@article {pmid42571023,
year = {2026},
author = {Frings, L and Brumberg, J and Meyer, PT},
title = {Semantic fluency predicts survival of memory clinic patients.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42571023},
issn = {1758-9193},
mesh = {Humans ; Female ; Male ; Aged ; Positron-Emission Tomography ; Neuropsychological Tests ; *Alzheimer Disease/mortality/diagnostic imaging ; Fluorodeoxyglucose F18 ; Aged, 80 and over ; *Semantics ; Predictive Value of Tests ; Registries ; Brain/diagnostic imaging/metabolism ; *Memory Disorders/mortality/diagnostic imaging ; },
abstract = {BACKGROUND: Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored.

METHODS: From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed.

RESULTS: 583 patients were included (age 68.9 ± 8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0 years [95% C.I. 7.7-8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR = 0.71 [0.63 - 0.80], Bonferroni-corrected p < 0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR = 0.75 [0.61 - 0.91], p = 0.0035). In patients with more than one assessment (N = 163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR = 0.66 [0.53-0.83], p < 0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p < 0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR = 0.68 [0.55 - 0.84], Bonferroni-corrected p < 0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right anterior cingulate (Bonferroni-corrected p = 0.078). Global amyloid load was not associated with survival.

CONCLUSIONS: Survival of memory clinic patients can be predicted by semantic fluency, independently from amyloid status and global cognitive impairment. Anterior cortical glucose metabolism is itself a significant predictor of survival and slightly improves prediction by semantic fluency.},
}

Humans
Female
Male
Aged
Positron-Emission Tomography
Neuropsychological Tests
*Alzheimer Disease/mortality/diagnostic imaging
Fluorodeoxyglucose F18
Aged, 80 and over
*Semantics
Predictive Value of Tests
Registries
Brain/diagnostic imaging/metabolism
*Memory Disorders/mortality/diagnostic imaging

@article {pmid42571045,
year = {2026},
author = {Marvanova, M},
title = {Comment on "Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges".},
journal = {The Senior care pharmacist},
volume = {41},
number = {5},
pages = {157-158},
doi = {10.4140/TCP.n.2026.157},
pmid = {42571045},
issn = {2639-9636},
}

@article {pmid42571047,
year = {2026},
author = {Qudoos, MA and Elliott, DP},
title = {Response to Comment on "Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges".},
journal = {The Senior care pharmacist},
volume = {41},
number = {5},
pages = {159-160},
doi = {10.4140/TCP.n.2026.159},
pmid = {42571047},
issn = {2639-9636},
}

@article {pmid42571168,
year = {2026},
author = {Oxenkrug, G and Comai, S},
title = {Up-Regulation of Anthranilic Acid Formation and Pro-Cognitive Effect of Indoleamine 2,3-Dioxygenase Inhibition.},
journal = {International journal of tryptophan research : IJTR},
volume = {19},
number = {},
pages = {11786469261472317},
pmid = {42571168},
issn = {1178-6469},
abstract = {Inhibition of indoleamine 2,3-dioxygenase (IDO) is a promising therapeutic strategy for cognitive impairment in Alzheimer's disease (AD). The pro-cognitive effect is often attributed to restoring glycolysis by preventing tryptophan (Trp) conversion to kynurenine (Kyn). However, this overlooks the metabolic fate of Trp when IDO is blocked. Since IDO and tryptophan 2,3-dioxygenase (TDO) compete for the same substrate, inhibiting IDO may shunt Trp toward TDO, potentially increasing Kyn and its downstream catabolites. This commentary explores the hypothesis that the upregulation of anthranilic acid (AA), a Kyn catabolite, contributes to the cognitive benefits of IDO inhibition. Recent evidence shows elevated AA in animal models of AD and individuals with mild cognitive impairment and preclinical AD, where it may serve as an early biomarker. Notably, these elevations and the pro-cognitive effects of AA-modulating compounds like sodium benzoate exhibit sex-specificity, being more prominent in females. The mechanism may involve AA's dual action on G-protein coupled receptors: antagonism of GPR17 promotes myelination, while agonism of GPR109A may protect myelin from degradation. Preserving myelin integrity is critical, as demyelination is an early event in AD pathogenesis. We propose that AA upregulation is not merely a biomarker but part of a compensatory defense mechanism. Therefore, the pro-cognitive effect of IDO inhibition may be partly mediated by the subsequent shunting of Trp toward TDO and production of the myelin-preserving metabolite, AA. This reframes the therapeutic goal from reducing neurotoxic kynurenines to leveraging the protective potential of the entire pathway.},
}

@article {pmid42571320,
year = {2026},
author = {Pinnelli, SP and T, SB and Ca, J and Pinnelli, VB and Harikrishna, GV and Mudamanchu, VK and Sam, KT and Ms, D and Bhupathiraju, P and Sucharitha, AS and Kandi, V},
title = {Artificial Intelligence for the Diagnosis and Management of Neurodegenerative Diseases: A Comprehensive Review With an Emphasis on Parkinson's and Alzheimer's Diseases.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112325},
pmid = {42571320},
issn = {2168-8184},
abstract = {Artificial intelligence (AI) is rapidly transforming research in neurodegenerative diseases, yet its clinical translation remains limited. We conducted a structured literature search across Google Scholar, PubMed, Scopus, and Web of Science, screening studies published between 2015 and April 2026 that applied machine learning (ML), deep learning (DL), and multimodal data integration to neuroimaging, biomarkers, and digital phenotyping. Our analysis revealed that AI models demonstrate strong potential for differentiating disease subtypes, predicting progression, and enhancing diagnostic accuracy, with notable advances in neuroimaging interpretation, fluid biomarker analysis, and wearable sensor data. In Parkinson's disease (PD), digital phenotyping through gait, speech, and handwriting analysis has enabled sensitive monitoring, while in Alzheimer's disease (AD), AI applied to imaging and plasma biomarkers has improved risk stratification. Despite these advances, barriers such as dataset heterogeneity, label noise, lack of external validation, and ethical concerns regarding bias, transparency, and patient trust persist. We conclude that while AI holds promise to revolutionize the care of PD and AD, real-world adoption requires multicenter validation, standardized reporting frameworks, regulatory guidance, and interdisciplinary collaboration, alongside prospective trials that embed AI tools into clinical workflows to ensure safety, equity, and effectiveness.},
}

@article {pmid42571323,
year = {2026},
author = {Jiménez-Mausbach, M and Tijms, BM and Paterson, C and Refsgaard, JC},
title = {Semaglutide attenuates a proteomics-based dementia risk signature in older adults with overweight or obesity and cardiovascular disease without diabetes: A post hoc analysis of the SELECT phase 3 trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70432},
pmid = {42571323},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma proteomics detect multi-pathway biological changes preceding dementia onset. The Dementia SomaSignal Test (dSST) is a validated 25-protein score predicting 5- and 20-year all-cause dementia risk. Preclinical and clinical data suggest glucagon-like peptide-1 receptor agonists may have neuroprotective effects.

METHODS: In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults ≥ 65 years with overweight/obesity and cardiovascular disease without diabetes (n = 2970) were randomized to semaglutide 2.4 mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST.

RESULTS: Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (β -0.44; P < 0.001).

DISCUSSION: Semaglutide slowed progression of a validated proteomics-based dementia risk signature.},
}

@article {pmid42571406,
year = {2026},
author = {Urso, D and Nichols, E and Giannoni-Luza, S and Brayne, C and Ray, N and Logroscino, G},
title = {Burden of Dementia in Europe, 1990-2023: a systematic analysis from the Global Burden of Disease Study 2023.},
journal = {The Lancet regional health. Europe},
volume = {68},
number = {},
pages = {101796},
pmid = {42571406},
issn = {2666-7762},
abstract = {BACKGROUND: Dementia is a leading cause of disability and mortality in Europe, yet no recent harmonised assessment has described its impact across the European Union (EU-27) and the WHO European Region.

METHODS: We used data from the Global Burden of Disease Study 2023 (GBD 2023) to estimate prevalence, mortality, and disability-adjusted life years (DALYs) for dementia from 1990 to 2023. Estimates were produced for the EU-27 and the WHO European Region, by age and sex. Non-fatal outcomes were modelled using DisMod-MR 2.1, and dementia-attributable mortality was estimated using an excess-mortality framework. We also quantified DALYs attributable to six modifiable risk factors.

FINDINGS: In 2023, 7.76 million people (95% UI 6.69-8.72) were living with dementia in the EU-27 and 12.28 million (10.44-13.90) in the WHO European Region, representing ∼90% increases since 1990 despite modest declines in age-standardised prevalence. Prevalence was nearly twice as high in women as in men. Dementia rose from the eighth to the third leading cause of death in the EU-27. Dementia accounted for 5.49 million DALYs (2.44-11.41) in the EU-27. An estimated 41% (24.4-57.4) of dementia DALYs in the EU-27 were attributable to modifiable risk factors, particularly ambient particulate matter pollution, high fasting plasma glucose, and high body-mass index, which are disproportionately concentrated in socioeconomically disadvantaged populations.

INTERPRETATION: Despite modest declines in age-standardised rates, the absolute burden of dementia in Europe continues to rise, driven by population ageing. The substantial contribution of modifiable risk factors highlights major opportunities for prevention. Robust, country-specific estimates are essential to guide integrated strategies combining prevention and care planning.

FUNDING: Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione; Regione Puglia for the national "Fund for Alzheimer's and Dementia 2021-2023" (Piano Regionale Demenze 2021/2023).},
}

@article {pmid42571433,
year = {2026},
author = {Kloosterman, M and Vongpromek, R and Friesema, ECH and Bramer, W and Verhoeven, AJM and Mulder, MT},
title = {LR11/SorLA and its role in cardiovascular disease.},
journal = {International journal of cardiology. Heart & vasculature},
volume = {66},
number = {},
pages = {101982},
pmid = {42571433},
issn = {2352-9067},
abstract = {Cardiovascular diseases account for the highest morbidity worldwide. LR11 (also called SorLA), an LDL receptor family member characterized as a sorting receptor, was initially identified in the brain and has a causative role in the development of Alzheimer's disease. However, LR11, and its circulating shed isoform, sLR11, are also associated to cardiovascular diseases and risk factors for atherosclerosis, such as obesity and diabetes. In the current narrative review, we discuss that elevation of plasma sLR11 levels can result from different forms of vascular injury, but also plays a role in subsequent vascular remodeling. We provide an overview of the mechanisms whereby LR11 promotes vascular remodeling and thereby atherosclerosis and how it could be involved in obesity and diabetes. Furthermore, we discuss the possibilities of (s)LR11 as a biomarker and therapeutic target for cardiovascular diseases.},
}

@article {pmid42571539,
year = {2026},
author = {Nguyen, HD and Siddiqui, S and Bohannon, DG and Blair, RV and Deng, HW and Prat, A and Kim, WK},
title = {Single-cell transcriptomic analysis reveals age-related remodeling of brain endothelial cells.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100164},
pmid = {42571539},
issn = {2589-9589},
abstract = {Blood-brain barrier (BBB) integrity naturally declines with age. Brain endothelial cells (ECs) and pericytes (PCs) form the BBB, and aging impairs tight junctions, likely via altered PC-to-EC signaling. However, the molecular mechanisms underlying this impairment remain unclear. Using single-cell RNA sequencing, we profiled 68,316 brain ECs expressing 15,564 genes from young and old mice. Unsupervised clustering and annotation revealed five distinct EC subtypes-Capillary EC1, Capillary EC2, Arterial EC, Venous EC1, and Venous EC2-defined by marker genes Mfsd2a, Plvap, Bmx, Nr2f2, and Vcam1, respectively. Aging shifted EC subtype distribution, with reduced Capillary EC1 (45% vs. 57%) and increased Arterial (33% vs. 16%) and Venous ECs (12% vs. 2%) compared with young mice. Mio analysis further showed that Capillary EC1 and Venous EC2 neighborhoods were less abundant in aged brains. Biotin metabolism was decreased in old vs. young mice, particularly within Capillary EC1, Capillary EC2, and Arterial EC. Although widespread gene downregulation was observed across EC subsets, overall expression trends were largely consistent among clusters. Key genes-Ramp2, Hbb-bs, Ly6c1, Calm1-were less abundant, whereas Rasgrf2 was uniquely enriched in aged mice. Immunohistochemistry confirmed reduced LY6C and RAMP2 and elevated RASGRF2 in aged mouse and human brains. Cell-cell interaction analyses revealed age-associated remodeling of ligand-receptor signaling. Enrichment analyses implicated pathways involved in neurovascular integrity, inflammation, amyloid processing, and vascular remodeling. Collectively, these findings show that aging reprograms EC subtype composition, gene expression, and metabolism, thereby contributing to BBB disruption and neurovascular dysfunction.},
}

@article {pmid42571702,
year = {2026},
author = {Dávila-Cervantes, CA and Agudelo-Botero, M},
title = {Uneven progress in Alzheimer's disease and other dementias across Mexico, 1990-2023: updated estimates from the Global Burden of Disease Study.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13607863.2026.2710256},
pmid = {42571702},
issn = {1364-6915},
abstract = {OBJECTIVES: To quantify the magnitude and trends the national and subnational burden of Alzheimer's disease and other dementias (ADOD) in Mexico from 1990 to 2023, analyzing patterns by sex and age and exploring their association with the Socio-Demographic Index (SDI) and the Healthcare Access and Quality Index (HAQI).

METHOD: A secondary ecological study was conducted using updated estimates from the Global Burden of Disease and Risk Factors Study (GBD) 2023. Prevalence, incidence, mortality, and disability-adjusted life years (DALYs) were examined. Temporal trends were assessed using joinpoint regression. Pearson correlation and linear regression were used to evaluate associations between DALYs rates and SDI and HAQI.

RESULTS: Between 1990 and 2023, ADOD prevalence and incidence increased, despite significant declines in age-standardized prevalence and incidence rates. Females consistently experienced higher mortality and disability, with age-standardized DALYs rates 1.28 times those of males. The ADOD burden increased sharply with age, peaking among those aged 85 years and older, with premature mortality accounting for 63.0% of total DALYs. A significant increase in DALYs rates occurred during 2020-2023 after previous periods of gradual decline. DALYs rates were negatively correlated with both SDI and HAQI.

CONCLUSION: ADOD disproportionately affect women, while higher modeled burden was observed in several states with lower socioeconomic development and weaker health system performance. The post-2020 increase represents an epidemiological signal warranting further investigation into excess mortality among people with dementia, healthcare disruption, social isolation, and changes in long-term care during the COVID-19 period. Strengthening early diagnosis, long-term care, and management of modifiable risk factors is essential to reduce the future burden and persistent regional and sex-based inequalities in ageing populations.},
}

@article {pmid42571730,
year = {2026},
author = {Li, Q and Li, M and Huang, X and Cao, C and Hu, Y},
title = {Integrative multi-omics analysis identifies AIF1 as an immune-associated factor linked to monocyte-centered inflammatory networks in Alzheimer's disease.},
journal = {Immunobiology},
volume = {231},
number = {5},
pages = {153229},
doi = {10.1016/j.imbio.2026.153229},
pmid = {42571730},
issn = {1878-3279},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which immune dysregulation has emerged as an important component of disease pathogenesis; however, the contribution of circulating proteins and their cellular context remains incompletely understood. Here, we performed an integrative multi-omics analysis combining Mendelian randomization (MR), bulk transcriptomics, single-cell RNA sequencing, and peripheral blood validation to systematically identify plasma proteins associated with AD. Proteome-wide MR analysis identified multiple circulating proteins associated with AD risk. Integration with transcriptomic data identified AIF1 (allograft inflammatory factor 1) as a shared candidate supported by both genetic prioritization and differential expression analysis. Although bulk transcriptomic data showed reduced AIF1 expression in AD, single-cell analysis revealed distinct cell type-specific expression patterns, with predominant enrichment in monocytes and other innate immune populations. PBMC-based qPCR further confirmed an overall reduction in AIF1 expression in AD. Further analyses suggested that AIF1-associated immune alterations were linked to changes in inflammatory signaling pathways, including STAT, IRF, and NF-κB-related activity, as well as differences in intercellular communication involving MIF, GALECTIN, ANNEXIN, and CypA-related signaling. Peripheral immune cell composition analysis indicated differences between AD and control samples, characterized by relative changes in innate immune cell proportions. Collectively, these findings identify AIF1 as an immune-associated factor linked to genetic and transcriptional alterations in AD and suggest its association with monocyte-related immune states and altered immune signaling patterns. This study provides a multi-layered framework for investigating peripheral immune involvement in AD and highlights potential directions for understanding immune-related alterations and biomarker discovery.},
}

@article {pmid42571753,
year = {2026},
author = {Rani, S and Mahesh, KV and Sandhir, R and Prabhakar, N},
title = {AuNP decorated-Ni-MOF nanosheet based cDNA sensor for detection of miRNA-128 in Alzheimer's disease.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130405},
doi = {10.1016/j.talanta.2026.130405},
pmid = {42571753},
issn = {1873-3573},
abstract = {A cDNA sensor based on gold nanoparticles (Au) supported on nickel metal-organic framework nanosheets (MOF-NS) modified fluorine-tin oxide (FTO) glass electrode for the ultrasensitive and selective detection of miRNA-128 biomarker associated with the progression of Alzheimer's disease (AD) has been reported. The MOF-NS and Au nanoparticles were electrodeposited onto FTO electrode using chronoamperometry to immobilize 5'-biotinylated DNA (btn-cDNA) complementary to miRNA-128 by streptavidin-biotin interaction, generating the modified electrode (btn-cDNA/SV/Au/MOF-NS/FTO). The fabricated electrode was characterized using various surface characterization techniques, including FESEM, XPS, FTIR, and electrochemical methods. The fabricated electrode was then utilized for the selective detection of miRNA-128 using electrochemical impedance spectroscopy. The results indicated a linear response range of 1.0 × 10[-1] fM-1.0 × 10[2] nM with limit of detection of 0.017 fM, and sensitivity of 180.11 Ω fM[-1]cm[-2]. Moreover, the cDNA sensor showed satisfactory performance with real serum samples from AD patients and healthy individuals, as validated by real time-PCR technique with area under curve of 0.93 and a sensitivity of 90%, respectively, demonstrating the potential of present cDNA sensing approach in the biomedical field.},
}

@article {pmid42571787,
year = {2026},
author = {Bhakta-Guha, D and Guha, G},
title = {Alzheimer's disease as a disorder of time-gated clearance: Circadian regulation of Glymphatic function in neurodegeneration.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115959},
doi = {10.1016/j.expneurol.2026.115959},
pmid = {42571787},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is traditionally defined by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and progressive neurodegeneration. However, increasing evidence suggests that impaired brain waste clearance represents an additional and clinically relevant dimension of disease pathogenesis. The glymphatic system, a perivascular cerebrospinal fluid-interstitial fluid exchange network, facilitates removal of soluble metabolites including Aβ and tau, and functions most efficiently during sleep. Recent studies indicate that glymphatic influx, meningeal lymphatic drainage, and blood-brain barrier (BBB) efflux transport are temporally regulated by circadian mechanisms, creating time-restricted windows of maximal clearance capacity. In AD, sleep fragmentation, suprachiasmatic nucleus degeneration, clock gene disruption, vascular stiffening, BBB tight junction failure, aquaporin-4 depolarization, and neuroinflammation may converge to impair this coordinated clearance network. We propose a time-gated clearance framework in which temporally misaligned or insufficient waste removal contributes to protein accumulation and disease progression. We also evaluate major controversies, including relative roles of advection and diffusion in parenchymal transport, predominance of rodent-derived data, and current limitations of human imaging biomarkers. Finally, we discuss therapeutic implications of circadian re-entrainment, sleep optimization, BBB restoration, vascular protection, and enhancement of glymphatic-lymphatic flow. This systems-level perspective complements established amyloid/tau models and identifies potentially modifiable targets for AD intervention.},
}

@article {pmid42571855,
year = {2026},
author = {Guo, X and Wu, S and Sun, Z and Jia, T and Ouyang, Y and Zhang, M and Kou, C and Bai, W},
title = {Peripheral GDF15 as an early biomarker for brain disorders: A large prospective cohort study.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111886},
doi = {10.1016/j.pnpbp.2026.111886},
pmid = {42571855},
issn = {1878-4216},
abstract = {BACKGROUND: Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine involved in metabolic and inflammatory pathways. We examined the associations of plasma GDF15 with incident brain disorders and explored potential mediating pathways and causality.

METHODS: UK Biobank participants were followed for a median of 14 years. Plasma GDF15 was measured at baseline. Cox proportional hazards models assessed associations with incident brain disorders, including all-cause dementia (ACD), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, depression, sleep disorders, stroke, and epilepsy. Mediation analyses evaluated biochemical and hematological pathways, and one-sample Mendelian randomization (MR) was used to assess potential causal effects.

RESULTS: Higher GDF15 levels were associated with increased risks of overall brain disorders and all examined subtypes. In continuous analyses (per 1-unit increase in log2-transformed GDF15), hazard ratios (95% CIs) were 1.54 (1.48-1.60) for overall brain disorders, 1.98 (1.80-2.17) for ACD, 1.84 (1.60-2.10) for AD, 1.37 (1.18-1.59) for PD, 1.26 (1.16-1.37) for anxiety, 1.38 (1.29-1.49) for depression, 1.40 (1.26-1.55) for sleep disorders, 1.92 (1.81-2.05) for stroke, and 1.71 (1.46-2.01) for epilepsy (all P < 0.001). Lipid- and inflammation-related markers appeared to partially mediate these associations. High-density lipoprotein cholesterol (HDL-C) accounted for an estimated 7.51% of the association with depression and 11.47% with sleep disorders, while neutrophil count showed relatively larger mediation estimates across multiple outcomes. MR analyses did not support a direct causal effect of GDF15.

CONCLUSION: Plasma GDF15 is associated with a broad range of incident brain disorders and may act partly through lipid- and inflammation-related pathways, particularly HDL-C and neutrophil count.},
}

@article {pmid42571862,
year = {2026},
author = {Ding, F and Yang, L and Qiao, S and Lam, TKY and Su, Z and He, Y and Chen, Z and Cui, X and Chan, Y and Zhang, W and Xu, J and Cai, Z and Lyu, A and Li, F},
title = {Targeting transthyretin tetramer with a novel blood-brain barrier-penetrating small-molecule stabilizer for the treatment of Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153998},
doi = {10.1016/j.ijbiomac.2026.153998},
pmid = {42571862},
issn = {1879-0003},
abstract = {The stability of the transthyretin (TTR) tetramer is critical for regulating cerebral amyloid-β (Aβ) homeostasis in Alzheimer's disease (AD). Stable TTR tetramer can directly bind Aβ and promote its clearance from the brain. However, current TTR tetramer stabilizers lack blood-brain barrier (BBB) penetration, limiting their clinical translation. Therefore, to fully realize the therapeutic potential of TTR in AD, novel TTR tetramer stabilizers with superior BBB penetration must be discovered. Here, we aim to identify TTR tetramer stabilizers with BBB penetration via a multidimensional virtual screening workflow, and perform preliminary validation of their biological activities. Finally, Z1097086893 was identified as the lead compound. In vitro, the compound exhibited significant BBB penetration and robust TTR tetramer stabilization activity. In vivo, Z1097086893 also crossed the BBB. MSI showed localization to the choroid plexus within the ventricular system, the principal site of TTR synthesis and secretion in the brain. In the 5xFAD mouse model, the compound significantly reduced hippocampal Aβ plaque burden, alleviated neuronal injury, and rescued spatial learning and recognition memory deficits. Safety assessments confirmed that Z1097086893 was well tolerated at therapeutic doses, with no detectable drug-induced organ toxicity or abnormalities in liver and kidney function. Our findings validate cerebral TTR tetramer stabilization as a promising therapeutic strategy for AD, and provide a lead compound for further clinical translation. Furthermore, the BBB-first screening workflow established in this work offers a generalizable technical framework for the development of brain-targeted therapeutics for AD.},
}

@article {pmid42571934,
year = {2026},
author = {Lee, SH and Kim, K and Bae, J and Choi, K and Jung, DH and Park, EJ and Ju, HC and Kang, WS and Moon, C},
title = {A Novel Methodology for Temporal Analysis of Consumer Wearable Sleep Data: Feasibility and Application to Early Cognitive Impairment.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26014},
pmid = {42571934},
issn = {1226-2560},
abstract = {While sleep disturbances are recognized as early markers of Alzheimer's disease (AD), the practical application of gold-standard polysomnography (PSG) for long-term monitoring is limited. This study aims to establish a novel methodological framework for the time-series analysis of sleep data collected via consumer-grade wearables and to explore whether this approach can detect differentiated signals across various stages of cognitive impairment. Daily sleep patterns of thirteen participants (5 healthy controls, 4 with aMCI, and 4 with mild AD) were monitored over three months using the Fitbit Charge 2. Rather than relying on aggregate nightly averages, we implemented a time-resolved analysis across 10-minute intervals to examine the temporal dynamics of sleep architecture. The proposed analysis revealed distinct, group-dependent temporal signatures. Specifically, the aMCI and AD groups exhibited shorter deep sleep during the early phase of the night, reduced REM sleep approximately three hours after sleep onset, and consistently elevated levels of light sleep and wake after sleep onset (WASO). These findings demonstrate that time-series analysis of wearable sleep data presents the potential to identify candidate digital phenotypes associated with cognitive decline. This study supports the feasibility of using longitudinal, dynamic sleep monitoring as an exploratory analytical framework warranting further validation for the detection of pathophysiological changes in older adults, shifting the focus from simple detection to the identification of candidate temporal sleep features. All reported findings are exploratory in nature and require replication in larger, independent cohorts.},
}

@article {pmid42572052,
year = {2026},
author = {Pradhan, S},
title = {Letter to the Editor "Therapeutic Time Window of Disease-Modifying Therapy for Early Alzheimer's Disease in Japanese Individuals: Analysis Based on J-ADNI Study".},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {8},
pages = {e70784},
doi = {10.1111/ggi.70784},
pmid = {42572052},
issn = {1447-0594},
}

@article {pmid42572115,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Teshima, T and Yang, S and Wu, Y and Hu, X and Abarca, GIF and da Cruz, KCT and Rodriguez, MFS and Rubatino, FVM and Yamakawa, M and de Godoy, MF and de Araújo Filho, GM},
title = {Replay Letter to: 'Loneliness as an Interface Between Alzheimer's Disease and Suicidal Behaviour: A Methodological Concern'.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70203},
doi = {10.1111/psyg.70203},
pmid = {42572115},
issn = {1479-8301},
}

@article {pmid42572118,
year = {2026},
author = {Indumathi, J and Arulappan, A and Ramasamy, S},
title = {Comment on "Executive and General Cognitive Domain as a Relevant Factor of Specific Neuropsychiatric Symptoms in Alzheimer's Disease".},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {8},
pages = {e70763},
doi = {10.1111/ggi.70763},
pmid = {42572118},
issn = {1447-0594},
}

@article {pmid42572565,
year = {2026},
author = {Song, Z and Xie, Y and Zhu, H and Li, J and Yang, C and Guo, Y and Nong, X and Zhu, Z and Chen, Z and Wang, Z},
title = {Evaluating the cognitive efficacy of marine-derived drugs in Alzheimer's disease: A systematic review and Bayesian network meta-analysis.},
journal = {Therapeutic advances in neurological disorders},
volume = {19},
number = {},
pages = {17562864261476868},
pmid = {42572565},
issn = {1756-2856},
abstract = {BACKGROUND: In recent years, marine-derived drugs for Alzheimer's disease (AD) have attracted growing attention, but their comparative cognitive efficacy and safety remain uncertain because of inconsistent findings across studies.

OBJECTIVES: To compare the efficacy and safety of marine-derived interventions for Alzheimer's disease.

DESIGN: Systematic review and Bayesian network meta-analysis of randomized controlled trials conducted in accordance with PRISMA 2020.

DATA SOURCES AND METHODS: We systematically searched PubMed and the Cochrane Library for randomized controlled trials (RCT) of marine-derived drugs in patients with AD. Continuous outcomes were synthesized as mean differences (MD) in change-from-baseline, and dichotomous outcomes were synthesized as odds ratios (OR), each with 95% credible intervals (CI).

RESULTS: A total of 16 eligible RCTs involving 4,158 patients were included. For the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), GV-971 (vs placebo; MD -1.85, 95% CI -2.89 to -0.82) and tramiprosate (vs placebo; MD -0.83, 95% CI -1.63 to -0.02) significantly improved cognitive function. For the Mini-Mental State Examination (MMSE), rifampicin (vs placebo; MD 1.90, 95% CI 0.25 to 3.56) was associated with greater improvement in MMSE scores, whereas tramiprosate (vs placebo; MD -2.40, 95% CI -4.67 to -0.09) was associated with poorer cognitive performance. No statistically significant differences among drugs were observed for the Clinical Dementia Rating-Sum of Boxes (CDR-SB) or for the incidence of adverse events. Overall, treatment effects were outcome-dependent, with significant benefits observed mainly in ADAS-Cog and MMSE, whereas no intervention demonstrated consistent superiority across all cognitive outcomes.

CONCLUSION: Marine-derived drugs showed generally acceptable safety and potential cognitive benefits in selected outcomes. GV-971 and tramiprosate improved ADAS-Cog scores, while rifampicin therapy showed a possible MMSE benefit. However, no intervention was consistently superior across cognitive outcomes, and the antibiotic finding was based on a single small trial. Current evidence is therefore insufficient to identify the optimal marine-derived therapy for AD, highlighting the need for larger, adequately powered RCTs.},
}

@article {pmid42573021,
year = {2026},
author = {Alsfouk, AA and El-Shiekh, RA and Kariuki, BM and Sabry, E and Abouelenein, MG and Saleh, A and Saleh, MGA and Srour, AM},
title = {Design, Synthesis, X-Ray Crystallographic Characterization, Anticholinesterase and Antioxidant Evaluation, and Molecular Modeling of Novel Dispiroindene-Pyrrolidine Derivatives as Multifunctional Anti-Alzheimer Agents.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70361},
doi = {10.1002/ddr.70361},
pmid = {42573021},
issn = {1098-2299},
support = {PNURSP2026R116//Princess Nourah Bint Abdulrahman University/ ; NBU-FFR-2026-145-02//Northern Border University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Pyrrolidines/chemistry/pharmacology/chemical synthesis ; Drug Design ; Crystallography, X-Ray ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Alzheimer Disease/drug therapy ; Animals ; Models, Molecular ; Structure-Activity Relationship ; Humans ; Molecular Docking Simulation ; },
abstract = {A novel series of 5-chloro-N-alkyl-1',1″-dimethyl-4'-aryldispiro[indene-2,3'-pyrrolidine-2',3″-indoline]-1,2″(3H)-diones (4a-r) was rationally designed and synthesized via a one-pot multicomponent reaction of N-alkylated 5-chloroisatin derivatives, 2-(arylmethylidene)-2,3-dihydro-1H-inden-1-ones (2a-i), and sarcosine (3). To assess their potential therapeutic efficacy, the entire library of synthesized compounds was screened for its inhibitory profiles against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), where most derivatives exhibited moderate to potent cholinesterase inhibitory activity. Notably, derivatives 4b, 4f, and 4o emerged as the most effective dual inhibitors, displaying strong potent activity against AChE (IC50 = 0.91 ± 0.02, 0.89 ± 0.01, and 0.74 ± 0.01 µM, respectively; donepezil IC50 = 0.68 ± 0.005 µM) alongside significant BChE inhibition (IC50 = 10.19 ± 0.16, 9.59 ± 0.08, and 9.11 ± 0.01 µM, respectively; donepezil IC50 = 2.97 ± 0.01 µM). The structure of the most active derivatives (4b, 4f, and 4o) was further confirmed by X-ray crystallographic analysis. In addition, antioxidant evaluation of compounds 4b, 4f, and 4o demonstrated that derivative 4f possessed the most superior radical scavenging profile (IC50 = 23.18 ± 0.33 µM), representing approximately a 5.5-fold enhancement in potency relative to ascorbic acid (IC50 = 128.20 ± 0.82 µM). Molecular docking studies revealed favorable binding interactions of the lead derivatives within the catalytic binding pockets of both AChE and BChE, with docking scores comparable to those of the standard inhibitor. Furthermore, in silico ADME profiling demonstrated promising pharmacokinetic behavior, characterized by robust gastrointestinal absorption and excellent predicted blood-brain barrier penetration, supporting the potential of these derivatives as promising multifunctional candidates for the development of anti-Alzheimer agents.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
*Antioxidants/pharmacology/chemistry/chemical synthesis
*Pyrrolidines/chemistry/pharmacology/chemical synthesis
Drug Design
Crystallography, X-Ray
Acetylcholinesterase/metabolism/chemistry
Butyrylcholinesterase/metabolism/chemistry
*Alzheimer Disease/drug therapy
Animals
Models, Molecular
Structure-Activity Relationship
Humans
Molecular Docking Simulation

@article {pmid42573081,
year = {2026},
author = {Saffour, S and Gul, TS and Gul, HI},
title = {Rational drug design for Alzheimer's disease: from approved therapies to next-generation clinical candidates and AI-guided innovation.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/17568919.2026.2714022},
pmid = {42573081},
issn = {1756-8927},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.},
}

@article {pmid42573117,
year = {2026},
author = {Abul, MS and Parvizi, J and Skowronek, P and Erdogan, F and Tuncay, İ and Hirschmann, MT and Kayaalp, ME},
title = {Osteoarthritis management through medical reversal: Glucosamine, Alzheimer's disease risk, and long-term outcomes after arthroscopic partial meniscectomy.},
journal = {Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA},
volume = {},
number = {},
pages = {},
doi = {10.1002/ksa.70578},
pmid = {42573117},
issn = {1433-7347},
abstract = {The adoption of interventions in osteoarthritis and musculoskeletal care frequently precedes the availability of robust long-term evidence, creating the conditions for subsequent medical reversal. Recent findings raising concern about possible adverse neurocognitive associations with glucosamine use challenge the assumption that widely used supplements are necessarily biologically inert, although their causal significance and direct relevance to routine osteoarthritis management remain uncertain. In contrast, 10-year follow-up evidence after arthroscopic partial meniscectomy for degenerative meniscal tears provides a more established example of medical reversal, demonstrating no sustained clinical benefit over sham surgery and raising concern regarding structural harm. Evidence concerning repeated intra-articular corticosteroid injections similarly illustrates the limitations of relying on biological plausibility or short-term symptomatic outcomes. These examples, while differing in evidentiary maturity, support a common principle: orthopaedic interventions should be evaluated according to rigorous comparative evidence and durable patient-centred outcomes. Clinicians should communicate uncertainty, avoid treating structural abnormalities or mechanistic rationale as sufficient indications for intervention, and remain willing to revise established practices when stronger evidence emerges.},
}

@article {pmid42573418,
year = {2026},
author = {Norevik, CS and Huuha, AM and Kobro-Flatmoen, A and Lydersen, S and Røsbjørgen, RN and Bækkerud, FH and Scrimgeour, N and Tari, AR},
title = {Effects of Intravenously Administered Plasma from Exercise-Trained Donors on Mitochondrial Respiration in a Rat Model of Alzheimer's Disease.},
journal = {Medicine and science in sports and exercise},
volume = {58},
number = {9},
pages = {1901-1913},
doi = {10.1249/MSS.0000000000004018},
pmid = {42573418},
issn = {1530-0315},
mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; Male ; *Mitochondria/metabolism ; Disease Models, Animal ; *Physical Conditioning, Animal/physiology ; Oxidative Phosphorylation ; Rats ; Hippocampus/metabolism ; Rats, Transgenic ; *Plasma ; Proteomics ; Blood Donation ; Cell Respiration ; },
abstract = {PURPOSE: Dysfunction of mitochondria is observed early in Alzheimer's disease (AD), possibly driving the pathogenesis of the disease. This study aims to assess whether plasma from exercise-trained donors can enhance mitochondrial function in a transgenic AD model and to gain insight into the proteomic profile of the donor plasma.

METHODS: Male McGill-R-Thy1-APP rats (n = 3 per treatment group) were treated at either an early preplaque stage (2.2 months) or a later stage (5.2 months) with plasma from exercise-trained donors (ExPlas), sedentary donors (SedPlas), or saline. The rats received 14 transfusions over 6 wk. Mitochondrial respiration was assessed in cornu ammonis (CA), dentate gyrus (DG), gastrocnemius, and left ventricle using high-resolution respirometry. Proteomic analyses were performed in donor blood using mass spectrometry.

RESULTS: In early-stage AD rats, ExPlas improved hippocampal mitochondrial respiration. Compared with saline, CA oxidative phosphorylation (OXPHOS) capacity for complex I increased by +30.8 pmol O2·s-1·mg-1 (P < 0.001) and CI+II by +37.8 pmol O2·s-1·mg-1 (P < 0.001). Compared with SedPlas, CA OXPHOS for CI increased by +16.9 pmol O2·s-1·mg-1 (P = 0.01) and CI+II by +23.8 pmol O2·s-1·mg-1 (P = 0.007). In DG, similar improvements were only seen compared with saline. In CA, but not DG, of later-stage rats, ExPlas produced smaller but significant increases in CI and CI+II OXPHOS compared with saline, but no significant differences compared with SedPlas. No changes were observed in muscle or heart. Proteomics revealed enrichment of complement and platelet-related pathways in ExPlas.

CONCLUSIONS: This proof-of-concept study shows that exercise-trained donor plasma enhances hippocampal mitochondrial respiration in early-stage AD rats and, to a lesser extent, in later-stage AD rats. The proteomic profile of the exercise-trained donor plasma indicates a role of altered complement and platelet functions.},
}

Animals
*Alzheimer Disease/therapy/metabolism
Male
*Mitochondria/metabolism
Disease Models, Animal
*Physical Conditioning, Animal/physiology
Oxidative Phosphorylation
Rats
Hippocampus/metabolism
Rats, Transgenic
*Plasma
Proteomics
Blood Donation
Cell Respiration

@article {pmid42573479,
year = {2026},
author = {Kang, S and Goodridge, HS},
title = {Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging-Associated Neurodegenerative Diseases.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70660},
doi = {10.1111/acel.70660},
pmid = {42573479},
issn = {1474-9726},
support = {ABA-25-1372697/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Microglia/metabolism ; *Aging/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Animals ; Metabolic Reprogramming ; },
abstract = {Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases-all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.},
}

Humans
*Microglia/metabolism
*Aging/metabolism
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
Animals
Metabolic Reprogramming

@article {pmid42573507,
year = {2026},
author = {Zhu, X and Wang, L and Tang, R and Huang, ZA and Huang, YA and Tan, F and Hu, L and You, Z and Hu, P},
title = {Spatial-Spectral Fusion Enables Drug Repositioning by Capturing Indirect and Long-Range Associations in Biological Networks.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag553},
pmid = {42573507},
issn = {1367-4811},
abstract = {MOTIVATION: Drug repositioning accelerates clinical translation by identifying new therapeutic indications for approved drugs. However, therapeutic associations in biomolecular networks often exist indirectly, through transitive chains and long-range mechanisms, rather than as directly observed links. Shallow methods are confined to direct similarity and miss such indirect associations, whereas deep graph neural networks suffer from over-smoothing and lose discriminative power in highly connected networks.

RESULTS: We propose a spatial-spectral collaborative framework. In the spatial domain, a wave-evolution process propagates similarity from local to global, capturing multi-hop transitive associations while preserving discriminative representations. In the spectral domain, network-specific spectral transforms model global connectivity for long-range dependencies over homogeneous similarity and heterogeneous drug-protein-disease networks, with the two views aligned by contrastive learning. On three benchmarks the method outperforms state-of-the-art baselines on most evaluation metrics; case studies on Alzheimer's and Parkinson's disease and molecular docking confirm its ability to recover non-explicit therapeutic associations.

AVAILABILITY: The source code and data are available at https://github.com/Juniper-cola/BIO_SSF.

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

@article {pmid42573665,
year = {2026},
author = {Mukim, RD and Xu, Y and Evola, V and Parmar, MS},
title = {Semaglutide as a potential neuroprotective agent for neurological and neurodegenerative disorders: Mechanisms, preclinical evidence, and translational challenges and opportunities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42573665},
issn = {1573-4978},
mesh = {Semaglutide ; Humans ; *Glucagon-Like Peptides/pharmacology/therapeutic use/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Biomarkers/metabolism ; Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established treatments for metabolic disease, with growing evidence suggesting neuroprotective potential in central nervous system (CNS) disorders. In preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, semaglutide has been reported to reduce neuroinflammatory and oxidative stress markers and improve selected pathological or behavioral outcomes, although the specific effects vary by model and indication. However, significant translational challenges remain. The Phase 3 EVOKE and EVOKE+ trials in early symptomatic AD failed to meet primary cognitive endpoints, although biological target engagement was reported, with improvements in selected AD-related biomarkers including p-tau181, p-tau217, neurogranin, YKL-40, and plasma hsCRP. This dissociation between biomarker changes and clinical benefit may reflect treatment timing, advanced neurodegeneration, limited CNS exposure, endpoint sensitivity, or other factors. In contrast, observational studies suggest an association between semaglutide or GLP-1 RA exposure and lower dementia-related risk in at-risk populations, although preservation of cognitive reserve has not been directly demonstrated and causality has not been established. This review evaluates the current mechanistic, preclinical, and emerging clinical evidence for semaglutide across neurodegenerative and neuroinflammatory disorders, with emphasis on distinguishing semaglutide-specific findings from broader GLP-1 RA class effects and identifying key translational limitations. Collectively, current evidence supports continued investigation of semaglutide as a potential neuroprotective strategy, while highlighting the need for earlier intervention studies, improved understanding of CNS target engagement, and further clinical validation.},
}

Semaglutide
Humans
*Glucagon-Like Peptides/pharmacology/therapeutic use/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
Biomarkers/metabolism
Oxidative Stress/drug effects
*Nervous System Diseases/drug therapy/metabolism

@article {pmid42573807,
year = {2026},
author = {Maman, D and Steinfield, Y and Berkovich, Y},
title = {Factors associated with selection of total hip arthroplasty versus hemiarthroplasty for femoral neck fracture in older adults: a nationwide analysis of 99,084 cases.},
journal = {Archives of orthopaedic and trauma surgery},
volume = {146},
number = {1},
pages = {},
pmid = {42573807},
issn = {1434-3916},
mesh = {Humans ; *Femoral Neck Fractures/surgery ; *Hemiarthroplasty/statistics & numerical data ; *Arthroplasty, Replacement, Hip/statistics & numerical data ; Aged ; Male ; Female ; Retrospective Studies ; Aged, 80 and over ; United States ; *Patient Selection ; Comorbidity ; Proximal Femoral Fractures ; },
abstract = {BACKGROUND: Surgical management of displaced femoral neck fractures in older adults typically involves hemiarthroplasty or total hip arthroplasty (THA). Although clinical guidelines suggest that THA may be considered in selected healthier and cognitively intact patients, real-world procedure selection varies widely. This study evaluated patient factors associated with selection of THA versus hemiarthroplasty in a contemporary U.S.

METHODS: A retrospective cohort study was conducted using the 2022 Nationwide Readmissions Database (NRD). Patients ≥ 65 years hospitalized with femoral neck fracture were identified using ICD-10-CM codes. Those treated with internal fixation or non-arthroplasty procedures were excluded. Weighted analyses characterized demographics, comorbidities, and hospital utilization between THA and hemiarthroplasty groups. A multivariable logistic regression model identified factors independently associated with receiving THA. All analyses accounted for NRD survey design.

RESULTS: Among 142,013 operative cases, 99,084 met inclusion criteria (81.8% hemiarthroplasty; 18.2% THA). Patients receiving THA were younger (76.6 vs. 81.9 years), had shorter length of stay (6.06 vs. 7.24 days), and were more frequently discharged home (17.5% vs. 6.2%). Metabolic conditions were associated with increased odds of THA, including obesity (OR 1.17) and sleep apnea (OR 1.12). Frailty-related conditions were associated with markedly reduced THA likelihood, including Alzheimer's disease (OR 0.48), Parkinson disease (OR 0.55), chronic kidney disease (OR 0.78), chronic lung disease (OR 0.72), and congestive heart failure (OR 0.77). Each additional year of age decreased the odds of THA by approximately 9%.

CONCLUSION: In this nationwide cohort, selection of THA rather than hemiarthroplasty was associated with younger age and lower prevalence of frailty- and cognition-related comorbidities, while several metabolic comorbidities showed modest positive associations with THA use. These findings describe contemporary national selection patterns but do not establish treatment appropriateness, clinical benefit, or guideline concordance, as key factors such as pre-fracture mobility, functional independence, and living situation were not available in the dataset.

LEVEL OF EVIDENCE: Level III.},
}

Humans
*Femoral Neck Fractures/surgery
*Hemiarthroplasty/statistics & numerical data
*Arthroplasty, Replacement, Hip/statistics & numerical data
Aged
Male
Female
Retrospective Studies
Aged, 80 and over
United States
*Patient Selection
Comorbidity
Proximal Femoral Fractures

@article {pmid42573852,
year = {2026},
author = {Nguyen, HM and Nguyen, LDT},
title = {Towards Structural Restoration: Epigenetic Reprogramming and Direct Astrocyte-to-Neuron Lineage Conversion as Next-Generation Regenerative Neurotherapeutics.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42573852},
issn = {1559-1182},
mesh = {Humans ; *Astrocytes/metabolism/cytology ; Animals ; *Neurons/metabolism/cytology ; *Epigenesis, Genetic ; *Cellular Reprogramming/genetics ; *Cell Lineage ; *Nerve Regeneration ; },
abstract = {While the recent clinical approval of amyloid-targeting monoclonal antibodies represents a landmark in Alzheimer's disease (AD) management, these immunotherapies fundamentally function as agents of mitigation rather than restoration, failing to reconstitute decimated neural circuitry. Direct in situ astrocyte-to-neuron reprogramming offers a compelling regenerative alternative by leveraging the abundant endogenous glial reservoir. However, translating this cellular plasticity in vivo is severely bottlenecked by the hostile pathological microenvironment and the deeply entrenched epigenetic memory of reactive astrocytes. In this review, we delineate a tripartite neuroregenerative framework. First, we evaluate the prerequisite use of senotherapeutics to engineer a permissive parenchymal niche for nascent neuronal survival. Second, we explore epigenomic editing strategies-including CRISPR-dCas9 platforms and targeted pharmacological modulators-required to dismantle repressive heterochromatin and unlock sequestered neurogenic loci. Third, we dissect the molecular execution of reprogramming via pioneer transcription factors (TFs), emphasizing the obligatory metabolic rewiring from astrocytic glycolysis to neuronal oxidative phosphorylation (OXPHOS). Finally, to overcome formidable translational hurdles, we highlight the convergence of AI-optimized lipid nanoparticles (LNPs) for non-viral blood-brain barrier (BBB) transcytosis alongside Neurological Digital Twins (NDTs) to computationally predict the optimal presymptomatic intervention window. By harmonizing microenvironmental conditioning, epigenetic rejuvenation, and precision delivery, this systems-level blueprint provides a promising rationale for transitioning AD therapeutics from passive deceleration to active structural restoration.},
}

Humans
*Astrocytes/metabolism/cytology
Animals
*Neurons/metabolism/cytology
*Epigenesis, Genetic
*Cellular Reprogramming/genetics
*Cell Lineage
*Nerve Regeneration

@article {pmid42573994,
year = {2026},
author = {Di Molfetta, G and Brum, WS and Pola, I and Tan, K and Benedet, AL and Sauer, M and Montoliu-Gaya, L and Janelidze, S and Mattsson-Carlgren, N and Rahmouni, N and Chan, T and Denkinger, MN and Proitsi, P and Zetterberg, H and Hansson, O and Rosa-Neto, P and Ashton, NJ},
title = {Plasma Biomarkers for Neocortical Tau Burden.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.2650},
pmid = {42573994},
issn = {2168-6157},
abstract = {IMPORTANCE: Phosphorylated tau-217 (p-tau217) is now an established plasma biomarker for assessing amyloid-β pathology in individuals at risk of Alzheimer disease. However, its performance in identifying advanced neocortical neurofibrillary tangle burden remains suboptimal. Precise assessment of tau pathology is increasingly critical for the rational implementation of anti-amyloid therapies and developing anti-tau interventions. Improved biofluid biomarker-based tau staging could enhance patient stratification and optimize participant selection for clinical care and therapeutic trials.

OBJECTIVE: To develop and validate a multiprotein plasma panel to improve identification of neocortical tau pathology beyond p-tau217 alone.

This multicenter cohort study included 2 independent observational cohorts, Swedish BioFINDER study and Translational Biomarkers in Aging and Dementia (TRIAD). Cross-sectional clinical data and blood samples were collected between 2017 and 2024. Participants included 560 individuals spanning the clinical spectrum from cognitively unimpaired to dementia. These data were analyzed from January 2025 to May 2026.

EXPOSURES: Plasma concentrations of 125 proteins measured using Nucleic Linked Immuno-Sandwich Assay central nervous system panel.

MAIN OUTCOME AND MEASURE: Advanced tau pathology defined as tau positron emission tomography (PET) uptake within Braak stage V and VI regions. Predictive performance of biomarker models was evaluated using area under the receiver operating characteristic curve (AUC).

RESULTS: The study included 560 amyloid-positive participants (BioFINDER: n = 431; mean [SD] age, 73.6 [7.0] years; 212 female [49.2%] and 219 male [51.8%]; TRIAD: n = 129; mean [SD] age, 70.4 [8.3] years; 76 female [58.9%] and 53 male [41.1%]). Using multivariable logistic regression approaches, a 7-protein panel was found in BioFINDER to identify tau PET uptake within Braak stage V and VI regions. When compared with p-tau217 (AUC, 0.86-0.88; 95% CI, 0.82-0.94), this multiprotein panel was associated with improved identification in both discovery and validation cohorts (AUC, 0.92-0.94; 95% CI, 0.89-0.98; DeLong P < .001). This reduced the proportion of individuals classified within the intermediate-risk range (between paired sensitivity and specificity thresholds) in the validation cohort by 14.7% to 21.0%.

CONCLUSIONS AND RELEVANCE: This multicohort study demonstrated how including additional plasma proteins significantly enhanced the performance of p-tau217 in predicting advanced tau pathology among amyloid-positive individuals. This suggests a multiprotein approach may offer a viable and scalable alternative to tau PET staging in clinical or research settings.},
}

@article {pmid42574041,
year = {2026},
author = {Sarathkumar, E and Sasi, R and Menon, RN and Jayasree, RS},
title = {Electrochemical profiling of plasma pTau-181 levels associated with mild cognitive impairment and Alzheimer's disease using an MXene-gold nanorod interface.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00880a},
pmid = {42574041},
issn = {2050-7518},
abstract = {Early diagnosis of Alzheimer's disease (AD) remains a major clinical challenge, particularly during the mild cognitive impairment (MCI) stage, where subtle cognitive changes overlap with normal ageing and reliable diagnostic indicators are limited. Plasma phosphorylated tau at threonine-181 (pTau-181) has emerged as a disease-specific biomarker associated with tau pathology and early neurodegenerative progression, with increasing evidence supporting its relevance for identifying individuals at risk of AD during the prodromal phase. However, accurate quantification of plasma pTau-181 is hindered by its extremely low concentration and the complex biochemical environment of blood. In this study, a label-free electrochemical impedance biosensor was developed for sensitive detection of plasma pTau-181 using a self-assembled two-dimensional MXene-gold nanorod (MXene-GNR) hybrid interface. Modification of a glassy carbon electrode with the MXene-GNR nanocomposite enhanced interfacial charge-transfer behaviour and increased the electroactive surface area by approximately 37%, enabling improved anti-pTau-181 immobilization and signal transduction. The biosensor exhibited a concentration-dependent impedance response toward pTau-181 over a wide dynamic range and achieved an ultrasensitive limit of detection of 12.561 fg mL[-1] in 10% plasma spiked samples while maintaining high analytical selectivity. Clinical plasma analysis demonstrated statistically significant differentiation of AD and MCI groups from healthy controls (p < 0.001), supporting the relevance of plasma pTau-181 measurement for assessing disease-associated cognitive impairment. These findings demonstrate the potential of the MXene-GNR electrochemical platform as a minimally invasive approach for plasma biomarker evaluation toward early AD diagnosis and monitoring.},
}

@article {pmid42574303,
year = {2026},
author = {Mena, D and Vincze, A and Shultz, A and Rauch, JN},
title = {A Split-Luciferase Complementation Assay for Temporally Resolved Measurement of Tau Clearance in Microglia.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {233},
pages = {},
doi = {10.3791/71870},
pmid = {42574303},
issn = {1940-087X},
mesh = {*tau Proteins/metabolism/analysis ; *Microglia/metabolism/cytology/chemistry ; Humans ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Luciferases/chemistry/metabolism/genetics ; *Luminescent Measurements/methods ; },
abstract = {As the resident immune cells of the central nervous system, microglia are central regulators of brain homeostasis and key mediators of neurodegenerative disease. These cells continuously survey the neural environment and play a critical role in the recognition, internalization, and degradation of extracellular substrates, including misfolded and aggregated proteins such as pathological tau. Despite growing evidence implicating microglia in tau clearance, existing approaches to measure tau uptake and degradation lack the temporal resolution and sensitivity needed to fully capture these dynamic processes. Here, we developed a luminescence-based assay to quantitatively monitor tau clearance in human induced pluripotent stem cell (iPSC)-derived microglia. This platform leverages a split-luciferase-based complementation system to enable highly sensitive, real-time detection of tau in live cells, allowing for precise tracking of its intracellular processing. This assay is scalable and adaptable across multiple cell types, providing a versatile tool to interrogate endolysosomal pathways and cellular mechanisms governing tau handling in neurodegenerative diseases, including Alzheimer's disease.},
}

*tau Proteins/metabolism/analysis
*Microglia/metabolism/cytology/chemistry
Humans
Induced Pluripotent Stem Cells/metabolism/cytology
*Luciferases/chemistry/metabolism/genetics
*Luminescent Measurements/methods

@article {pmid42574385,
year = {2026},
author = {Flores, R and Musenda, K and Barbosa, DB and Cheng, KH and Sikazwe, D},
title = {Bis-hydrophobic 5-(1,2-dithiolan-3-yl)pentanamide budding leads targeting brain sigma-1 receptors.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0352906},
doi = {10.1371/journal.pone.0352906},
pmid = {42574385},
issn = {1932-6203},
mesh = {*Receptors, sigma/metabolism/antagonists & inhibitors/chemistry ; Sigma-1 Receptor ; Hydrophobic and Hydrophilic Interactions ; *Amides/chemistry/pharmacology/chemical synthesis ; *Brain/metabolism/drug effects ; Animals ; Ligands ; Humans ; Thioctic Acid/chemistry ; Molecular Docking Simulation ; Pharmacophore ; Protein Binding ; },
abstract = {Multi-mechanistic sigma-1 (σ1) receptors are implicated in several neurodegenerative pathologies including Alzheimer's disease (AD). As part of an ongoing effort to create a collection of diverse, readily synthesizable, σ1 acting small molecules for anti-neurodegenerative applications, we opted to try lipoic acid (LA) derived amides. These amides are designated as "5-(1,2 dithiolan-3-yl)pentanamides" throughout this publication. Our design approach was σ1 pharmacophore based - that is, ligands possessing three key functionalities (a hydrophobic dithiolane group, a flexible amide H-bonding linker, a hydrophobic alkyl/aryl group). Twenty-one dithiolane pentanamides were therefore designed, docked, synthesized, and pharmacologically assessed for σ1/σ2 binding affinities. Compounds 2, 6, 17 possessed promising selective σ1 binding affinities (with respective Ki values of 256, 133 and 32 nM) versus the standard ligand PD144418 (Ki = 0.08 nM). The three compounds will be used as leads in follow-up structure activity optimizations.},
}

*Receptors, sigma/metabolism/antagonists & inhibitors/chemistry
Sigma-1 Receptor
Hydrophobic and Hydrophilic Interactions
*Amides/chemistry/pharmacology/chemical synthesis
*Brain/metabolism/drug effects
Animals
Ligands
Humans
Thioctic Acid/chemistry
Molecular Docking Simulation
Pharmacophore
Protein Binding

@article {pmid42574716,
year = {2026},
author = {Watry, RA and Hadidi, NN and Kreitzer, MJ and Bhimani, R and Yu, F and Salisbury, DL},
title = {Exercise Impact on Affective/Cognitive Symptoms and QoL in Subjective Cognitive Decline: An RCT.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261476974},
doi = {10.1177/15333175261476974},
pmid = {42574716},
issn = {1938-2731},
mesh = {Humans ; Female ; Aged ; *Quality of Life/psychology ; *Cognitive Dysfunction/therapy/psychology ; *Anxiety/therapy/psychology ; Male ; *Depression/therapy/psychology ; *Exercise Therapy/methods ; Aged, 80 and over ; *Exercise/psychology ; COVID-19 ; },
abstract = {IntroductionThe purpose of this secondary data analysis of an RCT, was to examine the preliminary efficacy of moderate-intensity cycling exercise versus control on cognitive and affective symptoms (i.e., depressive and anxiety), and quality of life (QoL) in older adults with subjective cognitive decline (SCD).MethodsCommunity-dwelling older adults with SCD (N=38) were randomized to 12 weeks/36 sessions. For this secondary data analysis, between-group change was evaluated by analysis of covariance, adjusting for baseline values.ResultsThe participants' mean age was 74.6(7.4) years, and 69% female. There were no significant between-group changes in all outcomes (p-values ranged from .06-.70. Large and moderate between-group effect sizes were seen in favor of the control group for anxiety symptoms (between-group change=-5.36 [4.74], ηp[2]=0.11.DiscussionAttention and social interaction received by this secluded population of older adults and COVID-19 losses likely impacted results. Further mixed-methods research with larger groups that does not span a pandemic, is necessary.Clinical Trial RegistryConcurrent Aerobic Exercise and Cognitive Training to Prevent Alzheimer's in At-risk Older Adults (Exergames): NCT04311736.},
}

Humans
Female
Aged
*Quality of Life/psychology
*Cognitive Dysfunction/therapy/psychology
*Anxiety/therapy/psychology
Male
*Depression/therapy/psychology
*Exercise Therapy/methods
Aged, 80 and over
*Exercise/psychology
COVID-19

@article {pmid42574828,
year = {2026},
author = {Lin, X and Wei, Z and Dong, X and Sun, Y},
title = {A sequential photodynamic-antioxidation therapy against Alzheimer's β-amyloid enabled by a dual‑carbon dots nanomotor.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 3},
pages = {141317},
doi = {10.1016/j.jcis.2026.141317},
pmid = {42574828},
issn = {1095-7103},
abstract = {Abnormal accumulation of β-amyloid protein (Aβ) in the brain is considered as the primary hallmark of Alzheimer's disease (AD). Beyond inducing neuronal metabolic disorders and apoptosis, Aβ activates oxidative stress pathways, thereby exacerbating reactive oxygen species (ROS) toxicity. Therefore, the design of effective multi-target synergistic therapeutics targeting Aβ and excessive ROS has emerged as a critical strategy for AD prevention and treatment. Herein, we propose a "Sequential Photodynamic-Antioxidation Therapy (SPAT)" against Alzheimer's Aβ, and the SPAT strategy is enabled by the design of a sub-10nm dual‑carbon dots Janus composite (SeRCD) composed of a newly designed and synthesized selenium-doped high-efficiency antioxidant carbon dot (SeCD) and a previously reported near-infrared (NIR) carbon dot (RCD) possessing both thermogenic and photodynamic functionalities. The thermogenic property of RCD in SeRCD endows the Janus composite with photo-propelled autonomous motion powered by "self-thermophoretic force" under NIR irradiation. Thus, SeRCD shows potent inhibition of Aβ fibrillization at low concentrations (0.5 to 5 μg/mL) via photooxygenation and the nanomotor effect under NIR irradiation for only 10 min. Under the subsequent NIR-off condition, SeCD in SeRCD effectively mitigates the oxidative damage to cells by scavenging ROS. Thus, the lifespan of AD nematodes is prolonged by the SPAT strategy from 12 to 19 d at 2 μg/mL. The results collectively demonstrate the effectiveness of the dual-CDs composite design and great potential of the SPAT strategy for application in fighting against AD.},
}

@article {pmid42570085,
year = {2026},
author = {Bu, Y and Fan, Z and Li, L},
title = {Bacterial outer membrane vesicles in oral diseases: from pathogenic mediators to theranostic platforms.},
journal = {Critical reviews in microbiology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1040841X.2026.2713518},
pmid = {42570085},
issn = {1549-7828},
abstract = {Bacterial outer membrane vesicles (bOMVs) are nanoscale structures derived from Gram-negative (G[-]) bacteria that play an important role in oral diseases. As key mediators of host-microbe interactions, bOMVs contribute to the pathogenesis of periodontitis, oral squamous cell carcinoma (OSCC), and oral lichen planus (OLP) by disrupting immune homeostasis and promoting tissue destruction. Beyond the oral cavity, bOMVs serve as critical vectors in the oral-systemic axis, disseminating virulence factors to distant organs and contributing to atherosclerotic cardiovascular diseases (ACVDs), Alzheimer's disease (AD), and gastrointestinal (GI) disorders. Concurrently, their inherent properties, including cargo-loading capacity, immunogenicity, and biofilm penetration, position them as promising platforms for noninvasive diagnostics and targeted therapeutics. This review systematically integrates current knowledge on bOMVs biogenesis, pathogenic mechanisms in oral and systemic diseases, and emerging applications in diagnosis and treatment. We also highlight key challenges and future directions for translating bOMVs-based strategies into clinical practice, emphasizing their potential as next-generation theranostic tools (combining therapeutic and diagnostic functions) for oral diseases.},
}

@article {pmid42570239,
year = {2026},
author = {Cruz-Sese, J and Mirón-Alcala, M and Alfonso-Triguero, M and Olalde, J and Ruiz, L and Galbis-Gramage, N and Cortes, L and Escobar, L and Preman, P and Snellinx, A and Saito, T and Saido, TC and Saiz-Aúz, L and Rábano-Gutiérrez, A and Aransay, AM and Diez, I and Tcw, J and Goate, A and De Strooper, B and Alberdi, E and Arranz, AM},
title = {APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117803},
doi = {10.1016/j.celrep.2026.117803},
pmid = {42570239},
issn = {2211-1247},
abstract = {Astrocytes and APOE are strongly implicated in Alzheimer's disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like astrocytes. APOE3 and APOE4 astrocytes differ in expression of APOE, which associates differentially with Aβ plaques. Notably, APOE3 astrocytes are associated with reduced Aβ burden, Tau pathology, and neuritic dystrophy, whereas APOE4 astrocytes exacerbate these processes. They also induce distinct microglial responses: APOE4 astrocytes enhance microglial clustering around Aβ plaques and promote a disease-associated microglia-like state, whereas APOE3 astrocytes reduce clustering and support a more homeostatic profile. These findings highlight a role for human astrocytes and APOE-dependent astrocyte functions in modulating AD-related pathology.},
}

@article {pmid42570244,
year = {2026},
author = {Sun, GG and Wang, C and Mazzarino, RC and Perez-Corredor, PA and Davtyan, H and Blurton-Jones, M and Lopera, F and Arboleda-Velasquez, JF and Shi, Y},
title = {Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117853},
doi = {10.1016/j.celrep.2026.117853},
pmid = {42570244},
issn = {2211-1247},
}

@article {pmid42570275,
year = {2026},
author = {Van Houwelingen, AS and Vernooij, MW and Vermeiren, MR and Ossenkoppele, R and Van De Giessen, E and Seelaar, H and Neitzel, J},
title = {Concordance between plasma biomarkers of phosphorylated tau and tau-PET: A narrative review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468708},
doi = {10.1177/13872877261468708},
pmid = {42570275},
issn = {1875-8908},
abstract = {Plasma phosphorylated tau (p-tau) and tau positron emission tomography (PET) are key biomarkers for detecting tau pathology in Alzheimer's disease (AD), offering both diagnostic and prognostic value. However, the concordance between plasma p-tau (p-tau217/p-tau181/p-tau231) positivity and tau-PET positivity remains incompletely understood. In this narrative review, we show that concordance varies by clinical disease stage, the plasma p-tau biomarker assessed, the definition of tau-PET positivity, and the presence of comorbidities and other risk factors. We also present evidence for a temporal sequence of plasma p-tau changes, with plasma p-tau231 positivity preceding p-tau181 positivity, followed by plasma p-tau217 reflecting more advanced stages of tau pathology. We highlight the relevance of these temporal dynamics for the potential development of a stage-specific trajectory framework for plasma p-tau and discuss how such a framework may support improved integration of plasma p-tau and tau-PET, thereby enhancing screening efficiency. Finally, we outline methodological challenges, highlight current efforts such as the development of tau-PET harmonization strategies, and identify priorities for future research. Taken together, this review provides a comprehensive overview of the factors influencing concordance between plasma p-tau positivity and tau-PET positivity. Careful consideration of these factors will be essential for the optimal integration of these biomarkers across the AD spectrum, with the potential to improve both diagnostic and therapeutic strategies.},
}

@article {pmid42570276,
year = {2026},
author = {Kurniadi, NE and Steele, JS and Mattek, N and Guevara, JE and Duff, K},
title = {Predicting progression from mild cognitive impairment to dementia with baseline neuropsychological test scores.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469182},
doi = {10.1177/13872877261469182},
pmid = {42570276},
issn = {1875-8908},
abstract = {BackgroundAlthough neuropsychological scores have predicted progression from mild cognitive impairment (MCI) to dementia, past work has limitations, including small samples, limited batteries, and research cohorts.ObjectiveThis study sought to identify which baseline cognitive scores predicted progression in clinical patients with MCI followed over 1.5 years.Methods243 individuals clinically diagnosed with MCI at a baseline visit completed neuropsychological testing at baseline and were followed approximately 1.5 years later. Using follow-up diagnoses from neurologists, they were grouped as "MCI-Stable" (i.e., MCI at baseline and follow-up, n = 131) or "MCI-Progressors" (i.e., MCI at baseline but dementia at follow-up, n = 112). Stepwise logistic regression examined follow-up group status predicted from demographics, baseline cognitive scores, and self-reported depressive symptoms.ResultsNeither baseline demographic variables nor depressive symptoms significantly predicted group status at follow-up. Conversely, worse baseline performance on tests of visuospatial construction and semantic fluency were significant predictors of progression from MCI to dementia. Longer follow-up interval also significantly predicted conversion.ConclusionsAlthough many individuals progress from MCI to dementia, there is considerable variability in the timing and cognitive performance among those who convert to dementia versus those who remain stable over time. The current findings identified multiple baseline neuropsychological test scores that predicted that progression over approximately 1.5 years. Such results have implications for clinical care (e.g., providing more services and closer monitoring of at-risk individuals) and research (e.g., enriching clinical trials with those more likely to progress).},
}

@article {pmid42570281,
year = {2026},
author = {Amemiya, S and Takao, H and Matsumoto, S and Umeda-Kameyama, Y and Niimi, Y and Kakumoto, T and Satake, W and Mitsui, J and Ogawa, S and Abe, O},
title = {Subthreshold early white-matter hyperintensity increase predicts accelerated hippocampal and whole-brain atrophy in anti-amyloid-β immunotherapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261475336},
doi = {10.1177/13872877261475336},
pmid = {42570281},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid-β (anti-Aβ) therapy slows cognitive decline but paradoxically accelerates whole-brain gray matter atrophy, complicating outcome prediction.ObjectiveTo identify early imaging markers that predict long-term prognoses.MethodsThis longitudinal cohort study prospectively enrolled participants with early Alzheimer's disease, initiating anti-Aβ therapy. We performed automated T1-weighted MRI volumetric analysis of the whole-brain gray matter, hippocampus, and white matter hyperintensities (WMH). Temporal dynamics were characterized using piecewise linear regression, and predictive utility was assessed using multivariate linear regression analyses.ResultsTwenty-two participants (74 ± 11 years; 14 women) were followed for 376 ± 146 days. Significant volume changes occurred in all regions (p < 0.01). No overt amyloid-related edema was detected, and hemorrhagic events were mild to moderate. Piecewise regression revealed an initial WMH surge that decelerated after 60 days (β=-0.19 [95%CI: -0.33, -0.042], p = 0.01), whereas gray matter regions showed linear volume decline. Early subthreshold WMH expansion predicted long-term atrophy independent of baseline covariates (age, sex, amyloid burden, mini-mental state examination score, drug, and hemorrhagic events) in the hippocampus (β=-0.058 [95%CI: -0.092, -0.025], p = 0.003), and whole-brain gray matter (β=-0.033 [95%CI: -0.065, -0.002], p = 0.04). Early whole-brain gray matter atrophy correlated with the WMH surge (β=-0.53 [95%CI: -0.69, -0.38], p < 0.001) and predicted long-term hippocampal atrophy (β=0.098 [95%CI: 0.038, 0.16], p = 0.004).ConclusionsA transient WMH surge within the first 60 days of therapy mirrors the known time course of amyloid-related imaging abnormalities. Along with concurrent early whole-brain volume loss, this surge independently predicts accelerated long-term hippocampal and whole-brain atrophy, highlighting its potential as an early prognostic imaging marker.},
}

@article {pmid42570282,
year = {2026},
author = {Fatima, SUK and Jabber, A and Khanam, MH and Khan, J and Talukder, MM and Hasnat, MA},
title = {Integrative machine learning reveals telomere-associated gene modules reflecting neuronal dysregulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476085},
doi = {10.1177/13872877261476085},
pmid = {42570282},
issn = {1875-8908},
abstract = {BackgroundTelomere dysfunction contributes to cellular aging and genome instability, but telomere-associated transcription in Alzheimer's disease (AD) is poorly characterized. Telomere genes are commonly tested gene by gene, leaving it uncertain whether they organize into reproducible, disease-linked co-expression programs across cohorts.ObjectiveTo identify AD linked telomere gene modules and evaluate their diagnostic and biological relevance.MethodsWe curated 157 telomere maintenance genes and analyzed two GPL570-platform GEO Series datasets: GSE5281 (n = 161; AD = 87, control = 74) and GSE48350 (n = 253; AD = 80, control = 173). In GSE5281 hippocampus, RMA + age-adjusted limma identified 38 AD-associated telomere genes (FDR<0.05). Ward clustering (silhouette) defined two modules, summarized as eigengenes (module PC1). Eigengenes were evaluated across seven classifiers with nested stratified 5 × 5 cross-validation; Youden's J thresholds from out-of-fold predictions were fixed and applied to GSE48350 using frozen z-scoring (GSE5281 μ/σ) and fixed cutoffs. Robustness used 500-bootstrap stability; hub genes from the dominant module were interpreted with BRETIGEA and Reactome/GO enrichment.ResultsPCA and t-SNE showed AD-associated structure in telomere-gene expression. With only two module features, models achieved ROC-AUC 0.722-0.780 internally and 0.689-0.695 externally. Bootstrap resampling converged on one dominant axis: Cluster 2 was consistently the strongest feature and was reduced in AD (Cohen's d = -1.07; Welch p = 8.13 × 10[-10]). Hub genes (TSPYL5, TUBB3, PLCL2, NHP2) were downregulated, tracked neuronal signatures positively, varied inversely with microglial/astrocytic signatures, and mapped to telomere/chromosome maintenance, DNA repair, and cell-cycle regulation.ConclusionsAD features a reproducible, resampling-stable telomere genome-maintenance module that provides an interpretable systems-level disease axis for mechanistic follow-up and integrative biomarker development.},
}

@article {pmid42570289,
year = {2026},
author = {Tian, Y and Qing, H and Quan, Z},
title = {A working feedback-based framework for goal-directed spatial memory deficits in Alzheimer's disease: Feedforward and feedback interactions along the RSC-MEC-CA1-RSC axis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261473933},
doi = {10.1177/13872877261473933},
pmid = {42570289},
issn = {1875-8908},
abstract = {Spatial navigation deficits are among the earliest and most clinically significant cognitive impairments in Alzheimer's disease (AD), particularly when navigation depends on goal-directed spatial memory. This review defines goal-directed spatial memory as a task-oriented construct and proposes a network-level framework for interpreting early AD navigation deficits. We synthesize anatomical, physiological, behavioral, and disease-related evidence concerning the retrosplenial cortex (RSC), medial entorhinal cortex (MEC), hippocampal CA1, and CA1-RSC feedback interactions. We propose the RSC-MEC-CA1-RSC axis as a testable working framework based on coordinated feedforward and feedback interactions. Within this system, the RSC integrates behaviorally relevant external cues and supports reference-frame transformation. The MEC contributes to path integration and self-goal relational coding, and CA1 consolidates these signals into functional goal-location representations. These representations can be retrieved, stabilized, and then transmitted back to cortical networks to guide continuous behavioral updating. Notably, we define the CA1-RSC pathway as a functional feedback route that supports iterative information updating, route correction and strategic adjustment. We argue that AD navigation deficits stem from the progressive breakdown of feedforward and feedback interactions across this axis, rather than from isolated dysfunction of single brain regions. The RSC-MEC-CA1-RSC framework offers a circuit-level mechanistic account for spatial disorientation in early AD. As a working model instead of a fully validated canonical circuit, it puts forward a series of testable hypotheses for future research, including cross-regional electrophysiological recordings, projection-specific circuit manipulation, imaging assessments, and differentiated navigation paradigms to examine cue use, path integration, goal retrieval and feedback-dependent updating.},
}

@article {pmid42570292,
year = {2026},
author = {Labbad, I and Youssef, LA and Rustom, M and Agha, MS},
title = {APOE ε4 and late-onset Alzheimer's disease in Syria: A case-control study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261475340},
doi = {10.1177/13872877261475340},
pmid = {42570292},
issn = {1875-8908},
abstract = {BackgroundThe apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD), but its prevalence and impact vary substantially across populations. No previous study has characterized APOE allele distribution among Syrian patients with AD.ObjectiveThis investigation aimed to assess the association between APOE genotypes and AD risk in a Syrian cohort.MethodsIn this case-control study, genomic DNA was extracted from 52 clinically diagnosed AD patients and 38 cognitively healthy controls. The APOE genotype was determined by direct sequencing of the rs429358 and rs7412 polymorphisms defining the ε2, ε3, and ε4 alleles. Genotypic and allelic frequencies were compared using Fisher's exact test, and Hardy-Weinberg equilibrium was assessed in the controls.ResultsThe ε3/ε3 genotype was predominant in both groups (73.1% of cases, 94.7% of controls). The ε3/ε4 genotype appeared in 23.1% of AD patients but was absent among controls (Corrected OR = 12.37, 95% CI = 0.65-233.7, p < 0.01). The overall ε4 allele frequency in patients (0.117) was significantly higher than in controls (0.000) (Corrected OR = 10.76, 95% CI = 0.59-195.7, p < 0.01). The ε2/2, ε4/4, and ε2/4 genotypes were not detected in any participants.ConclusionsThis study is the first to investigate the prevalence of the APOE ε4 allele in Syrian patients with Alzheimer's disease. These results underscore the importance of investigating genetic architectures when assessing AD risk and call for larger, multi-center studies across the Middle East to elucidate the interplay between APOE variants and metabolic determinants of cognitive decline.},
}

@article {pmid42570437,
year = {2026},
author = {Yan, Y and Tian, D and Yang, F and Zhao, R and Deng, L and Wang, Q and Xie, M},
title = {A brain-targeted biomimetic iron-porphyrin covalent organic framework nanoplatform for Alzheimer's disease: synergistic intervention via antioxidant, Aβ-regulating and immunomodulatory effects.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 3},
pages = {141264},
doi = {10.1016/j.jcis.2026.141264},
pmid = {42570437},
issn = {1095-7103},
abstract = {The pathological progression of Alzheimer's disease (AD) involves multiple interconnected pathways, including β-amyloid (Aβ) deposition, oxidative stress, and microglial dysfunction, which together form a self-reinforcing vicious cycle. This complexity poses a major challenge to conventional single-target therapeutic strategies. To address this limitation, we developed a biomimetic nanoplatform integrating active brain targeting, multiple therapeutic bioactivities, and immunomodulatory function. The core of this platform was an iron-porphyrin-based covalent organic framework (COF) that possesses enzyme-mimetic antioxidant activity, metal-ion-chelating capability, and Aβ-modulating properties. The COF core was cloaked with a BV2 microglial membrane (BM) to enhance biocompatibility and further functionalized with Angiopep-2 peptide to enable efficient blood brain barrier (BBB) penetration. In vitro studies demonstrated that the platform effectively scavenged various reactive oxygen species, achieved a copper-ion chelation rate of 41.78%, inhibited Aβ aggregation, and depolymerized pre-formed fibrils. At the cellular level, the nanoplatform not only protected neurons from β-amyloid-induced toxicity but also improved the redox status and mitochondrial function of microglia. Furthermore, it promoted the polarization of microglia from the pro-inflammatory M1 phenotype toward the neuroprotective M2 phenotype, which was correlated with enhanced β-amyloid phagocytic capacity. In APP/PS1 (APPswe/PSEN1dE9) transgenic mice, treatment with this nanoplatform markedly reduced cerebral Aβ plaque deposition, attenuated neuroinflammation and oxidative stress, and improved BBB integrity, ultimately leading to the remarkable recovery of spatial learning, memory, and spontaneous exploration abilities in mice. In summary, this integrated nano-strategy, which combines delivery, clearance, and modulation, represents an effective multi-target approach for intervening in the complex pathological network of AD.},
}

@article {pmid42570467,
year = {2026},
author = {Lin, CH and Hung, PH and Chung, MC and Wu, LY and Chung, CJ},
title = {Risk of Dementia after initiation of GLP-1 RA versus long-acting insulin in patients with type 2 Diabetes mellitus.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100645},
doi = {10.1016/j.tjpad.2026.100645},
pmid = {42570467},
issn = {2426-0266},
abstract = {BACKGROUND: Recent studies suggest a decreased risk of dementia in patients treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we compare the risk of dementia associated with GLP-1 RA versus long-acting insulin in adults aged over 50 years with type 2 diabetes (T2DM) using real-world administrative data from a large Taiwan cohort DESIGN: A population-based retrospective cohort study SETTING: We analyzed 10,783 propensity score-matched pairs of adults with T2DM who initiated either GLP-1 RA or long-acting insulin from Taiwan's National Health Insurance Research Database (2011-2021).

MEASUREMENTS: Primary outcome was new-onset dementia; secondary outcomes included dementia requiring treatment and specific dementia subtypes (Alzheimer's disease, vascular dementia, and unspecified dementia). Hazard ratios (HRs) were estimated using Cox models.

RESULTS: Analysis of matched pairs identified 375 cases of newly diagnosed dementia. The incidence rate was 4.86 per 1,000 person-years in GLP-1 RA users versus 7.56 in insulin users. GLP-1 RA use was associated with significantly lower risk of overall dementia (HR 0.64, 95% CI 0.46-0.89, P=0.0072) and unspecified dementia (HR 0.41, 95% CI 0.24-0.68, P=0.0006), but not for Alzheimer's disease (HR 1.48, 95% CI 0.61-3.63, P=0.3867) or vascular dementia (HR 1.66, 95% CI 0.21-13.03, P=0.6324). Among GLP-1 RAs, both liraglutide (HR 0.40, 95% CI 0.20-0.80, P=0.0091) and dulaglutide (HR 0.42, 95% CI 0.19-0.92, P=0.0311) showed significant protective effects against unspecified dementia.

CONCLUSIONS: GLP-1 RA use was associated with lower dementia risk versus long-acting insulin in T2DM patients, especially with liraglutide and dulaglutide. As observational, causality requires confirmation from randomized controlled trials.},
}

@article {pmid42570468,
year = {2026},
author = {Hüppi, RM and Langer, N and Hebling Vieira, B and , },
title = {Quantifying generalization error in machine learning prediction of cognitive decline.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100646},
doi = {10.1016/j.tjpad.2026.100646},
pmid = {42570468},
issn = {2426-0266},
abstract = {BACKGROUND: Predicting cognitive decline as a continuum, from healthy age-related decline to mild cognitive impairment and dementia, enables more precise individual-level predictions. However, the practical value of such models for early intervention and prevention depends on their ability to generalize to independent cohorts, a property that is often not evaluated.

OBJECTIVES: This study investigated whether adding structural magnetic resonance imaging (MRI) to non-brain data improved machine learning predictions of continuous cognitive decline and analyzed the models' generalizability.

DESIGN: Multi-target random forest regression models predicted annual decline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) using non-brain data, structural MRI data, or their combination from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1237) and Open Access Series of Imaging Studies (OASIS-3; N = 662) datasets. Cross-site generalizability was evaluated.

SETTING: Data from ADNI and OASIS-3 were used for this study.

PARTICIPANTS: A total of 1899 participants who had demographic, clinical, and brain imaging data from a baseline session and clinical data from at least 2 follow-up sessions were included.

MEASUREMENTS: Baseline non-brain (demographics, clinical and neuropsychological scores, information on APOE genotype, cognitive diagnosis, health, and number of sessions before baseline) and/or structural MRI data were used to predict the yearly rate of change in CDR-SOB and MMSE scores.

RESULTS: Including structural MRI data improved prediction of CDR-SOB and MMSE change, reaching respective R[2] values of .41 and .33 in ADNI and .42 and .33 in OASIS-3. Model performance for across-dataset predictions was reduced (R[2] between .18 and .35), unexplained by distributional shifts of target variables. Models using only top predictive features performed similarly to full models when tested externally (R[2] between .18 and .34), suggesting predictor redundancy.

CONCLUSIONS: Incorporating structural MRI data enhances within-dataset prediction of continuous cognitive decline, allowing for more precise individual-level prediction and advancing towards precision medicine. Even though external validation remains limited, quantifying the generalizability gap is a crucial step towards the responsible use of ML models in clinical intervention and prevention.},
}

@article {pmid42570561,
year = {2026},
author = {Kristiansen, S and Eriksen, S and Treviño, CS and Välimäki, T and Atladóttir, H and Gudmundsdottir, G and Engedal, K and Snædal, J and Rokstad, AMM and Konradsen, H},
title = {Patients' experiences of living with the risk of Alzheimer's disease - a multicentre qualitative study.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {73},
number = {},
pages = {104209},
doi = {10.1016/j.gerinurse.2026.104209},
pmid = {42570561},
issn = {1528-3984},
abstract = {AIMS AND OBJECTIVES: To explore the experiences of receiving and living with a diagnosis of prodromal Alzheimer's disease.

BACKGROUND: Alzheimer's disease is a progressive dementia disorder, with pathology potentially developing years before clinical symptoms. Evidence concerning patients' perspectives on living with a prodromal Alzheimer's disease diagnosis remains scarce.

DESIGN AND METHODS: A qualitative, descriptive design was employed. Semi-structured interviews were conducted with 16 participants diagnosed with prodromal Alzheimer's disease in memory clinics in Denmark, Norway and Iceland. The data were analysed using thematic analysis.

FINDINGS: Four main themes emerged: 1) what led to the assessment, 2) receiving the diagnosis of prodromal Alzheimer's disease, 3) everyday life after the diagnosis and 4) planning for the future. The participants experienced diverse trajectories to diagnosis, with some being alerted by others to symptoms and some recognising the symptoms themselves. The diagnostic process was often perceived as intimidating, and person-centred care was valued. After the diagnosis, the participants focused on managing daily life, experienced changes in relationships and harboured mixed emotions about the future.

CONCLUSION: Receiving a prodromal Alzheimer's disease diagnosis impacts patients' perceptions of their abilities, relationships and future. There is a need for interventions targeting both patients and their families to maintain a close bond between them and support hope. Clear communication about the distinction between prodromal Alzheimer's disease and Alzheimer's dementia is crucial.

No Patient or Public Contribution.},
}

@article {pmid42570638,
year = {2026},
author = {Zou, Y and Ou, Y and Zhao, H and Chen, G and Chen, Z and Li, Y and Jiang, J},
title = {Microglial immunometabolism in Alzheimer's disease: A stage-resolved trajectory from adaptive remodeling to the metabolic paradox.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {202},
number = {},
pages = {119841},
doi = {10.1016/j.biopha.2026.119841},
pmid = {42570638},
issn = {1950-6007},
abstract = {Microglia are central regulators of the cellular phase of Alzheimer's disease (AD). Under chronic exposure to amyloid-β, pathological tau, and aging-associated bioenergetic decline, these cells undergo immunometabolic remodeling that may initially be adaptive. As stress persists, this remodeling can become maladaptive, marked by disordered glycolysis, disturbed lipid handling, mitochondrial dysfunction, and compensatory failure. In this review, we organize these changes as a stage-dependent trajectory from adaptive remodeling to functional decompensation. We introduce the "metabolic paradox" as an operational descriptor: a concurrent, same-cell mismatch between increased substrate uptake or inflammatory activation and declining bioenergetic efficiency and homeostatic function. Along this trajectory we examine neurovascular energy bottlenecks, substrate redistribution, triggering receptor expressed on myeloid cells 2 (TREM2)/apolipoprotein E (APOE)-dependent lipid homeostasis, mitochondrial and proteostatic collapse, and their links to persistent neuroinflammation, defective phagocytosis, aberrant synaptic pruning, and senescence-like dysfunction. We synthesize prior primary findings and stratify each major claim by evidentiary strength, avoiding the overinterpretation of model-specific results as patient-level mechanisms. Finally, we frame immunoprevention as mechanism-based, early-stage metabolic intervention to preserve homeostatic microglial function, a strategy whose clinical benefit remains a hypothesis requiring prospective testing.},
}

@article {pmid42570705,
year = {2026},
author = {Li, N and Wu, Y and Feng, H and Jian, X and Yang, Z and Wang, X and Li, X and Yin, Y and Long, Y},
title = {Metabolic Reprogramming-Driven Neuroimmunoregulation: Key Mechanisms and Therapeutic Opportunities and Challenges in Central Nervous System Disorders.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103291},
doi = {10.1016/j.arr.2026.103291},
pmid = {42570705},
issn = {1872-9649},
abstract = {Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Critically, rather than presenting all reported metabolic alterations as equivalently established, we introduce an evidence-transparency framework that systematically distinguishes the nature of supporting data-ranging from direct metabolic flux measurements (Seahorse, isotope tracing, lipidomics) and molecular correlates, to genetic/pharmacological perturbations, human tissue validation, and model-specific observations-enabling readers to independently assess the strength of each major conclusion. We further delineate aging as an active analytical dimension, demonstrating how age-related changes in mitochondrial quality control, lipid handling, redox buffering, and glial-immune crosstalk establish a permissive baseline that modifies disease-specific reprogramming trajectories. By integrating analyses of intercellular crosstalk, neuroinflammation, blood-brain barrier integrity, and oxidative stress, we illustrate both convergent and divergent metabolic mechanisms across diseases. Finally, we critically assess therapeutic strategies targeting immunometabolism, emphasizing shared translational obstacles including target selectivity, blood-brain barrier penetration, stage-dependent efficacy, and the inherent challenge of pathway pleiotropy. This review provides a conceptually grounded framework for interpreting immunometabolic evidence, navigating the gap between correlative findings and causal mechanisms, and guiding future hypothesis-driven therapeutic design for CNS disorders.},
}

@article {pmid42570712,
year = {2026},
author = {Shokr, MM and Fawzy, MN},
title = {The gut-brain-mitophagy axis: Urolithin A as a transcriptional activator of Parkin in Alzheimer's and Parkinson's diseases.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104112},
doi = {10.1016/j.mcn.2026.104112},
pmid = {42570712},
issn = {1095-9327},
abstract = {Mitochondrial dysfunction is a cardinal, causative, and convergent hallmark in both Alzheimer's disease (AD) and Parkinson's disease (PD). However, therapeutics that target the process of mitophagy, the selective removal of damaged mitochondria, are relatively undeveloped. Prior work has largely centered around post-translational modifications of the PINK1-Parkin signaling pathway while ignoring the key need for sustained protein synthesis of Parkin. In this review, we explore an innovative transcriptional circuit involving the gut microbiome, AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and mitophagy: gut-derived metabolites, such as Urolithin A (UA), activate AMPK and SIRT1, both of which converge to deacetylate and phosphorylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The transcription of the mitophagy protein, Parkin, is then driven by activation of PGC-1α. This UA/AMPK/SIRT1/PGC-1α/Parkin/mitophagy pathway is disrupted in multiple layers in AD and PD; this includes impaired gut function, lowering the level of UA produced in the body, proteinopathy leading to reduced PGC-1α activity, and decreased transcription of Parkin. Therapeutic targets of these various nodes include UA, PGC-1α activator ZLN005, and SIRT1 activators, such as resveratrol or nicotinamide riboside. By shifting the paradigm from post-translational activation to transcriptional restoration of Parkin, this gut-brain metabolic axis offers a unifying, testable, and therapeutically tractable framework for mitigating mitophagy failure in AD and PD.},
}

@article {pmid42570809,
year = {2026},
author = {Wang, J and Liu, Y and Jiang, C and Wang, D and Wang, J and Feng, G and Zhong, B},
title = {Transferrin receptor upregulation mediates homocysteine-induced cytotoxicity in cerebral endothelial cells.},
journal = {Brain research},
volume = {},
number = {},
pages = {150486},
doi = {10.1016/j.brainres.2026.150486},
pmid = {42570809},
issn = {1872-6240},
abstract = {Hyperhomocysteinemia (HHcy) is a recognized risk factor for cognitive impairment, including Alzheimer's disease, but the mechanisms linking homocysteine (Hcy) accumulation to cerebral dysfunction remain unclear. Brain microvascular endothelial cells (BMECs) are an important cellular component of the blood-brain barrier (BBB) and play a key role in maintaining central nervous system homeostasis. However, how Hcy affects BMECs remains incompletely understood. In this study, we used the human brain microvascular endothelial cell line hCMEC/D3 to determine the half-maximal inhibitory concentration (IC50) of Hcy by CCK-8 assay, and then performed transcriptomic analysis to identify Hcy-regulated genes associated with endothelial cell injury. Hcy reduced hCMEC/D3 cell viability in a dose-dependent manner, with an IC50 of approximately 12.25 mM; therefore, 10 mM Hcy was selected for subsequent experiments. Transcriptomic sequencing revealed significant upregulation of the transferrin receptor (Tfrc) gene, which we confirmed by quantitative real-time PCR and Western blot analysis. Functionally, TFRC overexpression mimicked the Hcy-induced reduction in cell viability, whereas TFRC knockdown partially rescued cells from Hcy-induced cytotoxicity. TFRC overexpression reduced hCMEC/D3 cell viability, whereas TFRC knockdown partially alleviated Hcy-induced cytotoxicity. These results suggest that TFRC is involved in Hcy-induced injury of brain microvascular endothelial cells. Taken together, our in vitro findings provide a possible clue for future in vivo studies on HHcy-associated BBB dysfunction.},
}

@article {pmid42570992,
year = {2026},
author = {Cai, W and Pan, X and Qian, T and Yu, S and Zhao, R and Zhu, C and Sang, S and Zhong, C},
title = {An ApoE-Associated Low-Inflammatory Microglial State Emerges After Inflammatory Challenge in Alzheimer's Disease Mice.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42570992},
issn = {1995-8218},
abstract = {Patients with Alzheimer's disease (AD) frequently experience inflammatory insults; however, the mechanisms by which microglia respond to these challenges remain unclear. Although AD microglia have been proposed to be primed for exaggerated inflammatory responses, single-cell evidence remains limited. To investigate microglial responses to inflammation in AD, we challenged AD mouse models with intraperitoneal lipopolysaccharide (LPS) and used single-cell RNA sequencing to characterize microglial states, along with in vivo immunostaining and in vitro models to define their features and underlying mechanisms. We found that, in response to an inflammatory challenge, microglia adopted a low-inflammatory state accompanied by elevated expression of mitochondrial respiratory chain genes. This state was associated with the phagocytosis of dystrophic neurites and was recapitulated in vitro using an efferocytosis-based model, with apolipoprotein E implicated in its underlying mechanism. In summary, we identified a distinct microglial state that provides new insights into the dynamic role of microglia in AD.},
}

@article {pmid42565414,
year = {2026},
author = {Ramirez-Contreras, LA and Camargo-Hernández, G and Sanchez-Enriquez, S and Silva-Jara, JM and Hernández Estrada, S and Hernández Villaseñor, LA and Anaya Esparza, LM},
title = {Bioinformatic Tools to Explore the Mechanisms and the Multitarget Recognition of Huperzine A in Alzheimer's and Parkinson's Diseases.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501499352260714060149},
pmid = {42565414},
issn = {1873-5592},
abstract = {INTRODUCTION: Considering the shared physiological mechanisms between Alzheimer's disease (AD) and Parkinson's disease (PD), it is plausible that certain compounds may exert therapeutic effects on both neurological disorders. This study aimed to employ in silico techniques to investigate the pharmacological mechanisms of huperzine A (HA) as an alternative treatment for PD and AD.

METHODS: Molecular targets of HA and genes associated with AD and PD were identified from public databases. Gene Ontology analysis, metabolic pathway analysis, and protein-protein interaction (PPI) network construction were performed to identify shared molecular targets. Molecular docking was performed to assess HA affinity for hub proteins and to compare it with that of drugs used to treat AD and PD.

RESULTS: The results suggested that HA interacts with 77 molecular targets common to both diseases. Enrichment analysis revealed that proteins from these targets were involved in biological functions, such as serotonin and amine binding. Hub proteins (SRC, TP53, AKT1, and CASP3) were identified from the PPI network. Furthermore, molecular docking simulations showed favorable binding of HA to the hub proteins and adequate binding to the targets of standard drugs (MAOB and ACHE). On the other hand, molecular dynamics analyses were performed to compare the binding characteristics of HA with those of the control targets.

DISCUSSION: HA may modulate SRC, CASP3, and AKT1, suggesting a pleiotropic mechanism underlying the association between AD and PD. These computational findings provide a rational basis for experimental validation by modulating signaling pathways implicated in inflammatory processes and inhibiting enzymes involved in neurotransmitter degradation.

CONCLUSION: This study contributes to the understanding of the neuroprotective activity of HA in AD and PD. However, further in vitro and in vivo investigations are required to confirm the dual therapeutic potential of HA in the treatment of AD and PD.},
}

@article {pmid42565788,
year = {2026},
author = {Keller, JL and Pennartz, KJ and Sprick, JD and Hein, EJ and Irving, BA and Vann, CG and Butlig, ER and Al-Masri, S and Nelson, AR},
title = {A peripheral perspective on brain health: vascular and skeletal muscle contributions.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00462.2026},
pmid = {42565788},
issn = {1522-1539},
support = {AG079454//HHS | NIH | National Institute on Aging (NIA)/ ; NS135147//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; //Coins for Alzheimer's Research Trust (CART)/ ; AG070146//HHS | NIH | National Institute on Aging (NIA)/ ; AG054840//HHS | NIH | National Institute on Aging (NIA)/ ; AG000029//HHS | NIH | National Institute on Aging (NIA)/ ; HL153497//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
abstract = {Age- and disease-related declines in brain health contribute to impairments in physical function, yet effective approaches to lessen these declines remain limited. Overall health is governed by a network of interdependent organ systems, such that dysfunction in one system can propagate across others. Although the brain has been viewed as a top-down regulator of vital functions, evidence indicates that cognition is affected by signals from peripheral organs. This interorgan communication likely explains the coexistence of Alzheimer's disease and related dementias with cardiovascular and metabolic disorders characterized by overlapping pathophysiology. Skeletal muscle and the peripheral vasculature are key contributors to this and represent modifiable systems that can alter brain structure and function. Skeletal muscle regulates myokine release through motor neuron function, contractile activity, and metabolic perturbations, thereby influencing neuroplasticity, mitochondrial function, and inflammatory signaling, and may affect measures of peripheral vascular function, like reactive hyperemia. Other properties of the vasculature, including arterial stiffness, directly affect cerebral perfusion and blood-brain barrier permeability. These systems form a muscle-vascular-brain axis that contributes to brain health and impacts the risk of cognitive impairment. Therefore, our aim was to synthesize the current understanding of interactions among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in maintaining cognitive health. We also highlight recent clinical trials and emerging strategies affecting interorgan crosstalk. These conclusions support a model in which lifestyle interventions targeting peripheral systems, such as resistance training, may preserve brain health across all populations, offering scalable approaches applicable across the lifespan.},
}

@article {pmid42565943,
year = {2026},
author = {Liu, Z and Nie, JF and Liu, H and Liu, Z and Pang, Y and Fu, H and Zhang, Y},
title = {Integrating Metabolomics Data, Network Pharmacology, and Molecular Docking to Investigate the Effect of Aging Times on the Functional Activity of Liupao Tea.},
journal = {Plant foods for human nutrition (Dordrecht, Netherlands)},
volume = {81},
number = {3},
pages = {},
pmid = {42565943},
issn = {1573-9104},
support = {No. GuikeLT2600640006//Guangxi Science and Technology Innovation Platform Project/ ; No. GuikeAA23023006//Guangxi Science and Technology Major Project/ ; No. Guirencaiban202401//Guangxi Bagui Youth Talent Project/ ; Nos. 22464008 and 21765007//National Natural Science Foundation of China/ ; },
mesh = {Molecular Docking Simulation ; Metabolomics ; Oxidative Stress/drug effects ; *Antioxidants/analysis/pharmacology ; Network Pharmacology ; Humans ; *Tea/chemistry ; *Camellia sinensis/chemistry ; Time Factors ; },
abstract = {Liupao tea (LPT) undergoes significant bioactive changes during aging, while the link between these chemical shifts and the regulation of oxidative stress pathologies remains unclear. Therefore, this study integrated metabolomics, network pharmacology, and molecular docking to analyze Maosheng (MS) and Tianyu (TY) LPT samples aged 0-15 and 0-10 years, respectively, and elucidated the potential mechanisms of LPT in five oxidative stress - related diseases, including depression, obesity, Alzheimer's disease, diabetes, and hypertension. Metabolomics identified 42 and 13 core antioxidant metabolites in MS and TY samples, respectively. Among them, core metabolites in MS peaked at 5 years, while TY sustained high abundance levels from 3 to 8 years. Network pharmacology revealed synergistic regulation of all five pathologies by both LPTs, and eight key components were screened from MS, and nine from TY based on degree values. Interestingly, the highest node density was shown in depression, and Sankey connectivity confirmed its strongest modulatory effect. Besides, the core depression‑related components and targets were subjected to molecular docking simulations, and binding energies ranged from - 5.37 to -8.88 kcal/mol for MS components, as well as from - 4.11 to -8.39 kcal/mol for TY components. Importantly, oleaside A and CCRIS 7793 showed the strongest affinities for GAPDH and AKT1, respectively. In general, these results laid a practical foundation for developing an LPT product aimed at relieving oxidative stress-related health issues.},
}

Molecular Docking Simulation
Metabolomics
Oxidative Stress/drug effects
*Antioxidants/analysis/pharmacology
Network Pharmacology
Humans
*Tea/chemistry
*Camellia sinensis/chemistry
Time Factors

@article {pmid42566020,
year = {2026},
author = {Lövdal, S and Meles, SK and Carli, G and Dortmond, A and Kogan, RV and Goldstein, O and Gana-Weisz, M and Orad, RI and Alcalay, RN and Bregman, N and Leenders, KL and Shiner, T},
title = {Effect of genetic factors on [[18]F]FDG PET metabolic phenotypes in dementia with Lewy bodies.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42566020},
issn = {1619-7089},
abstract = {BACKGROUND: Neuroimaging with [[18]F]FDG PET can support the diagnosis of Dementia with Lewy Bodies (DLB), but it remains unclear how genetic factors influence metabolic phenotypes.

OBJECTIVES: To determine whether GBA1 and APOE ε4 status are associated with diverging [[18]F]FDG PET metabolic patterns in DLB.

METHODS: We analyzed [[18]F]FDG PET scans from 43 patients with DLB stratified by GBA1 and APOE ε4 status, and 35 from healthy subjects. Analyses included the cingulate island sign (CIS), regions of interest, SSM/PCA disease patterns, and a machine learning multi-class model. We evaluated the similarity of the DLB patient scans in our cohort with respect to typical DLB, Alzheimer's disease (AD) and Parkinson's disease (PD)-like patterns.

RESULTS: APOE ε4 status mainly influenced the CIS, with APOE ε4-negative patients showing greater preservation of the DLB-typical CIS pattern (p = 0.03) compared to APOE ε4 carriers. In contrast, GBA1 status influenced global metabolic phenotype. GBA1 carriers showed a more homogeneous PD/DLB-like metabolic pattern in the machine learning model (p = 0.003) compared to GBA1 non-carriers, whereas the latter group demonstrated greater heterogeneity and higher expression of the AD-related metabolic pattern (p = 0.004). These effects were observed along a metabolic spectrum rather than as distinct clusters.

CONCLUSIONS: APOE ε4 and GBA1 modulate distinct aspects of the metabolic phenotype in DLB. GBA1 non-carriers and APOE ε4 carriers showed a higher rate of atypical metabolic signatures, which may contribute to biological heterogeneity and increase the risk of diagnostic misclassification.},
}

@article {pmid42566137,
year = {2026},
author = {Barbosa, KA and Ribeiro, HM and Benevenuto, LGD and Maiorka, PC and Cominetti, MR and Amorim, RM and Cagnini, DQ},
title = {Advances in biomarker discovery for canine cognitive dysfunction: a comprehensive structured narrative review and future perspectives.},
journal = {Veterinary research communications},
volume = {50},
number = {5},
pages = {},
pmid = {42566137},
issn = {1573-7446},
mesh = {Animals ; Dogs ; *Biomarkers/cerebrospinal fluid/blood ; *Dog Diseases/diagnosis/cerebrospinal fluid/blood ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Glial Fibrillary Acidic Protein/cerebrospinal fluid/blood ; tau Proteins/cerebrospinal fluid/blood ; },
abstract = {Canine Cognitive Dysfunction (CCD) is a naturally occurring neurodegenerative syndrome in aging dogs that shares clinical and neuropathological parallels with Alzheimer's disease (AD). As the demand for objective diagnostic tools grows, identifying reliable biofluid biomarkers is essential for clinical staging and therapeutic monitoring. This review synthesizes evidence on cerebrospinal fluid (CSF) and blood-based biomarkers (BBM) of CCD, focusing on amyloid-β (Aβ), neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Evidence shows that Aβ42 and Aβ42/Aβ40 ratios exhibit stage-dependent, non-linear alterations resembling early compensatory phases in human AD. In contrast, tau pathology in CCD consists mainly of pre-tangle synaptic hyperphosphorylation rather than abundant neurofibrillary tangles, limiting its current diagnostic utility. GFAP, a marker of astroglial activation, shows inconsistent associations with cognitive decline and remains exploratory. Conversely, NfL has emerged as the most robust biomarker; CSF and plasma NfL levels consistently increase with age, correlate with cognitive impairment, and reflect central axonal pathology, making it the leading candidate for staging and monitoring disease progression. Overall, the CCD biomarker landscape supports a multimodal approach integrating Aβ dysregulation, axonal injury, and glial activation. Advancing this field requires harmonized diagnostic criteria, standardized sampling, and longitudinal studies. Such efforts will strengthen the translational value of CCD as a model for human dementia, accelerating discovery and therapeutic development across species.},
}

Animals
Dogs
*Biomarkers/cerebrospinal fluid/blood
*Dog Diseases/diagnosis/cerebrospinal fluid/blood
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid/blood
Amyloid beta-Peptides/cerebrospinal fluid/blood
Glial Fibrillary Acidic Protein/cerebrospinal fluid/blood
tau Proteins/cerebrospinal fluid/blood

@article {pmid42566636,
year = {2026},
author = {Chen, Y and Chen, X},
title = {Genetic evidence for a causal role of depression in late-onset Alzheimer disease: A Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {32},
pages = {e50116},
doi = {10.1097/MD.0000000000050116},
pmid = {42566636},
issn = {1536-5964},
mesh = {*Alzheimer Disease/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; *Depression/genetics/complications ; Genetic Predisposition to Disease ; Age of Onset ; },
abstract = {Observational studies link psychiatric disorders to Alzheimer disease (AD), but whether these associations are causal remains unclear due to confounding and reverse causality. We aimed to dissect these relationships using genetic evidence. We performed a two-sample Mendelian randomization (MR) study to assess the causal effects of 7 psychiatric and neurodevelopmental disorders on AD and its subtypes. The primary analysis utilized the inverse-variance weighted (IVW) method, supported by comprehensive sensitivity analyses (MR Steiger test, MR-Egger, and MR-PRESSO) and a supplementary analysis excluding single nucleotide polymorphisms (SNPs) associated with potential confounders. Depression showed a significant causal association with late-onset AD (odds ratio [OR] = 1.0736, 95% confidence interval [CI]: 1.0084-1.1431, P = .0264). No significant causal associations were found for other psychiatric disorders (all P > .05). A directionality test conducted by MR Steiger confirmed our estimation of potential causal direction (P < .001). Sensitivity analyses excluding pleiotropic SNPs yielded consistent results. The causal association for depression and late-onset AD remained significant after excluding pleiotropic SNPs linked to confounders (OR = 1.0726, 95% CI: 1.0069-1.1425, P = .03). Our study provides genetic evidence supporting a causal role for depression in the etiology of late-onset AD, a link not observed for other major psychiatric disorders tested. These findings highlight the specific importance of managing depression as a potential strategy for mitigating AD risk and suggest distinct etiological pathways between different mental health conditions and neurodegeneration.},
}

*Alzheimer Disease/genetics/epidemiology
Humans
*Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
*Depression/genetics/complications
Genetic Predisposition to Disease
Age of Onset

@article {pmid42566883,
year = {2026},
author = {Zhao, H and Gao, R and Zhang, B and Gao, J and Xue, B and Zhang, Y},
title = {Advances in dopamine transporter inhibitors: Design strategies, structural features, and pharmacological insights.},
journal = {European journal of medicinal chemistry},
volume = {318},
number = {},
pages = {119189},
doi = {10.1016/j.ejmech.2026.119189},
pmid = {42566883},
issn = {1768-3254},
abstract = {Dopamine transporter (DAT) plays a pivotal role in regulating synaptic dopamine homeostasis and is critically involved in various neuropsychiatric disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and substance use disorders. This review highlights cutting-edge advances in the development of DAT inhibitors, offering new insights into their structure-activity relationships, pharmacological mechanisms, and therapeutic potential. The core findings emphasize the significance of conformational selectivity in overcoming addiction-related limitations of typical inhibitors and uncover novel strategies for engineering atypical and allosteric inhibitors with improved efficacy and safety profiles. Furthermore, a comprehensive analysis of clinical trials reveals the main challenges in DAT inhibitor development, such as off-target toxicity and multitarget-related adverse effects, providing a foundation for addressing these issues. By distilling critical design strategies and lessons learned, this review provides a theoretical framework and actionable guidance for the future development of safe, selective, and effective DAT-targeting therapies.},
}

@article {pmid42566983,
year = {2026},
author = {Aaltonen, A and Palviainen, T and Heikkinen, S and Herukka, SK and Hiltunen, M and Kokkola, T and Kärkkäinen, S and Palotie, A and Runz, H and Julkunen, V and Kaprio, J and Saari, TT and Vuoksimaa, E and , },
title = {Genetic architecture of Alzheimer's disease-related plasma biomarkers.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {123-131},
doi = {10.1016/j.neurobiolaging.2026.07.010},
pmid = {42566983},
issn = {1558-1497},
abstract = {Alzheimer's disease-related plasma biomarker interrelationships and factors underlying these associations remain poorly understood. To address this, we studied the heritability of plasma biomarkers and their associations with cognition. This study included 696 twins, aged 65-85, without a diagnosis of Alzheimer's disease or related dementias. Plasma amyloid beta 42 and 40, phosphorylated tau (p-tau) 181 and 217, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified with Simoa HD-X, and cognition was assessed with cCOG. Heritability of plasma biomarkers was assessed with multivariate twin models and associations with cognition with linear mixed effect models. Phenotypic associations varied from 0.22 between p-tau181 and GFAP to 0.73 between p-tau181 and p-tau217, and the heritability estimates ranged from 0.39 (p-tau181) to 0.66 (GFAP). Genetic and environmental correlations were 0.32-0.67 and 0.06-0.78, with the strongest correlations observed between p-tau181 and p-tau217. P-tau181 and p-tau217 were associated with cognition (β = -0.12; 95% CI: -0.19--0.04 and β = -0.19; 95% CI: -0.26--0.12, respectively). The observed phenotypic and genetic associations highlight shared underlying mechanisms among plasma biomarkers. Despite p-tau181 and p-tau217 having the strongest genetic and environmental correlations, neither approached unity, implying unique genetic and environmental factors. Our results offer insight into the genetic architecture of diagnostic and progression markers of Alzheimer's disease and inform their use in future gene-finding studies.},
}

@article {pmid42567320,
year = {2026},
author = {Chen, H and Wu, Z and Ge, T and Wu, M and Ye, J and Shan, S and Gao, C and Yang, Y and Yuan, C},
title = {Low-carbohydrate and low-fat diets, genetic susceptibility, and long-term risk of dementia: A prospective cohort study.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101463},
doi = {10.1016/j.ajcnut.2026.101463},
pmid = {42567320},
issn = {1938-3207},
abstract = {BACKGROUND: Low-carbohydrate and low-fat diets (LCDs and LFDs) are promoted for cardiometabolic prevention.

OBJECTIVE: This study examined associations of LCDs and LFDs with incident dementia and evaluated modification by genetic susceptibility.

METHODS: We included 5301 dementia-free adults aged ≥55 years from the Health and Retirement Study. Overall LCD and LFD indices were constructed based on macronutrient composition rankings assessed using a food frequency questionnaire in 2013-2014. Plant-based, animal-based, healthy, and unhealthy sub-scores were derived to characterize macronutrient sources and quality. Incident dementia was defined using the Langa-Weir algorithm through 2022. Genetic susceptibility was assessed using APOE genotype and Alzheimer disease polygenic risk score (AD-PRS). Cox models estimated hazard ratios (HRs).

RESULTS: During the 9-year follow-up, 506 participants developed dementia. Greater LCD score was associated with lower dementia risk (HR per SD increment 0.90, 95% CI, 0.82, 0.99), whereas an overall LFD was not (1.05, 95% CI, 0.96, 1.15). Plant-based and healthy LCDs showed stronger inverse associations (0.85, 95% CI, 0.78, 0.94 and 0.82, 95% CI, 0.74, 0.90), while higher animal-based (1.10; 95% CI, 1.00, 1.20) and unhealthy LFDs (1.13; 95% CI, 1.04, 1.24) were linked to higher dementia risk. Associations were consistent across APOE genotype and AD-PRS strata. Higher plant-based and healthy LCDs were also associated with better global and domain-specific cognitive performance.

CONCLUSION: Adherence to LCDs, particularly plant-based and higher-quality LCDs, was associated with lower dementia risk, consistently across genetic susceptibility strata. These findings underscored the importance of macronutrient quality, in addition to quantity, in promoting cognitive health.},
}

@article {pmid42567350,
year = {2026},
author = {Yang, ZL and Zhang, C and Tang, S and Zhang, XY and Huang, LY and Tan, L and , and , },
title = {Valine modulates Alzheimer's disease risk in APOE ε4 carriers: evidence from two cohorts.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.08.014},
pmid = {42567350},
issn = {2090-1224},
abstract = {INTRODUCTION: The apolipoprotein E ε4 (APOE ε4) allele confers the greatest genetic risk for sporadic Alzheimer's disease (AD).

OBJECTIVES: To identify APOE ε4-associated metabolic factors related to AD risk and to provide preliminary insights into their biological and nutritional context.

METHODS: We leveraged multi-omics analyses across two independent cohorts to characterize biomarkers associated with AD. The effects of metabolite × APOE ε4 interactions were tested on incident AD and the ε4-specific metabolic signatures were pinpointed. Multimodal analyses were used to test the underlying mechanisms, including neuroimaging, cerebrospinal fluid (CSF), and PET biomarkers within the A/T/N framework, as well as plasma proteomics combined with bioinformatics enrichment analyses.

RESULTS: Across both cohorts, valine emerged as the only metabolite associated with a reduced risk of incident AD specifically among APOE ε4 carriers (P < 0.005). Significant interaction effects between valine and APOE ε4 were detected in both cohorts (P for meta-analyses < 0.005). Higher levels of valine were associated with greater total white matter and posterior cingulate cortex volumes, as well as with lower levels of CSF tau proteins. Higher valine levels also predicted a slower decline in FDG-PET metabolism. No association was found between valine and Aβ. Mediation analyses of plasma proteomic data suggested statistically significant mediation effects involving GFAP, NEFL, and APOE (P < 2 × 10[-16]).

CONCLUSION: Valine is a metabolite associated with lower AD risk in APOE ε4 carriers, with potential associations with tau pathology, neurodegeneration, and neuroinflammation-related processes. As this was an observational study, causality cannot be inferred.},
}

@article {pmid42567367,
year = {2026},
author = {Riffo-Lepe, N and Gonzalez-Sanmiguel, J and Meza, I and Saavedra-Sieyes, P and Armijo-Weingart, L and Zambrano, H and Riquelme, A and Salinas, A and Martín, LS and Aguayo, LG},
title = {Selective impairment of long-term depression in accumbal D1R+ MSNs involves calcium-permeable AMPARs in early Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107568},
doi = {10.1016/j.nbd.2026.107568},
pmid = {42567367},
issn = {1095-953X},
abstract = {Alzheimer's disease (AD) is increasingly associated with early circuit dysfunction preceding cognitive decline, including neuronal hyperactivity and neuropsychiatric symptoms linked to mesolimbic pathways. The nucleus accumbens (NAc), a central regulator of reward and motivational processing, exhibits early alterations in excitation/inhibition balance in patients and experimental models, yet the synaptic mechanisms underlying its vulnerability remain unclear. Using a double transgenic APP/PS1 mice crossed with a Drd1a-tdTomato reporter line, we combined cell-type-specific electrophysiology, immunohistochemistry, ex vivo photometry, and behavioral assays. At a pre-plaque stage, intraneuronal Aβ accumulated in both dopamine D1 receptor-positive (D1R+) and D1R-negative medium spiny neurons (MSNs). Despite comparable Aβ levels, both high-frequency stimulation-induced long-term depression (LTD) and mGluR1/5-dependent LTD were selectively impaired in D1R+ MSNs. This vulnerability was accompanied by an increased contribution of calcium-permeable AMPA receptors (CP-AMPARs). Subsequent CP-AMPAR blockade reduced the residual evoked excitatory postsynaptic current that persisted after mGluR1/5 activation in APP/PS1 D1R+ MSNs. Because paired-pulse ratios remained unchanged, this residual response was consistent with a predominantly postsynaptic mechanism. These synaptic changes were accompanied by reduced evoked dopamine signaling, increased chocolate consumption, and altered baseline context preference, whereas standard pellet consumption, conditioned place preference, anxiety-like behavior, and social behavior were unchanged. These findings define a pre-plaque, cell-type-specific synaptic phenotype in male APP/PS1 mice in which impaired mGluR1/5-dependent plasticity and persistent CP-AMPAR signaling in D1R+ MSNs coincide with selective reward-related alterations.},
}

@article {pmid42567407,
year = {2026},
author = {Rabinovich, M and Lacham-Hartman, S and Papo, N},
title = {Modulating amyloid-β 42 aggregation and neurotoxicity by Kunitz domains and their derived peptides.},
journal = {New biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.nbt.2026.08.001},
pmid = {42567407},
issn = {1876-4347},
abstract = {Alzheimer's disease is associated with the aggregation of amyloid-β42 (Aβ42) into species of varying sizes, with intermediate oligomers being the most neurotoxic. We recently reported that amyloid precursor protein inhibitor (APPI), a Kunitz-type protein, and a cyclic peptide derived from its β-domain reduced Aβ42-mediated neurotoxicity, the former by reducing Aβ42 aggregation and formation of toxic Aβ42 oligomers, and the latter by promoting Aβ42 aggregation to form fibrils rather than the neurotoxic Aβ42 oligomers. To address the question of whether these two inhibition mechanisms are controlled by the structure or the amino acid sequence of the protein/peptide, we exploited three Kunitz-type proteins, bikunin, bovine pancreatic trypsin inhibitor (BPTI) and tissue factor pathway inhibitor (TFPI) - chosen for their similar β-strand-rich structures but different sequences to one another and to APPI - and also short peptides that mimic their β-domains, in either cyclic or linear conformation. In-vitro studies showed that the formation of Aβ42 aggregates was reduced by the three Kunitz-type proteins and by their derived cyclic peptides, but not by the linear counterparts of the cyclic peptides. In SH-SY5Y neuroblastoma cells, the Kunitz-type proteins and the cyclic (but not the linear) peptides reduced the intracellular and extracellular accumulation of Aβ42 aggregates, respectively. Both the Kunitz-type proteins and the cyclic peptides inhibited Aβ42-induced mitochondrial membrane depolarization and reduced Aβ42-mediated apoptosis and cell death. Overall, this study thus reveals the potential of the β-hairpin structure, whether as a segment within the Kunitz-type proteins or isolated as a cyclic peptide, to interact with Aβ42, thereby reducing Aβ42 aggregation and hence its neurotoxicity.},
}

@article {pmid42567574,
year = {2026},
author = {Chen, Y and Zhang, B and Yang, S and Wang, P and Wang, X and He, H},
title = {Ultrasensitive detection of blood-based p-tau217 for Alzheimer's disease integrated antibody-oligonucleotide conjugates and RCA/Cas12a system.},
journal = {Analytica chimica acta},
volume = {1418},
number = {},
pages = {345836},
doi = {10.1016/j.aca.2026.345836},
pmid = {42567574},
issn = {1873-4324},
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *tau Proteins/blood/immunology ; *Oligonucleotides/chemistry ; Immunoassay/methods ; Limit of Detection ; Phosphorylation ; },
abstract = {Tau phosphorylated at threonine 217 (p-tau217) is interesting increasingly as "star biomarker" in the field of Alzheimer's disease (AD) diagnosis due to the highest accuracy in detecting AD pathology and predicting future cognitive decline. Here, we developed an ultra-trace blood-based diagnostic platform for p-tau217, termed magnetic-particle-based Immunol Rolling-circle-amplification/Cas12a Assay (MPIRCA). In this approach, the operational process included two main stages: the preparation of All@MP (encompassing immobilization, capture, and binding) and the subsequent one-pot RCA/Cas12a reaction. Through the Ab-DNA, immunoassay was successfully converted into DNA-based molecular diagnostic technology (one-pot RCA/Cas12a reaction) to achieve ultra-high sensitivity with 1 fg/mL limitation of detection. The optimized assay exhibited excellent linearity across a range from 1 fg/mL to 1 ng/mL. The study presents a high feasible diagnostic strategy that combines one-pot operation, high sensitivity and selectivity, offering considerable potential for blood-based diagnosis and management of Alzheimer's disease (AD).},
}

*Alzheimer Disease/blood/diagnosis
Humans
*tau Proteins/blood/immunology
*Oligonucleotides/chemistry
Immunoassay/methods
Limit of Detection
Phosphorylation

@article {pmid42567782,
year = {2026},
author = {Risby-Jones, G and Lee, JD and Fung, JN},
title = {Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.07.002},
pmid = {42567782},
issn = {1878-108X},
abstract = {Interleukin-6 (IL-6) exerts protective and pathogenic effects in the central nervous system through distinct receptor-signalling modes. Classical signalling via membrane-bound IL-6 receptor (IL-6R) is often associated with homeostatic and reparative functions, whereas trans-signalling, mediated by soluble IL-6R, expands IL-6 responsiveness to gp130-expressing cells and may promote chronic inflammation. Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Here, we review mechanisms linking IL-6 trans-signalling to immune, glial, neuronal, and vascular dysfunction in neurodegeneration. We highlight key knowledge gaps and discuss whether selective targeting of trans-signalling can limit inflammatory pathology while preserving beneficial classical IL-6 functions.},
}

@article {pmid42567789,
year = {2026},
author = {Hotta, M and Tabira, T and Murata, M and Yoshiura, K and Ishikawa, T and Tanaka, H and Nagata, Y and Hashimoto, M and Ikeda, M},
title = {Patterns of ADL and IADL independence across MMSE score ranges in Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia: A cross-sectional analysis of a memory-clinic cohort.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100250},
doi = {10.1016/j.inpsyc.2026.100250},
pmid = {42567789},
issn = {1741-203X},
abstract = {BACKGROUND: Domain-level ADL and IADL independence across MMSE score ranges has been less well described in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). This study described the observed proportions of basic ADL and IADL independence across MMSE score ranges in these three neurodegenerative dementias.

METHODS: In a cohort of 650 patients (524 AD, 90 DLB, 36 FTD), cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily function was evaluated using the Physical Self-Maintenance Scale and the Lawton IADL scale. Patients were grouped into MMSE score ranges. For each diagnosis and MMSE score range, we calculated the observed proportion of participants rated as independent in each ADL/IADL domain and Wilson score 95% confidence intervals. Because the FTD sample was small (n = 36), with only 1-11 participants in individual five-point MMSE score ranges, and several MMSE-specific subgroup counts were sparse, the analyses were descriptive.

RESULTS: Observed independence proportions varied across ADL/IADL domains, MMSE score ranges, and diagnostic groups. In AD and DLB, shopping, food preparation, and medication management had low observed independence proportions even in higher MMSE ranges. In the MMSE 21-30 stratum, selected absolute numerical contrasts between DLB and AD ranged from 7.2 percentage points for feeding to 18.4 percentage points for bathing. Estimates for FTD, which were based on only 1-11 participants per five-point MMSE score range, and for DLB in the MMSE 0-10 stratum were based on small denominators and were therefore imprecise.

CONCLUSIONS: This study provides descriptive estimates of domain-level ADL and IADL independence across MMSE score strata in AD, DLB, and FTD. The results may contribute to domain-specific assessment and support planning for people living at home with MCI or dementia. These findings should be regarded as hypothesis-generating for future studies.},
}

@article {pmid42567790,
year = {2026},
author = {Xu, D and Zhang, H and Piao, Z and He, Y and Li, H and Zhang, N},
title = {Functional heterogeneity across structural MRI-based atrophy subtypes in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100255},
doi = {10.1016/j.inpsyc.2026.100255},
pmid = {42567790},
issn = {1741-203X},
abstract = {OBJECTIVES: This study explored whether distinct Alzheimer's disease (AD) structural atrophy subtypes exhibit divergent functional profiles.

DESIGN: A cross-sectional multimodal neuroimaging and electrophysiological study.

SETTING: Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.

PARTICIPANTS: A total of 116 patients with AD and 74 cognitively unimpaired controls underwent structural MRI. Patients with AD were stratified into three MRI-derived atrophy-pattern groups corresponding to hippocampal-sparing (HpSp-MRI), typical (tAD-MRI), and limbic-predominant (LP-MRI) subtypes.

MEASUREMENTS: Resting-state functional MRI was used to assess intra- and internetwork functional connectivity, and EEG was used to evaluate spectral power and microstate dynamics.

RESULTS: The HpSp-MRI subtype showed lower intranetwork connectivity than both the LP-MRI and tAD-MRI subtypes in the visual, somatomotor, and dorsal attention networks. The LP-MRI and tAD-MRI subtypes differed in ventral attention network connectivity. Moreover, the LP-MRI subtype exhibited stronger internetwork connectivity in specific network pairs compared with the other subtypes. EEG analysis suggested a possible difference in the microstate 3-to-1 transition between the LP-MRI and tAD-MRI groups.

CONCLUSIONS: MRI-derived atrophy-pattern subtypes showed different resting-state functional connectivity profiles, providing a potential basis for personalized brain network-targeted interventions in AD.},
}

@article {pmid42567919,
year = {2026},
author = {Mogavero, F and Galluzzi, G and Dolce, E and Malangone, D and Raimo, S and Di Vita, A and Galosi, E and Bruno, G and Sepe Monti, M and Talarico, G and D'Antonio, F and Palermo, L},
title = {Inside and outside the body space: a study on environmental knowledge, interoceptive and functional body representations in the prodromal stage of dementia.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {9},
pages = {},
pmid = {42567919},
issn = {1590-3478},
mesh = {Humans ; Female ; Male ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/physiopathology/psychology ; *Spatial Navigation/physiology ; *Prodromal Symptoms ; *Interoception/physiology ; *Body Image/psychology ; Neuropsychological Tests ; Middle Aged ; Space Perception/physiology ; *Dementia/psychology/physiopathology ; },
abstract = {BACKGROUND: There is increasing interest in identifying sensitive cognitive markers for the early detection of Alzheimer's disease (AD). Spatial navigation has emerged as a promising marker, as impairments in both egocentric and allocentric navigation have been reported in preclinical AD and mild cognitive impairment (MCI). However, findings regarding the relative involvement of these navigational representations remain inconsistent. Moreover, little is known about how MCI affects other forms of spatial representation beyond navigation.

OBJECTIVE: The present study aims to investigate navigational, inner, and outer bodily representations in individuals with MCI to provide a broader characterization of the cognitive changes associated with this condition across different bodily and navigational space representations.

METHODS: We conducted a cross-sectional comparative study involving 28 healthy controls (HC) and 25 participants diagnosed with MCI (PtwMCI). All participants completed tasks and questionnaires probing: (a) different interoceptive dimensions (interoceptive accuracy [IAcc], awareness [IAw], and sensibility [ISe]); (b) action-oriented (aBR) and nonaction-oriented (NaBR) body representations; (c) landmark, route, and survey knowledge of a virtual environment.

RESULTS: PtwMCI showed reduced IAcc and ISe and performed less accurately in landmark and route tasks compared to HC.

CONCLUSIONS: Our findings indicate early impairments in interoceptive (inner body) and navigational processing, even in the initial stages of cognitive decline. These difficulties may thus represent an early marker of neurodegeneration. The observed co-occurrence of alterations across these domains highlights the need for future studies to clarify the relationship between body-related cognitive processes and broader cognitive functions in the Alzheimer's disease continuum.},
}

Humans
Female
Male
Aged
Cross-Sectional Studies
*Cognitive Dysfunction/physiopathology/psychology
*Spatial Navigation/physiology
*Prodromal Symptoms
*Interoception/physiology
*Body Image/psychology
Neuropsychological Tests
Middle Aged
Space Perception/physiology
*Dementia/psychology/physiopathology

@article {pmid42568007,
year = {2026},
author = {Wang, Z and Chen, J},
title = {ARG128-associated recognition of nobiletin by BACE1 revealed by triplicate molecular dynamics, MM-GBSA, and residue-level decomposition.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42568007},
issn = {1573-501X},
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide, and beta-secretase 1 (BACE1) remains a high-priority target for reducing amyloid-beta production. Nobiletin, a polymethoxylated flavonoid from citrus peel, has reported neuroprotective and amyloid-lowering effects in AD models, and previous enzymatic work suggested weak BACE1 inhibition; however, its replica-level binding stability and residue-level energetic determinants remain unresolved. Here, we analyzed the nobiletin-BACE1 complex using ChEMBL-based chemical-space contextualization, qualitative QSAR uncertainty assessment, molecular docking, triplicate 200-ns all-atom molecular dynamics simulations, molecular mechanics generalized Born surface area (MM-GBSA) end-point scoring, residue-level decomposition, ProLIF interaction fingerprints, electrostatic surface analysis, and a same-protocol OM99-2 structural control. The ligand remained locally accommodated within the BACE1 cleft across the sampled trajectories, with a mean internal MM-GBSA score (DeltaG_bind) of - 15.71 +/- 0.76 kcal/mol (n = 3: - 14.20, - 16.35, and - 16.57 kcal/mol). Residue-level decomposition identified ARG128 as the dominant computed hotspot (total mean = - 11.13 +/- 0.38 kcal/mol), with favorable van der Waals (VDW mean = - 6.88 +/- 0.21 kcal/mol) and Coulombic (Coulomb mean = - 4.25 +/- 0.53 kcal/mol) components. Additional hydrophobic/aromatic packing involved VAL69, TYR71, PRO70, PHE38, and PRO129, while ASP32/ASP228 were positioned outside the dominant nobiletin contact pattern. Together, these results support a putative ARG128-associated, non-dyad-dominant catalytic-cleft recognition model that should be interpreted as a hypothesis-generating computational framework for future biochemical testing and scaffold optimization.},
}

@article {pmid42568064,
year = {2026},
author = {Yang, J and Zhao, X and Liu, Y and Cai, Y and Fan, Y and , },
title = {Interactive Effects of Plasma Alzheimer Disease Biomarkers and White Matter Hyperintensities on Cognitive Decline and Clinical Progression in Nondemented Adults.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e050676},
doi = {10.1161/JAHA.126.050676},
pmid = {42568064},
issn = {2047-9980},
abstract = {BACKGROUND: Alzheimer disease pathology and cerebral small-vessel disease frequently coexist in older adults, yet how their interaction influences early clinical progression remains poorly understood, particularly in individuals without dementia. We aimed to investigate how plasma Alzheimer disease biomarkers and white matter hyperintensities (WMHs) interact to influence cognitive trajectories and the risk of progression to cognitive impairment and dementia.

METHODS: We studied 463 nondemented participants from the ADNI (Alzheimer's Disease Neuroimaging Initiative). Linear mixed-effects models assessed interactions between plasma biomarkers and WMHs on cognitive trajectories. Cox models examined incident cognitive impairment and dementia. Moderated mediation analyses explored potential biological pathways.

RESULTS: Among 463 participants, plasma phosphorylated tau 217 to β-amyloid 42 ratio was the only biomarker that consistently interacted with WMHs across multiple stages of disease progression, including cognitive decline (Mini-Mental State Examination: β=-0.05 [95% CI, -0.06 to -0.03]; executive function: β=-0.02 [95% CI, -0.03 to -0.01]; memory: β=-0.03 [95% CI, -0.04 to -0.02]; language: β=-0.03 [95% CI, -0.04 to -0.02]; visuospatial function: β=-0.02 [95% CI, -0.04 to -0.01]) and increased clinical risk (cognitive impairment: χ[2]=15.67, P=0.047; dementia: χ[2]=15.88, P=0.044). These interactive associations were most pronounced in cognitively normal individuals and men. Moderated mediation analyses indicated that plasma glial fibrillary acidic protein partially mediated the interaction between phosphorylated tau 217 to β-amyloid 42 ratio and WMHs for executive function and language performance.

CONCLUSIONS: These findings indicate that phosphorylated tau 217 to β-amyloid 42 ratio and WMHs jointly contribute to clinical progression in nondemented individuals, with astrocytic activation potentially involved in this process.},
}

@article {pmid42568124,
year = {2026},
author = {Blujus, JK and Oh, H and , },
title = {The Impact of Denoising Approaches on the Relationship Between Alzheimer's Disease Diagnostic Status and Network Topology Measures.},
journal = {Human brain mapping},
volume = {47},
number = {11},
pages = {e70622},
doi = {10.1002/hbm.70622},
pmid = {42568124},
issn = {1097-0193},
support = {R01AG068990/NH/NIH HHS/United States ; R01AG069265/NH/NIH HHS/United States ; S10OD025181/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging/methods/standards ; Female ; *Cognitive Dysfunction/diagnostic imaging/physiopathology ; Male ; *Brain/diagnostic imaging/physiopathology ; Aged ; *Nerve Net/diagnostic imaging/physiopathology ; *Image Processing, Computer-Assisted/methods/standards ; Aged, 80 and over ; Artifacts ; *Connectome/methods/standards ; },
abstract = {Graph theory provides a promising technique to investigate Alzheimer's disease (AD)-related alterations in brain network properties. However, there are discrepancies in the reported disruptions that occur to network topology across the AD continuum. In this study, we examined whether diagnostic group differences in graph metrics are attributed to differences in denoising approach used in fMRI processing. Resting state data from 60 cognitively normal (CN), 55 Mild Cognitive Impairment (MCI), and 38 AD participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were denoised using 11 pipelines including combinations of confound regression (head motion parameters, white matter [WM], cerebrospinal fluid [CSF], global signal), volume censoring (scrubbing, spike regression), and component-based noise removal (Independent Component Analysis-based Automatic Removal of Motion Artifacts [ICA-AROMA], anatomical and temporal component correction). Graph metrics representing network segregation (clustering coefficient, modularity, local efficiency), network integration (largest connected component, path length, global efficiency), and small-worldness were calculated. The results revealed that diagnostic group differences in modularity and local efficiency were dependent on denoising approach, especially in high-parameter regression models in combination with censoring methods (36 parameters and spike regressor or volume censoring). Independent of denoising approach, CN exhibited more segregated (clustering coefficient) but less integrated (largest component, path length, global efficiency) networks than MCI and AD. Independent of diagnosis, denoising strategy significantly affected the magnitude of all metrics, particularly models including global signal regression. Collectively, these results suggest that the directionality of the diagnostic differences in network topology, particularly in global metrics of network segregation, can vary based upon the denoising approach employed, although the effect size is small. Transparent reporting of preprocessing decisions is critical for the accurate interpretation of graph theoretical findings in the context of AD and a better understanding of the mechanisms underlying pathological aging.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology
*Magnetic Resonance Imaging/methods/standards
Female
*Cognitive Dysfunction/diagnostic imaging/physiopathology
Male
*Brain/diagnostic imaging/physiopathology
Aged
*Nerve Net/diagnostic imaging/physiopathology
*Image Processing, Computer-Assisted/methods/standards
Aged, 80 and over
Artifacts
*Connectome/methods/standards

@article {pmid42568171,
year = {2026},
author = {Lv, J and Cai, X and Yang, Z and Li, B and Zhou, Y and Li, F and Fu, H},
title = {A comprehensive assessment of cholinesterase inhibitors for the treatment of Alzheimer's disease based on drug selection recommendations for Chinese Medical Institutions.},
journal = {Expert review of pharmacoeconomics & outcomes research},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737167.2026.2715983},
pmid = {42568171},
issn = {1744-8379},
abstract = {BACKGROUND: Cholinesterase inhibitors (ChEIs) are widely used to treat Alzheimer's disease (AD), yet the optimal choice remains unclear.

RESEARCH DESIGN AND METHODS: This study aimed to comprehensively evaluate the overall clinical value of seven ChEI formulations (donepezil tablets, rivastigmine capsules, rivastigmine patches, galantamine tablets, galantamine orally disintegrating tablets, and two huperzine A formulations) to provide evidence-based guidance for rational AD pharmacotherapy selection. The evaluation framework used in this study was derived from the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition). This framework integrates mini-health technology assessment (mini-HTA) with the System of Objectified Judgment Analysis (SOJA). Seven formulations were assessed across five weighted dimensions: pharmacological properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points). A systematic literature search was performed using PubMed, CNKI, Wanfang, and official regulatory databases.

RESULTS: Within this assessment framework, donepezil tablets achieved the highest score (74.86), followed by rivastigmine patches (73.50) and rivastigmine capsules (72.28). These three formulations are recommended as priority options for inclusion in Chinese hospital formularies. The remaining four drugs may be prescribed according to individual patient conditions and institutional available resources.

CONCLUSIONS: This evaluation provides evidence-based guidance for clinical and institutional decision-making in AD management and delivers a generalizable assessment framework adaptable to local real-world data for healthcare institutions globally.},
}

@article {pmid42568185,
year = {2026},
author = {Larimi, MG and Thurber, KR and Tycko, R},
title = {Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.08.003},
pmid = {42568185},
issn = {1542-0086},
abstract = {Fibrils formed by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, containing molecular structures that vary with growth conditions in ways that are not fully understood. Here we use cryogenic electron microscopy to characterize the structure of rapidly twisting Aβ40 fibrils, for which the distance between apparent width minima in electron microscope images ("cross-over distances") is approximately 25 nm. From samples grown under a single set of growth conditions, we obtain high-resolution structures for three different rapidly twisting polymorphs. Although their cross-over distances are similar, the three rapidly twisting polymorphs differ in twist handedness, symmetry, molecular conformations, and intermolecular contacts. Two of the rapidly twisting polymorphs resemble Aβ40 polymorphs with longer cross-over distances that have been described previously, including polymorphs extracted from brain tissue of Alzheimer's disease patients or created by seeded growth from amyloid in brain tissue, but have shorter conformationally ordered segments and other specific conformational differences. These results contribute to our understanding of amyloid polymorphism, connections between morphology and molecular structure, and relationships between brain-derived and in vitro-grown fibrils.},
}

@article {pmid42568190,
year = {2026},
author = {Kim, B and Belza, B and Johnson, S and Waddington, E and Moczygemba, W and Fazio, S and Prophater, L},
title = {Evaluating a Coaching Intervention for Dementia Care Practice Recommendations in Care Communities: A Cluster Randomized Controlled Trial.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag183},
pmid = {42568190},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Within care communities, including nursing home and assisted living settings, person-centered dementia care, outlined by the 2018 Alzheimer's Association Dementia Care Practice Recommendations (DCPR), is foundational to quality care and improving staff outcomes. This study evaluates the effectiveness of a six-month Care Community Coaching Program in enhancing person-centered dementia care and staff outcomes in alignment with the DCPR.

RESEARCH DESIGN AND METHODS: A cluster randomized controlled trial was conducted with 77 care communities and 434 staff members-227 from 38 intervention communities and 207 from 39 control communities. Outcomes included employee satisfaction (areas: job satisfaction, team building and communication, scheduling and staffing, training, and management and leadership), person-centered care practices (areas: workplace practices, individualized care and services, caregiver-resident relationships), and dementia care confidence, measured pre- and post-intervention and at three-month follow-up. A generalized Estimating Equations (GEE) model was used to estimate intervention effects.

RESULTS: Care communities assigned to the coaching intervention showed statistically significant improvements in employee satisfaction and staff perceptions of workplace practices and individualized care. No statistically significant effects on staff perceptions of caregiver-resident relationships or on dementia care confidence were noted.

DISCUSSION AND IMPLICATIONS: Findings provide direction for future research and intervention development, including examining coaching's impact on resident quality outcomes, and incorporating skills training into future models. Collectively, findings provide evidence of the effectiveness of a Care Community Coaching Program in improving staff outcomes and person-centered practices, offering a practical path towards improving the lived experience of residents and staff in care communities.},
}

@article {pmid42568211,
year = {2026},
author = {Uruk, G and Youssef, H and Gatto, RG and Hossain, N and Whitwell, JL and Reichard, RR and Josephs, KA},
title = {Artificial intelligence-based 3D segmentation of tangle-associated TDP-43 in neurodegeneration.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70131},
doi = {10.1111/bpa.70131},
pmid = {42568211},
issn = {1750-3639},
support = {R01-AG37491/NH/NIH HHS/United States ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP-43 are yet to be elucidated. We investigate relationships between TDP-43 inclusions and the tangle maturation continuum in AD, PART, and co-pathologies by multiplex immunostaining combined with artificial intelligence (AI)-based segmentation via object recognition, reconstruction, and quantification. We performed anti-phosphorylated TDP-43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP-43 (PART-TDP), five cases with high likelihood AD and TDP-43 (AD-TDP), and four cases of high likelihood AD with TDP-43 and Lewy Body disease (AD-TDP-LBD). Confocal imaging was taken from eight regions: amygdala (amygdala-BL and amygdala-CM) and hippocampus (Cornu Ammonis (CA)-1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP-43 (TAT) inclusions. TATs, which were either identified by pTDP-43 and AT8 or pTDP-43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre-TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre-TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI-based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP-43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region-specific dynamics in the neurodegenerative processes of PART and AD.},
}

@article {pmid42568438,
year = {2026},
author = {Sun, C and Zhang, T and Fan, B and Zhang, X and Zhao, N},
title = {Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT abnormality.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1876444},
pmid = {42568438},
issn = {1664-3224},
mesh = {Animals ; *Nicotinamide Phosphoribosyltransferase/metabolism ; *Alzheimer Disease/therapy/pathology/metabolism ; *Piperidines/pharmacology ; Mice ; Amyloid beta-Protein Precursor/genetics ; *Acrylamides/pharmacology ; Mice, Transgenic ; *Physical Conditioning, Animal ; Disease Models, Animal ; *Cytokines/metabolism ; Presenilin-1/genetics ; NAD/metabolism ; Mitochondria/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Brain/metabolism/pathology ; Humans ; },
abstract = {Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD[+] salvage pathway, has emerged as an important regulatory node linking metabolic homeostasis to neuroinflammatory responses. However, although pharmacological inhibition of NAMPT may attenuate inflammatory activation, it may also reduce intracellular NAD[+] availability, thereby exacerbating mitochondrial dysfunction and disturbances in energy metabolism. Here, we found that 6-month-old APP/PS1 mice exhibited an abnormal, cell type-specific distribution of NAMPT in the brain, characterized by reduced neuronal NAMPT and increased microglial NAMPT. This abnormality was accompanied by disrupted NAD[+] homeostasis, marked neuroinflammatory activation, mitochondrial structural and functional impairment, increased β-amyloid (Aβ) burden, and impaired learning and memory ability. FK866 (1 mg/kg per injection, once every other day for 12 weeks) alone exerted limited effects and was insufficient to ameliorate the overall pathological phenotype. By comparison, a 12-week aerobic treadmill exercise program markedly ameliorated cognitive impairment, attenuated Aβ pathology, suppressed neuroinflammation, and improved mitochondrial integrity and bioenergetic function in APP/PS1 mice. More importantly, under NAMPT-inhibited conditions, exercise still preserved hippocampal NAD[+] homeostasis and maintained significant neuroprotective effects. Compared with exercise alone, the combined intervention with exercise and FK866 further improved selected indices related to Aβ pathology, neuroinflammation, oxidative stress, and mitochondrial damage. These additional effects may be associated with increased NAD[+] biosynthesis through the NMNAT3 pathway, as well as reduced NAD[+] consumption and neuroinflammatory activation through the suppression of CD38 and PARP1 expression.},
}

Animals
*Nicotinamide Phosphoribosyltransferase/metabolism
*Alzheimer Disease/therapy/pathology/metabolism
*Piperidines/pharmacology
Mice
Amyloid beta-Protein Precursor/genetics
*Acrylamides/pharmacology
Mice, Transgenic
*Physical Conditioning, Animal
Disease Models, Animal
*Cytokines/metabolism
Presenilin-1/genetics
NAD/metabolism
Mitochondria/metabolism
Amyloid beta-Peptides/metabolism
Male
Brain/metabolism/pathology
Humans

@article {pmid42568451,
year = {2026},
author = {Guo, J and Li, J and Gao, B and Liu, K and Sun, X and Ye, D and Mao, Y},
title = {Independent and combined associations of diabetes and thyroid disorders with risks of incident dementia.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1874555},
pmid = {42568451},
issn = {1664-2392},
mesh = {Humans ; *Thyroid Diseases/complications/epidemiology ; Female ; *Dementia/epidemiology/etiology ; Male ; Risk Factors ; *Diabetes Mellitus/epidemiology ; Incidence ; Aged ; United Kingdom/epidemiology ; Middle Aged ; },
abstract = {BACKGROUND: Diabetes and thyroid disorders are modifiable risk factors for cognitive impairment. However, no studies have been conducted to comprehensively examine associations of different types of the two diseases, as well as their combinations, with dementia risks.

METHODS: Based on the data from UK Biobank study, patients with different types of diabetes and thyroid disorders were identified with the hospital inpatient record. Status of dementia was assessed with multi-source information. Independent and combined associations of diabetes and thyroid disorders with dementia were estimated with Cox regression models.

RESULTS: Among 284,081 participants, 8,236 incident cases of all-cause dementia (ACD) [3,755 Alzheimer's disease (AD) cases, 1,893 vascular dementia (VD) cases] were identified over a mean [standard deviation (SD)] follow-up of 13.03 (2.29) years. Four types of diabetes and two types of thyroid disorders were significantly associated with increased risks of dementia. Compared with participants without diabetes and thyroid disorders, those with only thyroid disorders [hazard ratio (HR) = 1.33, 95% confidence interval (CI) = 1.21 to 1.47, P < 0.001], only diabetes (HR = 1.76, 95% CI = 1.64 to 1.89, P < 0.001), and both (HR = 2.16, 95% CI = 1.84 to 2.53, P < 0.001) had elevated risks of ACD (P trend < 0.001), as well as higher risks of AD and VD. Combined associations of hypothyroid and diabetes and of hyperthyroid and diabetes were also significantly positive (all P values < 0.05). Moreover, cumulative years of diabetes and thyroid were related to higher risks of dementia.

CONCLUSIONS: Diabetes, thyroid disorders, and their combinations were associated with increased risks of dementia in adults aged 55 years and older.},
}

Humans
*Thyroid Diseases/complications/epidemiology
Female
*Dementia/epidemiology/etiology
Male
Risk Factors
*Diabetes Mellitus/epidemiology
Incidence
Aged
United Kingdom/epidemiology
Middle Aged

@article {pmid42568502,
year = {2026},
author = {Han, D and Yang, C},
title = {Infection-driven gut dysbiosis and epigenetic programming of microglia: toward a systems level framework linking microbial metabolites, neuroinflammation, synaptic dysfunction, and probiotic modulation.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1815265},
pmid = {42568502},
issn = {2235-2988},
mesh = {*Microglia/metabolism/immunology ; Humans ; *Epigenesis, Genetic ; *Dysbiosis/microbiology ; *Probiotics ; Animals ; *Neuroinflammatory Diseases ; *Gastrointestinal Microbiome ; Inflammation ; Neurodegenerative Diseases ; Synapses ; },
abstract = {Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are increasingly viewed as conditions influenced by systemic immune and metabolic disturbances beyond the central nervous system (CNS). Emerging evidence suggests that infection-driven intestinal dysbiosis may function as an upstream contributor to systemic inflammation through disruption of gut barrier integrity. Increased permeability can facilitate the translocation of microbial components and metabolites into circulation, potentially influencing host immune programming via epigenetic mechanisms. Among CNS immune cells, microglia appear particularly susceptible to such peripheral cues due to their longevity and capacity for stimulus-dependent transcriptional adaptation. Experimental studies indicate that transient systemic immune challenges may induce persistent chromatin-level alterations within microglial regulatory regions, thereby reshaping their responsiveness to subsequent inflammatory stimuli or age-related stressors, including oxidative stress, chronic low-grade inflammation (inflammaging), and age-associated decline in cellular homeostatic and repair mechanisms. This phenomenon, often described as innate immune memory, may contribute to sustained neuroinflammatory activity and impaired synaptic function across the lifespan. Microbiota-derived metabolites, including short-chain fatty acids and tryptophan catabolites, have been implicated in modulating host transcriptional pathways through histone deacetylase inhibition and receptor-mediated signaling.},
}

*Microglia/metabolism/immunology
Humans
*Epigenesis, Genetic
*Dysbiosis/microbiology
*Probiotics
Animals
*Neuroinflammatory Diseases
*Gastrointestinal Microbiome
Inflammation
Neurodegenerative Diseases
Synapses

@article {pmid42568632,
year = {2026},
author = {Liu, J and Chen, W},
title = {Identification and validation of mitophagy and astrocyte-related molecular signature in the pathogenesis of Alzheimer's disease: evidence from ensemble learning-driven multi-omics and clinical validation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1910621},
pmid = {42568632},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited diagnostic tools and therapeutic options. Dysregulated mitophagy in astrocytes plays a pivotal role in AD pathogenesis. This study aims to identify a mitophagy and astrocyte (MA)-associated molecular signature for AD diagnosis and therapeutic targeting.

METHODS: Limma, WGCNA, xCell, PPI network and integrated machine learning pipeline coupled with SHAP were deployed on AD patient hippocampal bulk profiles (GSE28146, GSE36980, GSE29378, GSE48350) for identification of MA-associated predictive model and hub gene. Next, astrocyte patten and MA-associated hub gene molecular performance were estimated in hippocampal single-cell profile of AD patients (GSE163577) via advanced analytical frameworks. In addition, active learning framework and molecular docking was deployed in GSE29378 for identification of therapeutic candidate for AD patients by targeting MA-associated hub gene. Furthermore, AD hippocampal tissues were collected, and then MA-associated hub gene expression was estimated.

RESULTS: A core 8-gene MA signature (ITSN1, VLDLR, CYP7A1, SREBF2, RASL12, TPMT, CYP4X1, ARHGEF) was identified, which can guide the molecular subgroup identification and predictive model construction for AD patients. ITSN1 can be considered as the MA-associated hub gene in AD pathogenesis, which was up-regulated and predominantly expressed in astrocytes. Drug repositioning identified BRD-K10008415 as the potential compound predicted to reverse the AD signature by targeting ITSN1.

CONCLUSIONS: This study identified ITSN1 as a MA-associated critical hub potential connecting mitophagy dysregulation and astrocyte dysfunction in AD. We also identified MA-associated molecular signatures that can potentially elaborate predictive effects on AD pathogenesis. BRD-K10008415 can be considered as potential candidate for AD treatment by targeting ITSN1.},
}

@article {pmid42569056,
year = {2026},
author = {Dowjat, WK and Hwang, YW},
title = {Overexpression of DYRK1A in down syndrome: Analysis of kinase activity.},
journal = {Biochemistry and biophysics reports},
volume = {47},
number = {},
pages = {102722},
pmid = {42569056},
issn = {2405-5808},
abstract = {DYRK1A (dual-specificity tyrosine phosphorylation regulated kinase 1A) is known to play critical roles in regulating numerous cellular functions like cell cycle, neuronal development, and immune homeostasis. Altered expression DYRK1A is implicated in Alzheimer's Disease and various features of Down Syndrome (DS). The DYRK1A gene is located on chromosome 21 and due to trisomy of this chromosome in DS, the level of DYRK1A is elevated in the gene-dosage dependent manner. Nevertheless, how an increase in DYRK1A protein level would affect its activity in DS remains to be determined. The question was examined by performing side by side comparison of protein levels and the activity of DYRK1A extracted from control and DS samples. We show that DYRK1A activity elevation in DS is in parallel to that of DYRK1A protein level regardless of the status of kinase phosphorylation. This suggests that DYRK1A catalytic activity in DS is mainly regulated by protein level.},
}

@article {pmid42569203,
year = {2026},
author = {Wu, HY and Hou, JH and Huang, LY and Tan, L and Xu, W},
title = {APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.},
journal = {Biological psychiatry global open science},
volume = {6},
number = {5},
pages = {100773},
doi = {10.1016/j.bpsgos.2026.100773},
pmid = {42569203},
issn = {2667-1743},
abstract = {BACKGROUND: Gene-environment interplay contributes to the heterogeneous etiology of Alzheimer's disease (AD). Hypertension (HTN) is a major modifiable vascular risk factor, but whether its association with AD differs across APOE genotypes remains unclear. We examined the interaction between HTN and APOE genotypes in relation to incident AD and explored plasma proteomic correlates as potential biological clues.

METHODS: Longitudinal data from 318,923 UK Biobank participants without dementia were analyzed; participants had a mean age of 56.24 years, an APOE ε4 frequency of 28.29%, and a median follow-up period of 13 years. Cox proportional hazards models with competing-risk adjustment for death were used to assess additive and multiplicative interactions between HTN and APOE genotypes. Plasma proteomic data from 34,141 participants, covering 2790 proteins, were further analyzed using mediation and bioinformatics approaches.

RESULTS: HTN showed a significant multiplicative interaction with APOE ε4 status for incident AD (p < .001). The association between HTN and AD risk was strongest among APOE ε2 carriers, followed by ε33 carriers and ε4 carriers, with hazard ratios of 1.570, 1.213, and 1.129, respectively. Among APOE ε2 carriers, prosaposin and ganglioside GM2 activator significantly mediated the HTN-AD association, with mediation proportions of 10.46% and 3.37%, respectively. These proteins were enriched in sphingolipid metabolism and lysosomal function.

CONCLUSIONS: The association between HTN and incident AD varies across APOE genotype strata, with the strongest relative association observed among APOE ε2 carriers. These findings suggest genotype-dependent heterogeneity in vascular contributions to AD risk. Proteomic results should be interpreted as exploratory biological clues and require further validation.},
}

@article {pmid42569234,
year = {2026},
author = {Rizvi, B and Adams, JN and Bamford, A and Kim, S and Sathishkumar, M and Tustison, NJ and Taylor, L and Tuteja, N and McMillan, L and Nan, B and Cai, H and Escalante, YY and Meza, NJ and Harris, AL and Malhas, R and Brickman, AM and Mapstone, M and Thomas, EA and Yassa, MA},
title = {Parallel neuroinflammatory pathways to cerebrovascular burden and amyloid beta in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70415},
doi = {10.1002/dad2.70415},
pmid = {42569234},
issn = {2352-8729},
abstract = {INTRODUCTION: Upstream neuroinflammation plays an important role in Alzheimer's disease (AD) but remains poorly understood. We tested whether two distinct neuroinflammatory markers are associated with cerebrovascular burden and amyloid beta (Aβ), and downstream, with plasma phosphorylated tau (p-tau217), medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits.

METHODS: Cognitively unimpaired older adults without dementia or mild cognitive impairment were recruited from a community sample (Biomarker Exploration in Aging, Cognition, and Neurodegeneration; [BEACoN]; N = 126). We used structural equation modeling to test whether plasma chitinase-3-like protein 1 (YKL-40) and glial fibrillary acidic protein (GFAP) contribute to distinct pathways.

RESULTS: Higher plasma YKL-40 was associated with greater white matter hyperintensity (WMH), whereas higher plasma GFAP was related to increased 18F-florbetapir (FBP) standardized uptake value ratio (SUVR). Higher plasma GFAP, WMH, and FBP SUVR were independently associated with increased p-tau217. Plasma p-tau217 was associated with reduced MTL cortical thickness and hippocampal volume. Reduced hippocampal volume was related to worse memory.

DISCUSSION: Future work can further investigate these neuroinflammatory pathways as potential therapeutic targets for AD.},
}

@article {pmid42569297,
year = {2026},
author = {Ortuño-Sahagún, D and Carrera-Quintanar, L},
title = {Editorial: Nutrients and bioactive compounds: preventing and treating neurodegenerative diseases and disorders.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1908638},
doi = {10.3389/fnut.2026.1908638},
pmid = {42569297},
issn = {2296-861X},
}

@article {pmid42569462,
year = {2026},
author = {Alruwais, N and Althobaiti, GA and Alaql, YB and Almutairi, SAH and Alshareef, WM and Mahrous, FA and Aloqaybi, SAS and Lasloom, RAA and Aljasser, AA},
title = {Retinal Microvascular Biomarkers Measured by Optical Coherence Tomography Angiography in Neurodegenerative and Neurovascular Disorders: A Systematic Review and Meta-Analysis.},
journal = {Clinical ophthalmology (Auckland, N.Z.)},
volume = {20},
number = {},
pages = {609387},
doi = {10.2147/OPTH.S609387},
pmid = {42569462},
issn = {1177-5467},
abstract = {PURPOSE: Neurodegenerative and neurovascular disorders are increasingly recognized as major causes of disability worldwide and require accessible biomarkers for early detection and monitoring. Given the close anatomical and microvascular relationship between the retina and the central nervous system, optical coherence tomography angiography (OCTA) has emerged as a promising non-invasive technique for assessing retinal microvascular alterations associated with neurological disease. This systematic review and meta-analysis evaluated OCTA-derived retinal microvascular parameters as potential biomarkers of neurovascular dysfunction.

METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD420261305354). PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from January 2015 to December 2025. Studies comparing OCTA-derived retinal vascular parameters between patients with neurodegenerative or neurovascular disorders and healthy controls were included. Primary outcomes were superficial capillary plexus vessel density (SCP-VD), deep capillary plexus vessel density (DCP-VD), and foveal avascular zone (FAZ) area. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random-effects models.

RESULTS: Thirteen studies were included in the quantitative synthesis. Compared with healthy controls, patients with neurodegenerative or neurovascular disorders demonstrated significantly reduced SCP vessel density (SMD -0.60, 95% CI -0.78 to -0.43; I[2] = 43%) and DCP vessel density (SMD -0.84, 95% CI -1.15 to -0.53; I[2] = 78%). FAZ area was significantly enlarged in disease groups (SMD 0.62, 95% CI 0.29 to 0.94; I[2] = 83%). Disease-specific subgroup analyses demonstrated generally consistent trends across the included disorders.

CONCLUSION: OCTA-derived retinal microvascular alterations were consistently associated with neurodegenerative and neurovascular disorders. Reduced retinal vessel density, particularly within the deep capillary plexus, and enlargement of the FAZ may reflect underlying neurovascular dysfunction. While these findings support the potential role of OCTA as a non-invasive biomarker of neurological disease, the available evidence remains limited by methodological heterogeneity and predominantly observational study designs. Further longitudinal studies using standardized OCTA protocols are needed to establish the diagnostic and prognostic utility of these biomarkers.},
}

@article {pmid42569517,
year = {2026},
author = {Chen, M and Cao, C and Chen, T and Alhamad, D and Liu, T and Su, L and Zhu, D},
title = {Fine-scale individualized gyral folding-based cortical similarity networks reveal distinct organizational patterns in Alzheimer's disease and Lewy body dementia.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
doi = {10.1162/IMAG.a.1322},
pmid = {42569517},
issn = {2837-6056},
abstract = {Alzheimer's disease (AD) and Lewy body dementia (LBD) are common neurodegenerative dementias with overlapping clinical presentations, making differential diagnosis challenging. While structural magnetic resonance imaging (MRI) has revealed characteristic regional atrophy patterns, regional morphometric measures alone may not fully capture distributed cortical alterations. Morphometric similarity networks (MSNs) offer a systems-level framework to characterize coordinated structural organization, but existing approaches typically rely on atlas-based parcellations that may obscure individual-specific cortical folding geometry. Here, we propose a fine-scale, folding-informed cortical similarity network framework based on automatically detected three-hinge gyral (3HG) landmarks. Using a thickness-constrained arealization strategy in native surface space, we define individualized cortical regions and construct subject-specific MSNs without cross-subject registration. We then investigate how network topology relates to landmark-defined node count and how these properties differ between AD and LBD. We find that several graph theoretical metrics, particularly global efficiency and characteristic path length, exhibit clear associations with the number of detected landmarks, indicating that topology in individualized networks is partly shaped by node availability. When accounting for landmark count, several apparent group differences in global topology are attenuated, whereas multiple heterogeneity-related metrics remain significant, indicating that node-count scaling substantially influences the interpretation of individualized network topology. Nevertheless, multivariate topological patterns remain informative for AD/LBD classification after residualizing for node count, and landmark count itself provides modest diagnostic information. These findings highlight node-count scaling as a key methodological consideration in individualized structural networks and suggest that folding-based MSNs capture disease-related variation in cortical network organization between AD and LBD.},
}

@article {pmid42569620,
year = {2026},
author = {Ip, J and Heindel, WC and Ott, BR and Festa, EK},
title = {Distinct theta and alpha electrophysiological dynamics during audiovisual semantic processing in healthy aging and mild cognitive impairment.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100163},
doi = {10.1016/j.nbas.2026.100163},
pmid = {42569620},
issn = {2589-9589},
abstract = {Semantic memory decline is increasingly recognized as an early feature of Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), yet the neural dynamics supporting automatic and controlled semantic retrieval in healthy aging remain poorly defined. This study examined task-evoked oscillatory activity during audiovisual object recognition in young adults (YA; N = 27), healthy older adults (OA; N = 33), and individuals with amnestic MCI (N = 21). Participants judged object orientation while viewing living and nonliving images paired with congruent or incongruent characteristic sounds, allowing semantic relationships to be manipulated under implicit retrieval demands. Accuracy was high across groups, although participants with MCI showed reduced performance under the more perceptually challenging inverted conditions. Reaction times were slower in OA than YA and further slowed in MCI, with group differences varying by object animacy and semantic congruency. Event-related spectral perturbation analyses revealed distinct group-related patterns. Healthy older adults showed reduced early and increased late theta activity in frontocentral and parieto-occipital regions, consistent with delayed recruitment of control-related and perceptual-attentional processes. In contrast, MCI participants showed elevated and less condition-sensitive posterior alpha power, together with task- and condition-specific differences in frontocentral theta. The principal pattern of delayed theta recruitment in healthy aging and elevated posterior alpha in MCI was also observed in a supplementary task requiring explicit audiovisual semantic judgments. These findings provide preliminary evidence that healthy aging and amnestic MCI are associated with partly distinct patterns of task-evoked oscillatory activity during audiovisual semantic processing.},
}

@article {pmid42569823,
year = {2026},
author = {Oblak, AL and Sasner, M and Carter, GW and Howell, GR and Sukoff Rizzo, SJ and Leal, K and Territo, PR and Lamb, BT},
title = {The past, the present, and the future of preclinical mouse models for Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71741},
doi = {10.1002/alz.71741},
pmid = {42569823},
issn = {1552-5279},
support = {U54AG054345/NH/NIH HHS/United States ; },
mesh = {Animals ; *Disease Models, Animal ; *Alzheimer Disease/genetics/pathology ; Humans ; Mice ; },
abstract = {Over the past decade, the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium has transformed preclinical Alzheimer's disease (AD) research by addressing critical limitations in traditional mouse models that failed to translate to human disease. By leveraging human genetic discoveries, MODEL-AD has developed > 70 genetically informed mouse models, standardized phenotyping pipelines, and an open-access data infrastructure aligned with late-onset AD biology. These models incorporate human risk variants, environmental factors, and aging to better capture disease complexity, including emerging recognition of mixed pathologies such as vascular contributions, Lewy body disease, and TDP-43 proteinopathy. Despite substantial progress, key challenges remain, including modeling multimorbidity, integrating aging, and improving translational predictability. Here, we outline a strategic roadmap spanning short-, intermediate-, and long-term approaches to refine disease modeling, enhance preclinical testing rigor, and support precision medicine. Continued investment in MODEL-AD will be essential to accelerate therapeutic discovery and establish a scalable framework for studying complex neurodegenerative diseases.},
}

Animals
*Disease Models, Animal
*Alzheimer Disease/genetics/pathology
Humans
Mice

@article {pmid42569825,
year = {2026},
author = {Zhu, X and Haure-Mirande, JV and Bicak, M and Dong, P and Kruglikov, I and Li, A and Al-Subaie, A and Fossati, V and Noggle, S and Gandy, S and Ehrlich, ME},
title = {miR155, triplicated in Down syndrome, regulates the development of neural stem cells and GABAergic interneurons in Alzheimer's disease mouse and human iPSC models.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71684},
doi = {10.1002/alz.71684},
pmid = {42569825},
issn = {1552-5279},
support = {RF1AG058469/NH/NIH HHS/United States ; },
mesh = {Animals ; *MicroRNAs/genetics/metabolism ; Humans ; *Down Syndrome/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Interneurons/metabolism ; *Neural Stem Cells/metabolism ; Disease Models, Animal ; Mice ; *GABAergic Neurons/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; Mice, Knockout ; },
abstract = {INTRODUCTION: Dysfunctional microRNAs and GABAergic interneurons are features of Alzheimer's disease (AD). The role of neuronal microRNA155 (miR155), elevated in both AD and Down syndrome (DS), remains unknown.

METHODS: We utilized in silico analyses of published databases, MIR155-deleted and -overexpressing human induced pluripotent stem cell (hiPSC)-derived cells, cortical organoids, and amyloid beta precursor protein (APP)/PS1-miR155 knockout mouse.

RESULTS: MIR155HG (miR155 host gene) colocalizes with APP in a neuron-specific, topologically associated domain (TAD) in chromosome 21. In human neural stem cells (NSCs), neurons, and cortical organoids, MIR155 deletion enhanced NSC proliferation and GABAergic interneuron generation. MIR155 overexpression inhibited NSC marker expression and GABAergic interneuron generation. In APP/PS1 mice, miR155 deletion induced the expansion of hippocampal NSCs and increased hippocampal GABAergic interneurons.

DISCUSSION: Our findings, alongside the extensive studies of the role of microglial miR155 in neuroinflammation, reveal previously unrecognized miR155 roles in hippocampal NSC dynamics and GABAergic interneuron development, highlighting miR155 as a therapeutic target.},
}

Animals
*MicroRNAs/genetics/metabolism
Humans
*Down Syndrome/genetics/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
*Induced Pluripotent Stem Cells/metabolism
*Interneurons/metabolism
*Neural Stem Cells/metabolism
Disease Models, Animal
Mice
*GABAergic Neurons/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
Mice, Transgenic
Mice, Knockout

@article {pmid42569826,
year = {2026},
author = {Groeneveld, J and Perlaza, D and Olivé, C and Grangeon, L and Tesi, N and Nicolas, A and Jiang, C and de Rojas, I and Wallon, D and Rousseau, S and Rovira, M and de Asúa, DR and Moldenhauer, F and Mu, R and Cassinari, K and Zarea, A and Escabias, JA and Lambert, JC and Pijnenburg, YAL and Hulsman, M and Vijverberg, EGB and Levin, J and Jucker, M and McDade, E and Fortea, J and Holstege, H and Duits, FH and Vermunt, L and Patel, M and Johnson, M and Renton, AE and Goate, AM and Cruchaga, C and Pottier, C and Fernandez, MV and Belbin, O and Nicolas, G and Dols-Icardo, O and van der Lee, SJ and , },
title = {APOE and genetic risk variants influence Alzheimer's disease onset in carriers of an extra copy of APP, with and without Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71738},
doi = {10.1002/alz.71738},
pmid = {42569826},
issn = {1552-5279},
support = {1051003212000/ZONMW_/ZonMw/Netherlands ; #73305095007/ZONMW_/ZonMw/Netherlands ; //Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam/ ; //Stichting Dioraphte/ ; #LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; //SURF Cooperative/ ; 15318/NWO_/Dutch Research Council/Netherlands ; 17232/NWO_/Dutch Research Council/Netherlands ; PI21/01395//Institute of Health Carlos III/ ; PI24/01087//Institute of Health Carlos III/ ; FI20/00215//Institute of Health Carlos III/ ; PI19/01301//Institute of Health Carlos III/ ; PI19/01240//Institute of Health Carlos III/ ; P22/I01403//Institute of Health Carlos III/ ; FI24/00029//Institute of Health Carlos III/ ; INT21/00073//Institute of Health Carlos III/ ; PI20/01473//Institute of Health Carlos III/ ; PI23/01786//Institute of Health Carlos III/ ; //Fondo Europeo de Desarrollo Regional, Unión Europea, "Una manera de hacer Europa./ ; PDC-2023-51//Jerome Lejeune Foundation/ ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; SG-20-690363-DIAN/ALZ/Alzheimer's Association/United States ; //Fundación bancaria "La Caixa," Fundación ADEY, Fundación Echevarne and Grífols SA (GR@ACE project)/ ; //Ace Alzheimer Center Barcelona is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO)/ ; AC19/00097//PREADAPT Joint Program for Neurodegenerative Diseases (JPND)/ ; //German Research Foundation/ ; //Fondo de Investigaciones Sanitario/ ; CB06/05/2004//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII)/ ; CB18/05/00010//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII)/ ; //Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa/ ; 1R01AG056850-01A1//National Institutes of Health grants/ ; R21AG056974//National Institutes of Health grants/ ; R01AG061566//National Institutes of Health grants/ ; 1R01AG081394-01//National Institutes of Health grants/ ; 1R61AG066543-01//National Institutes of Health grants/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; IIBSP-DOW-2020151//Fundación Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon2020-Research and Innovation Framework Programme from the European Union/ ; U19AG032438//Institute on Aging/ ; //German Center for Neurodegenerative Diseases/ ; //Raul Carrea Institute for Neurological Research (FLENI)/ ; //Research and Development/ ; //Research and Development Grants for Dementia from Japan Agency for Medical Research and Development (AMED)/ ; //Korea Health Industry Development Institute (KHIDI), Korea Dementia Research Center (KDRC)/ ; RS-2024-00344521//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; #733050512//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; 2023-1334//Pascual Maragall Researchers Program/ ; },
mesh = {Humans ; *Down Syndrome/genetics/complications ; *Alzheimer Disease/genetics/epidemiology/complications ; *Amyloid beta-Protein Precursor/genetics ; Female ; Age of Onset ; Male ; Middle Aged ; *Genetic Predisposition to Disease ; *Apolipoproteins E/genetics ; Heterozygote ; Genetic Risk Score ; Risk Factors ; Apolipoprotein E4/genetics ; },
abstract = {INTRODUCTION: An extra copy of the amyloid precursor protein (APP) gene causes autosomal dominant Alzheimer's disease (AD) and AD in Down syndrome (DS), but the factors underlying variability in age at onset (AAO) remain unclear. We investigated whether sporadic AD risk variants modify AAO.

METHODS: We analyzed clinical and genetic data from 100 APP duplication (APPdup) carriers and 957 individuals with DS. Cox models assessed associations of apolipoprotein E (APOE) ε2 and ε4 and the AD genetic risk score (AD-GRS; excluding APOE and chromosome 21 variants) with AAO.

RESULTS: Mean AAO was earlier in APPdup than DS (51 ± 7 vs. 53 ± 6 years; P = 0.0005). APOE ε2 delayed onset (hazard ratio [HR] = 0.47, P < 0.0001), whereas APOE ε4 (HR = 1.5, P = 0.0003) and higher AD-GRS (HR = 1.3 per standard deviation, P < 0.0001) accelerated onset. Predicted median AAO differed by 10 years between lowest and highest genetic risk.

DISCUSSION: Sporadic AD genetic risk factors are important modifiers of AAO in APPdup and DS, explaining part of the marked variability in onset.},
}

Humans
*Down Syndrome/genetics/complications
*Alzheimer Disease/genetics/epidemiology/complications
*Amyloid beta-Protein Precursor/genetics
Female
Age of Onset
Male
Middle Aged
*Genetic Predisposition to Disease
*Apolipoproteins E/genetics
Heterozygote
Genetic Risk Score
Risk Factors
Apolipoprotein E4/genetics

@article {pmid42569829,
year = {2026},
author = {Ehrenberg, AJ and Falgàs, N and Jacobs, HIL and Grinberg, LT and , },
title = {Neuromodulatory subcortical systems in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71747},
doi = {10.1002/alz.71747},
pmid = {42569829},
issn = {1552-5279},
}

@article {pmid42569895,
year = {2026},
author = {Qi, X and Belloy, ME and Gu, J and Liu, X and Tang, H and He, Z},
title = {Robust Inference With Ghostknockoffs in Genome-Wide Association Studies With Sample Relatedness.},
journal = {Genetic epidemiology},
volume = {50},
number = {6},
pages = {e70051},
doi = {10.1002/gepi.70051},
pmid = {42569895},
issn = {1098-2272},
support = {AG066206/NH/NIH HHS/United States ; GM127063/NH/NIH HHS/United States ; AG066515/NH/NIH HHS/United States ; },
mesh = {*Genome-Wide Association Study/methods ; Humans ; *Models, Genetic ; Alzheimer Disease/genetics ; Polymorphism, Single Nucleotide ; Computer Simulation ; Phenotype ; UK Biobank ; },
abstract = {Genome-wide association studies (GWASs) have been extensively adopted to depict the underlying genetic architecture of complex traits. Recent studies show that knockoff-based methods can identify variants with unique, potentially causal effects on phenotypes. However, their statistical validity and effectiveness in studies with related individuals, such as the UK Biobank, remain unexplored. In this paper, we extensively evaluate a simple and effective analytical strategy that integrates GhostKnockoffs and state-of-the-art marginal association tests. We show that this approach is robust to arbitrary relatedness structure as long as the input Z-scores are derived from valid generalized linear mixed models. This robustness also extends GhostKnockoffs to other GWASs settings, including meta-analysis of studies with sample overlap when the input score test Z-scores are properly calibrated, and association test statistics beyond score tests in independent sample settings. We demonstrate the method's validity and practical utility using simulation studies and a meta-analysis of nine European ancestral genome-wide association studies and whole exome/genome sequencing studies for the Alzheimer's disease.},
}

*Genome-Wide Association Study/methods
Humans
*Models, Genetic
Alzheimer Disease/genetics
Polymorphism, Single Nucleotide
Computer Simulation
Phenotype
UK Biobank

@article {pmid42570063,
year = {2026},
author = {Paelaong, N and Sripha, K and Boondam, Y},
title = {Discovery of Anti-Neuroinflammatory Compounds in Alzheimer's Disease: Current Trends and Future Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42570063},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; Animals ; *Drug Discovery/trends/methods ; *Anti-Inflammatory Agents/therapeutic use/chemistry/pharmacology ; *Neuroinflammatory Diseases/drug therapy ; Inflammation/drug therapy ; },
abstract = {Chronic neuroinflammation in response to abnormal protein aggregates has been implicated as a critical mechanism in several neurodegenerative diseases, and the modulation of signaling pathways associated with inflammation is being explored as a potential strategy for new therapeutics. In Alzheimer's disease (AD), the neuroinflammation hypothesis also starts to influence the landscape of drug discovery in place of the previously regarded amyloid hypothesis. As such, the objective of this review is to compile recent advanced in the discovery of anti-neuroinflammatory compounds developed through chemical synthesis and structural modification, providing an overview of current trends in drug discovery strategies and scaffold redesign for the development of the next-generation of anti-neuroinflammatory therapeutics. It was found that the compounds described in the publications could be categorized into four groups: modification of natural compounds, rational drug design, drug screening approaches, and drug repurposing. While the categorization seems to be similar to drug discoveries in other fields, with the modification of natural compounds accounting for most publications, specific observations could still be made. Namely, the growing interest in the multitarget-directed ligand approach reflects the increasing recognition of AD as a multifactorial disease. Despite this, further research is required to identify additional effective activities or the appropriate combinations besides anti-neuroinflammatory activity. Lastly, this review also gives brief overview regarding physicochemical properties of central nervous system-active agents, of which anti-neuroinflammatory compounds are parts of, and suggests the adoption of in silico prediction models as screening tools before the use of in vitro or in vivo models.},
}

*Alzheimer Disease/drug therapy
Humans
Animals
*Drug Discovery/trends/methods
*Anti-Inflammatory Agents/therapeutic use/chemistry/pharmacology
*Neuroinflammatory Diseases/drug therapy
Inflammation/drug therapy

@article {pmid42471758,
year = {2026},
author = {Zhang, T and Dai, L and Ma, Y and Xu, S and Liu, X and Zhao, M and Li, W and Wang, J and Liu, Y},
title = {Conformational bifurcation of tau R3-R4 oligomers underlies fibril polymorphism.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.07.020},
pmid = {42471758},
issn = {1542-0086},
abstract = {Tau aggregation into amyloid fibrils is a central pathological feature of multiple neurodegenerative diseases, yet identical tau sequences can adopt structurally distinct fibril conformations associated with different disorders. How such disease-specific folds emerge from the same sequence remains poorly understood. Here, we use metadynamics and all-atom molecular dynamics simulations to elucidate the folding mechanisms of tau trimers comprising the R3-R4 region, the minimal aggregation nucleus of tau fibrils. By constructing the folding free-energy landscape within a pre-organized fibril-like scaffold, we identify a shared, partially folded intermediate from which two energetically comparable minimum free-energy pathways diverge, leading to either a compact Alzheimer's disease-like or a more open chronic traumatic encephalopathy-like C-shaped conformation. Structural analysis reveals that the β4-β6 triangular region acts as the central determinant of this bifurcation. Hydrophobic-core rearrangements within this region provide the primary energetic driving force for compaction, whereas the conformational flexibility of the 332PGGG335 hinge modulates whether this tendency can be structurally realized. Additional simulations show that stable formation of the triangular region requires cooperative multichain interactions; reducing oligomer size destabilizes this scaffold and abolishes ordered folding. Together, our results establish a mechanistic framework in which identical tau sequences access alternative folding routes through a common intermediate, explaining the emergence of disease-specific fibril polymorphism at the oligomeric level and highlighting early folding intermediates as potential targets for therapeutic intervention.},
}

@article {pmid42560407,
year = {2026},
author = {Feng, X and Yu, W and Guo, S and Ji, Y and Li, J and Wang, L and Zhong, G and Li, S and Niu, L and Zhu, D and Zhou, K and Du, Y},
title = {Aurantio-Obtusin Attenuates Aβ-Induced Cognitive Impairment and Synaptic Dysfunction by Suppressing Neuroinflammation in Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42560407},
issn = {1557-1904},
support = {82371194//the National Natural Science Foundation of China/ ; CSTB2024NSCQ-QCXMX0004//the Natural Science Foundation of Chongqing Municipality/ ; },
mesh = {Animals ; Male ; Mice ; *Amyloid beta-Peptides/toxicity ; Mice, Inbred C57BL ; *Neuroinflammatory Diseases/drug therapy/chemically induced/metabolism ; *Synapses/drug effects/metabolism ; *Anthraquinones/pharmacology/therapeutic use ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) features Aβ-driven neuroinflammation and synaptic dysfunction that converge on cognitive decline, underscoring the potential value of multi-target interventions. Aurantio-obtusin (AO), a bioactive anthraquinone from Cassia obtusifolia L., exhibits reported anti-inflammatory and antioxidant activities; however, whether AO counteracts Aβ-associated behavioral impairment through coordinated modulation of inflammatory and synaptic alterations remains unclear. Here, we investigated whether AO alleviates Aβ1-42-induced cognitive deficits and examined synapse- and inflammation-related molecular correlates. Male C57BL/6 mice received intracerebroventricular Aβ1-42 to establish an acute AD-like model and were treated with AO (10 mg/kg/day, oral gavage) for consecutive weeks. The results showed that AO improved spatial learning and memory in the Morris water maze, recognition memory in the novel object recognition test, and working memory in the Y-maze, without affecting spontaneous locomotor activity. Furthermore, AO alleviated synaptic dysfunction by restoring synaptophysin expression and upregulating GAD65, and mitigated neuroinflammation by elevating anti-inflammatory factors (IL-4, IL-10, ARG1) and reducing TNF-α. In vitro experiments confirmed that AO was non-cytotoxic to N2A[APP] cells across 0-80 μM, mildly downregulated BACE1 expression, and suppressed the Aβ-induced upregulation of pro-inflammatory mediators (IL-6, iNOS) in BV2 microglial cells. Overall, AO attenuated Aβ1-42-driven behavioral impairment in parallel with improvements in synapse-associated markers and inflammatory readouts. These findings support further evaluation of AO as a natural compound associated with modulation of Aβ-related neuroinflammatory and synapse-associated alterations.},
}

Animals
Male
Mice
*Amyloid beta-Peptides/toxicity
Mice, Inbred C57BL
*Neuroinflammatory Diseases/drug therapy/chemically induced/metabolism
*Synapses/drug effects/metabolism
*Anthraquinones/pharmacology/therapeutic use
*Peptide Fragments/toxicity
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
Maze Learning/drug effects

@article {pmid42560467,
year = {2026},
author = {Brimson, S and Thitilertdecha, P and Kumaree, KK and Brimson, JM},
title = {Sigma-1 Receptor Ligand Blarcamesine (ANAVEX 2-73) for Alzheimer's Disease: A Systematic Review.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {42560467},
issn = {1179-1934},
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) remains a major cause of dementia, and currently available therapies provide only modest clinical benefit or are limited by intravenous administration and treatment-related adverse effects. Blarcamesine (ANAVEX 2-73) is an orally administered sigma-1 receptor (S1R) agonist that has demonstrated neuroprotective effects in preclinical studies and has progressed through Phase I, Phase II and Phase IIb/III clinical trials. This systematic review evaluated the current clinical evidence for the efficacy and safety of blarcamesine in early-stage and mild-to-moderate AD.

METHODS: A systematic literature search was conducted in PubMed (including MEDLINE), Scopus, and Google Scholar, together with clinical trial registries, with the final search performed in September 2025. Reference sections of manuscripts were searched, and authors were contacted for additional data. Studies investigating only blarcamesine in participants with mild-to-moderate AD were included. Blarcamesine for other diseases or severe AD were excluded. Data were summarised descriptively in accordance with PRISMA guidelines. The risk of bias was assessed using version 2 of the Cochrane Risk of Bias tool (RoB2) for randomised, placebo-controlled trials, and an adapted version of RoB2 for cross-over trials.

RESULTS: One Phase I first-in-human study in healthy volunteers and ten reports describing two randomised clinical trials (NCT02244541, a randomised open-label study, and NCT03790709, a randomized placebo-controlled study) and their associated open-label extension studies (NCT02756858 and NCT04314934) were identified, including two peer-reviewed manuscripts, two preprints, and six conference abstracts. Thirty-two participants were enrolled in the Phase IIa open-label dose-finding study, where outcome measures were compared to baseline (NCT02244541). In the extended open-label study exploring the cognitive effect for another 52 weeks, 21 of 32 remained in the study (NCT02756858). The randomised placebo-controlled trial (NCT03790709) enrolled 509 participants and randomised them into three groups: 167 treated with 30 mg blarcamesine, 168 treated with 50 mg blarcamesine and 168 treated with placebo (for 30 mg blarcamesine, 112 completed the study; for 50 mg blarcamesine, 90 completed the study; and for placebo, 136 completed the study). Subsequently, 300 of 509 participants remained in the open-label extension (NCT04314934). Across these two studies, blarcamesine was generally well tolerated, with adverse events that were predominantly mild, transient, and dose-related. Treatment was associated with slower cognitive and functional decline, improvements in multiple clinical outcome measures, and reduced brain atrophy in genetically defined subgroups. Participants carrying the SIGMAR1 and COL24A1 wild-type genotypes were associated with greater therapeutic benefit, supporting the potential value of pharmacogenomic patient stratification.

CONCLUSIONS: Current clinical evidence suggests that blarcamesine is a promising orally administered therapeutic candidate for early-stage AD with an acceptable safety profile and encouraging efficacy, particularly in genetically defined populations. However, the available evidence is derived from a limited number of clinical studies, including secondary analyses and conference reports. Additional independent randomised clinical trials are required to confirm these findings and further define the role of blarcamesine in the treatment of AD.

PROSPERO REGISTRATION: CRD420251142826.},
}

@article {pmid42560687,
year = {2026},
author = {Joyce, NR and Balog, S and Gaither, R and Pfeiffer, MR and Bhondoekhan, F and Ott, BR and Margolis, SA and Curry, AE and Zullo, AR},
title = {A Motor Vehicle Crash as an Early Signal of Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70630},
pmid = {42560687},
issn = {1532-5415},
support = {R01HD096221//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01AG065722/AG/NIA NIH HHS/United States ; R01AG065722-S1/AG/NIA NIH HHS/United States ; R01AG079295/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: People with Alzheimer's disease and related dementias (ADRD) are at increased risk of motor vehicle crash (MVC) due to cognitive decline, which often begins years before diagnosis. MVC could serve as an indicator of ADRD-related cognitive impairment and facilitate earlier diagnosis.

METHODS: We conducted a matched cohort study of Medicare beneficiaries in New Jersey aged ≥ 69 years with incident ADRD diagnoses from 2010 to 2017 compared to individuals without ADRD and with four other medical conditions: acute myocardial infarction (AMI), asthma, chronic obstructive pulmonary disease (COPD), and diabetes. Comparison groups were sampled with replacement and matched on sex, age, and calendar quarter of diagnosis or claim (for the non-ADRD group). Crash prevalence at 6 months and 1, 2, and 3 years before diagnosis was compared using chi-square tests, and the monthly prevalence was plotted to examine longitudinal trends in crashes.

RESULTS: We identified 43,115 eligible individuals with incident ADRD diagnosis from 2010 to 2017. MVC crash prevalence was higher in the ADRD group than in non-ADRD and negative control groups at all measured pre-diagnosis time points: 6 months (2.99% vs. 2.31%-2.53%), 1 year (5.26% vs. 4.18%-4.65%), 2 years (9.52% vs. 7.88%-8.67%), and 3 years (13.64% vs. 11.29%-12.37%). The ADRD group was more likely to have multiple crashes in the pre-diagnosis period, but multiple events were rare overall (< 3%). Differences were statistically significant but represented small changes in prevalence. Crash prevalence did not reveal a clear signal of cognitive decline in the years leading up to the index diagnosis.

CONCLUSIONS: Older adults with ADRD had slightly higher prevalence of MVC in the 3 years before diagnosis than matched comparison groups, but absolute differences were small and recurrent crashes were rare. MVC alone is too rare to serve as a signal of incipient ADRD, highlighting the need for more sensitive measures.},
}

@article {pmid42560912,
year = {2026},
author = {Zhao, BW and Zhao, HF and Huang, YA and Hu, PW and You, ZH and Hu, L},
title = {A Novel Graph Transformer Framework for Predicting Drug-Disease Associations with Structural Awareness.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3721658},
pmid = {42560912},
issn = {2998-4165},
abstract = {Accurately predicting drug-disease associations (DDAs) is essential for accelerating the discovery of novel therapeutics. Graph representation learning-based computational models have become increasingly popular for this task due to their efficiency and cost-effectiveness. However, existing approaches often suffer from structural inductive biases and a limited ability to capture the rich heterogeneous context of biomedical molecules, which constrains their capacity to learn expressive drug and disease representations. To address this issue, we propose SGTL-DDA, a novel graph transformer framework designed to incorporate structural information and domain-specific knowledge from heterogeneous biological information networks (HBINs). SGTL-DDA integrates a meta-path-guided sampling strategy with a multi-level attention mechanism, enabling the model to jointly learn from both structural dependencies and attribute semantics in an end-to-end manner. Extensive experiments on two benchmark datasets demonstrate that SGTL-DDA consistently outperforms state-of-the-art methods in terms of Accuracy, F1-score, and AUC under a ten-fold cross-validation scheme. Furthermore, case studies on Alzheimer's disease and breast cancer confirm the predictive capability of SGTL-DDA, as it successfully identifies both known therapeutics and novel repositioning candidates, supported by molecular docking results and literature evidence.},
}

@article {pmid42560982,
year = {2026},
author = {Takeoka, C and Yada, T and Yamazaki, T and Kuroiwa, Y and Hirai, T and Fujino, K and Mizusawa, H and Takao, M and Terao, Y and Yamada, M},
title = {Classification of sporadic Creutzfeldt-Jakob disease based on resting state scalp-recorded electroencephalogram-derived indices.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0355367},
pmid = {42560982},
issn = {1932-6203},
mesh = {Humans ; *Creutzfeldt-Jakob Syndrome/classification/diagnosis/physiopathology ; *Electroencephalography/methods ; Aged ; Female ; Male ; *Scalp/physiopathology ; Alzheimer Disease/physiopathology/diagnosis ; Middle Aged ; Rest ; },
abstract = {Prion disease is a general term for a disease that causes cognitive disorders due to the accumulation of abnormal prion protein in the brain. Creutzfeldt-Jakob disease (CJD) is the most common case of prion disease, and sporadic Creutzfeldt-Jakob disease (sCJD) accounts for more than 70% of CJD cases. Early and accurate diagnosis of sCJD remains challenging. The aim of this study is to classify 6 sCJD patients from 10 healthy older adults and 23 Alzheimer's disease (AD) patients using resting-state scalp-recorded electroencephalogram (EEG)-derived indices. Power spectrum, SL values by Synchronization Likelihood (SL), and graph metrics by SL values were calculated for 5 frequency bands as EEG-derived indices. In addition, power spectrum and SL values were standardized and exponentially transformed for each subject and each frequency band. Graph metrics were calculated by these SL values. These indices were used as features for classification. Classifiers were constructed by features selected by Recursive Feature Elimination (RFE). The highest classification accuracy was 97.44% using a 12-dimensional feature. This accuracy was confirmed by indices after standardization and exponential transformation. Additional validation analyses were performed to assess the reliability of the selected classifier. Accuracy of nested LOOCV was 84.62%, supporting meaningful classification ability under a leakage-controlled validation framework. An analysis of robustness removing a group of subjects with high similarity with many others showed that the selected classifier maintained a micro-F1 score of 90.32%. Permutation test indicated that the observed performance was significantly higher than chance level, and repeated stratified 10-fold cross-validation showed relatively stable performance across different data partitions. These findings suggest that resting-state EEG-derived indices may provide useful candidate features for classification of sCJD, AD, and healthy older adults. However, further validation using larger independent cohorts is required to establish the generalizability and clinical reliability of the proposed classifier.},
}

Humans
*Creutzfeldt-Jakob Syndrome/classification/diagnosis/physiopathology
*Electroencephalography/methods
Aged
Female
Male
*Scalp/physiopathology
Alzheimer Disease/physiopathology/diagnosis
Middle Aged
Rest