li, J},
title = {Multimodal Characterization of Age-Dependent Susceptibility to High-Cholesterol-Diet-Induced AD-like Alterations in WHBE Rabbits.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106229},
doi = {10.1016/j.neuint.2026.106229},
pmid = {42486339},
issn = {1872-9754},
abstract = {Rabbit models induced by a high-cholesterol diet can exhibit Alzheimer's disease (AD)-like neuropathological features, but susceptibility to diet-induced pathological alterations may vary with age and strain. This study aimed to investigate age-dependent susceptibility to high-cholesterol-diet-induced AD-like alterations in white-haired and black-eyed (WHBE) rabbits using a multimodal approach. Compared with the normal control group (NC), juvenile rabbits (2 months old) in the 2% high-cholesterol diet (CD) group showed disturbed plasma lipid and glucose metabolism, increased body weight, and reduced encephalization quotient (EQ). Neuropathologically, juvenile CD rabbits exhibited enhanced hippocampal Tau hyperphosphorylation and Aβ deposition. MRI demonstrated significant hippocampal atrophy and lateral ventricular enlargement, while [1]H-MRS revealed significant reductions in hippocampal N-acetylaspartate/Cr, glutamate (Glu)/Cr, and glycerophosphocholine (GPC)+phosphocholine (PCH)/Cr ratios. In the overall cohort, Tau protein expression was negatively correlated with (Glu+Gln)/Cr (rho = -0.50, P = 0.0096) and positively correlated with (GPC+PCH)/Cr (rho = 0.42, P = 0.0167), although these correlations lost significance after FDR correction in subgroup analyses. Additionally, Aβ expression was negatively correlated with age in pooled WHBE rabbits (rho = -0.35, P = 0.0437), with no significant metabolite correlations observed after multiple testing correction. Multiple linear regression further confirmed a significant 'Diet×Age' interaction for both Tau and Aβ, indicating the pathological effect of high-cholesterol diet was most prominent in juvenile animals. These findings suggest that juvenile WHBE rabbits are more vulnerable to high-cholesterol-diet-induced AD-like changes. This study provides a multimodal reference for optimizing rabbit AD models and exploring age-related neurodegenerative vulnerability.},
}

@article {pmid42486379,
year = {2026},
author = {LeFevre, JD and Robb, WH and Liu, D and Jackson, TB and Pechman, KR and Shashikumar, N and Vyas, Y and Landman, BA and Davis, LT and Hohman, TJ and Jefferson, AL},
title = {A comparative evaluation of multiple enlarged perivascular space segmentation tools.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110749},
doi = {10.1016/j.mri.2026.110749},
pmid = {42486379},
issn = {1873-5894},
abstract = {BACKGROUND: Enlarged perivascular spaces (ePVS) are a marker of cerebral small vessel disease, potentially reflecting reduced waste clearance. Because manual quantification is unfeasible in large datasets, we developed and evaluated an automated tool.

METHODS: Detection Of Regions of Enlarged perivascular Spaces (DORES), a 3D nnU-Net-based deep learning algorithm was developed for ePVS segmentation using T1-weighted and fluid-attenuated inversion recovery magnetic resonance imaging (MRI). DORES was developed in two stages: an initial model trained on 35 manually segmented scans and a final model on 1460 pseudo-labeled sessions from the Vanderbilt Memory and Aging Project (VMAP). A subset of VMAP participants with 3 T brain MRI underwent whole-brain manual ePVS tracing (n = 35, 73 ± 9 years, 51% male) and visual rating (n = 388, 71 ± 8 years, 54% male) by a neuroradiologist. DORES was evaluated and compared against three other segmentation tools using Dice and F1 scores, absolute volume and element differences, correlation, and agreement. External validation used an Alzheimer's Disease Neuroimaging Initiative 3 subset with manual tracings (ADNI3, n = 18, 73 ± 9 years, 67% female).

RESULTS: DORES achieved Dice scores of 0.61 ± 0.16 (white matter) and 0.72 ± 0.08 (basal ganglia) in VMAP, with strong correlations and agreement for ePVS count and volume. Performances modestly declined in ADNI3 across algorithms. Scanner-stratified analyses showed stronger correlations for Philips versus Siemens images in the basal ganglia, indicating scanner-dependent differences in measurement consistency.

CONCLUSIONS: DORES provides a multimodal nnU-Net-based pipeline for ePVS segmentation in older adults. The model demonstrates robust within-cohort performance and reasonable external validity, though scanner-related effects limit application across sites.},
}

@article {pmid42486551,
year = {2026},
author = {Supuran, CT and Capasso, C},
title = {Carbonic anhydrases I and II.},
journal = {The Enzymes},
volume = {59},
number = {},
pages = {29-67},
doi = {10.1016/bs.enz.2026.06.005},
pmid = {42486551},
issn = {0423-2607},
mesh = {Humans ; *Carbonic Anhydrase Inhibitors/pharmacology/therapeutic use/chemistry ; Animals ; *Carbonic Anhydrase II/metabolism/antagonists & inhibitors/chemistry/genetics ; *Carbonic Anhydrase I/metabolism/antagonists & inhibitors/chemistry/genetics ; },
abstract = {Carbonic anhydrase (CA, EC 4.2.1.1) isoforms I (CA I) and II (CA II) are widespread cytosolic proteins in most vertebrates. They are abundant in the red blood cells and many other tissues, being involved in physiological processes such as pH regulation, CO2/bicarbonate homeostasis, respiration, and secretion of electrolytes rich in acid or bicarbonate in the stomach, kidneys, cerebrospinal fluid, eyes, and bones. The genetics, biochemistry, expression, localization in tissues and organs, kinetic properties, and catalytic mechanisms of these enzymes are well understood at the molecular level. At least five different inhibition mechanisms were described with more than 50 chemotypes acting as inhibitors. The activation with amine/amino acid activators was also well studied. The physiological role of CA I is poorly understood, whereas CA II is a physiologically dominant isoform, playing crucial functions in a host of tissues/organs. Interfering with its activity by means of inhibitors has been and is currently exploited in therapy for the management of edema, glaucoma, epilepsy, obesity, acute mountain sickness, and idiopathic intracranial hypertension. Promising preclinical data pointed to the potential use of CA II inhibitors for the management of other conditions, such as neuropathic pain, cerebral ischemia, rheumatoid arthritis, Alzheimer's disease, osteoporosis, and obstructive sleep apnea. Many CA inhibitors are in clinical use for the management of such conditions, among which are acetazolamide, thiazides and high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, and antiepileptics such as sulthiame, topiramate and zonisamide, whereas SLC-0111 is in clinical development as an antitumor agent. CA activators are not yet used clinically, but they might have pharmacological applications in the management of neurodegeneration, emotional memory disorders, obsessive-compulsive disorders, phobias, generalized anxiety, and post-traumatic stress. Finding novel modulators of activity for these enzymes may lead to innovative therapeutic applications and deepen our understanding of enzymes, their inhibitors, and their activators.},
}

Humans
*Carbonic Anhydrase Inhibitors/pharmacology/therapeutic use/chemistry
Animals
*Carbonic Anhydrase II/metabolism/antagonists & inhibitors/chemistry/genetics
*Carbonic Anhydrase I/metabolism/antagonists & inhibitors/chemistry/genetics

@article {pmid42486687,
year = {2026},
author = {Fang, Q and Guo, Y and Chen, L and Li, Y and Cai, Q and Zhang, J and Ma, X and Zeng, Y and Bai, G},
title = {A multimodal machine learning model integrating plasma biomarkers and MRI metrics for non-invasive prediction of amyloid-β pathology in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465672},
doi = {10.1177/13872877261465672},
pmid = {42486687},
issn = {1875-8908},
abstract = {BackgroundAccurate, non-invasive prediction of cerebral amyloid-β (Aβ) pathology in mild cognitive impairment (MCI) remains challenging yet critical for early intervention.ObjectiveTo develop a multimodal machine learning model integrating clinical features, plasma biomarkers, and structural MRI metrics for non-invasive Aβ prediction.MethodsData were obtained from the Alzheimer's Disease Neuroimaging Initiative. Participants with concurrent plasma biomarkers, 3D T1-weighted MRI, and amyloid assessments were included. Logistic Regression, Decision Tree, and Support Vector Machine models were constructed using clinical, plasma, MRI, and combined features. Performance was evaluated via internal validation and external testing in a cognitively unimpaired cohort using AUC, calibration curves, and decision curve analysis. The prognostic value of the model-derived Aβ risk probability was assessed using Cox regression in an independent longitudinal MCI cohort.ResultsThe optimal Logistic Regression model incorporated APOE ε4 status, Mini-Mental State Examination score, plasma p-Tau217, Aβ42/Aβ40 ratio, and bilateral hippocampal and left amygdalar volumes. The combined model achieved an AUC of 0.875 in internal validation and maintained robust performance in the external unimpaired cohort (AUC = 0.883), outperforming single-modality models. The predicted Aβ-positive risk probability effectively stratified disease progression risk in MCI patients (C-index = 0.771).ConclusionsA multimodal model integrating plasma and MRI features accurately predicts Aβ pathology and progression risk, offering a practical non-invasive tool for early Alzheimer's disease screening and risk stratification.},
}

@article {pmid42486877,
year = {2026},
author = {Kurz, C and Wüsten, NC and Tegethoff, P and Taute, M and Kehrls, M and Hufnagel, A and de Jonge, S and Deckert, A and Suchsland, MZ and König, A and Feustel, E and Heindl, P and Mattke, S and Perneczky, R},
title = {Adaptive pathways for multimodal community-based detection of cognitive impairment: the CogScreen I study.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42486877},
issn = {2045-2322},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/blood ; Biomarkers/blood ; Female ; Aged ; Male ; Surveys and Questionnaires ; Dementia/diagnosis ; Aged, 80 and over ; Early Diagnosis ; Independent Living ; Amyloid beta-Peptides/blood ; },
abstract = {Early detection of cognitive impairment is essential for dementia prevention and timely care. However, implementation in primary care and community settings remains limited. Building dementia-prepared health systems requires scalable and adaptive pathways that integrate subjective, digital and biological indicators, while accounting for heterogeneity in risk, education and age. CogScreen I was a cluster-randomized trial conducted in Munich senior centers from March 2023 to March 2024. Recruitment focused on community-dwelling adults aged ≥ 60 years reporting subjective cognitive concerns. Centers were randomized to: (A) the Subjective Cognitive Decline Questionnaire (SCD-Q) only, (B) SCD-Q plus digital cognitive testing, or (C) SCD-Q plus digital testing plus blood biomarkers (Aβ1-42/1-40, pTau181, GFAP, NfL). The primary endpoints were feasibility and acceptability, assessed through structured questionnaires and follow-up interviews with participants and general practitioners. Secondary endpoints examined latent cognitive structures and biomarker associations. Exploratory factor and clustering analyses revealed multimodal subgroups across subjective, digital, and biological measures, which informed a hypothesis-generating three-tier adaptive detection framework (low, medium, high intensity). Among the 473 participants (mean age 74.1 ± 7.6 years; 66% female; 63% with tertiary education), both feasibility and acceptability were high: Participants described the assessments as personally relevant, clearly communicated, and medically meaningful, and appreciated the added value of digital testing and biomarkers. Digital cognitive testing and biomarkers captured distinct latent dimensions of learning/working memory, psychomotor attention, and glial and amyloid pathology. Exploratory multimodal clustering identified three dementia risk profiles-low concern, intermediate, and at risk-which informed an adaptive, tiered detection model. Notably, subjective cognitive concerns assessed by the SCD-Q were strongly associated with overall subjective symptom burden, supporting the use of brief self-report questionnaires as a pragmatic and scalable first-step stratification approach in community-based dementia detection. Community-based, tiered detection pathways for cognitive decline are feasible, acceptable, and meaningful to older adults. Exploratory multimodal profiling suggests that combining subjective, digital, and biological measures may support individualized assessment strategies. However, limited GP engagement highlights the need for stronger integration with primary care to ensure downstream diagnostics and prevention pathways. The proposed framework remains hypothesis-generating and requires prospective validation.Clinical trials registeredCogScreen has been registered at clinical trials (NCT06191952, 2023-12-20).},
}

Humans
*Cognitive Dysfunction/diagnosis/blood
Biomarkers/blood
Female
Aged
Male
Surveys and Questionnaires
Dementia/diagnosis
Aged, 80 and over
Early Diagnosis
Independent Living
Amyloid beta-Peptides/blood

@article {pmid42487022,
year = {2026},
author = {Xu, W and Chen, J and Zhou, Y and Liu, C and Han, Y and Zheng, K},
title = {Comparative efficacy and safety of photobiomodulation, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation in Alzheimer's disease: a network meta-analysis of randomized controlled trials.},
journal = {Lasers in medical science},
volume = {41},
number = {1},
pages = {},
pmid = {42487022},
issn = {1435-604X},
support = {82371442//National Natural Science Foundation of China/ ; 2020YFC2004803//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy ; *Transcranial Direct Current Stimulation/adverse effects/methods ; *Transcranial Magnetic Stimulation/adverse effects/methods ; Randomized Controlled Trials as Topic ; *Low-Level Light Therapy/adverse effects/methods ; Treatment Outcome ; Cognition ; Cognitive Enhancement ; Bayes Theorem ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which current pharmacological therapies provide only modest and transient benefits, underscoring the need for effective non-pharmacological interventions. Non-invasive brain stimulation (NIBS), including photobiomodulation (PBM), transcranial direct current stimulation (tDCS), and repetitive transcranial magnetic stimulation (rTMS), is a promising approach. This study compared the efficacy, feasibility, and safety of PBM, tDCS, and rTMS in AD. We conducted a Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs), prospectively registered in PROSPERO (CRD420251006868) and reported according to PRISMA-NMA. The primary outcome was global cognitive performance, assessed by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were feasibility and safety, evaluated by dropout rates and adverse events, respectively. A total of 34 studies, comprising 35 RCTs (n = 1,559), were included, with one study contributing two independent randomized controlled trials. All three interventions improved global cognitive performance compared with control. PBM showed the highest estimated effects on both MMSE (MD = 3.14, 95% CrI: 1.71 to 4.60) and ADAS-Cog (MD = - 8.01, 95% CrI: -12.82 to - 3.13). In indirect comparisons, PBM was superior to rTMS for ADAS-Cog (MD = - 5.24, 95% CrI: -10.23 to - 0.12), while the MMSE comparison narrowly missed statistical significance (MD = 1.57, 95% CrI: -0.02 to 3.18). These findings were generally consistent across subgroups stratified by baseline cognition and intervention duration. PBM tended to rank highest for cognitive improvement with feasibility and safety comparable to tDCS and rTMS in AD. These findings support the therapeutic potential of PBM, and large-scale RCTs are needed to guide individualized treatment strategies, with implications for clinical decision-making in geriatric care.},
}

Humans
*Alzheimer Disease/therapy
*Transcranial Direct Current Stimulation/adverse effects/methods
*Transcranial Magnetic Stimulation/adverse effects/methods
Randomized Controlled Trials as Topic
*Low-Level Light Therapy/adverse effects/methods
Treatment Outcome
Cognition
Cognitive Enhancement
Bayes Theorem

@article {pmid42487135,
year = {2026},
author = {Waghmare, SG and Krishna, MM and Maccoux, EC and Franitza, AL and Link, BA and E, L},
title = {Functional analysis of late-onset Alzheimer's disease risk genes in Caenorhabditis elegans identifies regulators of neuronal aging.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42487135},
issn = {2047-9158},
support = {5520760//Advancing a Healthier Wisconsin Endowment/ ; 5520482//Advancing a Healthier Wisconsin Endowment/ ; AG087390/NH/NIH HHS/United States ; },
}

@article {pmid42487153,
year = {2026},
author = {Magalhães, TNC and Casseb, RF and Moraes, AS and Teixeira, CVL and Carletti, AM and De Rezende, TJR and Joaquim, HPG and Talib, LL and Forlenza, O and Cendes, F and Balthazar, MLF and Teunissen, CE},
title = {Relation of fluid neurodegeneration biomarkers with white matter integrity in Alzheimer's disease patients in Latin America.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467065},
doi = {10.1177/13872877261467065},
pmid = {42487153},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is increasingly prevalent in Latin America. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising biomarkers of neurodegeneration, but their relationship with white matter (WM) integrity remains unclear.ObjectiveTo investigate associations between fluid neurodegeneration biomarkers and WM microstructure in a Brazilian cohort of individuals across the AD continuum and cognitively healthy controls.MethodsNinety-one participants were included: 27 cognitively healthy controls (mean age = 68.3 ± 5.2 years) and 64 amyloid-positive individuals with mild cognitive impairment or AD dementia (mean age = 70.6 ± 6.9 years). AD participants were characterized by low cerebrospinal fluid (CSF) Aβ42 concentrations (<540 pg/mL) and altered Aβ42/p-Tau and Aβ42/t-Tau ratios. Serum and CSF concentrations of NfL and GFAP were measured using single-molecule array technology and examined in relation to diffusion tensor imaging metrics, including fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity (AxD).ResultsWithin the clinical AD group, higher serum NfL levels were associated with lower AxD in the left cingulum tract (r = -0.372, p = 0.007). In cognitively healthy controls, serum NfL showed positive correlations with AxD and mean diffusivity in the right cingulum (r = 0.650, p = 0.001 and r = 0.607, p = 0.003, respectively). No significant associations were observed between serum or CSF GFAP concentrations and diffusion tensor imaging metrics.ConclusionsSerum NfL was associated with anatomically specific WM microstructural changes, with differing patterns across clinical groups.},
}

@article {pmid42487190,
year = {2026},
author = {Aschenbrenner, DS},
title = {Antidepressant is approved to treat agitation in Alzheimer disease.},
journal = {The American journal of nursing},
volume = {126},
number = {8},
pages = {18-19},
doi = {10.1097/AJN.0000000000000354a},
pmid = {42487190},
issn = {1538-7488},
}

@article {pmid42487544,
year = {2026},
author = {Zhou, J and Li, S and Liu, H and Sun, Y and Wang, Z},
title = {The Effectiveness of Animal-Assisted Interventions for People Living With Dementia: An Overview of Systematic Reviews and Meta-Analysis.},
journal = {International journal of nursing practice},
volume = {32},
number = {4},
pages = {e70172},
pmid = {42487544},
issn = {1440-172X},
support = {72274007//National Natural Science Foundation of China/ ; LJRC22YB03//Incubation Fund for Scientific Research and Innovation of Leading Talents of Unnamed Nursing of Peking University/ ; XJRC-2025-JY-YJ-GX-QNQZ-068//Xinjiang Talent Development Fund/ ; },
mesh = {*Dementia/therapy/psychology ; Humans ; *Animal Assisted Therapy ; Animals ; Quality of Life ; Systematic Reviews as Topic ; Activities of Daily Living ; },
abstract = {AIMS: This overview aims to provide high-quality evidence synthesis of animal-assisted interventions (AAIs) among people living with dementia.

BACKGROUND: Dementia has become the seventh leading cause of death in the world. Unfortunately, currently effective pharmacological interventions remain elusive. As a non-pharmacological treatment, AAI is gaining more attention while the effectiveness of AAI for people living with dementia remains unclear.

METHODS: EMBASE, PubMed, Cochrane Library, CINAHL, CNKI, VIP, CBM and Wanfang databases were searched from inception to March 2026. The AMSTAR2 was used to assess the methodological quality of the included reviews. Meta-analysis was conducted using STATA 16 for the original studies identified from the included reviews. Evidence quality of main outcomes was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.

RESULTS: Sixteen systematic reviews were included in the overview. A significant improvement was found in depression among dementia patients, but not in agitation, quality of life (QOL), cognition and activities of daily living (ADL).

CONCLUSIONS: There is moderate evidence that AAI has positive effects on depression for people living with dementia. Despite searches, no sufficient evidence has been found to substantiate the positive effects of AAI on other outcomes in people living with dementia. Due to the small number of studies, small sample sizes and significant heterogeneity, more randomised controlled trials with large samples are needed.},
}

*Dementia/therapy/psychology
Humans
*Animal Assisted Therapy
Animals
Quality of Life
Systematic Reviews as Topic
Activities of Daily Living

@article {pmid42487594,
year = {2026},
author = {Lonlab, K and Nitjapol, A and Thummayot, S and Tiyaboonchai, W and Jumnongprakhon, P},
title = {Targeting Aβ25-35-Induced Neuronal Senescence-Like Features Using Curcumin-Loaded Solid Self-Emulsifying Drug Delivery Systems.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098440081260430205824},
pmid = {42487594},
issn = {1874-6128},
abstract = {INTRODUCTION: Curcumin is widely recognized for its anti-neurodegenerative properties. However, its clinical utility is hindered by poor aqueous solubility and low bioavailability. To address these limitations, Curcumin-loaded Solid Self-Emulsifying Drug Delivery Systems (C-SSEDDS) have been formulated to improve pharmacokinetics and neuronal targeting. Despite these advancements, the molecular mechanisms underlying curcumin in Alzheimer's Disease (AD)-related neuronal senescence remain poorly understood. Therefore, this study provides novel molecular insights into the therapeutic potential of C-SSEDDS for targeting neuronal senescence- like features in the AD context.

METHODS: An in vitro model of neuronal senescence-like features was established by exposing SK-N-SH cells to 0.075 μM Aβ25-35 for 24 hours, resulting in a 20-30% decline in cell viability. Subsequently, cells were post-treated with C-SSEDDS at optimized non-toxic concentrations (0.1, 1, and 10 μg/mL curcumin equivalent) and 10 μg/mL commercial curcumin for 24, 48, and 72 hours in Aβ25-35-free media. The study comprehensively assessed cell viability, morphological alterations, and key biomarkers associated with neuronal senescence-like features, including senescence- associated beta-galactosidase (SA-β-gal) positive cells, Reactive Oxygen Species (ROS) levels, NLRP3, Sirt-1, and synaptophysin expression.

RESULTS: C-SSEDDS post-treatment significantly improved cell viability, reduced apoptotic cells, and decreased SA-β-gal positive cells in Aβ25-35-induced senescence-like SK-N-SH cells compared to the untreated Aβ25-35 group. It also effectively decreased intracellular ROS level and NLRP3 expression, and markedly upregulated Sirt-1 and synaptophysin expression. Notably, CSSEDDS demonstrated therapeutic efficacy superior to commercial curcumin and comparable to N-acetylcysteine (NAC).

DISCUSSION: In SK-N-SH cells exhibiting senescence-like features, the C-SSEDDS formulation effectively counteracts Aβ25-35-induced damage. It mitigates key drivers of cellular stress, including oxidative stress, inflammation-related markers, and apoptosis, while also enhancing Sirt-1 activity and promoting synaptic plasticity.

CONCLUSION: C-SSEDDS demonstrates significant potential as a promising therapeutic strategy against Aβ25-35 -induced neuronal stress and senescence-like changes in AD.},
}

@article {pmid42488138,
year = {2026},
author = {Magee, RG and Li, Y and Rovine, MJ and Pelak, VS and Hamedani, AG},
title = {Epidemiology of visuospatial impairment in older adults: the Harmonized Cognitive Assessment Protocol.},
journal = {Innovation in aging},
volume = {10},
number = {8},
pages = {igag059},
pmid = {42488138},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: This study aimed to determine the prevalence of visuospatial impairment in a nationally representative sample of older adults and identify self- and informant-reported functional measures associated with visuospatial dysfunction.

METHODS: We analyzed data from 3496 participants aged ≥65 years in the 2016 Harmonized Cognitive Assessment Protocol (HCAP), a sub-study of the Health and Retirement Study. Visuospatial function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease constructional praxis and Mini Mental State Examination pentagon copy tasks. Impairment was defined as a factor score >1.5 SDs below expected relative to a robust normative sample. Cognitive status was classified by HCAP as normal, mild cognitive impairment (MCI), or dementia. Logistic regression models examined associations between visuospatial impairment and functional outcomes, adjusting for demographic, health, and general cognitive factors.

RESULTS: Visuospatial impairment was present in 435 participants (11.33%). Among these, 49.85% had MCI, and 39.97% had dementia. Over half of those with MCI and visuospatial impairment had no other cognitive domain affected. Visuospatial impairment was associated with increased odds of self-reported visual difficulty (OR 1.60, 95% CI: 1.20-2.15), difficulty using a map (OR 3.35, 95% CI: 2.35-4.80), and informant-reported navigation difficulties, including getting lost at home (OR 17.30, 95% CI: 8.02-37.31). Associations with driving, map use, and getting lost at home remained significant after adjusting for general cognition.

DISCUSSION AND IMPLICATIONS: Visuospatial impairment is common among older adults, frequently occurs in isolation in MCI, and is strongly associated with functional limitations, particularly in navigation and driving.},
}

@article {pmid42488179,
year = {2026},
author = {Taheri, H and Musaie, F and Mohammadzadeh, N and Tavassoli Naini, P and Novin, N and Salimi, O and Amini, A and Malekpour, H and Panahiyan, P and Malek, M and Fathiazar, A and Namadkolahi, R},
title = {Optimizing Alzheimer's prediction with dental care: comparing robust deep learning models in health and retirement study of America.},
journal = {American journal of neurodegenerative disease},
volume = {15},
number = {2},
pages = {16-24},
pmid = {42488179},
issn = {2165-591X},
abstract = {BACKGROUND: Previous research has illustrated links between dental care and Alzheimer's disease, the aim of this study was to examine whether dental care variables can enhance Alzheimer's risk prediction using two models including Long Short-Term Memory (LSTM) and Temporal Convolutional Network (TCN) models with health and retirement study data.

METHODS: 9,979 HRS participants without cognitive impairment were analysed in this study (mean age 67 years; and 59.8% female, waves 11-15: 2006/2008-2016). Analysis included 52 predictors including demographic, genetic (APOE ε4), health (including dental visit frequency), and psychosocial domains. The outcomes as cognitive impairment and dementia were defined by Langa-Kabeto-Weir criteria. Class imbalance was addressed by SMOTE and missing data were mean imputed. We standardized and reshaped features into five-wave temporal sequences. Data were split into 3 sets: 70% training, 10% validation, and 20% test. LSTM (single layer, 64 units) and TCN (two dilated convolutional layers, 32 channels) models were trained for up to 50 epochs using binary cross-entropy loss with Adam optimizer, learning-rate reduction on plateau, and early stopping based on validation F1. The accuracy, precision, recall, F1, and AUC-ROC were evaluated via Five-fold stratified cross-validation; the optimization of classification thresholds was done by maximizing F1. McNemar's test compared final predictions.

RESULTS: It was evident that LSTM consistently outperformed TCN as demonstrated by the following results: test accuracy 99.78% vs 79.01%; AUC-ROC 99.95% vs 92.74%; F1-score 99.67% vs 75.27%. Cross-validation consistency (LSTM F1 ~99.6%±0.1% vs TCN ~76.6%±1.5%) and stable validation-test metrics (final validation loss 0.0136 vs 0.3312) showed robust LSTM performance without overfitting. moreover, McNemar's test showed a significant difference (statistic = 2605.36; P<0.001). models with dental care variables showed high sensitivity (~99.8%).

CONCLUSIONS: Enhancement in Alzheimer's disease risk prediction in older adults was evident when incorporating dental care variables in LSTM-based sequential modeling which suggest potential for early detection. However, further studies in diverse populations and assessment of feature importance is necessary because of reliance on self-reported dental care data and the study's HRS-specific sample.},
}

@article {pmid42488183,
year = {2026},
author = {Singhal, M and Lin, J and Delehanty, M and Karimi, A and Rittner, L and Bento, M},
title = {Geographic and demographic gaps in publicly available Alzheimer's disease datasets: A large language model-based discovery and analysis.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261470698},
pmid = {42488183},
issn = {2055-2076},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects millions worldwide, and researchers heavily rely on datasets for diagnosis and treatment. Identifying relevant datasets is challenging due to data gaps and bias related to the demographics and geographic origin.

METHOD: We investigated AD data gaps by identifying and manually curating publicly accessible AD datasets containing imaging and/or tabular data. We also extracted key information such as data availability, geographic location, and participant demographics. We used five Large Language Models (LLMs) to identify AD datasets, allowing us to explore potential datasets while also evaluating retrieval consistency across models.

RESULT: We identified 24 publicly accessible AD datasets (open access or controlled access via registration). These datasets enabled us to emphasize three critical gaps: (1) variability in AD dataset retrieval, as observed through differences in LLM outputs, related to dataset visibility and accessibility; (2) geographical imbalance, with North America contributing 55.6% of datasets, US alone 66.7%, followed by Europe at 36.1%, and smaller shares from South America 11.1%, Asia 8.3%, and Africa 2.8%; and (3) demographic deficits, with the majority of datasets predominantly White, as 9 of 24 had over 80% White participants. Among the seven datasets that reported any Black participant representation, the proportion of Black participants ranged from 15.3% to 18.8%.

CONCLUSION: These findings reveal significant disparities in the availability and retrieval of AD datasets, with most data concentrated in Western countries and critical gaps in demographic representation. LLMs show inconsistent retrieval, particularly for newer, smaller, or region-specific datasets, which may perpetuate existing biases.},
}

@article {pmid42488212,
year = {2026},
author = {Li, Z and Ming, Q and Fu, L and Yang, J and Lv, Y and Chen, B and Lu, Z},
title = {Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1886340},
pmid = {42488212},
issn = {2296-861X},
abstract = {Alzheimer's disease is increasingly viewed as a disorder in which age-related disturbances in microglial metabolism and the handling of nutritional substrates contribute to progressive loss of protective function. This review examines how lipids and ketone bodies shape microglial metabolic fitness in the aging brain and in Alzheimer's disease, and how these effects intersect with triggering receptor expressed on myeloid cells 2 (TREM2) signaling and translational biomarkers. Available evidence indicates that early compensatory glycolysis may give way to chronic bioenergetic failure, while cholesterol and lipoprotein trafficking, lipid droplet accumulation, ketone-body signaling, and TREM2-associated lysosomal pathways influence plaque engagement, phagocytosis, and inflammatory responses. The review also considers how apolipoprotein E genotype, brain region, sex, disease stage, and model system condition translation from experimental models to human disease. Fluid, imaging, and tissue readouts are therefore discussed as stage- and context-dependent proxies rather than fixed signatures. Overall, nutritional strategies and microglia-targeted interventions are most likely to be informative when aligned with disease stage and biological context.},
}

@article {pmid42488516,
year = {2026},
author = {Hajihosseini, S and Panahandeh, E and Rashidi, A and Soleimani, K and Parvandi, F and Rostami, N and Mottaghi, H and Rahmani, S and Belbasi, M and Bideshki, F and Faramin Lashkarian, M and Ebrahimi, MA and Alizadeh, H},
title = {Difficulty with taking medications and the future risk of Alzheimer's disease and related dementias: Health and Retirement Study of Americans.},
journal = {American journal of neurodegenerative disease},
volume = {15},
number = {1},
pages = {1-15},
pmid = {42488516},
issn = {2165-591X},
abstract = {BACKGROUND: This study aims to determine if self-reported issues with managing medication could be an early sign of cognitive decline, possibly pointing to a future diagnosis of Alzheimer's Disease and Related Dementias (ADRD). There is currently very little information available about the link between issues with medication management and the later diagnosis of an ADRD, despite the potential clinical importance of such a link.

METHODS: We analyzed Health and Retirement Study participants present and interviewed at Wave 11 (2012) and followed them through Wave 16 (2020). Medication-taking difficulty (R11MEDS) was classified as no difficulty/don't do vs. difficulty/can't do. Separate cohorts excluded prevalent dementia (R11DEMENE) or AD (R11ALZHEE). Incident outcomes were first respondent-reported physician diagnoses (RwDEMENE, RwALZHEE). Kaplan-Meier curves and multivariable Cox models estimated associations.

RESULTS: Of 18,878 dementia-free and 19,348 AD-free HRS respondents at Wave 11, 3.0-3.9% reported difficulty/could not take medications. Kaplan-Meier curves diverged early between exposure groups. In fully adjusted Cox models, medication-taking difficulty predicted higher hazards of incident all-cause dementia (HR 1.59, 95% CI 1.23-2.06) and AD (HR 1.57, 95% CI 1.09-2.27), with corroborating pooled logistic estimates.

CONCLUSION: Difficulty in Managing Medications is considered to be a robust prodromal indicator of ADRD, regardless of demographic influences. Therefore, the evaluation of an individual's ability to manage medications within routine assessment may represent a practical, costeffective means to identify cognitive decline and develop appropriate management strategies.},
}

@article {pmid42488555,
year = {2026},
author = {Zhao, Q and Li, S and Ju, Y and Kong, X and Liu, X},
title = {Modeling Alzheimer's disease with brain organoids: mechanisms, applications, and future directions.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1791272},
pmid = {42488555},
issn = {2296-634X},
abstract = {Human pluripotent stem cell-derived brain organoids have emerged as a transformative platform for modeling Alzheimer's disease (AD), thus addressing long-standing translational obstacles posed by the disease's complex etiology and interspecies differences. This review systematically examines methodological advances in brain organoid technology, from basic fabrication and brain-region-specific organoids to multicellular assembloids that incorporate microglia and vascular components, with an emphasis on strategies for overcoming fetal-like phenotypes. We surveyed literature published between 2018 and April 2026 that focused on human iPSC-derived organoid models that recapitulate core AD pathologies, including Aβ plaques, tau tangles, neuroinflammation, and blood-brain barrier dysfunction. Key findings demonstrate that organoids effectively capture genotype-phenotype relationships for major AD genes (APP, PSEN1, PSEN2, and APOEε4), enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms. Organoids have also been successfully applied to patient-specific "avatar" models and high-throughput drug screening, thus advancing precision medicine approaches. However, current technological bottlenecks-including a lack of functional vascularization, batch-to-batch variability, and insufficient standardization-limit the full recapitulation of chronic, age-dependent AD pathology. This review critically evaluates these limitations, addresses ethical considerations surrounding neural organoids, and looks forward to future integration with artificial intelligence, spatial omics, and multi-organ systems to accelerate the translation of organoid-based discoveries into clinical applications.},
}

@article {pmid42488639,
year = {2026},
author = {Zhao, X and Zhang, G and Wang, Z and Zhang, D and Xia, Z and Huo, C},
title = {Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1893167},
pmid = {42488639},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Dementia/immunology/pathology ; *Autoimmunity ; *Neurodegenerative Diseases/immunology/pathology ; Adaptive Immunity ; Autoantibodies/immunology ; *Central Nervous System/immunology/pathology ; T-Lymphocytes/immunology ; },
abstract = {Neurodegenerative dementias, including Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, and related tauopathies, are traditionally defined by protein aggregation, neuronal dysfunction, synaptic loss, and glial-mediated neuroinflammation. However, emerging evidence indicates that adaptive immunity may also contribute to disease heterogeneity and progression. These disorders should not be considered classical autoimmune diseases, but they may display autoimmune-like signatures, including neural antigen-specific T cell responses, clonal expansion of T cells in blood or cerebrospinal fluid, CNS infiltration of adaptive immune cells, and brain-targeting autoantibodies. Recent studies have linked α-synuclein-specific T cell reactivity to early Parkinson's disease, identified clonally expanded CD8[+] T cells in Alzheimer's disease cerebrospinal fluid, and provided direct evidence of adaptive immune involvement in Lewy body dementia, including altered peripheral immunophenotypes and CD4[+] T cell-associated neurodegenerative mechanisms. Experimental tauopathy models further show that microglia-mediated T cell infiltration can drive neurodegeneration. Humoral autoreactivity and progression-associated immune changes further suggest that adaptive immune profiles may help define biologically distinct dementia subgroups. In this mini review, we summarize evidence connecting peripheral immune activation, intrathecal adaptive immune remodeling, and CNS pathology in neurodegenerative dementias. We also discuss how longitudinal blood-CSF profiling, single-cell/TCR/BCR sequencing, autoantibody profiling, and mechanistic validation may clarify whether these immune signatures are pathogenic, compensatory, or bystander responses.},
}

Humans
Animals
*Dementia/immunology/pathology
*Autoimmunity
*Neurodegenerative Diseases/immunology/pathology
Adaptive Immunity
Autoantibodies/immunology
*Central Nervous System/immunology/pathology
T-Lymphocytes/immunology

@article {pmid42488724,
year = {2026},
author = {Liu, F and Huang, Y and Wang, A and Liu, P and Wu, H and Fan, H},
title = {BDNF-amyloid-β Axis in Alzheimer's disease: molecular mechanisms and therapeutic perspectives.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1884003},
pmid = {42488724},
issn = {1662-5099},
abstract = {Alzheimer's disease (AD), the most common cause of dementia in older adults, is characterized by progressive cognitive decline, synaptic dysfunction, and neuronal loss. Among the multifactorial mechanisms implicated in AD, reciprocal interactions between brain-derived neurotrophic factor (BDNF) and amyloid-β (Aβ) have attracted increasing attention as a convergent axis linking amyloid pathology to impaired neurotrophic support. BDNF promotes neuronal resilience, synaptic plasticity, and cognitive function primarily through the activation of its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and downstream signaling pathways, including PI3K-Akt and MAPK/ERK. Human postmortem and biomarker studies mainly support associations between reduced BDNF signaling, synaptic dysfunction, and AD-related pathology. In contrast, cell-based and animal studies provide mechanistic evidence that BDNF/TrkB signaling may influence amyloid precursor protein (APP) processing and neuronal resistance to Aβ-induced stress. Conversely, mechanistic studies indicate that Aβ accumulation can suppress CREB-dependent BDNF expression, disturb BDNF transport, and impair TrkB receptor function. Thus, the BDNF-Aβ relationship is better interpreted as a stage- and context-dependent pathogenic coupling rather than a simple causal loop. This review synthesizes evidence from human studies, animal models, and cellular systems to clarify how BDNF-Aβ dysregulation contributes to AD progression and to discuss the translational potential of BDNF-oriented interventions.},
}

@article {pmid42488747,
year = {2026},
author = {Jiang, W},
title = {Pharmacological advances of honokiol: Mechanisms, targets and therapeutic potential (Review).},
journal = {Biomedical reports},
volume = {25},
number = {3},
pages = {103},
pmid = {42488747},
issn = {2049-9442},
abstract = {Honokiol (HKL), a bioactive biphenolic lignan isolated from the bark of Magnolia officinalis, possesses diverse pharmacological properties, including neuroprotective, antitumor, anti-inflammatory and metabolic regulatory effects. Despite its therapeutic promise, the clinical application of HKL is severely restricted by its hydrophobicity and low oral bioavailability. The present review systematically summarized 99 studies (90 original articles and nine reviews) on the pharmacological profile of HKL. It detailed HKL's molecular interactions with key signaling targets, such as sirtuin 3, NOD-like receptor family pyrin domain containing 3-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes, Yes-associated protein/transcriptional coactivator with PDZ-binding motif, adenosine monophosphate-activated protein kinase and signal transducer and activator of transcription 3, which underly its efficacy against cancer (ovarian, liver, breast, colorectal, and lung), neurodegeneration (Alzheimer's and Parkinson's disease), metabolic disorders (diabetes, nonalcoholic fatty liver disease and obesity) and inflammatory and infectious diseases. Furthermore, the present review critically evaluated recently developed strategies to overcome its pharmacokinetic limitations. The present review offered an updated theoretical basis for understanding the structure-activity relationship of HKL and provided insights into its translation from bench to bedside.},
}

@article {pmid42488757,
year = {2026},
author = {Jorge, L and Oliveira, J and Martins, R and Lopes, T and Quental, H and Castelo-Branco, M},
title = {Distinct brain regions are affected by neurodevelopmental or pre-dementia changes in Down syndrome.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag269},
pmid = {42488757},
issn = {2632-1297},
abstract = {Down syndrome, a condition characterized by triplication of chromosome 21, leads to a complex interplay between neurodevelopmental and dementia-related changes similar to the ones observed in Alzheimer's disease. Here we aimed to understand this interplay by using imaging biomarkers for different cognitive profiles in Down syndrome, and by analysing early developmental differences versus age-related changes. We analysed voxel-based morphometric measures of grey matter volume from high-resolution T1-weighted MRI in 23 adults with Down syndrome (18-59 years, five female) in preclinical/prodromal stages of Alzheimer's disease and 24 age- and sex-matched controls, along with cognitive assessments. Neuroanatomical group differences were assessed using two-sample t-tests. Age-related effects on brain integrity, and cognitive function were examined through voxel-wise regression analyses and correlation tests, respectively. Finally, structural correlates of episodic memory were explored across the whole brain at the voxel level within the Down syndrome group. Results revealed a neuroanatomic phenotype with both regional increases and decreases in grey matter volume compared to controls (false discovery rate, q ≤ 0.05). Based on regression analysis, we found the following patterns in regions that were differentially reduced in Down syndrome: same intercept and different age-related slope (defining specific age-related differences), different intercept (implying initial neurodevelopmental differences) and same slope (signalling no age-related differences). A notable example of the first was the left hippocampus and its subfields, and of the second was the orbitofrontal cortex. Follow-up whole brain analyses confirmed age-related changes in Down syndrome (false discovery rate, q ≤ 0.05) in the parietal and temporal cortices, extending into hippocampus, as compared to controls, independent of neurodevelopmental (non-age related) features, and most pronounced in the right hemisphere. Episodic and associative memory declined significantly with age (P = 0.016) in Down syndrome and correlated with shrinkage in regions vulnerable to Alzheimer's disease (P < 0.01), including the precuneus and posterior cingulate cortex. Our findings suggest that individuals with Down syndrome undergo early brain atrophy that occurs independently of baseline neurodevelopmental changes, particularly in the hippocampus and temporoparietal regions. Notably the posterior cingulate cortex and precuneus showed an association with episodic memory loss, a pattern that is consistent with Alzheimer's Disease. In sum we found a dichotomic distinction between brain regions affected by developmental or ageing changes in Down syndrome.},
}

@article {pmid42488758,
year = {2026},
author = {Krohn, F and Sarkar, M and Schütze, H and Iliopoulos, P and Penalba-Sánchez, L and Hämmerer, D and Yakupov, R and Lüsebrink, F and Spottke, A and Schneider, A and Roy, N and Incesoy, E and Heneka, M and Kilimann, I and Kleineidam, L and Teipel, SJ and Brosseron, F and Goerss, D and Glanz, W and Schmid, M and Rostamzadeh, A and Wagner, M and Fliessbach, K and Jessen, FO and Düzel, E and Betts, MJ},
title = {Substantia Nigra MRI markers are lower in Alzheimer's disease and are linked to general cognitive function.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag238},
pmid = {42488758},
issn = {2632-1297},
abstract = {Individuals with Alzheimer's disease dementia show Alzheimer's disease pathology and a heterogeneous degeneration of the Substantia Nigra (SN) post-mortem. However, it is unclear how SN degeneration is related to cognitive dysfunction across the Alzheimer's disease dementia continuum. In this study, using data from the prospective DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), we investigated whether in vivo SN MRI measures are lower in individuals with clinically defined Alzheimer's disease dementia than in healthy control subjects (HC) and if they are associated with hippocampal functional activity during the processing of novel visual stimuli and subsequent recognition memory. One hundred and sixty DELCODE participants (69 years ± 6 years, 88 men), including 79 HC, 70 individuals with subjective cognitive decline (SCD), 17 individuals with mild cognitive impairment (MCI) and 10 individuals with Alzheimer's disease dementia, completed a scene novelty and encoding task and a 3T SN-sensitive MRI scan, from which the two in vivo SN measures MRI contrast and volume were calculated and harmonized between scanner sites while preserving diagnostic group differences. For 71 individuals, CSF levels of phosphoTau, total tau and amyloid-beta 42/40 ratio (Aß42/40) were available. All individuals completed a neuropsychological task battery from which a global cognitive score was calculated. In separate models, we assessed the relationship between SN MRI markers and CSF levels of Alzheimer's disease, the global cognitive score, hippocampal novelty activation and recognition memory while accounting for age, sex, years of education and total intracranial volume (TIV). SN volume but not SN MRI contrast was lower in individuals with clinical Alzheimer's disease dementia [one-way analyses of covariance (ANCOVA); F(156,4) = 5.6665, P = 0.0010, n = 160]. SN MRI contrast and volume were not associated with Aß42/40, ptau and total tau CSF levels (all P > 0.1) or hippocampal novelty activation (all P > 0.1). Moreover, SN volume was positively associated with recognition memory (R [2] = 0.07, P < 0.001, n = 159), global cognition (R [2]= 0.38, P < 0.0001, n = 160) and years of education (R [2] = 0.03, P = 0.036, n = 160). Our study emphasizes the potential of using in vivo SN MRI markers to study the impact of SN degeneration on general cognitive impairment and recognition memory in an Alzheimer's disease dementia cohort. Our results motivate future longitudinal studies to explore how SN volume and SN contrast change with disease progression, how these are differentially associated with cognitive decline, and how SN volume and SN contrast might be related to other dopamine-dependent cognitive functions and dysfunctions.},
}

@article {pmid42489128,
year = {2026},
author = {Shen, Q and Chang, H and Li, J and Guo, H and Shi, W and Yan, Y and Ouyang, W and Zhang, Z and Wu, X and Xing, D and Yang, S},
title = {Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag247},
pmid = {42489128},
issn = {1460-2156},
abstract = {Peripheral immune cell infiltration and crosstalk with brain-resident cells critically drive Alzheimer's disease (AD)-associated neuroinflammation, highlighting its therapeutic potential. Here, we found that photobiomodulation (PBM) markedly reduced cerebral CD8+ T cells infiltration in the cortex of AD (APP/PS1 and 3×Tg) mice, thereby improving cognition, and alleviating AD-related pathology by mitigating neuronal damage and gliosis. Immunofluorescence and transcriptomic analyses revealed that PBM inhibited the release of chemokines and pro-inflammatory cytokines from microglia, reducing endothelial adhesion molecules-mediated T cell migration. Concurrently, reduced secretion of tumor necrosis factor-α, interleukin-1α, and complement component 1q by pro-inflammatory microglia further diminished neurotoxic A1 astrocyte induction. Genetic overexpression or pharmacological inhibition further validated that PBM disrupted microglia NOD-like receptor protein 3 inflammasomes activation, attenuating astrocyte reactivity and T cells recruitment. These findings collectively suggest that the PBM-induced modulation of crosstalk between microglia, astrocytes, and CD8+ T cells is closely related to cognitive improvement. Reprogramming central-peripheral immune crosstalk with PBM resolves neuroinflammation and restores cognition in AD models-a translatable strategy for combating neurodegeneration.},
}

@article {pmid42489215,
year = {2026},
author = {Liu, C and Sakha, K and Anton, J and Cardenas-Rivera, A and Yaseen, MA},
title = {Prolonged systemic inflammation worsens impairments to astrocyte Ca[2+] and functional hyperemia in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71607},
doi = {10.1002/alz.71607},
pmid = {42489215},
issn = {1552-5279},
support = {//National Cancer Institute Cancer Center/ ; R01AA27097//Northeastern College of Engineering and the National Institutes of Health/ ; R56AG058849//Northeastern College of Engineering and the National Institutes of Health/ ; R21AG085655//Northeastern College of Engineering and the National Institutes of Health/ ; R01AA27097/AA/NIAAA NIH HHS/United States ; R56AG058849/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Astrocytes/metabolism ; *Alzheimer Disease/metabolism/pathology/physiopathology ; Mice ; *Inflammation/metabolism ; Mice, Transgenic ; *Hyperemia/metabolism/physiopathology ; *Calcium/metabolism ; Disease Models, Animal ; Lipopolysaccharides ; Male ; Calcium Signaling ; *Neuroinflammatory Diseases ; },
abstract = {INTRODUCTION: Chronic neuroinflammation in Alzheimer's disease (AD) alters astrocyte physiology and neurovascular unit function. AD patients frequently experience recurrent systemic inflammatory insults from comorbid conditions, which act as "secondary-hits" believed to worsen cognitive decline. The impact of these secondary insults on astrocyte-mediated neurovascular regulation remains unknown.

METHODS: We applied intravital two-photon microscopy to longitudinally investigate astrocytic Ca[2] [+] dynamics and functional hyperemia during sensory stimulation in APP/PS1dE9 mice before and during secondary lipopolysaccharide (LPS)-induced systemic inflammation.

RESULTS: AD mice exhibited diminished stimulation-evoked astrocytic Ca[2] [+] activity, while functional hyperemia remained largely preserved. LPS further suppressed astrocytic Ca[2] [+] responses and produced temporally specific vascular alterations, with AD and wild-type mice following divergent inflammatory trajectories.

DISCUSSION: Our findings provide the first in vivo longitudinal characterization of how secondary systemic inflammation disrupts astrocyte-mediated neurovascular regulation. The selective vulnerability of astrocytic Ca[2] [+] signaling relative to vascular output implicates recurrent inflammatory insults as a clinically relevant contributor to neurovascular dysfunction in preclinical AD.},
}

Animals
*Astrocytes/metabolism
*Alzheimer Disease/metabolism/pathology/physiopathology
Mice
*Inflammation/metabolism
Mice, Transgenic
*Hyperemia/metabolism/physiopathology
*Calcium/metabolism
Disease Models, Animal
Lipopolysaccharides
Male
Calcium Signaling
*Neuroinflammatory Diseases

@article {pmid42489430,
year = {2026},
author = {Ishihara, K and Yasui, H and Harada, K and Amano, K and Saito, M and Kaneda, K and Katsuda, M and Kawashita, E and Hata, T and Annoura, R and Nishimura, K and Terasaki, R and Sago, H and Shimohama, S and Akiba, S and Yamakawa, K and Takata, K},
title = {Down syndrome-associated trisomic chromosomal regions modify amyloid-β accumulation and cause early death in a mouse model of aspects of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469121},
doi = {10.1177/13872877261469121},
pmid = {42489430},
issn = {1875-8908},
abstract = {BackgroundIndividuals with Down syndrome (DS), caused by triplication of chromosome 21 (Hsa21), face a significantly increased risk of early-onset Alzheimer's disease (AD) and epilepsy. However, the specific impact of Hsa21 genes on these risks is not yet fully understood.ObjectiveTo investigate how triplication of mouse chromosome 16 (Mmu16), homologous to Hsa21, affects amyloid-β (Aβ) accumulation in the brain and epileptic seizures in AD-DS model mice.MethodsTo generate AD-DS model mice, we crossed a mouse model of aspects of AD-an APPswe/PS1[dE9] mouse exhibiting brain Aβ accumulation and sudden death associated with epileptic seizures with DS mouse models carrying an extra copy of partial segments of mouse chromosome 16. We used three DS model lines: Ts1Cje, harboring a triplicated region encoding ∼70 Hsa21-homologous genes (Scaf4-Zbtb21); Ts1Rhr with triplication of the Cbr3-Fam3b region; and a newly developed Ts1Kei mouse carrying an extra copy of the Scaf4-Cbr1 region. Aβ accumulation was assessed by immunohistochemistry and enzyme-linked immunosorbent assay.ResultsCompared with APPswe/PS1[dE9] mice, Aβ deposition and insoluble Aβ levels in the brain decreased in APPswe/PS1[dE9]-Ts1Cje mice but not in APPswe/PS1[dE9]-Ts1Rhr mice. The high mortality in APPswe/PS1[dE9] mice was suppressed by either Ts1Cje- or Ts1Rhr-triplicated region. Despite a tendency for decreased Aβ accumulation in APPswe/PS1[dE9]-Ts1Kei mice, the study could not be finished due to the extremely high mortality.ConclusionsThe trisomic region in Ts1Kei mice is suggested to harbor genes associated with decreased Aβ accumulation. Alternatively, the trisomic region in Ts1Rhr mice contains genes suppressing sudden death in APPswe/PS1[dE9] mice.},
}

@article {pmid42489432,
year = {2026},
author = {Custodio, B and Montesinos, R and Agüero, K and Huilca, JC and Verastegui, G and Bartolo, P and Nuñez-Huanca, M and Albujar Pereira, MF and Godoy, ME and Ibáñez, A and Custodio, N},
title = {Recruitment challenges and strategies for engaging the Peruvian population in the ReDLat Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467782},
doi = {10.1177/13872877261467782},
pmid = {42489432},
issn = {1875-8908},
abstract = {BackgroundRecruitment for Alzheimer's disease and related dementias research remains challenging, particularly when reaching underrepresented groups such as Latin Americans.ObjectiveThis study aimed to (1) assess recruitment rates across strategies in the ReDLat study and (2) discuss lessons learned to inform future recruitment practices.MethodsThis retrospective study outlines the recruitment for ReDLat, a multi-partner consortium expanding dementia research in Latin America. Participants were recruited using: printed flyers, social media, word-of-mouth, and professional referrals. At initial contact, participants were asked how they learned about the study. Enrollment rates were calculated for each source, and differences across sources were examined using a Pearson chi-square test.ResultsBetween January 2023 and March 2025, 577 individuals expressed interest, of whom 69% (n = 397) were enrolled. Enrollment rates differed significantly across sources (χ[2] (3) = 41.66, p < 0.001); professional referrals achieved a substantially higher rate (81%) than printed flyers (51%), social media (55%), and word-of-mouth (60%), which showed broadly comparable rates. Printed flyers and social media generated broad interest but lower enrollment conversion. Among the 180 individuals not enrolled, the most frequent reason for non-participation was failure to meet inclusion criteria (54%), particularly among those reached via social media and word-of-mouth. Loss of contact accounted for 36% of non-participation.ConclusionsProfessional referrals were associated with the highest enrollment rate for the ReDLat study. These findings highlight the importance of leveraging community trust and professional networks to improve recruitment outcomes for dementia research in underrepresented populations.},
}

@article {pmid42489435,
year = {2026},
author = {El Jaouhari, S and Geetan, C and Farousi, B and Pilli, LI and Neal, D and Engelsma, T and Vullings, I and Uysal-Bozkir, Ö and Van Deudekom, F and Muller, M and Vroomen, JM},
title = {Aging in place preferences of older adults with cognitive impairment and informal caregivers: A qualitative analysis of a discrete choice experiment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469138},
doi = {10.1177/13872877261469138},
pmid = {42489435},
issn = {1875-8908},
abstract = {BackgroundThe Netherlands spends more on long-term care than any other country. In 2015, reforms aimed to promote aging in place (AIP) but have been associated with increased crisis-related hospitalizations, rising caregiver burden, and a need for safer AIP strategies. Little is known about how people with dementia and informal caregivers prioritize AIP care and how their preferences differ.ObjectiveTo identify and compare AIP care preferences of people with dementia and informal caregivers, highlighting shared and individual priorities.MethodsWe used a think-aloud protocol within a discrete choice experiment (DCE). Participants were recruited from outpatient clinics, daycare centers, and cultural organizations. To ensure inclusivity, a formal dementia diagnosis was not required given documented diagnostic delays, particularly in migrant communities. Forty participants (20 care recipients, 20 informal caregivers) completed choice tasks comparing care packages. The DCE comprised three rounds: an online survey for informal caregivers, interviews with the person with dementia, and a dyadic round. Think-aloud responses illuminated decision-making; audio was transcribed verbatim and thematically analyzed.ResultsFive themes shaped preferences: (1) burden of in-home care and care planning, (2) role of case managers, (3) accessibility and inclusivity of social activities, (4) trust in healthcare providers, and (5) reimbursements for home adaptations. Care recipients prioritized in-home care and social activities; caregivers emphasized case management. Both valued emotional support and full reimbursements for home adaptations.ConclusionsTailoring AIP strategies to the distinct needs of both groups is essential and can support more equitable, effective AIP models.},
}

@article {pmid42489438,
year = {2026},
author = {Saadawy, M and Majeed, M and Saadawy, E and , },
title = {APOE4-specific glymphatic effects on clinical progression in the Alzheimer's Disease Neuroimaging Initiative with pathological correlates in the A4 study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469565},
doi = {10.1177/13872877261469565},
pmid = {42489438},
issn = {1875-8908},
abstract = {BackgroundThe APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, some carriers show "clinical resilience", maintaining their cognition despite high risk.ObjectiveWe hypothesized that the glymphatic system, the brain's waste clearance pathway, may attenuate APOE ε4-mediated neurodegeneration, and tested this in two independent cohorts.MethodsWe analyzed 625 cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) discovery cohort and 447 amyloid-positive participants from the preclinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) validation cohort. Glymphatic function was estimated using the analysis of diffusional kurtosis imaging along the perivascular space (DTI-ALPS) index in ADNI and choroid plexus (CP) [18]F-Flortaucipir PET uptake in the A4 study. Primary outcomes were clinical conversion to dementia (ADNI) and hippocampal tau pathology (A4).ResultsIn the discovery cohort, we observed a trend toward ALPS × APOE4 interaction (p = 0.057, not reaching conventional statistical significance). Carriers with preserved function (high ALPS) showed a reduced conversion risk (hazard ratio = 0.52, 95% CI: 0.27-0.99) compared to those with low function. In the validation cohort, glymphatic interface dysfunction (higher CP tau) strongly predicted hippocampal tau burden (p < 0.0001). However, the gene-specific interaction was not replicated (p = 0.928); clearance failure predicted pathology regardless of genotype. Exploratory fluid biomarker analyses in ADNI did not reveal significant interactions.ConclusionsThese findings suggest that preserved glymphatic function is associated with clinical resilience in APOE ε4 carriers, though the interaction was borderline (p = 0.057) and should be considered hypothesis-generating. The strong pathological associations with clearance integrity highlight a biologically plausible mechanism in AD pathogenesis that warrants further investigation.},
}

@article {pmid42489439,
year = {2026},
author = {Szapary, CL and Syme, M and Lyons, KS and Monin, JK and Cornelius, T and Heffner, KL and Vranceanu, AM},
title = {"From theory to methodology": Evaluating a workshop for designing mechanistic interventions for dementia dyads.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467779},
doi = {10.1177/13872877261467779},
pmid = {42489439},
issn = {1875-8908},
abstract = {Background: Coping with the challenges of Alzheimer's disease and related dementias is a shared experience, impacting individuals living with the disease, their care partners, and their relationship. As the number of people affected by dementia continues to rise, so does the demand for evidence-based psychosocial interventions that support the well-being of both members of the dyad. However, the current dyadic dementia intervention (DDI) landscape remains limited in scope and rigor, often lacking strong relational theoretical underpinnings and clear mechanisms of action. Objective: To address this gap, a four-hour workshop was offered at the 2024 Gerontological Society of America Annual Scientific Meeting to equip researchers with the knowledge, confidence, and skills necessary to conduct methodologically rigorous DDI studies. Methods: The first hour of the workshop included didactic presentations on dyadic theory, intervention design, statistics, and dementia-specific considerations. Attendees then participated in small-group, problem-based experiential activities, applying the learned content to their own research projects with individualized feedback from workshop leaders. Results: Participants, primarily from the disciplines of nursing, psychology, and the social sciences, reported significant improvements in perceived knowledge and confidence from pre- to post-workshop and rated the experience as highly satisfactory. Conclusions: These findings suggest that a workshop combining didactic instruction with experiential, problem-based learning is both feasible and effective in strengthening researchers' self-efficacy and skills to advance DDI research.},
}

@article {pmid42489441,
year = {2026},
author = {Drenth, N and van Dijk, SE and Hafkemeijer, A and Rombouts, SARB and van der Grond, J and van Rooden, S},
title = {Early cerebral amyloid angiopathy-related pathology is associated with localized functional brain connectivity.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469189},
doi = {10.1177/13872877261469189},
pmid = {42489441},
issn = {1875-8908},
abstract = {BackgroundThe mechanisms of early brain damage in cerebral amyloid angiopathy (CAA), a highly prevalent comorbid condition in Alzheimer's disease, are not completely understood. While current CAA diagnosis relies on late-stage MRI markers, impaired neurovascular coupling (NVC) has emerged as a promising early marker.ObjectiveTo investigate whether early vascular changes in CAA are associated with functional brain consequences, we examined the association between NVC and various functional connectivity metrics.MethodsWe analyzed MRI data from 93 older adults (71 ± 9 years old). A subgroup meeting Boston criteria v2.0 for possible or probable CAA (n = 46) was analyzed separately to investigate associations in confirmed CAA-related pathology. NVC (time to peak, time to baseline, and BOLD amplitude) was assessed in the occipital cortex using a visual stimulation task. Functional connectivity was assessed at multiple scales using resting-state fMRI, including within ten standard networks, between individual brain regions (edgewise analysis), and across the whole brain (graph theory).ResultsGeneral linear models, adjusted for age, sex, and clinical diagnosis, showed no significant associations between NVC and global connectivity metrics (networks and graph theory). Edgewise analyses revealed limited significant localized functional connections for each NVC measure. Findings were consistent across the total sample and the CAA subgroup.ConclusionsEarly CAA-related pathology is associated with localized rather than global functional connectivity. While large-scale connectivity remains preserved, edgewise analyses indicate subtle localized functional alterations. This suggests that functional connectivity disruption may originate as small-scale deficits that only progress into widespread, global impairment in advanced disease stages.},
}

@article {pmid42489442,
year = {2026},
author = {Keith, CM and Haut, MW and Worhunsky, P and Vieira Ligo Teixeira, C and Mehta, RI and Malone, J and Phelps, H and Ward, M and Miller, M and Pockl, S and Rajabalee, N and Marano, G and McCuddy, WT and D'Haese, PF and Rezai, A},
title = {Episodic memory and associated cortical atrophy in amnestic early-onset and late-onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469183},
doi = {10.1177/13872877261469183},
pmid = {42489442},
issn = {1875-8908},
abstract = {BackgroundMemory consolidation problems are often prototypical in Alzheimer's disease (AD). However, it remains undetermined whether episodic memory presents similarly in early-onset Alzheimer's disease (EOAD) relative to the more commonly occurring late-onset Alzheimer's disease (LOAD).ObjectiveThis study examined episodic memory and its neuroanatomical correlates in amnestic early-onset (aEOAD) relative to amnestic late-onset AD (aLOAD).MethodsUsing our single center data set obtained from a memory clinic setting (N = 180), we examined group differences in multiple markers of episodic memory along with associations with volume and thickness of underlying signature brain regions.ResultsWe did not observe any difference for examined measures of memory performance between aEOAD and aLOAD. Associations between episodic memory processes and volume and thickness of the brain regions examined were also largely similar, except for a stronger relationship between memory consolidation and thinner left supramarginal gyrus observed in the aEOAD group.ConclusionsOverall, the current results support similar memory consolidation processes in early- and late-onset amnestic Alzheimer's disease, though the parietal cortex may play a larger role in memory consolidation in aEOAD.},
}

@article {pmid42489457,
year = {2026},
author = {Liu, Y and Qiu, Q and Yue, L and Hong, B and Su, N and Li, W and Xiao, S and Sun, L and Chen, J and , },
title = {Precuneus amyloid-β deposition involving the association of irritability and cognitive decline: A multi-cohort longitudinal study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467432},
doi = {10.1177/13872877261467432},
pmid = {42489457},
issn = {1875-8908},
abstract = {BackgroundIrritability is increasingly recognized for its association with cognitive function, though its impact on cognitive decline and underlying mechanisms remain unclear.ObjectiveTo investigate the associations between irritability and cognition, identify potential neurobiological mechanisms.MethodsThis study included three cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 722), the UK Biobank (UKB, N = 405,112), and the China Longitudinal Aging Study (CLAS, N = 240). Participants were classified into irritability-positive (+) and irritability-negative (-) groups based on assessment of irritability.We used Linear mixed-effects models to assess irritability-related cognitive trajectory, Cox regression to estimate cognitive decline, mediation analysis to test the effect of amyloid-β (Aβ) on the relationship between irritability and cognitive decline, and enrichment analysis to identify the underlying pathological mechanisms of irritability.ResultsIrritability was associated with increased cognitive decline in both ADNI (HR = 1.49, 95% CI: 1.12-1.98) and UKB (HR = 1.09, 95% CI: 1.04-1.15) cohorts, with baseline irritability linked to faster Mini-Mental State Examination decline (2.76 versus 1.88). Mediation analysis showed that cerebrospinal fluid (CSF) Aβ mediated 19-24% of irritability's effect on cognitive decline, while precuneus Aβ pathology mediated 30-41%. Imaging analysis revealed significant thinning of the left precuneus cortex in individuals with irritability. Proteomic analysis indicated underlying pathways involving enhanced energy metabolism and suppressed signal transduction, with modifiable factors (air pollution and physical inactivity) associated with irritability-related pathological proteins.ConclusionsOur findings indicate that irritability is significantly associated with cognitive decline. This association may be driven by mechanisms involving precuneus pathology, increased energy metabolism, and suppressed signal transduction, though these results warrant confirmation in future studies.},
}

@article {pmid42489522,
year = {2026},
author = {Denier-Fields, DN and Gangnon, RE and Rivera-Rivera, LA and Betthauser, TJ and Bendlin, BB and Johnson, SC and Engelman, CD},
title = {Better cardiovascular health, measured by Life's Simple 7, is associated with lower white matter hyperintensity burden and greater cerebral blood flow over time.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467045},
doi = {10.1177/13872877261467045},
pmid = {42489522},
issn = {1875-8908},
abstract = {BackgroundLifestyle factors have been studied for dementia risk, but few studies have comprehensively assessed both Alzheimer's disease (AD) and cerebrovascular disease (CBVD) pathologies.ObjectiveOur research aims to determine the relationships between lifestyle and dementia pathologies.MethodsWe analyzed data from 1208 Wisconsin Registry for Alzheimer's Prevention (WRAP) participants. The cohort is enriched for participants with a family history of AD and a higher proportion of APOE ε4 carriers (n = 478); participants are primarily female (n = 827), non-Hispanic white (n = 1088), and highly educated (≥3 years professional or college education; n = 803), with an average baseline age of 64. Life's Simple Seven (LS7) scores were calculated from questionnaire data and clinical vitals. Brain health outcomes included CBVD biomarkers (white matter hyperintensities and arterial spin labeling [ASL] cerebral perfusion), AD biomarkers (amyloid Pittsburgh compound B index and tau standardized uptake value ratio Mayo meta-temporal composite), and cognitive outcomes (Preclinical Alzheimer Cognitive Composite Score 3 [PACC3], Delayed Recall, Immediate Learning, and Executive Function).ResultsHigher LS7 scores were significantly associated with lower white matter hyperintensity burden and higher ASL perfusion at the 6-8 year interval, with nominal associations observed at earlier time points and for global cognition (PACC3). No consistent associations were observed with amyloid or tau PET measures.ConclusionsThis study provides evidence that the beneficial effects of LS7 on cognition are primarily through cerebrovascular pathways rather than through AD pathology.},
}

@article {pmid42489523,
year = {2026},
author = {Gobbo, S and Romano, D},
title = {Reduced differentiation of personality in Alzheimer's disease-like dementia and associations between informant report of personality change and cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469839},
doi = {10.1177/13872877261469839},
pmid = {42489523},
issn = {1875-8908},
abstract = {BackgroundPersonality changes are documented in Alzheimer's disease (AD), but research has focused almost exclusively on how much traits change rather than how the underlying personality structure reorganizes. Recent evidence from healthy aging shows that personality traits can de-differentiate over time, suggesting a decline of coherence of traits with age. Whether such personality de-differentiation also occurs in neurodegeneration and how personality and cognitive changes relate remains unknown.ObjectiveThis study aimed to examine structural changes in personality traits in individuals with AD-like dementias, using the HEXACO personality model administered cross-sectionally to informants and to a control group of informants of healthy older adults, and explore dimensional changes in the relationship between reported changes in personality and cognition.Methods207 informants of persons with AD-like dementia and 201 informants of healthy older adults completed the Hexaco Adjective Scales, referring both to the present time and to perceived changes in personality, and a questionnaire (e-Cog) to assess cognitive changes.ResultsPrincipal component analysis revealed a simplified personality structure in persons with AD but not in healthy older adults, with Emotionality not emerging as an independent factor in persons with AD. Network analyses indicated significant links between personality trait changes and declines across cognitive domains that differed between the two groups.ConclusionsAD-like dementias are characterized by a reduced differentiation of personality structure paralleling the simplification of cognitive organization, with the strongest impact observed in the Emotionality domain. Personality changes also co-occur with perceived cognitive decline, underscoring the need to integrate personality assessment in evaluating dementia.},
}

@article {pmid42489525,
year = {2026},
author = {Hewan, P and Wearn, A and Hogeveen, J and Williams, K and Spreng, RN and Turner, GR and , },
title = {Cortical microstructural integrity predicts an exploitation bias in older adulthood.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag132},
pmid = {42489525},
issn = {1758-5368},
abstract = {OBJECTIVES: Prefrontal regions are implicated in explore-exploit decision-making during foraging. Older adults often show an exploitation bias, and this age period is also marked by deteriorating prefrontal myelination. To investigate whether these phenomena are linked, we examined whether lower magnetization transfer saturation (MTsat), a myelin-sensitive quantitative MRI (qMRI) measure, in these regions predicts greater exploitation bias during foraging, and whether cortical microstructure is a better predictor of bias than macrostructure (i.e., cortical thickness).

METHODS: Cognitively healthy older adults with familial risk of Alzheimer's disease (AD) (N=118, 60-88 years) completed a foraging task indexing explore-exploit decision-making. qMRI was used to derive MTsat values for the frontopolar cortex (FPC), medial orbitofrontal cortex (OFC), rostral middle frontal gyrus (rMFG), dorsal anterior cingulate cortex (dACC), as well as the locus coeruleus (LC), a core subcortical region strongly implicated in explore-exploit decision-making. Secondary analyses examined associations between available AD risk markers and foraging.

RESULTS: Lower MTsat in the FPC, OFC, rMFG, and LC was associated with an exploitation bias, with LC and FPC emerging as the strongest predictors. No relationship was observed for the dACC. MTsat remained a significant predictor of foraging after controlling for cortical thickness. Observed associations were largely unrelated to AD risk markers.

DISCUSSION: Individual differences in cortical microstructural integrity within a well-defined explore-exploit circuit are associated with an exploitative decision-making bias in older adults. These findings highlight the value of qMRI microstructural integrity markers, beyond standard macrostructural assays, in characterizing the neural correlates of exploitation biases in later life.},
}

@article {pmid42489527,
year = {2026},
author = {Streit, WJ and Kuhrt, H and Bechmann, I},
title = {Elevated ferritin expression in microglia and extracellular amyloid-β deposition are associated with reduced neurofibrillary degeneration in human isocortex, but not allocortex.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470454},
doi = {10.1177/13872877261470454},
pmid = {42489527},
issn = {1875-8908},
abstract = {BackgroundPrior work in preclinical late-onset Alzheimer's disease (LOAD) focused on neuritic plaque development suggested that intracellular ferritin expression in microglia and extracellular deposition of amyloid-β (Aβ) are innate neuroprotective mechanisms geared specifically towards limiting aging-dependent increases in intracerebral free iron which likely contribute to development of neurofibrillary degeneration (NFD).ObjectiveImprove understanding of LOAD pathogenesis.MethodsImmunohistochemical comparison of the extent of NFD with the intensity of ferritin expression and Aβ deposition in three brain regions, including temporal lobe (entorhinal cortex, hippocampus), frontal, and occipital cortex in 34 non-demented human subjects at Braak stages II-III.ResultsFerritin-positive microglia are present with similar quantity and intensity in the allo- and isocortices of every individual in the cohort. Extracellular Aβ deposition in the isocortex is observed before substantial NFD develops, but in the allocortex (temporal lobe) there are no Aβ deposits in 50% of subjects despite extensive NFD. Cytoskeletal lesions in the allocortex consist of atrophic grid cells, abundant pretangles, neuropil threads, neurofibrillary tangles, and neuritic plaques; isocortical sites show either no NFD at all or only minimal NFD presenting as solitary pretangles or tangles, neuropil threads, or droplet degeneration spheres from ferroptotic neurons. Presence of degenerating grid neurons in entorhinal cortex coincides with microglial apoptosis.ConclusionsNeuroprotection via ferritin expression and Aβ deposition is more effective in the isocortex than in allocortex. Findings support the hypothesis that degeneration or death of neuroprotective microglia promotes neuronal degeneration.},
}