@article {pmid42014405,
year = {2026},
author = {Da Silva, IIN and Ramirez, D and Parylak, SL and Wallace, LA and Tucker, JK and Erberich, JM and Katariya, R and McDonald, AH and Gallina, IS and Tucker, AL and Burgado, J and Jaeger, BN and Barron, JJ and Pratt, JM and Pena, M and Racha, V and Lim, CK and Fernandes, S and Benassi, S and Randolph-Moore, L and Vadodaria, KC and Marchetto, MC and Allen, NJ and Gage, FH},
title = {CK2 inhibition suppresses glial inflammation in models of neuroinflammation and neurodegeneration.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-71736-x},
pmid = {42014405},
issn = {2041-1723},
abstract = {Neuroinflammation plays a key role in Alzheimer's disease (AD) and many other neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis, yet glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK2α2, as a key driver of astrocytic inflammation. CK2 enhances NF-κB activity by phosphorylating NF-κB S529 and IκBα S32, promoting pro-inflammatory gene expression. Genetic or chemical CK2 inhibition dampens inflammation, including IL-6 and IL-8 expression in a TNFα acute neuroinflammation mouse model. CK2α2 is upregulated in AD postmortem tissues and patient-derived astrocytes. AD astrocytes exhibit a hyperinflammatory state that can be attenuated by CK2 inhibition. Overexpression of CK2α2 in cortical organoids mimics AD pathology, whereas CK2 inhibition using the potent, selective, and brain-penetrant probe TAL606 rescues inflammatory markers in AD APP/PS1 mice. These findings position CK2 as a central regulator of neuroinflammation and a promising therapeutic target for AD and related disorders.},
}

@article {pmid42014422,
year = {2026},
author = {Choi, KE and Pae, AN and Cho, NC},
title = {Mechanistic insights into the disaggregation of amyloid-β fibrils by EPPS via replica-exchange molecular dynamics simulations.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42014422},
issn = {2045-2322},
}

@article {pmid42014587,
year = {2026},
author = {Williams, J},
title = {Are we fully exploiting genetic discoveries to understand and treat Alzheimer's disease?.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {37},
number = {1},
pages = {},
pmid = {42014587},
issn = {1432-1777},
}

@article {pmid42014693,
year = {2026},
author = {Liu, P and Xu, Y and Che, P and Wang, Y and Zhang, Y and Ji, D and Wang, C and Ma, X and Sun, M and Zhang, N},
title = {Establishment and validation of an Alzheimer's disease diagnostic model on the basis of exhaled volatile organic compound characteristics.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04048-9},
pmid = {42014693},
issn = {2158-3188},
abstract = {Exhaled volatile organic compounds (VOCs) have been investigated in some diseases, including cognitive impairment, in pilot studies. The present study aimed to explore the role of exhaled VOCs in identifying and differentiating patients with Alzheimer's disease (AD). The identification cohort included 241 participants: 99 AD patients (dementia=74, mild cognitive impairment (MCI) = 25), 59 non-AD dementia patients, and 83 cognitively unimpaired controls (CUCs). Proton transfer reaction time-of-flight mass spectrometry (PTR-TOFMS) was employed to detect exhaled VOCs. The differences in VOCs between the AD and CUC groups and between the AD dementia and non-AD dementia groups were compared separately. Furthermore, machine learning models for discriminating AD from CUC as well as AD dementia from non-AD dementia were established. The AD diagnostic model was further validated in an independent cohort of 44 AD patients (dementia=33, MCI = 11) and 35 CUCs. Moreover, we explored the possible metabolic pathways of AD-specific exhaled VOCs with the Human Metabolome Database (HMDB). We detected 60 different VOCs between the AD and CUC groups, among which the top ten were C4H10S, C2H6N2O2, C3H6O3, C4H7F2NO, C6H5NO2, C8H6N2, C3HN, C9H21N, C15H24, and C8H12 (P < 0.001). The AD diagnostic model had an accuracy of 0.93 in the identification cohort according to internal validation and 0.75 in the validation cohort for external validation. The model for discriminating AD dementia patients from non-AD dementia patients had an accuracy of 0.90. Fourteen of the 60 AD-specific VOCs were retrieved from the HMDB, from which the three most significant metabolic pathways were identified, namely, butyrate metabolism, pyruvate metabolism, and glycolysis/gluconeogenesis. These results indicate that exhaled VOC measurement may be a promising approach for diagnosing and differentiating AD, but further validation is needed.},
}

@article {pmid42014714,
year = {2026},
author = {Finney, CA and Shvetcov, A},
title = {Mild cognitive impairment cases affect the predictive power of Alzheimer's disease diagnostic models using routine clinical variables.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00390-w},
pmid = {42014714},
issn = {2731-6068},
abstract = {Diagnostic models using primary care routine clinical variables have been limited in their ability to identify Alzheimer's disease (AD) patients. In this study, we sought to better understand the effect of mild cognitive impairment (MCI) on the predictive performance of AD diagnostic models. We sourced data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. CatBoost was used to assess the utility of routine clinical variables that are accessible to primary care physicians, such as hematological and blood tests and medical history, in multiclass classification between healthy controls, MCI, and AD. Our results indicated that MCI indeed affected the predictive performance of AD diagnostic models. Of the three subgroups of MCI that we found, this finding was driven by a subgroup of MCI patients who likely have prodromal AD. This work highlights the importance of continuing to focus on better classification of the different types of MCI to improve diagnostic models of AD, rather than focusing on binary classifications between AD and control cases. Future research should focus on distinguishing MCI from prodromal AD as the utmost priority for improving translational AD diagnostic models for primary care physicians.},
}

@article {pmid42014786,
year = {2026},
author = {Kim, OH and Shin, CH and Cho, MW and Ha, JY and Choung, JJ and Song, DK and Choi, JY and Chang, ES and Lee, HJ and Ku, SK},
title = {Transcranial vibrotactile stimulation enhances hippocampal cholinergic signaling and memory through frequency-dependent mechanotransduction.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49377-3},
pmid = {42014786},
issn = {2045-2322},
abstract = {Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline.},
}

@article {pmid42014834,
year = {2026},
author = {Wang, X and Liu, L and Yang, F and Huang, C and Mei, Z and Li, J and Ma, S},
title = {Identifying omic biomarkers for chronic inflammatory diseases associated with periodontitis using percolation on multi-disease gene co-expression networks.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01591-w},
pmid = {42014834},
issn = {2730-664X},
abstract = {BACKGROUND: Chronic inflammatory diseases, such as ulcerative colitis (UC), Crohn's disease (CD), Alzheimer's disease (AD) and Parkinson's disease (PD) are clinically related to periodontitis. However, the computation of omic biomarkers regarding these diseases has not leveraged this association.

METHODS: We developed PMGCN, a computational framework that employs optimal percolations on multi-disease gene co-expression networks derived from bulk transcriptomic gene expression profiles to identify a parsimonious set of key nodes as candidate omic biomarkers.

RESULTS: Evaluation of PMGCN on independent clinical studies of four chronic inflammatory diseases demonstrates improved predictive performance evaluated via cross validation with bootstrapping compared to commonly used univariate differentially expressed genes. Specifically for UC, three key gene biomarkers (CXCL5, FOSB, PTGR1) are identified by PMGCN, and public single-cell RNA-seq datasets confirm that the mainly altered inflammation signaling pathways in three cell clusters are connected to UC and periodontitis progression.

CONCLUSIONS: PMGCN proposes a computational biomarker identification approach leveraging multi-disease association, the discovered gene biomarkers demonstrate improved prediction of chronic inflammatory diseases and provide novel insights into disease progression.},
}

@article {pmid42014975,
year = {2026},
author = {McGlinchey, E and Pape, S and Zaman, SH and Eustace-Cook, J and Stockbauer, A and Baldimtsi, E and Langballe, EM and Larsen, FK and Sandkühler, K and Ivain, P and Rebillat, AS and Ecrement, P and McCarron, M and Benejam, B and Khoo, WM and Fortea, J and Levin, J and Öhman, F and Granholm-Bentley, AC and Strydom, A and Nübling, G},
title = {Lifestyle intervention and cognitive outcomes in Down syndrome: a horizon 21 European Down syndrome consortium scoping review.},
journal = {Journal of neurodevelopmental disorders},
volume = {},
number = {},
pages = {},
doi = {10.1186/s11689-026-09694-0},
pmid = {42014975},
issn = {1866-1955},
support = {IDS-TILDA-2021-001/HRBI_/Health Research Board/Ireland ; IDS-TILDA-2021-001/HRBI_/Health Research Board/Ireland ; UK-20-641398//Global Brain Health Institute/ ; AS-CP-118-0020//Alzheimer's Society Fellowship/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; 2022_EKEA.133//Else Kröner-Fresenius-Stiftung/ ; 2022_EKEA.133//Else Kröner-Fresenius-Stiftung/ ; 2022_EKEA.133//Else Kröner-Fresenius-Stiftung/ ; 2022_EKEA.133//Else Kröner-Fresenius-Stiftung/ ; MRC MR/S011277/1, MR/S005145/1, MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; MRC MR/S011277/1, MR/S005145/1, MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; 1R01AG056850-01A1, R21AG056974, R01AG061566, 1R01AG081394-01, 1R61AG066543-01/NH/NIH HHS/United States ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; IIBSP-DOW-2020-151//Fundación Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme from the European Union/ ; },
}

@article {pmid42014980,
year = {2026},
author = {Kruijff, I and van Wegen, EEH and Mul, JD and Jaspers, RT and Schrantee, A and Scherder, EJA and Lucassen, PJ and van Dam, AM},
title = {Effects of physical exercise on cognitive impairment in patients with Alzheimer's disease, Parkinson's disease or mild cognitive impairment: a systematic review and meta-analysis.},
journal = {European review of aging and physical activity : official journal of the European Group for Research into Elderly and Physical Activity},
volume = {},
number = {},
pages = {},
doi = {10.1186/s11556-026-00412-2},
pmid = {42014980},
issn = {1813-7253},
}

@article {pmid42015047,
year = {2026},
author = {Prada, D and Morava-Kozicz, E and Rajendrakumar, AL and Kupsco, A and Lesseur, C and Irizar, H and Cantú-de-Leon, D and García-Cuellar, C and Ramírez, A and González-Ruíz, J and Horowitz, CR and Cushman, M and Manly, J and Judd, S and Bagiella, E and Baccarelli, A and Parks, R},
title = {Blood mitochondrial heteroplasmic variants and cognitive performance in late midlife: REGARDS study.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {42015047},
issn = {1471-2377},
support = {U01 NS041588/AG/NIA NIH HHS/United States ; U01 NS041588/NS/NINDS NIH HHS/United States ; U54CA267776/CA/NCI NIH HHS/United States ; U01AG088684//National Institute of Aging/ ; },
}

@article {pmid42015131,
year = {2026},
author = {Wu, J and Lu, ZK and Davis-Ajami, ML},
title = {Hospitalization costs associated with 30-day unplanned readmissions and potentially preventable readmissions in US older patients with Alzheimer's disease and related dementias.},
journal = {BMC health services research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12913-026-14601-3},
pmid = {42015131},
issn = {1472-6963},
}

@article {pmid42015224,
year = {2026},
author = {Atzeni, A and Mingaila, J and Alzbutas, G and Lukoševičius, R and Drūteika, J and Łuczyńska, K and Ramonaitė, R and Pietras, T and Sipowicz, K and Kiudelytė, D and Keršytė, K and Keževičiūtė, E and Najūtė, G and Kupčinskas, J and Mayneris-Perxachs, J and Baltriukienė, D and Burokas, A},
title = {Comorbid Alzheimer's Disease and Type 2 Diabetes Microbiota Shape Age-Associated Gut-Brain Axis Profiles.},
journal = {Aging cell},
volume = {25},
number = {5},
pages = {e70488},
doi = {10.1111/acel.70488},
pmid = {42015224},
issn = {1474-9726},
support = {S-PD-24-95//Research Council of Lithuania/ ; },
mesh = {*Alzheimer Disease/microbiology/epidemiology ; Humans ; *Diabetes Mellitus, Type 2/microbiology/epidemiology ; *Gastrointestinal Microbiome ; Female ; Aged ; Animals ; Male ; Mice ; Middle Aged ; Aged, 80 and over ; *Aging ; *Brain/metabolism ; Comorbidity ; Fecal Microbiota Transplantation ; },
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic and inflammatory mechanisms, potentially mediated by the gut microbiota, yet the neurobiological impact of comorbid AD+T2DM microbiota from elderly donors remains unexplored. Fecal microbiota from healthy, AD, T2DM, and AD+T2DM postmenopausal female donors (aged 56-89 years) was transplanted into antibiotic-treated male mice. Behavioral testing, blood profiling, hippocampal neurotrophic gene expression, and 16S rRNA sequencing with taxonomic, functional, and metabolic analyses were performed. Human AD+T2DM microbiota displayed the greatest dysbiosis, characterized by enrichment of pro-inflammatory taxa, depletion of butyrate-producing genera, and loss of neuroprotective metabolic pathways. FMT induced robust engraftment, with AD+T2DM recipients diverging most from controls (PERMANOVA R[2] = 0.209, p = 0.001) and healthy recipients (PERMANOVA R[2] = 0.111, p = 0.002). Donor age contributed significantly to recipient microbiota variation (R[2] = 0.028, p = 0.006), suggesting transmission of aging-associated microbial signatures. Hippocampal neurotrophic gene expression was most suppressed in AD+T2DM recipients (adjusted p value < 0.05) and negatively correlated with disease- and aging-associated taxa and microbial functions (|r| > 0.4, FDR p < 0.05). AD recipients showed reduced olfactory discrimination and increased daytime locomotor activity. Metabolic network analysis revealed depletion of flavonoid, isoflavonoid, and lignan biosynthesis pathways in disease recipients. These findings suggest that microbiota from elderly donors with comorbid AD+T2DM may induce gut-brain axis alterations, linking aging, metabolic dysfunction, and neurodegeneration through convergent taxonomic, functional, and neurotrophic changes. We underscore the potential role of age-associated gut microbial signatures in modulating neurobiological outcomes.},
}

*Alzheimer Disease/microbiology/epidemiology
Humans
*Diabetes Mellitus, Type 2/microbiology/epidemiology
*Gastrointestinal Microbiome
Female
Aged
Animals
Male
Mice
Middle Aged
Aged, 80 and over
*Aging
*Brain/metabolism
Comorbidity
Fecal Microbiota Transplantation

@article {pmid42015253,
year = {2026},
author = {Reetz, K and Liepelt-Scarfone, I and Häger, A and Flöel, A and Schulz, JB and , },
title = {The best treatment is prevention: prevention of cognitive decline and dementia - current state, gaps and next steps.},
journal = {Neurological research and practice},
volume = {8},
number = {1},
pages = {},
pmid = {42015253},
issn = {2524-3489},
}

@article {pmid42015258,
year = {2026},
author = {Hao, JP and Cheng, ZZ and Wang, MY and Zhu, YP and Chen, N and Zhu, D and Zhang, L and Li, YL and Li, L and Bai, ZF and Xiao, XH and Wang, JB and Zhang, L and Gao, D},
title = {Tet2 deficiency orchestrates Alzheimer's pathogenesis through oxidative mtDNA-driven cGAS-STING activation.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03820-4},
pmid = {42015258},
issn = {1742-2094},
support = {82274611//National Natural Science Foundation of China/ ; 82274121//National Natural Science Foundation of China/ ; 7232267//Natural Science Foundation of Beijing Municipality/ ; H2025112023//Natural Science Foundation of Hebei Province/ ; HZ2025PYYX010//Xuanwu Hospital Talent Convergence Program/ ; },
}

@article {pmid42015285,
year = {2026},
author = {Huang, S and Ran, Q and Tang, J and Wang, X and Xi, J and Ma, S and Xi, R},
title = {SpaNiche: spatial niche analysis to explore colocalization patterns and cellular interactions in spatial transcriptomics data.},
journal = {Genome biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13059-026-04069-z},
pmid = {42015285},
issn = {1474-760X},
support = {2023YFC3603200//National Key Research and Development Program of China/ ; 2024YFF0507404//National Key Research and Development Program of China/ ; 23YF1421000//Shanghai Rising-Star Program/ ; JWAIYB-3//Shanghai Municipal Commission of Education/ ; 20234Y0285//Clinical Research Project of Shanghai Municipal Health Commission in Health Industry/ ; YG2023QNA01//Fundamental Research Funds for the Central Universities/ ; 2025YFHZ0069//Sichuan Science and Technology Program/ ; 2024-YF05-01784-SN//Chengdu Municipal Science and Technology Program/ ; 12425110//National Natural Science Foundation of China/ ; JYB2025XDXM118//Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China/ ; },
abstract = {We propose a computational framework for spatial niche analysis (SpaNiche) in spatial transcriptomics data to uncover colocalization patterns and infer potential ligand-receptor interactions. SpaNiche leverages graph-regularized joint non-negative matrix factorization to integrate information from cell abundance and ligand-receptor expression, identifying spatial colocalization patterns among cell types while providing insights into associated ligand-receptor interactions. Besides, SpaNiche employs consensus clustering to define "ecotypes", enhancing its utility in multi-sample spatial transcriptomics datasets. We investigate microenvironmental ecotypes in colorectal cancer, prostate cancer and cerebral cortex in early Alzheimer's disease, highlighting the broad applicability in dissecting complex colocalization patterns within spatial tissue microenvironments.},
}

@article {pmid42015299,
year = {2026},
author = {Ge, C and Wang, K and Tang, H and Ke, Y and Wang, H and Fu, Q and Xiu, Y and Guo, Y and Jia, YF and Long, Z and He, G and Tang, Q},
title = {NDST3 suppression restores lysosomal acidification and ameliorates amyloid-β and MAPT/tau pathology in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42015299},
issn = {2047-9158},
support = {BJRC202310//Project of the Top-Notch Talent Cultivation Program for the Graduate Students of Chongqing Medical University/ ; W0168//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; 82371203//National Natural Science Foundation of China/ ; 82201582//National Natural Science Foundation of China/ ; CSTB2024NSCQ-MSX0483//Natural Science Foundation of Chongqing, China/ ; KJQN202200457//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; },
mesh = {Animals ; *Lysosomes/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism ; Mice ; Humans ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Histone Deacetylase 6/metabolism ; Hippocampus/metabolism/pathology ; },
abstract = {BACKGROUND: Impairment of lysosomal acidification has recently been identified as a critical driver of amyloid-β and MAPT/tau pathology in Alzheimer's disease (AD). Restoring lysosomal acidification is a promising strategy for AD treatment. N-deacetylase and N-sulfotransferase 3 (NDST3) is a newly discovered tubulin deacetylase that regulates lysosomal acidification by influencing the recruitment of V-ATPase V1 subunits to lysosomes. Nevertheless, the role of NDST3 in AD remains entirely unexplored.

METHODS: We began by comparing the effects of NDST3 and histone deacetylase 6 (HDAC6), a well-known tubulin deacetylase with established roles in AD, on lysosomal acidification. Using HT22 cell-based models of AD, we knocked down NDST3 to examine its role in lysosomal acidification and degradative function in the context of this disease. We also evaluated the expression profile of NDST3 in both in vitro and in vivo models of AD. Finally, we investigated the consequences of NDST3 suppression on lysosomal acidity and related AD pathological features in the hippocampi of 3 × Tg-AD mice.

RESULTS: NDST3 differs from HDAC6 in the subcellular spatial patterns of catalyzing microtubule deacetylation but parallels HDAC6 in regulating lysosomal pH. In HT22 cells with APP695[Swe] overexpression, knockdown of NDST3 lowered lysosomal pH by promoting the assembly of the V-ATPase holoenzyme on the lysosomal membrane and enhanced the autophagic degradation of aberrant Aβ and MAPT/tau. Notably, NDST3 levels were found to be elevated in the brains of AD models and patients. Reducing NDST3 expression in the hippocampi of 3 × Tg-AD mice facilitated lysosomal reacidification, which decreased the abnormal accumulation of amyloid plaques and MAPT/tau tangles, mitigated neuronal damage, and ameliorated cognitive deficits.

CONCLUSIONS: Our study identified NDST3 as a key factor regulating lysosomal acidity in AD. Suppressing NDST3 restores lysosomal function in AD and protects against AD pathology, highlighting NDST3 as a promising therapeutic target for AD.},
}

Animals
*Lysosomes/metabolism/pathology
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism
Mice
Humans
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Histone Deacetylase 6/metabolism
Hippocampus/metabolism/pathology

@article {pmid42015324,
year = {2026},
author = {Li, R and Langford, O and Insel, PS and Sperling, RA and Raman, R and Aisen, PS and Donohue, MC},
title = {Divergent patterns of cognitive decline in preclinical Alzheimer's disease: Implications for secondary prevention trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71366},
doi = {10.1002/alz.71366},
pmid = {42015324},
issn = {1552-5279},
support = {//Epstein Family Foundation/ ; //Avid Radiopharmaceuticals/ ; //GHR Foundation/ ; //Foundation for the National Institutes of Health/ ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; U24AG057437/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging/prevention & control ; Aged ; Positron-Emission Tomography ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; Biomarkers ; *Secondary Prevention ; Disease Progression ; Prodromal Symptoms ; Hippocampus/pathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Biomarkers identify Alzheimer's disease pathology in cognitively unimpaired adults, but the timing and rate of cognitive decline vary widely. This study aimed to identify subgroups of cognitive decline and baseline predictors of heterogeneity in preclinical progression.

METHODS: Data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study, which enrolled amyloid beta-positive (Aβ+) participants, and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study, which enrolled amyloid beta-negative (Aβ-) individuals. Latent class mixed-effects models identified cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker variables were evaluated. The primary outcome was change in the Preclinical Alzheimer Cognitive Composite.

RESULTS: Three trajectory classes were identified: stable, slow decliners, and fast decliners. Higher phosphorylated tau at 217 (p-tau217), smaller hippocampal volume, and elevated tau positron emission tomography were associated with declining classes. About 70% of Aβ+ individuals were stable.

DISCUSSION: Latent class modeling reveals substantial heterogeneity in preclinical trajectories with important implications for prevention trial design.},
}

Humans
*Alzheimer Disease
Male
Female
*Cognitive Dysfunction/diagnostic imaging/prevention & control
Aged
Positron-Emission Tomography
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Longitudinal Studies
Biomarkers
*Secondary Prevention
Disease Progression
Prodromal Symptoms
Hippocampus/pathology/diagnostic imaging
Neuropsychological Tests

@article {pmid42015334,
year = {2026},
author = {van Etten, ES and Mahinrad, S and Grill, JD and Salloway, S and Atri, A and Cogswell, PM and Benzinger, TLS and Iwatsubo, T and Iadecola, C and Lemere, CA and Nicoll, JAR and Greenberg, SM and Carrillo, MC and Jack, CR and Sperling, RA},
title = {Amyloid-related imaging abnormalities (ARIA) in anti-amyloid therapies for Alzheimer's disease: An update from the Alzheimer's Association ARIA workgroup.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71361},
doi = {10.1002/alz.71361},
pmid = {42015334},
issn = {1552-5279},
support = {09150162410011/ZONMW_/ZonMw/Netherlands ; 642991//Alzheimer Nederland/ ; R01NS136122/NH/NIH HHS/United States ; R01AG084531/NH/NIH HHS/United States ; P30AG066519/NH/NIH HHS/United States ; P01AG003991/NH/NIH HHS/United States ; ARUK-PPG2023B-023//Alzheimer Research UK/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/therapy/metabolism ; *Neuroimaging/methods ; *Brain/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; },
abstract = {In 2011, a workgroup of the Alzheimer's Association Research Roundtable introduced recommendations for detecting and monitoring amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease (AD) clinical trials. Since then, anti-amyloid immunotherapies have received regulatory approval for AD treatment and are beginning to enter clinical practice, underscoring the importance of informing healthcare providers, researchers, and patients about ARIA's implications in real-world settings. In response, the Alzheimer's Association convened a new workgroup to review current knowledge of ARIA, including underlying mechanisms, clinical presentations, associated risk factors, mitigation strategies, radiologic detection methods, patients' perspectives in treatment decision-making, and outstanding challenges. Here, we outline key insights from this workgroup, highlighting that effective ARIA detection and monitoring in clinical practice requires adherence to robust protocols to mitigate risks and enhance patient safety. Limited availability of clinical and pathologic data on predictors of symptomatic and severe ARIA underscores the importance of continued real-world data collection.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy/therapy/metabolism
*Neuroimaging/methods
*Brain/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
*Amyloid/metabolism

@article {pmid42015354,
year = {2026},
author = {Doiron, D and Jovanovic Andersen, Z and Bozigar, M and Habre, R and Hystad, P and Jarvis, I and Knapp, D and Luben, TJ and Patel, P and Pinto, JM and Ritz, B and Volckens, J and Wellenius, GA and Lee, J and Brauer, M and Brook, J and Adar, SD},
title = {Integrating the physical environment into Alzheimer's disease and Alzheimer's disease related dementias research: A Gateway Exposome Coordinating Center (GECC) agenda on gaps and priorities.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71429},
doi = {10.1002/alz.71429},
pmid = {42015354},
issn = {1552-5279},
support = {U24AG088894/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; *Exposome ; *Environmental Exposure ; *Dementia ; *Environment ; },
abstract = {The physical environment is an important yet underexplored domain in Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD), shaping exposures and health-related behaviors across the life course. We identified key gaps and priorities for incorporating physical environment measures into population-based research, with an emphasis on geospatial data that can be applied in large cohorts and administrative datasets. The Gateway Exposome Coordinating Center (GECC) synthesized input from six town halls, a 4-day expert workshop, and the literature to build consensus on priority physical environment exposures and a roadmap for advancing exposure data. We also identified four methodological imperatives: developing pathway-relevant metrics, addressing temporality, incorporating behavior into exposure estimation, and integrating co-occurring exposures. Advancing guidance and exposure metrics in these areas can support prevention-oriented, policy-relevant research and improve understanding of how physical environments influence brain health.},
}

Humans
*Alzheimer Disease/epidemiology
*Exposome
*Environmental Exposure
*Dementia
*Environment

@article {pmid42015507,
year = {2026},
author = {Mohammed, SGAA and Qoronfleh, MW and Alawi, RA and Al-Siyabi, S},
title = {Therapeutic Potential of Select Berry Varieties in Mitigating Cognitive Decline via Oxidative Stress and Insulin Resistance in AlCl3-Exposed Mice.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71411},
doi = {10.1002/brb3.71411},
pmid = {42015507},
issn = {2162-3279},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Insulin Resistance/physiology ; Mice ; Aluminum Chloride/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; *Fruit/chemistry ; Antioxidants/pharmacology ; Male ; Disease Models, Animal ; Alzheimer Disease/metabolism/drug therapy ; Morus/chemistry ; Plant Extracts/pharmacology ; Flavonoids/pharmacology ; Maze Learning/drug effects ; },
abstract = {PURPOSE: Oxidative stress damage and impaired insulin receptor (IR) signaling are critical risk factors for contributing to cognitive impairment in Alzheimer's disease (AD) and other neurological disorders. The beta-amyloid peptide (Aβ) oligomer deposition in the hippocampal region decreases the IR expression. This study aimed to assess whether berries grown in Oman (Morus alba, Morus macroura, and Sideroxylon mascatense) could ameliorate dysfunction of the antioxidant system and restore the IR expression thereby improve the cognitive performance in aluminum chloride (AlCl3) induced AD mouse model.

METHODS: Various biochemical assays were conducted to estimate antioxidant capacity. The total phenolic (TPC) and flavonoid (TFC) contents for the three varieties were quantified using Folin-Ciocalteu and AlCl3 calorimetric methods, respectively. The antioxidant properties of the three berries were analyzed using thiobarbituric acid reactive substances assay (TBARS), superoxide dismutase assay (SOD), glutathione assay (GSH), glutathione peroxidase assay (GPx), and estimation of glutathione reductase (GR). Cognitive performance was measured using Morris water maze (MWM) and T-maze.

FINDINGS: Berries, particularly M. alba and S. mascatense, demonstrated the highest phenolic and flavonoid content and exhibited strong antioxidant activity across all assays. Mice fed with M. alba, M. macroura, and S. mascatense showed better performance parameters in both MWM (spatial learning and memory) and T-maze (time taken to reach the platform) tests, along with enhanced IR signaling (p < 0.01).

CONCLUSION: These findings suggest that supplementation with mulberries may improve cognitive decline and insulin resistance induced by AlCl3, highlighting their potential as neuroprotective agents in AD.},
}

Animals
*Oxidative Stress/drug effects
*Insulin Resistance/physiology
Mice
Aluminum Chloride/pharmacology
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
*Fruit/chemistry
Antioxidants/pharmacology
Male
Disease Models, Animal
Alzheimer Disease/metabolism/drug therapy
Morus/chemistry
Plant Extracts/pharmacology
Flavonoids/pharmacology
Maze Learning/drug effects

@article {pmid42015638,
year = {2026},
author = {Gao, W and Li, X and Liu, AN and Li, JH and Ye, QY and Huang, Y and Yang, FG and Song, J and Xing, LP and Li, HL},
title = {[Study on the mechanism of scalp-acupoint cluster puncture in improving hippocampal synaptic plasticity by regulating the cAMP/PKA/CREB signaling pathway in APP/PS1 mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {4},
pages = {465-473},
doi = {10.13702/j.1000-0607.20250733},
pmid = {42015638},
issn = {1000-0607},
mesh = {Animals ; *Neuronal Plasticity ; *Hippocampus/metabolism/physiopathology ; Male ; Mice ; *Cyclic AMP Response Element-Binding Protein/metabolism/genetics ; *Acupuncture Therapy ; Mice, Inbred C57BL ; Humans ; Signal Transduction ; *Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Mice, Transgenic ; *Alzheimer Disease/therapy/genetics/metabolism/physiopathology/psychology ; Acupuncture Points ; *Cyclic AMP/metabolism/genetics ; Scalp ; Amyloid beta-Protein Precursor/genetics/metabolism ; },
abstract = {OBJECTIVES: To observe the effect of scalp-acupoint cluster puncture on hippocampal synaptic plasticity and the activity of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway in APP/PS1 mice, so as to explore its possible mechanism underlying improvement of Alzheimer's disease (AD).

METHODS: Male APP/PS1 transgenic mice were randomly divided into model, acupuncture, and sham acupuncture groups, with 12 mice in each group. In addition, 12 male C57BL/6 mice with the same genetic background were used as the control group. The mice of the acupuncture group received cluster-needle stimulation at "Baihui"(GV20) and 2 spots (2 mm to GV20 on the left and right sides), and those of the sham acupuncture group received cluster-needle stimulation at the bilateral hypochondrial non-acupoints. Following insertion, the needles were twisted rapidly for about 1 min, then retained for 30 min in the acupuncture group. The intervention was conducted once a day, for a total of 28 d. The Morris water maze test and Barnes maze test were used to evaluate the mouse's learning-memory and cognitive ability. The immunohistochemical staining was employed to detect amyloid-β (Aβ) deposition in the hippocampus. The Nissl staining was used to observe the changes of the number of neurons in the hippocampal CA1 area. A transmission electron microscopy was employed to observe the ultrastructure of hippocampal synapses. The Golgi staining was used to observe the dendritic spine density of hippocampal neurons. The protein expressions of cAMP, PKA, CREB, phosphorylated (p)-CREB, postsynaptic density protein 95 (PSD-95), and synapsin Ⅰ (SYN1) was detected using Western blot.

RESULTS: Compared with the control group, the model group showed a significant increase in the escape latency of Morris water maze test and the latency to enter the target hole of Barnes maze test and the percentage of Aβ-positive area (P<0.01, P<0.001), and a striking reduction in the number of target platform crossings in the Morris water maze test, residence time in the target quadrant of the escape box and the number of correct hole entries in the Barnes maze test, number of neurons, dendritic spine density, and the expression levels of cAMP, PKA, PSD-95, SYN1 and p-CREB/CREB ratio (P<0.01, P<0.001). After the intervention, both the increase and decrease of the indexes mentioned above were reversed in the acupuncture group (P<0.01, P<0.001), but not in the sham acupuncture group. Morphological results showed irregular shapes and disordered arrangement of the hippocampal neurons with shrunken nucleoli, atrophied mitochondria, broken mitochondrial cristae, decreased synapses and vesicles in the model group, which was relatively milder in the injury degree, for example, increase in the number of synapses and vesicles, relatively complete mitochondrial cristae, etc., in the acupuncture group.

CONCLUSIONS: Scalp-acupoint cluster puncture can improve the learning-memory ability in APP/PS1 mice, which may be associated with its functions in enhancing the hippocampal synaptic plasticity and up-regulating the cAMP/PKA/CREB signaling.},
}

Animals
*Neuronal Plasticity
*Hippocampus/metabolism/physiopathology
Male
Mice
*Cyclic AMP Response Element-Binding Protein/metabolism/genetics
*Acupuncture Therapy
Mice, Inbred C57BL
Humans
Signal Transduction
*Cyclic AMP-Dependent Protein Kinases/metabolism/genetics
Mice, Transgenic
*Alzheimer Disease/therapy/genetics/metabolism/physiopathology/psychology
Acupuncture Points
*Cyclic AMP/metabolism/genetics
Scalp
Amyloid beta-Protein Precursor/genetics/metabolism

@article {pmid42015730,
year = {2026},
author = {Sander, FW and Pittet, M and Manera, V and Krebs, C and Brill, E and Brioschi-Guevara, A and Ryvlin, P and Anguera, JA and Gazzaley, A and Robert, P and Klöppel, S and Démonet, JF and Binarelli, G and Sokolov, AA},
title = {Mood and Age Predict Cognitive Complaints in Memory Clinic Patients: A Machine-Learning and Linear Modeling Approach.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70583},
doi = {10.1111/ene.70583},
pmid = {42015730},
issn = {1468-1331},
support = {2019-CDA03//Stiftung Synapsis - Alzheimer Forschung Schweiz AFS/ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Machine Learning ; Middle Aged ; Aged, 80 and over ; *Affect/physiology ; Neuropsychological Tests ; Linear Models ; *Cognitive Dysfunction/diagnosis/psychology ; *Aging/psychology ; *Memory Disorders/diagnosis/psychology ; Age Factors ; },
abstract = {INTRODUCTION: Cognitive complaints are often considered early indicators of Alzheimer's disease (AD) and commonly lead to memory clinic consultations. Prior studies suggest stronger associations between cognitive complaints and mood than with objective cognition, but this interplay remains poorly understood. Using a machine learning-supported approach, we aimed to (1) identify key predictors of cognitive complaints, and (2) compare the value of gamified versus standard neuropsychological testing in detecting subtle deficits.

METHODS: In this international multi-center study, 98 participants (57 females; mean age 71.9, range 55-86) from three memory clinics completed the Cognitive Failures Questionnaire (CFQ), mood and apathy questionnaires, the tablet-based gamified Adaptive Cognitive Evaluation Explorer (ACE-X), and standard neuropsychological tests. Predictors of CFQ scores were examined using elastic net regression and the Boruta algorithm, followed by linear mixed-effects modeling.

RESULTS: Greater mood symptoms were associated with more cognitive complaints, whereas increasing age was linked to fewer complaints. Study center accounted for additional variance. The final model explained a substantial proportion of variance (conditional R[2] = 0.48, marginal R[2] = 0.33). Participants had lower z-scores on ACE-X compared to standard testing, but neither predicted the severity of cognitive complaints.

DISCUSSION: Mood and age were main predictors of cognitive complaints in memory clinic patients. Although ACE-X yielded lower normative scores than standard tests, neither cognitive measure was linked to complaints. These findings highlight the importance of systematically assessing mood, adopting personalized approaches when evaluating subjective and objective cognition, and the potential value of gamified assessments for screening populations at risk of AD.},
}

Humans
Female
Male
Aged
*Machine Learning
Middle Aged
Aged, 80 and over
*Affect/physiology
Neuropsychological Tests
Linear Models
*Cognitive Dysfunction/diagnosis/psychology
*Aging/psychology
*Memory Disorders/diagnosis/psychology
Age Factors

@article {pmid42015793,
year = {2026},
author = {Gao, L and Watson, R and Yassi, N},
title = {Cost-Effectiveness of Donanemab for Early Alzheimer Disease in Australia.},
journal = {The Medical journal of Australia},
volume = {224},
number = {4},
pages = {e70186},
doi = {10.5694/mja2.70186},
pmid = {42015793},
issn = {1326-5377},
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; Cost-Benefit Analysis ; Australia ; Quality-Adjusted Life Years ; Aged ; Markov Chains ; *Antibodies, Monoclonal, Humanized/economics/therapeutic use ; Male ; Disease Progression ; Female ; Amyloid beta-Peptides ; },
abstract = {OBJECTIVES: To evaluate the cost-effectiveness of donanemab, an anti-amyloid-β monoclonal antibody recently approved in Australia, for treating early-stage Alzheimer disease with confirmed amyloid-β pathology from healthcare system and societal perspectives.

DESIGN: A Markov microsimulation model simulating long-term Alzheimer disease progression, treatment costs and health outcomes for donanemab compared with standard care.

SETTING, PARTICIPANTS: Australian healthcare context, applying published clinical and economic inputs. A hypothetical cohort of people with early symptomatic Alzheimer disease, consistent with TRAILBLAZER-ALZ eligibility criteria: mean age 75 years, amyloid-β-positive, with mild cognitive impairment or mild dementia because of Alzheimer disease and excluding individuals with APOEE4 homozygotes, in line with the Australian labelling. Donanemab administered every 4 weeks with magnetic resonance imaging (MRI)-based amyloid-β-related imaging abnormalities monitoring and treatment suspension upon amyloid-β clearance or progression to severe Alzheimer disease, compared with standard care.

MAIN OUTCOME MEASURES: Incremental costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Secondary analyses included sensitivity and distributional equity analyses.

RESULTS: Donanemab increased total healthcare costs ($300,689 vs. $178,121) and societal costs ($389,113 vs. $283,618) compared with standard care per capita, while improving health outcomes (4.38 vs. 4.01 QALYs) per capita. The ICER was $342,424 per QALY from the healthcare perspective and $294,701 per QALY from the societal perspective, exceeding frequently cited Australian willingness-to-pay thresholds. Sensitivity analyses identified drug cost and efficacy as key drivers of uncertainty. Distributional analysis suggested inequitable health gains by remoteness because of differences in diagnostic and treatment infrastructure.

CONCLUSION: Donanemab provides clinical benefits but is unlikely to be cost-effective under current Australian thresholds. Policymakers should balance economic evidence with unmet need, equity considerations and healthcare sustainability when making reimbursement decisions. Further research using real-world evidence and disaggregated analyses by geography and socioeconomic status is warranted.},
}

Humans
*Alzheimer Disease/drug therapy/economics
Cost-Benefit Analysis
Australia
Quality-Adjusted Life Years
Aged
Markov Chains
*Antibodies, Monoclonal, Humanized/economics/therapeutic use
Male
Disease Progression
Female
Amyloid beta-Peptides

@article {pmid42015794,
year = {2026},
author = {Mendez Campos, B and Cho, TC and Lai, W and Smith, J and Choi, H},
title = {Family caregiving job disruptions and later life cognition: Intersections of race/ethnicity and gender.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394339},
doi = {10.1177/13872877251394339},
pmid = {42015794},
issn = {1875-8908},
abstract = {BackgroundContinuous paid work supports cognitive health, but employment disruptions, especially among historically marginalized groups, may increase the risk of cognitive decline and Alzheimer's disease and related dementias (ADRD). Limited evidence exists on the relationship between caregiving-related job disruptions and cognitive outcomes, which may exacerbate disparities in ADRD risk.ObjectiveThis study examines the association between caregiving-related job disruptions and late-life cognitive outcomes, with a focus on gender and racial/ethnic differences.MethodsData from 7759 U.S. adults aged 55 and older in the 2018 Health and Retirement Study (HRS) and Life History Mail Survey (LHMS) were analyzed. Employment disruptions were classified as caregiving-related, other reasons, or continuous employment. Sequence analysis summarized employment history patterns, and multivariable linear regression models evaluated the association between the years of caregiving-related job disruptions between ages 18 and 50 and cognitive function scores at ages 55 and older, adjusting for demographic covariates.ResultsWomen experienced more caregiving-related job disruptions than men (0.57 versus 0.04 years, p < 0.001), and Hispanics had more disruptions than non-Hispanic Whites (0.84 versus 0.28 years, p = 0.01). Caregiving-related disruptions were significantly associated with lower cognitive scores among non-Hispanic White males, non-Hispanic Black males, and non-Hispanic Black females, but not among non-Hispanic White females or Hispanic males and females.ConclusionsCaregiving-related job disruptions may contribute to cognitive decline, particularly among non-Hispanic White males and non-Hispanic Black caregivers. Targeted policies and interventions addressing these disparities are essential to reduce ADRD risk across diverse caregiving populations.},
}

@article {pmid42015806,
year = {2026},
author = {Zhang, X and Elmansy, R},
title = {Exploring Influencing Factors of Medication Adherence Among Chinese Patients With Alzheimer Disease: Delphi Study Informing Future Artificial Intelligence-Supported Interventions.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e89508},
doi = {10.2196/89508},
pmid = {42015806},
issn = {2561-326X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Delphi Technique ; *Artificial Intelligence ; Male ; Female ; China ; *Medication Adherence/psychology ; Aged ; Middle Aged ; East Asian People ; },
abstract = {BACKGROUND: Alzheimer disease (AD) affects cognition, treatment adherence, family connections, and health care resource allocation. Most patients with AD have low adherence to medication therapy due to the limitations associated with cognitive impairment. Therefore, increasing the involvement of patients and their family members in medication management is important to improve treatment outcomes and reduce the burden of care.

OBJECTIVE: This study explores the potential application of artificial intelligence (AI) in medication management for Chinese patients with early- to mid-stage AD focusing on enhancing medication adherence. The study first predicts and evaluates key factors through an online Delphi study, which provides a basis for their subsequent incorporation into the AI model as input variables to enable prediction of medication-taking behaviors. Since AI research in medication management for this population is still undeveloped, this paper further explores the multiple potentials of AI from a theoretical view, including drug dosage optimization, multidrug interaction detection, and family education support. It will provide a preliminary direction and theoretical basis for the development of an intelligent medication management system in the future.

METHODS: The exploratory online Delphi study with no modification predicted the key factors influencing medication adherence. Based on the results, the study confirmed the potential of AI to improve adherence. Participation by 12 experts in 3 rounds systematically assessed the core elements influencing patients' adherence to their medication.

RESULTS: Family care, social support, environmental factors, emotional support, and patient behaviors were identified as the primary factors influencing medication adherence among Chinese patients with AD. These factors were validated and ranked through iterative Delphi rounds, with family care and social support receiving the highest importance scores. The Wilcoxon signed-rank test indicated no significant difference between rounds (P=.06), supporting the stability of the consensus. These findings establish a foundational set of variables for AI systems that predict and enhance medication adherence.

CONCLUSIONS: This study highlights the critical factors affecting medication adherence by Chinese patients with AD. It was designed as an exploratory online Delphi study to identify and prioritize key influencing factors, rather than to validate a specific AI-based system, and the findings provide a theoretical foundation for future AI-informed interventions. The results also indicate theoretical potential roles for AI in supporting medication management, such as optimizing drug dosage, detecting multidrug interactions, and enhancing family education.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
Delphi Technique
*Artificial Intelligence
Male
Female
China
*Medication Adherence/psychology
Aged
Middle Aged
East Asian People

@article {pmid42015895,
year = {2026},
author = {He, Y and Hu, W and Hiutung, C and Han, Z},
title = {Serum Creatinine Clearance and Cognitive Function in Older Adults: Mediating Effects of Systemic Inflammatory Response Index.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71413},
doi = {10.1002/brb3.71413},
pmid = {42015895},
issn = {2162-3279},
support = {//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Creatinine/blood ; *Cognition/physiology ; *Cognitive Dysfunction/blood/physiopathology ; *Inflammation/blood ; Nutrition Surveys ; Aged, 80 and over ; Neuropsychological Tests ; },
abstract = {BACKGROUND: The association between renal dysfunction and cognitive decline in older adults has been increasingly recognized, although the underlying mechanisms remain poorly understood. This study explored the association between serum creatinine clearance (Ccr) and cognitive function, and evaluated whether the Systemic Inflammatory Response Index (SIRI) mediates this relationship.

METHODS: We analyzed 2482 adults aged ≥ 60 years from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) using survey-weighted regression models. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Memory Test, Animal Fluency Test (AFT), Digit Symbol Substitution Test (DSST), and global cognitive performance (Z-GCP). Associations among Ccr, SIRI, and cognitive outcomes were evaluated using regression models, subgroup and interaction analyses, restricted cubic splines, and mediation analysis with 10,000 bootstrap samples.

RESULTS: Higher Ccr was independently associated with better cognitive performance across all domains. In fully adjusted models, each unit increase in Ccr was significantly associated with higher cognitive scores (CERAD: β = 0.021, 95% CI: 0.010-0.032; AFT: β = 0.014, 95% CI: 0.003-0.025; DSST: β = 0.082, 95% CI: 0.029-0.134; Z-GCP: β = 0.003, 95% CI: 0.002-0.005; all p < 0.05). Participants in the highest Ccr tertile had better cognitive performance and lower odds of impairment, especially in CERAD, DSST, and Z-GCP (p-trend < 0.05). Receiver operating characteristic analysis showed moderate discriminative ability of Ccr for cognitive impairment (AUCs: 0.736-0.843), and restricted cubic spline analyses revealed significant nonlinear associations for CERAD and DSST domains (p for nonlinearity < 0.05). Subgroup analyses indicated effect modification by age, sex, diabetes, hypertension, and stroke (p-interaction < 0.05). Mediation analysis showed that SIRI partially mediated the association between Ccr and cognitive outcomes, accounting for 3%-6.6% of the mediated proportions in CERAD, DSST, and Z-GCP domains (all p < 0.05).

CONCLUSION: Ccr is independently associated with cognitive performance in older adults, particularly in the CERAD, DSST, and Z-GCP domains. Systemic inflammation, as indicated by the SIRI, partially mediates these associations.},
}

Humans
Male
Female
Aged
Middle Aged
*Creatinine/blood
*Cognition/physiology
*Cognitive Dysfunction/blood/physiopathology
*Inflammation/blood
Nutrition Surveys
Aged, 80 and over
Neuropsychological Tests

@article {pmid42015950,
year = {2026},
author = {Spirig, SE and Frei, S and Jaeggi, AV and Bender, N},
title = {Systematic Review on the Association Between Sleep and the Risk of Alzheimer's Disease: An Evolutionary Perspective.},
journal = {Evolutionary applications},
volume = {19},
number = {3},
pages = {e70223},
pmid = {42015950},
issn = {1752-4571},
abstract = {Alzheimer's disease (AD) is an important, non-curable disease today. Several possible risk factors have been discussed, among others sleep. Evolutionary hypotheses were proposed to explain sleep variation and AD risk, such as a potential advantage of short or interrupted sleep in ancient insecure environments, the evolution of increased plasticity of the human brain, or antagonistic pleiotropy with increased AD risk. The aim of this systematic review was to investigate in which way sleep is associated with AD risk, in the light of evolutionary hypotheses. Following PRISMA guidelines, the databases PubMed and Embase were searched for longitudinal observational studies on the association between sleep and incident AD in cognitively healthy people at baseline. Potential confounders were assessed (e.g., age, sex, country, etc.). Search results were deduplicated and assessed for inclusion or exclusion by two independent reviewers. We summarized the results in tables and performed meta-analyses in risk factor subgroups where appropriate. Out of 5800 studies, 39 were suitable for this review and 35 were meta-analyzed. Long sleep duration showed a positive association with AD (HR = 1.35, 95% CI = 1.12-1.63) that was not significant after accounting for heterogeneity using prediction intervals (95% CI = 0.74-2.49). Short sleep duration showed a weak, non-significant association with AD risk (HR = 1.07, 95% CI = 0.98-1.18). Several measures of sleep quality (hypnotics use, daytime sleepiness, bad overall sleep quality, and early bedtime) showed an increased risk for AD, while others (e.g., late bedtime) showed a protective effect. This systematic review showed possible associations between sleep characteristics and the risk for AD. However, several results showed heterogeneity that we could not explain with the information given in the publications. More work is therefore needed to assess the risk factors for AD connected to sleep.},
}

@article {pmid42016208,
year = {2026},
author = {Shah, KB and Xiang, L and Shah, SK and Adler, RR and Weissman, JS},
title = {Dementia Is Associated With Higher One-Year Mortality and Worse Patient-Centered Outcomes in Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction and Cardiogenic Shock.},
journal = {Cardiology research},
volume = {17},
number = {2},
pages = {128-135},
pmid = {42016208},
issn = {1923-2829},
abstract = {BACKGROUND: Recent trial data demonstrates improved outcomes for the treatment of ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock (CS) with percutaneous coronary intervention (PCI) supported by mechanical circulatory support (MCS). Clinical outcomes in patients with Alzheimer's disease and related dementias (ADRD), however, remain unknown, as these patients were excluded from relevant trials. Physicians and caregivers struggle to navigate time-sensitive decision making for patients with ADRD presenting with STEMI or CS. The aims of this study were to assess the association of ADRD with outcomes of PCI with MCS in the setting of STEMI or CS.

METHODS: We compared outcomes among Medicare fee-for-service (FFS) beneficiaries aged 66 years or older, with and without ADRD, who underwent PCI with MCS for STEMI or CS from July 1, 2017 to December 31, 2019. The primary clinical outcome was inpatient mortality, and secondary clinical outcomes were 1-year mortality, complications, and readmissions. Patient-centered outcomes were time-at-home ratio and discharge to a higher level of care.

RESULTS: A total of 13,110 patients undergoing PCI with MCS for STEMI or CS met study criteria, and 988 (7.5%) patients carried a diagnosis of ADRD. Patients with ADRD were more likely to be older (81.1 vs. 75.5, P < 0.001) and frail (47.0% vs. 22.0%, P < 0.001). Inpatient mortality was similar between groups (odds ratio (OR), 1.05; 95% confidence interval (CI), 0.92-1.21), but 1-year mortality was higher among patients with ADRD (OR, 1.41; 95% CI, 1.21-1.64). Major complications and readmissions were similar between groups. Patients with ADRD were more likely to be discharged to a higher level of care (OR, 1.46; 95% CI, 1.16-1.82) than those without ADRD but demonstrated a similar time-at-home ratio.

CONCLUSIONS: Patients with ADRD demonstrate similar rates of inpatient mortality and major complications but have higher rates of 1-year mortality and discharge to higher levels of care.},
}

@article {pmid42016241,
year = {2026},
author = {Sun, M and He, J and Song, H and Ma, Z and Zhang, X and Li, J and Yao, Y},
title = {Structural Characterization and Anti-Alzheimer's Disease Effect of Polysaccharides From Stellariae Radix.},
journal = {Food science & nutrition},
volume = {14},
number = {3},
pages = {e71604},
pmid = {42016241},
issn = {2048-7177},
abstract = {Stellariae Radix, a frequently employed traditional Chinese medicine, originates from the dried roots of Stellaria dichotoma L. var. lanceolata Bge. To elucidate the structural characteristics and anti-Alzheimer's disease (AD) efficacy of S. dichotoma polysaccharides (SDP), SDP was extracted and comprehensively characterized using ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC). The results revealed that SDP is composed of galactose, glucose, arabinose, galacturonic acid, mannose, and rhamnose at a molar ratio of 5.561:2.224:0.802:0.616:0.613:0.184. In vitro experiments demonstrated that SDP exhibited potent scavenging activities against ABTS, DPPH, and hydroxyl radicals in a dose-dependent manner, with the average scavenging rates reaching 99.07%, 89.44% and 56.43% respectively at the concentration of 5 mg/mL. In a C57BL/6J mouse model of AD, administration of SDP (50-200 mg/kg) significantly ameliorated cognitive dysfunction, increased the hippocampal levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the malondialdehyde (MDA) content, and regulated the expression of oxidative stress-related proteins, including Nrf2, Keap1 and NQO1. These findings indicate that SDP possesses antioxidant and neuroprotective properties, suggesting its potential therapeutic value for the treatment of AD.},
}

@article {pmid42016243,
year = {2026},
author = {Chen, YH and Liu, TT and Chen, LM},
title = {Relationship Between Dietary Choline Intake and Cognitive Function in the United States: A Cross-Sectional Study of the 2011-2014 NHANES Cycle.},
journal = {Food science & nutrition},
volume = {14},
number = {3},
pages = {e71631},
pmid = {42016243},
issn = {2048-7177},
abstract = {BACKGROUND: Current evidence on the correlation between dietary choline intake and Cognitive function is inconsistent. Therefore, this study examines the relationship between dietary choline intake and Cognitive function among noninstitutionalized older adults in the United States based on individuals in the National Health and Nutrition Examination Survey (NHANES) database.

METHODS: This cross-sectional analysis used data from the NHANES conducted from 2011 to 2014. Two 24-h dietary recalls were used to measure choline intake, which was then weighted. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, the Digit Symbol Substitution Test (DSST), and the Animal Fluency Test (AFT) were used to evaluate cognitive function. People were considered to have low cognitive function if their scores on each cognitive test fell below the lowest quartile for their respective age group. The association between choline intake and cognitive function was evaluated using restricted cubic splines (RCS) and binary logistic regression.

RESULTS: In the fully corrected model, the odds ratio (OR) and 95% confidence intervals (CI) of CERAD-WL test scores, CERAD-DR test scores, AFT scores, and DSST scores for the highest quartile of dietary choline intake were 0.61 (0.46 ~ 0.81), 0.66 (0.51 ~ 0.85), 0.66 (0.50 ~ 0.88), and 0.58 (0.42 ~ 0.80); the OR and 95% CI of CERAD-WL test scores, CERAD-DR test scores, AFT scores, and DSST scores for the highest quartile of total choline intake were 0.62 (0.47 ~ 0.83), 0.68 (0.53 ~ 0.88), 0.65 (0.49 ~ 0.86), and 0.57 (0.42 ~ 0.79). Subgroup analysis suggests that the interaction between gender, hypertension status, and choline intake has some impact on the relationship model. In dose-response relationship studies, dietary choline intake and total choline intake are both U-shaped correlated with DSST scores.

CONCLUSION: Choline intake can improve cognitive function scores, and a nonlinear relationship exists between the two.},
}

@article {pmid42016382,
year = {2026},
author = {Yi, S and Zou, J and He, X and Chen, H and Lin, Z and Zhang, L and Zhu, Y and Zuo, Z and Chen, Z and Hu, X and Niu, L},
title = {Transcranial Ultrasound Stimulation Pulsed at 40 Hz Improves Cognition and Neuroinflammation in Female Mice with Alzheimer's Disease.},
journal = {Research (Washington, D.C.)},
volume = {9},
number = {},
pages = {1244},
pmid = {42016382},
issn = {2639-5274},
abstract = {Recent advances in transcranial ultrasound stimulation (TUS) pulsed at 40 Hz have demonstrated the potential to ameliorate cognitive deficits in mouse models of Alzheimer's disease. However, technical barriers remain as general anesthesia is required for mice, which restricts the accurate elucidation of biological mechanisms and behavioral effects under awake physiological conditions. Here, we report a wearable, free-moving ultrasound stimulation system that delivers TUS pulsed at 40 Hz to female 5xFAD transgenic mice to systematically evaluate the behavioral outcomes and underlying mechanistic pathways. Among the treatment groups, a 14-d regimen at an acoustic intensity of 2.14 W/cm[2] yielded the optimal cognitive outcome in Alzheimer's disease mice, which was consistently verified across Y-maze and Morris water maze tests. Additionally, this group showed reduced Aβ plaque deposition and increased plaque-associated microglial activity. Furthermore, enhanced gamma oscillations in the hippocampus were detected following treatment. RNA sequencing revealed modulation of innate immune and inflammatory pathways. Corresponding molecular analysis demonstrated a marked down-regulation in RIPK1, phosphorylated NF-κB, and necroptosis markers, alongside reductions in key pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). Collectively, our findings suggest that the cognitive improvement observed after treatment with TUS pulsed at 40 Hz may be linked to the modulation of neuroinflammatory and necroptotic pathways, possibly involving RIPK1/NF-κB signaling.},
}

@article {pmid42016469,
year = {2026},
author = {Qureshi, AJ and Iftikhar, M and Mahato, RK},
title = {Methodological concerns regarding mortality trends in CVD and Alzheimer's disease comorbidity.},
journal = {American heart journal plus : cardiology research and practice},
volume = {65},
number = {},
pages = {100780},
pmid = {42016469},
issn = {2666-6022},
}

@article {pmid42016561,
year = {2026},
author = {Chang, W and Chen, Y and Kan, J and Huang, X and Luo, K},
title = {Integrated Network Pharmacology, Molecular Docking, and Experimental Validation Elucidating the Therapeutic Mechanism of Idesia polycarpa Crude Oil in Aluminum Chloride-Induced Alzheimer's Rat Models.},
journal = {Food science & nutrition},
volume = {14},
number = {4},
pages = {e71702},
pmid = {42016561},
issn = {2048-7177},
abstract = {While mounting evidence points to a potential link between industrial aluminum exposure and neurodegenerative diseases like Alzheimer's disease (AD), the precise intervention strategies remain an area of active research. This study proposes a "multi-target synergy and dose threshold control" exploratory framework for evaluating Idesia polycarpa crude oil (IPCO) in an aluminum-induced AD model. An integrated analytical approach employing GC-MS and network pharmacology was used to identify three candidate core components-(Z,Z)-9,12-octadecadienoic acid, Beta-amyrin, and 2,4-di-tert-butylphenol-that were computationally predicted to influence a network of 35 ad-related pathways (e.g., Calcium and PPAR signaling) via eight potential key targets (including PTGS2, PPARG, and AKT1). In vivo experiments revealed a dose-dependent modulation of AD-related pathology following IPCO intervention. The high-dose group showed the most marked improvements in several therapeutic markers, including reduced aluminum load, an anti-inflammatory shift in cytokine levels (elevated IL-10, decreased IL-4, IL-6, IL-1β, and TNF-α), and remodeling of the gut microbiota characterized by an increase in putative short-chain fatty acid (SCFA)-producing genera such as the [Eubacterium]-xylanophilum-group and NK4A214-group (Firmicutes). Paradoxically, this same high dose was associated with a decline in spatial cognitive performance. This biphasic effect may be preliminarily explained by a dual microbial mechanism: the inhibition of the pro-inflammatory associated [Eubacterium]-oxidoreducens-group alongside the expansion of taxa linked to a neuroprotective SCFA metabolic network. As one of the first studies to map these multi-dimensional "constituent-microbiota-neuroinflammation" interactions for IPCO, our findings highlight its complex, dose-sensitive bioactivity. Importantly, they underscore the critical need for subsequent pharmacokinetic and direct target engagement studies.},
}

@article {pmid42016760,
year = {2026},
author = {Zhang, B and Shi, C and Zhao, J and Hua, Q and Zhang, H and Gao, H and Qian, Y and Cha, J and Li, J and Chen, J and Kim, TH and Xue, J and Hou, Y and Zhang, R},
title = {RBFOX1 Dysfunction Unlocks APOE4-Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids.},
journal = {Exploration (Beijing, China)},
volume = {6},
number = {2},
pages = {70160},
pmid = {42016760},
issn = {2766-2098},
abstract = {Alzheimer's disease (AD) pathogenesis is strongly influenced by APOE4, though how cooperative genetic factors modulate this relationship remains unclear. While genomic studies have tentatively linked RBFOX1 to AD susceptibility, its functional synergy with APOE4 has never been experimentally defined. We engineered APOE3 or APOE4 isogenic human cerebral organoids with CRISPR/Cas9-mediated RBFOX1 knockout. Remarkably, RBFOX1 depletion selectively triggered robust microglial generation exclusively in APOE4 organoids. Time-course gene expression revealed that this APOE4-specific effect correlated with prolonged mesodermal priming during early embryoid body differentiation, creating a permissive niche for microglial lineage specification. The emergent microglia exhibited pronounced neurotoxic phenotypes, including pro-inflammatory factor secretion, synaptic architecture remodeling, and lipid droplet accumulation in organoids. These changes coincided with aggravated Tau hyperphosphorylation and electrophysiological abnormalities, collectively mirroring multifaceted AD pathology. Our findings establish RBFOX1 as a potential AD protective factor, a critical suppressor of APOE4-glia crosstalk, and demonstrate that its loss unleashes a microglia-mediated neurodegenerative cascade. By developing cerebral organoids with autonomous microglial networks, we present a platform capable of modeling genotype-dependent neuron-glia interactions in AD, opening new avenues for mechanistic and therapeutic exploration.},
}

@article {pmid42016779,
year = {2026},
author = {Rivas-Fernández, MÁ and Basanta-Torres, S and Lindín, M and Zurrón, M and Díaz, F and Pereiro, AX and Lojo-Seoane, C and Rodríguez-Pérez, AI and Labandeira, JL and Galdo-Álvarez, S},
title = {Associations of plasma phosphorylated tau217 with cognitive impairment and brain microstructural alterations in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70333},
pmid = {42016779},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma phosphorylated tau217 (p-tau217) is a promising biomarker for Alzheimer's disease (AD) risk detection. Its relationship with brain microstructure and cognitive impairment remains unclear. Multi-component T2-relaxometry is an MRI technique sensitive to myelin content, axonal degeneration, and neuroinflammation.

METHODS: A total of 229 participants classified by p-tau217 levels into p-tau217- (n = 176), p-tau217+ (n = 26), and intermediate (n = 27) underwent neuropsychological testing and MRI. Voxel-wise general linear models controlling for age, sex, education, apolipoprotein E (APOE, and white matter lesions were performed for total water content (TWC), myelin water fraction (MWF), intra-/extracellular water fraction (IEWF), geometric mean of intra-/extracellular water (T2[IE]), and free/quasi-free water fraction (FQFWF).

RESULTS: The p-tau217+ participants showed poorer cognition, increases in FQFWF and TWC, and reductions in IEWF and T2[IE] across cortical and subcortical regions and white matter tracts.

DISCUSSION: High p-tau217 level associates with brain microstructure alterations and poorer cognition, supporting it as a biomarker of AD-related neuropathology and the utility of T2-relaxometry for detecting tissue integrity.},
}

@article {pmid42016780,
year = {2026},
author = {Jabeen, T and Karimi, F and Zomorrodi, AR and Khalilpour, K},
title = {Multi-modal machine learning and gut microbiome pathway analysis for Alzheimer's risk prediction.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70340},
pmid = {42016780},
issn = {2352-8729},
abstract = {INTRODUCTION: Early Alzheimer's disease (AD) risk assessment requires accessible alternatives to invasive biomarkers. We developed a multi-modal machine learning framework using questionnaire metadata from participants with concurrent microbiome sequencing data.

METHODS: We analyzed 9832 participants with 120 metadata features across five categories (demographic, dietary, lifestyle, nutritional, medical). Features were selected via Pearson correlation and chi-squared tests. Four algorithms were trained using 10-fold cross-validation with synthetic minority oversampling technique (SMOTE), validated on 1967 samples. The 16S rRNA sequencing data from the same cohort with 2000 samples enabled microbiome composition analysis.

RESULTS: Medical history (area under the curve [AUC] = 0.871) and dietary patterns (AUC = 0.874) achieved best performance, outperforming demographic (0.795), lifestyle (0.660), and nutritional (0.569) domains (p < 0.001). Microbiome analysis revealed dysbiosis markers (Prevotella/Bacteroides ratio: 1.921) linking dietary factors to potential neuroinflammatory pathways.

DISCUSSION: These findings support non-invasive, multi-modal screening combining medical and dietary evaluation for AD risk stratification, with preliminary microbiome evidence suggesting gut-brain axis dysbiosis as a mechanistic pathway warranting validation in larger cohorts.},
}

@article {pmid42016909,
year = {2026},
author = {Darbinian, N and Darbinyan, A and Pozniak, P and Amini, S and Selzer, ME},
title = {Neuroprotective Role of DING Protein in Normal Aging and Alzheimer's Disease.},
journal = {Archives of internal medicine research},
volume = {9},
number = {1},
pages = {53-63},
pmid = {42016909},
issn = {2688-5654},
abstract = {INTRODUCTION: Previously, we showed that the phosphatase DING extracted from St. John's wort (p38SJ) is neuroprotective against EtOH-mediated toxicity in rat and human fetal neurons in vitro. Now, we assess the role of human DING in Alzheimer's disease (AD). DING (p38SJ/p38hu), a member of the DING family of proteins, has been shown to be neuroprotective against cellular stress injury induced by alcohol, HIV-1, and in cancer cells. DING has demonstrated phosphatase activity on MAPK substrates, but its effect on Tau phosphorylation, which is involved in AD, has not yet been explored.

METHODS: Expression of DING protein levels was studied in human postmortem brain using histochemistry and quantitative western blot with ANOVA. Five patients with dementia, of whom 3 had AD neuropathology, a fourth had AD/Parkinson complex, and one had cerebrovascular dementia, were compared with 5 non-dementia controls.

RESULTS: DING was present in the neuronal cell bodies and processes of both normal and AD-affected human brain tissue. DING demonstrated phosphatase activity in PC12 cells (a cell line derived from rat pheochromocytoma) and inhibited Tau phosphorylation in these cells and in human brain tissue (both normal and AD). Increasing DING by transduction and overexpression in PC12 cells was associated with increased cell survival. In human brains (age=72-92 years), levels of endogenously expressed 38 kDa DING protein correlated positively with Tau dephosphorylation.

CONCLUSIONS: Excess Tau phosphorylation leads to the formation of neurofibrillary tangles in neurons, a hallmark of neurodegeneration in Alzheimer's disease. DING inhibits Tau phosphorylation and increases cell viability in non-proliferating neuronal cells overexpressing Tau, while reducing the viability of proliferating cells. Thus, DING may be neuroprotective in AD.},
}

@article {pmid42017160,
year = {2026},
author = {Kermaninia, S and Farnia, M and Mahdavi, M and Iraji, A},
title = {Coumarin bearing triazole hybrids as cholinesterase inhibitors targeting Alzheimer's disease.},
journal = {RSC advances},
volume = {16},
number = {22},
pages = {20364-20380},
pmid = {42017160},
issn = {2046-2069},
abstract = {A series of novel coumarin-triazole hybrids (12a-s) were synthesized and evaluated for their inhibitory activities against cholinesterase including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes related to Alzheimer's disease. The structure-activity relationship (SAR) analysis revealed that substitutions at the 2-position of the aromatic ring significantly enhanced anti-BChE potency, with compound 12c (2-fluorophenyl) exhibiting moderate activity with IC50 = 4.37 ± 0.91 µM for BChE and 7.17 ± 0.42 µM for AChE. Docking studies demonstrated strong binding interactions of 12c with critical residues in the active site of the enzyme. Molecular dynamics simulations confirmed the stability of the 12c-AChE and 12c-BChE complexes over 100 ns, with low RMSD values and stable hydrogen bonding. These findings highlight the importance of electronic and steric effects in optimizing cholinesterase inhibition and provide insights into the design of effective agents for Alzheimer's disease therapy.},
}

@article {pmid42017176,
year = {2026},
author = {Zhong, F and Wu, J and Deng, Z and Yu, W and Song, J and Chen, Y and Yu, W and Lü, Y},
title = {ATOX1 overexpression mitigates copper homeostasis in microglia: Implications for Alzheimer's disease therapy.},
journal = {Genes & diseases},
volume = {13},
number = {4},
pages = {101888},
pmid = {42017176},
issn = {2352-3042},
abstract = {Copper (Cu[2+]) is a known contributor to the pathogenesis of Alzheimer's disease (AD). However, it is uncertain whether proteins regulating copper homeostasis affect Cu[2+] in microglia. Antioxidant protein 1 (ATOX1) plays a key role in Cu[2+] homeostasis, oxidative stress, and cell protection. Despite its critical functions, the role of ATOX1 in AD pathology remains poorly defined. This study aims to examine the effects of ATOX1 on oxidative stress, apoptosis, and neuroinflammation in microglia by modulating Cu[2+] homeostasis. In vivo, a 5 × FAD mouse model was used to investigate the localization and expression of ATOX1 in AD by immunofluorescence and three-dimensional reconstruction. The Aβ1-42 oligomer was used to establish an AD model in vitro. The role of ATOX1 in Cu[2+] homeostasis regulation in microglia was further studied using co-immunoprecipitation, Western blotting, quantitative real-time PCR, and spectrophotometry. A reduction in ATOX1 expression was noted in Aβ-plaques-associated microglia compared with normal microglia. Cu[2+] levels were elevated in the in vitro AD model, and ATOX1 directly regulated copper homeostasis via P1B-ATPase (ATP7B) in microglia. Excessive Cu[2+] induced oxidative stress, neuroinflammation, and apoptosis. Overexpression of ATOX1 alleviated this neurotoxicity, indicating its potential to alleviate oxidative stress, cell apoptosis, and neuroinflammation in AD. ATOX1 overexpression offers protective effects on microglia through Cu[2+] homeostasis, which may lead to potential therapeutic strategies for AD.},
}

@article {pmid42017264,
year = {2026},
author = {Mock, L and Mork, D and Audirac, M and Braun, D and Zanobetti, A and Delaney, SW},
title = {Hospitalization risk with and without dementia by region and race in the US.},
journal = {American journal of epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/aje/kwag087},
pmid = {42017264},
issn = {1476-6256},
abstract = {Understanding regional and racial variation in the risk of hospitalization with Alzheimer's disease and related dementias (ADRD)-and how it differs from other conditions-is required to inform effective practice and policy. However, no prior studies have simultaneously estimated county-level regional and race-specific variation in hospitalization risk. We assessed hospitalizations with and without ADRD diagnoses among Black and White Medicare Fee-for-Service beneficiaries from 2000-2018 and used Bayesian shared component models to estimate geographic variation in hospitalizations jointly for both racial groups. We decomposed hospitalization risk across 3037 counties into (1) risk shared by all beneficiaries and (2) risk specific to either Black or White beneficiaries. We analyzed 143 891 769 hospitalizations (13.2% with ADRD). For hospitalization with ADRD, shared risk was elevated in southern and eastern states; Black-specific risk was elevated in the Midwest, Florida, and California; and White-specific risk was elevated in Appalachia. Black relative risk was significantly higher than White relative risk in 90.2% (2740/3037) of counties for hospitalization with ADRD and 44.7% (1359/3037) of counties for hospitalization without ADRD. These findings underscore the importance of considering regional differences in race-specific risk when assessing hospitalization disparities.},
}

@article {pmid42017332,
year = {2026},
author = {Arce Rentería, M and Strangmann, IM and Ghazi Saidi, L and Subina, MM and Paplikar, A and Dash, T and Costa, AS and Lahiri, D and Page, ZA and Bose, A and Ahmed, S and Stites, SD and D'Souza, A and Ellajosyula, R and Franzen, S and Alladi, S and de Leon, J and Calabria, M and Tee, BL and Babulal, GM and Grasso, SM},
title = {Deconstructing bilingualism and its sociocultural determinants in cognitive aging and Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71393},
doi = {10.1002/alz.71393},
pmid = {42017332},
issn = {1552-5279},
support = {//NIH/ ; R01AG080473/AG/NIA NIH HHS/United States ; R00AG066932/AG/NIA NIH HHS/United States ; R01AG068183/AG/NIA NIH HHS/United States ; R01AG067428/AG/NIA NIH HHS/United States ; R01AG074302/AG/NIA NIH HHS/United States ; R01AG080469/AG/NIA NIH HHS/United States ; R01AG080396/AG/NIA NIH HHS/United States ; K23DC018021/AG/NIA NIH HHS/United States ; 1K23AG065442/AG/NIA NIH HHS/United States ; R01AG080470/AG/NIA NIH HHS/United States ; 73305095007//The Dutch Medical Research Council (ZonMw)/ ; 1051003210004//The Dutch Medical Research Council (ZonMw)/ ; LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; //Clinician Scientist Program of the Faculty of Medicine, RWTH Aachen University/ ; //Dementia Centre for Research Collaboration (DCRC) PhD Scholarship/ ; //the Centre for Healthy Brain Ageing (CHeBA) Josh Woolfson Memorial Scholarship/ ; //an Australian Government Research Training Program (RTP) Fee Offset/ ; //Spanish Ministry of Science, Innovation and Universities (MCIU)/ ; //the State Research Agency (AEI)/ ; PID2023-149755OB-I00//the European Regional Development Fund (FEDER/EU)/ ; },
mesh = {Humans ; *Multilingualism ; *Alzheimer Disease/psychology ; *Cognitive Aging/psychology ; *Dementia/psychology ; },
abstract = {Despite bilingualism being highly prevalent worldwide, the role of bilingualism in cognitive aging and Alzheimer's disease and related dementias (ADRD) remains inconclusive. Gaps include whether bilingual adults show reduced ADRD risk, how cognitive decline manifests across both languages, and what considerations are needed for accurate clinical assessment and intervention. The Bilingualism, Languages and Literacy Special Interest Group, part of the Diversity and Disparities Professional Interest Area, gathered an international, interdisciplinary group of researchers to identify key methodological factors impacting the study of bilingualism in cognitive aging and ADRD. Factors identified ranged from the operationalization and measurement of bilingualism, heterogeneity of bilingual populations, inconsistent accounting of sociocultural influences, scarcity of best practices in the clinical assessment and interventions of/for bilingual adults, and limited inclusion of conceptual frameworks. Findings generated reporting recommendations designed to increase rigor, comparability, and reproducibility across studies, and provide guidance for strengthening future research involving bilingual adults.},
}

Humans
*Multilingualism
*Alzheimer Disease/psychology
*Cognitive Aging/psychology
*Dementia/psychology

@article {pmid42017417,
year = {2026},
author = {Yang, Y and Jung, KJ and Kwak, YT},
title = {Dual-threshold plasma Aβ oligomerization for postoperative delirium risk stratification.},
journal = {Age and ageing},
volume = {55},
number = {4},
pages = {},
doi = {10.1093/ageing/afag106},
pmid = {42017417},
issn = {1468-2834},
support = {HI22C0667//Ministry of Health and Welfare, Republic of Korea/ ; //Korea Health Technology R&D Project/ ; },
mesh = {Humans ; Male ; Female ; Aged ; Risk Assessment ; *Amyloid beta-Peptides/blood ; Biomarkers/blood ; Aged, 80 and over ; *Delirium/blood/diagnosis/etiology ; Risk Factors ; Predictive Value of Tests ; *Orthopedic Procedures/adverse effects ; *Postoperative Complications/blood/diagnosis ; Elective Surgical Procedures/adverse effects ; Protein Multimerization ; },
abstract = {BACKGROUND: Postoperative delirium is common in older surgical patients, but simple blood tests to identify risk are lacking. Plasma amyloid-β oligomers measured by multimer detection (MDS-OAβ) may reflect neurodegenerative vulnerability.

METHODS: We enrolled 101 patients aged ≥65 years undergoing elective orthopaedic surgery with general anaesthesia. Blood was drawn preoperatively and at first delirium diagnosis or on postoperative Day 4 if no delirium. MDS-OAβ was quantified blinded. Delirium was assessed daily on postoperative Days 1-3 (DRS-R-98 and DSM). Propensity-score matching on APOE ε4 status and clinical covariates addressed Alzheimer-type vulnerability. Discrimination and thresholds (0.60, 0.72, 0.85 ng/ml) were evaluated using logistic regression and ROC analyses.

RESULTS: Among 101 patients (44 with delirium; 57 without), preoperative MDS-OAβ concentrations were higher in those who developed delirium and correlated with delirium severity. In the overall cohort, preoperative MDS-OAβ discriminated delirium with an area under the curve of 0.855 (95% CI 0.777-0.919); in a pooled postoperative dataset (n = 205), discrimination was similar (AUC 0.884, 95% CI 0.837-0.925). The dual-threshold approach identified a low-risk group with high negative predictive value and a high-risk group with high positive predictive value, leaving an intermediate group for closer observation.

CONCLUSIONS: Preoperative plasma MDS-OAβ may provide a scalable biomarker for perioperative risk stratification of postoperative delirium in older adults, supporting a dual-threshold strategy for targeted prevention and monitoring. Low MDS-OAβ values indicate lower risk but do not exclude POD; biomarker-guided stratification should complement, not replace, routine perioperative delirium surveillance.},
}

Humans
Male
Female
Aged
Risk Assessment
*Amyloid beta-Peptides/blood
Biomarkers/blood
Aged, 80 and over
*Delirium/blood/diagnosis/etiology
Risk Factors
Predictive Value of Tests
*Orthopedic Procedures/adverse effects
*Postoperative Complications/blood/diagnosis
Elective Surgical Procedures/adverse effects
Protein Multimerization

@article {pmid42017463,
year = {2026},
author = {Migeot, J and Wen, O and Gonzalez-Gomez, R and Hernandez, H and Aguillon, D and Avila-Funes, JA and Behrens, MI and Bruno, MA and Custodio, N and Delgado, C and Duran-Aniotz, C and Duron-Reyes, D and García, AM and Godoy, ME and Hu, K and Lawlor, B and Li, P and Maito, MA and Matallana, DL and Miller, B and de Oliveira, MO and Pina-Escudero, SD and Possin, KL and Resende, EPF and Reyes, P and Santamaria-Garcia, H and Slachevsky, A and Takada, LT and Vergara, P and Yaffe, K and Yokoyama, JS and Romero-Ortuño, R and Ibanez, A},
title = {Neural embedding of frailty in cognitively unimpaired aging and dementia across Latin America.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71232},
doi = {10.1002/alz.71232},
pmid = {42017463},
issn = {1552-5279},
support = {1250091//(ANID/FONDECYT) Regular/ ; 1210176//(ANID/FONDECYT) Regular/ ; 1220995//(ANID/FONDECYT) Regular/ ; //ANID/FONDAP/15150012/ ; /AG/NIA NIH HHS/United States ; //NIDA/ ; //Ache for Educational Materials (2024)/ ; //Novo Nordisk for Lectures and Congress Participation (2023-2024)/ ; //Lilly for Training Activities (2024)/ ; //Davos Alzheimer's Collaborative/ ; FONDECYT Regular 1250317 1250091//ANID/ ; 032351GDAS//DICYT-USACH/ ; //Agencia Nacional de Promoción Científica y Tecnológica/ ; 1210622//ANID/FONDECYT Regular/ ; 1250091//ANID/FONDECYT Regular/ ; //ANID/NAM22I0007/ ; //ANID/PIA/ANILLOS ACT210096/ ; //ANID/FOVI240065/ ; 13240170//ANID/Proyecto Exploración/ ; 15150012//ANID/FONDAP/ ; 1231839//ANID/FONDECYT/ ; ID22I10251//ANID/FONDEF/ ; 13220082//ANID/Proyectos de Exploración/ ; //ReDLat/ ; //ANID/FONDEF/ ID18I10113/ ; //ANID/Fondecyt 123183/ ; Provided in the ms/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Male ; Female ; Latin America/epidemiology ; Aged ; *Frailty ; *Brain/pathology/diagnostic imaging/physiopathology ; *Aging ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Dementia ; Magnetic Resonance Imaging ; *Frontotemporal Lobar Degeneration/physiopathology/diagnostic imaging ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Frailty influences dementia risk and severity. However, its role in differentiating dementia subtypes and associations with brain structural and functional alterations remain understudied, especially in Latin America.

METHODS: Multi-Partner Consortium to Expand Dementia Research in Latin America data included 3461 participants (cognitively unimpaired [CU], Alzheimer's disease [AD], and frontotemporal lobar degeneration [FTLD]) from Latin America using a frailty index constructed from 32 health-related variables. XGBoost-logistic regression models tested group discrimination, and voxel-based morphometry plus functional connectivity analyses explored neural correlates.

RESULTS: Frailty distinguished CU from AD (area under the curve [AUC] = 0.85) and CU from FTLD (AUC = 0.88) but not AD from FTLD (AUC = 0.59). Higher frailty was linked to widespread gray matter loss, with temporal involvement in CU and stronger frontotemporal effects in dementia, particularly FTLD. Connectivity analyses showed fronto-temporo-posterior reductions and increased connectivity across the frailty network.

DISCUSSION: Findings position frailty as a promising marker for identifying AD and FTLD relative to CU individuals, linked with brain health alterations in Latin American populations.},
}

Humans
Male
Female
Latin America/epidemiology
Aged
*Frailty
*Brain/pathology/diagnostic imaging/physiopathology
*Aging
*Alzheimer Disease/diagnostic imaging/physiopathology
*Dementia
Magnetic Resonance Imaging
*Frontotemporal Lobar Degeneration/physiopathology/diagnostic imaging
Middle Aged
Aged, 80 and over

@article {pmid42017806,
year = {2026},
author = {Scalzo, P and Clevenger, C and Romano, RR},
title = {Nurse practitioner-directed continuing education leads to knowledge, confidence, and practice changes related to Alzheimer disease early diagnosis and disease-modifying treatments.},
journal = {Journal of the American Association of Nurse Practitioners},
volume = {},
number = {},
pages = {},
pmid = {42017806},
issn = {2327-6924},
abstract = {Alzheimer disease (AD) continues to be underdiagnosed and undertreated in primary care despite the high and growing prevalence. Lack of diagnosis becomes more pressing with the availability of disease-modifying therapies (DMTs) that can slow disease progression during a narrow window of time in the course of the disease. Nurse practitioners (NPs) are central to closing these practice gaps, but persistent deficiencies in knowledge and confidence highlight the need for focused continuing education (CE). A 1.6-hour CE activity was developed on the importance of early AD diagnosis, interpretation of DMT clinical trial data, and strategies to improve DMT access. Outcomes were assessed using pre- and post-activity surveys and a 60-day follow-up survey. A total of 6,541 learners completed the program, the majority of whom were practicing NPs providing direct patient care. Collectively, these providers reported caring for over 35,000 patients at risk for cognitive impairment each week. The CE program led to a remarkable 38% improvement in knowledge, with significant gains across all assessment items (p < .001). The greatest gains were in recognizing the prolonged asymptomatic phase of AD (418% improvement) and identifying risk factors for the primary adverse effect of DMTs (50% improvement). Confidence in key domains improved significantly, with 75%-79% of follow-up respondents who see patients reporting sustained confidence gains. At 60 days, 59% had implemented at least one practice change. This CE program reached a large NP audience and improved knowledge, confidence, and reported practice behaviors related to AD early diagnosis and DMTs.},
}

@article {pmid42017968,
year = {2026},
author = {Yuan, S and Essepian, N and Roberts, R and Sherman, E and Wang, Q and Erisir, A and Jiang, L},
title = {Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42017968},
issn = {1432-0533},
support = {R01AG091577//NIH/NIA/ ; },
mesh = {*tau Proteins/metabolism ; *Alzheimer Disease/pathology/metabolism/genetics ; Humans ; Animals ; *Nuclear Lamina/metabolism/pathology ; Mice ; *Chromatin Assembly and Disassembly/physiology ; Mice, Transgenic ; Female ; Neurons/metabolism/pathology ; Male ; Brain/metabolism/pathology ; Lamin B Receptor ; Disease Models, Animal ; },
abstract = {The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer's disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. Using the tauopathy mouse model (P301S PS19), we demonstrate that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), inducing nuclear envelope invaginations as revealed by electron microscopy. These structural alterations are accompanied by chromatin remodeling and gene expression dysregulation. To dissect the underlying mechanism, we employed a light-inducible OptoTau system (4R1N Tau::mCherry::Cry2Olig) in human iPSC-derived neurons, enabling real-time visualization of tau aggregation dynamics. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.},
}

*tau Proteins/metabolism
*Alzheimer Disease/pathology/metabolism/genetics
Humans
Animals
*Nuclear Lamina/metabolism/pathology
Mice
*Chromatin Assembly and Disassembly/physiology
Mice, Transgenic
Female
Neurons/metabolism/pathology
Male
Brain/metabolism/pathology
Lamin B Receptor
Disease Models, Animal

@article {pmid42017988,
year = {2026},
author = {Hill, E and Linehan, J and Farmer, M and Jakubcova, T and Hamdan, S and Tomlinson, A and Purro, S and Argentina, F and Jones, E and Kaye, N and Fitzhugh, C and de Silva, R and Brandner, S and Collinge, J and Cunningham, TJ and Mead, S},
title = {Modification of early behavioural, physiological and neuropathological endpoints by syntaxin-6 knockout in a humanised P301S transgenic model of tauopathy.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42017988},
issn = {1432-0533},
mesh = {Animals ; *Tauopathies/pathology/genetics/metabolism/physiopathology ; *Qa-SNARE Proteins/genetics/metabolism/deficiency ; Disease Models, Animal ; Mice, Transgenic ; Humans ; Mice ; tau Proteins/genetics/metabolism ; Mice, Knockout ; *Brain/pathology/metabolism ; Male ; },
abstract = {Genetically mediated increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk mechanism for progressive supranuclear palsy and sporadic prion disease. Increased syntaxin-6 protein levels are also causally associated with Alzheimer's disease, suggesting it may have shared roles across multiple neurodegenerative diseases. However, no study has validated its functional role in tauopathies. To validate a role for syntaxin-6 in tauopathy pathogenesis, we knocked out syntaxin-6 in humanised P301S tauopathy mice. Mice underwent longitudinal rotarod testing, gait analysis, frailty and weight assessment, with neuropathological, biochemical and pathological analyses at 3 and 5 months. Stx6[+/+];hTau[P301S/P301S] mice showed motor impairment from 1 month of age, which was partially rescued by syntaxin-6 knockout from months 1 to 4, with additional protection of gait at 5.5 months. Physiologically, syntaxin-6 knockout exerted a protective effect on weight trajectories and measures of frailty. Reduced neurodegeneration in the superficial cortex was observed at 3 months, as well as higher synaptic coverage at 5 months of age, supporting preserved neuropathological measures related to function. We further observed localised increases in tau pathology in the spinal cord and defined brain regions in young Stx6[-/-];hTau[P301S/P301S] mice, despite total tau levels being comparable, in keeping with altered trafficking of pathological tau species with syntaxin-6 knockout. Despite a partial, early phenotypic rescue of functional measures, terminal endpoint comparisons were confounded by a 20% weight loss culling rule, as knockout mice maintained higher absolute weight. Taken together, this study functionally validates a role for syntaxin-6 in tauopathy pathogenesis, with syntaxin-6 knockout resulting in an early protective effect on multiple disease-relevant phenotypes in a humanised tauopathy model.},
}

Animals
*Tauopathies/pathology/genetics/metabolism/physiopathology
*Qa-SNARE Proteins/genetics/metabolism/deficiency
Disease Models, Animal
Mice, Transgenic
Humans
Mice
tau Proteins/genetics/metabolism
Mice, Knockout
*Brain/pathology/metabolism
Male

@article {pmid42018225,
year = {2026},
author = {Liu, L and Zhu, B},
title = {Advancements in the Study of Missense Mutations in ABCA7 in Alzheimer's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42018225},
issn = {1559-1166},
}

@article {pmid42018322,
year = {2026},
author = {Falzarano, FB and Greenfield, A and Saviano, SC and Kolla, S and Korian, S and Osso, F and Miller, J and Whitson, HE and Maciejewski, PK and Prigerson, HG},
title = {Digital Reminiscence for Predeath Grief Among Family Caregivers of Patients With Dementia: A Pilot Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {9},
number = {4},
pages = {e268278},
doi = {10.1001/jamanetworkopen.2026.8278},
pmid = {42018322},
issn = {2574-3805},
mesh = {Humans ; *Caregivers/psychology ; Female ; Male ; Pilot Projects ; Aged ; Middle Aged ; *Grief ; *Dementia/nursing/psychology ; Aged, 80 and over ; Feasibility Studies ; Adult ; },
abstract = {IMPORTANCE: Family caregiving for individuals with Alzheimer disease and related dementias (ADRD) is associated with significant distress related to physical, emotional, and interpersonal losses. Reminiscence therapy may help family caregivers preserve connection, reframe loss, and reduce predeath grief, although its evaluation among caregivers remains underexplored.

OBJECTIVE: To assess the feasibility, acceptability, and preliminary efficacy of a digital reminiscence platform (Living Memory Home for Dementia Care Pairs [LMH-4-DCP]) for ADRD caregiver-care recipient dyads.

This multisite, participant-blinded pilot randomized clinical trial was conducted virtually at Weill Cornell Medicine, New York, New York, and the University of Southern California, Los Angeles. Eligibility included being a primary caregiver for a family member with ADRD, age 18 years or older, and fluency in English. Participants were randomized in a 1:1 ratio and completed baseline and 2-week postintervention assessments. Enrollment occurred between November 6, 2024, and April 15, 2025. Data analyses were conducted from August 1 to 31, 2025.

INTERVENTION: LMH-4-DCP is a digital intervention for ADRD caregiver-care recipient dyads to engage in reminiscence activities. Participants were randomized to the LMH-4-DCP or an attention control condition, which included a restricted version of the platform without reminiscence features.

MAIN OUTCOMES AND MEASURES: Outcomes, including feasibility, acceptability, predeath grief, and relationship quality were assessed at baseline and 2-week follow-up.

RESULTS: Of 174 screened caregivers, 106 were eligible, and 68 enrolled. Among the enrolled participants, the mean (SD) age was 49.4 (13.7) years (range, 23-90 years). Fifty-four participants (79.4%) were female, and 39 (57.4%) were caring for a parent. Fifty-four randomized participants completed follow-up assessments (27 per group). Feasibility and acceptability of LMH-4-DCP was demonstrated by a study completion rate of 120 of 136 assigned assessments (88.2%). Most participants in the intervention group reported that LMH-4-DCP was easy to use (20 of 27 [74.1%]) and had well-integrated features (21 of 27 [77.8%]). Intervention participants showed reduced predeath grief (Cohen d = -0.38; mean [SD] reduction, -3.29 [8.64]; P = .03) after 2 weeks of using LMH-4-DCP. Compared with controls, intervention participants demonstrated greater reductions in predeath grief. Improvements in relationship quality were observed for intervention participants, but the difference was not significant.

CONCLUSIONS AND RELEVANCE: This pilot randomized clinical trial demonstrated the feasibility, acceptability, and preliminary efficacy of LMH-4-DCP in reducing caregiver grief, with improvements in caregiver-care recipient relationship quality. These findings should inform platform refinements and a future, definitive efficacy trial.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06225986.},
}

Humans
*Caregivers/psychology
Female
Male
Pilot Projects
Aged
Middle Aged
*Grief
*Dementia/nursing/psychology
Aged, 80 and over
Feasibility Studies
Adult

@article {pmid42018938,
year = {2026},
author = {Haghighi, FH and Xie, J and Ebert, ET and Siahaan, TJ},
title = {Progress and challenges in drug delivery for the treatment of Alzheimer's disease.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2026.2663114},
pmid = {42018938},
issn = {1744-7593},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder marked by declining memory and cognitive function. Despite recent advances to slowdown early-stage progression, no curative therapies exist due to challenges in delivering neuroregenerative agents to the brain.

AREAS COVERED: This review examines recent research on strategies to modulate the blood-brain barrier (BBB) to enhance delivery of small-to-large molecules through the paracellular pathway into the brain for potential treatments of AD. A literature search was conducted using PubMed and Scopus covering studies published between 2016 and 2026.

EXPERT OPINION: BBB modulation technologies are advancing rapidly and offer real potential to improve delivery of therapeutics in AD patients. Hyperosmotic method has been successfully used to deliver anticancer drugs to treat brain tumor patients and can be used for AD. Recently, focused ultrasound (FUS) has been used to disrupt the BBB at a targeted brain region to enhance paracellular permeation of drug molecules to the brain. Finally, drug permeation through the BBB paracellular pathway can also be enhanced by modulating the protein-protein interactions in the intercellular junctions using BBB modulators (BBBMs). This review covers the mechanisms, advantages, and limitations of these methods as well as recent studies to enhance therapeutic agents for AD and other brain diseases.},
}

@article {pmid42018962,
year = {2026},
author = {Tai, XY and Zhao, S and Liem, B and Galovic, M and Husain, M and Sen, A and Manohar, S},
title = {The Relationship Between Sleep, Cognition, and Dementia Risk in People With Focal Epilepsy.},
journal = {Neurology},
volume = {106},
number = {10},
pages = {e214985},
doi = {10.1212/WNL.0000000000214985},
pmid = {42018962},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; *Epilepsies, Partial/complications/epidemiology/psychology/physiopathology ; Middle Aged ; *Dementia/epidemiology/etiology ; Aged ; Adult ; *Sleep/physiology ; Prospective Studies ; *Cognition/physiology ; Stroke/epidemiology ; Risk Factors ; *Cognitive Dysfunction/epidemiology ; Executive Function/physiology ; Cohort Studies ; *Sleep Wake Disorders/epidemiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Sleep disruption and cognitive impairment are important comorbidities of focal epilepsy. However, the nature to which sleep affects cognition and long-term dementia risk in focal epilepsy, compared with other brain conditions, remains unclear. We examined the relationship between sleep, cognition, and dementia risk in patients with focal epilepsy compared with healthy controls and stroke patients.

METHODS: We conducted an analysis of the prospective UK Biobank cohort study, with baseline assessments performed between 2006 and 2010 and follow-up until 2021. Study groups were mutually exclusive participants with focal epilepsy and stroke at baseline assessment and healthy controls. Sleep characteristics included reports of sleep duration, obstructive sleep apnea, insomnia, napping, and dozing. Main outcomes were risk of incident all-cause dementia and Alzheimer disease from Cox proportional hazard modeling and comparison of executive function measures and brain total hippocampal and gray matter volumes using generalized linear modeling.

RESULTS: We examined a sample of 482,207 participants, aged between 38 and 72 years (mean [SD] 57.6 [8.1] years; 53.8% female), without dementia at baseline and a nested imaging subsample of 42,345 participants. Optimal sleep duration (6-8 hours) was associated with better executive function in control, focal epilepsy, and stroke groups. The impact of optimal sleep was significantly higher in individuals with focal epilepsy compared with controls (interaction term, p = 0.009), but not in the stroke group (interaction term, p = 0.574). Nonoptimal sleep was associated with worse executive function up to 8 years before the diagnosis of focal epilepsy. A 5-fold increased risk of developing dementia was seen in individuals with focal epilepsy and nonoptimal sleep (hazard ratio [HR] 5.15, 95% CI 3.77-7.04, p < 0.001) compared with healthy controls with optimal sleep. This was greater than in stroke individuals with poor sleep (HR 3.48, 95% CI 2.82-4.26, p < 0.001). Optimal sleep compared with nonoptimal sleep modified the dementia risk in in individuals focal epilepsy, with a significantly greater improvement compared with healthy controls (interaction term p = 0.017), while no significant difference was seen in the stroke group (interaction term p = 0.991).

DISCUSSION: Optimal sleep modified both cognitive performance and dementia risk in individuals with focal epilepsy compared with stroke patients and healthy controls. Based on self-reported sleep data, these findings suggest that improving sleep may be an impactful intervention to improve cognition and reduce dementia risk particularly in focal epilepsy.},
}

Humans
Female
Male
*Epilepsies, Partial/complications/epidemiology/psychology/physiopathology
Middle Aged
*Dementia/epidemiology/etiology
Aged
Adult
*Sleep/physiology
Prospective Studies
*Cognition/physiology
Stroke/epidemiology
Risk Factors
*Cognitive Dysfunction/epidemiology
Executive Function/physiology
Cohort Studies
*Sleep Wake Disorders/epidemiology

@article {pmid42019008,
year = {2026},
author = {Corriveau-Lecavalier, N and Dicks, E and Martin, PR and Wiste, HJ and Gunter, JL and Kamykowski, MG and Senjem, ML and Schwarz, CG and Botha, H and Graff-Radford, J and Machulda, MM and Fields, JA and Boeve, BF and Lowe, VJ and Knopman, DS and Petersen, RC and Jack, CR and Jones, DT},
title = {Default mode network failure across the Alzheimer's disease spectrum.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag146},
pmid = {42019008},
issn = {1460-2156},
abstract = {Alzheimer's disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.},
}

@article {pmid42019071,
year = {2026},
author = {Liu, Y and Zhang, W and Zuo, F and Jing, P and Ji, Y and Kung, SY},
title = {Depth-Induced Saliency Comparison Network for the Diagnosis of Alzheimer's Disease via Joint Analysis of Stimuli and Eye Movements.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3686608},
pmid = {42019071},
issn = {2168-2208},
abstract = {Alzheimer's disease (AD) poses a growing global health challenge, with visuospatial impairments emerging as early indicators that can be detected through eye movement analysis. However, existing methods face two key limitations: first, they often analyze eye movements in isolation, without exploiting explicit saliency patterns for comparison; second, temporal attentional dynamics across sequences remain underexplored and fail to capture the temporal evolution of abnormal visuospatial patterns. To address these challenges, we propose a depth-induced saliency comparison network (DISCN). The DISCN first employs a depth-included salient attention module (DSAM) to construct comprehensive objective-subjective saliency priors from the saliency of RGB-D visual stimuli and normal control eye movements. A saliency-aware serial attention module (SSAM) then applies temporal attention to eye movements elicited by sequential stimuli to characterize dynamic visuospatial abnormalities. Experimental results on both internal and external cohorts demonstrate that the DISCN achieves robust performance in terms of distinguishing AD patients from normal controls by using eye movements.},
}

@article {pmid42019114,
year = {2026},
author = {Liu, Y and Jiang, Z and Chen, D and He, Z and Ning, W and Wang, S and Guan, L},
title = {Design, synthesis, and biological evaluation of Chromene-Phenylpiperazine-Chalcone hybrids as multi-target-directed ligands for the treatment of Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry},
volume = {138},
number = {},
pages = {118670},
doi = {10.1016/j.bmc.2026.118670},
pmid = {42019114},
issn = {1464-3391},
abstract = {A novel series of chromene-phenylpiperazine-chalcone hybrids was rationally designed, synthesized and evaluated as multi-target-directed ligands (MTDLs) for Alzheimer's disease (AD). Among them, compound 9 s exhibited selective equine serum butyrylcholinesterase (eqBuChE, IC50 = 0.13 μM) and concurrent monoamine oxidase B (MAO-B, IC50 = 1.63 μM) inhibitory activities. Kinetic and molecular docking studies indicated that 9 s acts as a mixed-type dual-site inhibitor. In silico modeling suggests that the binding pose is stabilized by a predicted pseudo-seven-membered ring. Furthermore, 9 s facilitated the disassembly of self-aggregated and Cu[2+]-induced Aβ1-42 fibrils. In BV-2 microglial cells, it demonstrated a high safety margin (> 380-fold effective concentration), accelerated intracellular Aβ clearance, and subsequently attenuated LPS-induced NO production. In vivo evaluations revealed low acute toxicity (LD50 > 1000 mg/kg). Oral administration of 9 s successfully reversed scopolamine-induced spatial working memory deficits in mice. These findings validate the drug-like 9 s as an orally efficacious MTDL candidate that provides symptomatic cognitive relief, while possessing promising in vitro disease-modifying potential for AD therapy.},
}

@article {pmid42019137,
year = {2026},
author = {Otani, K and Ishihara, H and Nakamura, T and Kawabe, K},
title = {Implementation and service impact of anti-amyloid therapy in a psychiatry-led dementia care program: Real-world evidence from a Japanese regional dementia center.},
journal = {General hospital psychiatry},
volume = {100},
number = {},
pages = {208-214},
doi = {10.1016/j.genhosppsych.2026.04.006},
pmid = {42019137},
issn = {1873-7714},
abstract = {BACKGROUND: Amyloid-targeting antibody therapies for Alzheimer's disease require substantial diagnostic infrastructure including amyloid PET imaging, repeated MRI monitoring, and specialized clinical evaluation. In Japan, psychiatrists frequently lead dementia diagnosis and treatment in general hospitals through designated Regional Dementia Medical Centers; however, the real-world service impact of implementing these therapies in psychiatry-led dementia care remains poorly described.

METHODS: We conducted a retrospective analysis of administrative and billing data from a Regional Dementia Medical Center at Kakogawa Central City Hospital, Japan. Data included amyloid PET imaging, anti-amyloid monoclonal antibody therapy (lecanemab and donanemab), and associated reimbursement and acquisition costs between May 2024 and January 2026. This study was conducted as part of institutional quality improvement activities.

RESULTS: During the observation period, 72 amyloid PET examinations were performed. Results were amyloid-positive in 50 cases (69%) and negative in 22 cases (31%). Of 50 amyloid-positive patients, 38 (76%) initiated anti-amyloid therapy (lecanemab: 14; donanemab: 24), with 389 total treatment administrations. ARIA was detected in 8 treated patients (21%), all asymptomatic. MRI examinations for ARIA monitoring increased from 5 in FY2023 to 58 in FY2024 and 139 in FY2025. Total reimbursement amounted to 35.4 million yen for lecanemab and 25.7 million yen for donanemab. Drug acquisition costs represented approximately 97% of reimbursement, with margins averaging 3%. Outpatient revenue per visit increased 141% from 5560 yen in FY2022 to 13,401 yen in FY2025, despite stable visit volumes (FY2022: 11,203; FY2024: 10,223).

CONCLUSIONS: Implementation of amyloid-targeting antibody therapy in psychiatry-led dementia care substantially increases service activity and hospital revenue streams but generates narrow financial margins due to high drug acquisition costs. All ARIA cases were asymptomatic, supporting the feasibility of systematic monitoring within a psychiatry-led model in this setting. These findings highlight important structural and economic considerations for the sustainability of these programs in general hospital psychiatry.},
}

@article {pmid42019491,
year = {2026},
author = {Huang, AY and Zhou, Z and Talukdar, M and Enyenihi, L and Miller, MB and Chhouk, B and Rosen, I and Zheng, M and Zhou, M and Yang, A and Stronge, E and Durens, M and Nguyen, M and Choi, J and Zhao, B and Khoshkhoo, S and Kim, J and Andersen, R and An, Z and Cheng, Y and Ganz, J and Mekerishvili, L and Travaglini, KJ and Gabitto, MI and Hodge, RD and Kaplan, ES and Belk, JA and Landau, D and Lein, ES and De Jager, PL and Bennett, DA and Marro, SG and Papapetrou, EP and Lee, EA and Walsh, CA},
title = {Somatic cancer variants enriched in Alzheimer's disease microglia-like cells drive inflammatory and proliferative states.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.03.040},
pmid = {42019491},
issn = {1097-4172},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood, suggesting a likely hematopoietic origin. Single-nucleus RNA sequencing data from 62 additional AD and control brains revealed increased somatic copy number variants (sCNVs) associated with CH in AD MLBMs, whereas single-cell multi-omic analyses demonstrated that sSNV- and sCNV-carrying MLBMs exhibited inflammatory and proliferative transcriptional signatures characteristic of disease-associated microglia. These signatures were recapitulated in induced pluripotent stem cell-derived microglia-like cells with TET2, ASXL1, and DNMT3A variants. These findings suggest that clonal somatic driver variants in MLBMs are enriched in AD, potentially promoting neuroinflammation and neurodegeneration.},
}

@article {pmid42019799,
year = {2026},
author = {Wood, KA and Ko, YA and Bunch, TJ and Han, F and Wharton, W},
title = {Effect of Atrial Fibrillation on Progression of Cognitive Impairment in Patients with and without Prior Stroke.},
journal = {Heart rhythm},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.hrthm.2026.04.024},
pmid = {42019799},
issn = {1556-3871},
abstract = {BACKGROUND: Atrial fibrillation (AF) increases risk of stroke and cognitive impairment.

OBJECTIVE: Identification of the unique AF contributions to cognitive impairment progression in patients with or without a stroke history.

METHODS: Associations between AF, stroke history, and cognitive impairment (i.e., advancing from normal to mild cognitive impairment or dementia) were examined using Cox proportional hazards regression with the National Alzheimer's Coordinating Center clinical case series.

RESULTS: Of 19,533 participants, 16,727 had no AF/no stroke, 548 had no AF/stroke, 2,121 AF/no stroke, and 137 AF/stroke. Cognitive decline was common [no AF/no stroke: 4,482 (27%), no AF/stroke: 222 (41%), AF/no stroke: 662 (31%), and AF/stroke: 59 (43%), p<0.0001] despite few new covert strokes. Females with AF experienced more cognitive decline over time compared to those without AF among subjects without a stroke history (hazard ratio [HR] 1.18, 95% CI [1.00-1.40]), but AF was not associated with cognitive decline in males. Stroke history was associated with cognitive decline in males with AF (HR 2.33, CI [1.31, 4.12) and without AF (HR 1.65, CI [1.09, 2.50) and females without AF (HR 1.84, CI [1.43, 2.38]).

CONCLUSION: Important sex-specific differences were observed. AF was associated with cognitive decline primarily in females without prior stroke, whereas prior stroke was a predictor of decline in males regardless of AF status. In females, the association between stroke and cognitive decline was evident mainly in those without AF. Findings underscore the complex interplay between AF, stroke, and sex in shaping cognitive trajectories and highlight need for sex-specific risk stratification in patients with AF.},
}

@article {pmid42019901,
year = {2026},
author = {Tseng, CH},
title = {The hidden link between diabetes and dementia: Findings from recent epidemiological studies.},
journal = {Biomedical journal},
volume = {},
number = {},
pages = {100985},
doi = {10.1016/j.bj.2026.100985},
pmid = {42019901},
issn = {2320-2890},
abstract = {Recent epidemiological studies investigating the link between diabetes mellitus and dementia or Alzheimer's disease are narratively reviewed. Diabetes mellitus is associated with a significantly higher risk of dementia by 56%, more predominant for vascular dementia than Alzheimer's disease and tau pathology is more remarkable than amyloid β deposition. The increased risk is related to the burden of microvascular and macrovascular diseases in a dose-response pattern; and a threshold effect between glycemic control and dementia risk is observed. A treatment target of hemoglobin A1c < 7% may be optimal for reducing the risk of dementia but hypoglycemia should be avoided. Antidiabetic drugs such as metformin, pioglitazone, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists may show beneficial effects on dementia in observational studies. In a Taiwanese cohort study acarbose is also associated with a lower risk of dementia in female diabetes patients. When considering the repurposing of antidiabetic drugs in the treatment of patients with Alzheimer's disease, low-dose insulin detemir shows a promising effect in a network meta-analysis. A phase 3 clinical trial (MET-FINGER) is being conducted to investigate whether metformin plus lifestyle intervention can be effective in the prevention of Alzheimer's disease. Hyperuricemia, though considered a potential component of metabolic syndrome, seems to be associated with a lower risk of dementia. Sex hormones play some roles in cognitive function and females present a higher risk of dementia than males. However, additional studies are required to explore the impacts of sex and sex hormones on the development of dementia and Alzheimer's disease.},
}

@article {pmid42020091,
year = {2026},
author = {Mewton, L and Winter, V and Hoy, N and Visontay, R and Davies, S and Kochan, N and Baillie, A and Chapman, C and Newton, NC and Sunderland, M and Sachdev, PS and Teesson, M},
title = {Effect of the online Rethink My Drink alcohol intervention on alcohol use and cognition in older adults in Australia: a randomised controlled trial.},
journal = {The Lancet. Public health},
volume = {11},
number = {5},
pages = {e318-e328},
doi = {10.1016/S2468-2667(26)00056-3},
pmid = {42020091},
issn = {2468-2667},
mesh = {Humans ; Aged ; Male ; Female ; Middle Aged ; Australia/epidemiology ; *Alcohol Drinking/prevention & control/epidemiology ; *Cognitive Dysfunction/prevention & control ; *Cognition ; *Internet-Based Intervention ; },
abstract = {BACKGROUND: Alcohol use is increasing among older adults and is associated with cognitive impairment and dementia. The efficacy of scalable approaches to reduce alcohol use and related harms in older adults has not been tested. This study aimed to evaluate the efficacy of an online alcohol intervention in reducing alcohol use and cognitive decline in older adults.

METHODS: We did a two-arm, parallel-group, randomised controlled trial online among community-based older adults (aged 60-75 years) who screened as having high-risk alcohol use (scoring ≥5 on the Alcohol Use Disorder Identification Test). Exclusion criteria included diagnosis of a neurological disorder (eg, dementia, Parkinson's disease, or multiple sclerosis), previous prescription of medication for the treatment of Alzheimer's disease, and non-correctable visual impairment. Participants across Australia were randomly assigned (1:1) to the Rethink My Drink programme (a four-module online intervention designed specifically for older adults) or an active control group (online information booklet), stratified by age and gender. Participants and the lead statistician were masked to group assignment. Number of drinks in the past month and global cognition Z scores assessed via the Cambridge Neuropsychological Test Automated Battery were the primary outcomes, assessed at the 12-month follow-up. Intention-to-treat analyses were conducted using generalised mixed effects regression. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000292875; March 16, 2021), and is completed.

FINDINGS: Between Oct 29, 2021, and June 6, 2022, 3766 participants were screened for eligibility, 2878 were excluded (1390 did not meet inclusion criteria, 1047 declined to participate, and 441 had incomplete baseline assessments), and 888 completed baseline assessments and were randomly assigned. 448 participants were assigned to the Rethink My Drink intervention and 440 were assigned to receive the online patient information booklet. Data from 445 participants in the intervention group and 438 participants in the control group were analysed. Most participants (872 [99%] of 883) identified as White, 685 (78%) participants were female and 198 (22%) were male, and the mean age was 65·3 years (SD 3·9). At 12 months, those in the intervention group had greater reductions in their monthly number of standard drinks when compared with the control group (difference, 5·02 standard drinks [95% CI 1·81 to 8·24]; p<0·0001). For global cognition, the difference between the two groups was not significant at 12 months (difference 0·12 SDs [95% CI -0·05 to 0·29]; p=0·16). Two participants (one in the control group and one in the intervention group) spontaneously reported non-serious adverse events that were assessed as unrelated to the trial.

INTERPRETATION: Rethink My Drink is an effective and scalable intervention that has considerable potential for reducing alcohol use among older adults.

FUNDING: Dementia Centre for Research Collaboration.},
}

Humans
Aged
Male
Female
Middle Aged
Australia/epidemiology
*Alcohol Drinking/prevention & control/epidemiology
*Cognitive Dysfunction/prevention & control
*Cognition
*Internet-Based Intervention

@article {pmid41814325,
year = {2026},
author = {Zhang, J and Zhou, Y and Mei, X and Yan, S and Mao, J and Li, Y and Bian, Z and Li, L and Ji, D and Lu, T and Chen, J and Su, L},
title = {Molecular mechanisms and therapeutic potential of tryptophan metabolism in gut-brain signaling transduction: a narrative review.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41814325},
issn = {1742-2094},
support = {2023YFC3504200//National Key Research and Development Program of China/ ; ZYXYL2024-006//The "leading plan" project of the first-class discipline of Nanjing University of Chinese Medicine/ ; 82304723//National Natural Science Foundation of China/ ; },
abstract = {As an essential amino acid, tryptophan (Trp) serves as a pivotal mediator in gut-brain axis (GBA) communication through three primary metabolic pathways: kynurenine (Kyn), indole, and serotonin (5-HT), which together regulate neuroimmune and neuroendocrine homeostasis via the vagus and spinal afferent nerves, circulatory system, and hypothalamic-pituitary-adrenal (HPA) axis. This review systematically examines Trp metabolism’s critical roles in GBA, emphasizing molecular pathways, rate-limiting enzymes, and receptor-mediated signaling. We discuss the bidirectional interplay between gut microbiota and host Trp metabolism, encompassing microbial modulation of host enzyme activities such as indoleamine 2,3-dioxygenase and direct production of bioactive indole derivatives like indole-3-propionic acid. Characteristic disruptions in Trp metabolism patterns are identified across GBA-associated disorders including irritable bowel syndrome, inflammatory bowel disease, depression, Alzheimer’s disease, schizophrenia and Parkinson’s disease, marked by aberrant neurotoxic to neuroprotective metabolite ratios and enzymatic dysregulation. The aryl hydrocarbon receptor (AhR) emerges as a molecular hub connecting Trp metabolites to GBA functions, with distinct metabolites eliciting opposing effects through AhR activation. Therapeutic strategies targeting Trp metabolism are critically evaluated, including fecal microbiota transplantation, probiotic supplementation, metabolite administration, and enzyme inhibitors. Future research directions address mechanistic gaps and translational challenges in restoring GBA homeostasis via Trp pathway modulation.},
}

@article {pmid42007396,
year = {2026},
author = {Al Khzem, AH and Gomaa, MS},
title = {Peptide-Based Therapeutics for Alzheimer's Disease: Medicinal Chemistry, AI-Guided Computational Design, and Blood-Brain Barrier Delivery.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {597087},
pmid = {42007396},
issn = {1177-8881},
mesh = {Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; *Drug Delivery Systems ; Chemistry, Pharmaceutical ; *Artificial Intelligence ; *Peptides/chemistry/pharmacology/administration & dosage ; Animals ; },
abstract = {Alzheimer's disease (AD) represents a pressing challenge in modern medicine, with current therapeutics offering only symptomatic relief. Peptide-based therapeutics have emerged as promising candidates owing to their target specificity, favorable safety profiles, and ability to modulate protein-protein interactions inaccessible to small molecules. This narrative review evaluates medicinal chemistry and artificial intelligence (AI)-driven approaches that are reshaping peptide drug discovery for AD, spanning target selection, sequence design, synthesis optimization, and central nervous system (CNS) delivery. Peptides targeting key AD pathological mechanisms-including amyloid-β (Aβ) aggregation inhibition, tau hyperphosphorylation disruption, and neurotrophic signaling enhancement-are discussed alongside strategies such as cyclization, D-amino acid incorporation, PEGylation, and peptidomimetic design to improve metabolic stability and blood-brain barrier (BBB) penetration. We review automated fast-flow peptide synthesis with inline UV-vis monitoring as a platform for rapid, high-fidelity preparation of complex sequences suitable for translational development. Delivery platforms-including cell-penetrating peptides, intranasal formulations, and nanocarrier systems-which primarily increase systemic exposure or fundamentally alter CNS distribution mechanisms are presented. AI and machine-learning (ML) technologies, molecular simulations, and structure-prediction systems are examined as an integrated pipeline that supports end-to-end design, validation, and optimization, with emphasis on rigorous QSAR and docking/MD validation practices. Clinical translation is analyzed through peptide repurposing (e.g. GLP‑1 receptor agonists, intranasal insulin, oxytocin), dedicated peptide candidates, and evolving regulatory expectations. Finally, we outline concrete design checklists for CNS ready peptides, discuss key translational bottlenecks, and propose priorities for the next 5-10 years of peptide-based AD therapy development.},
}

Humans
*Blood-Brain Barrier/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism
*Drug Design
*Drug Delivery Systems
Chemistry, Pharmaceutical
*Artificial Intelligence
*Peptides/chemistry/pharmacology/administration & dosage
Animals

@article {pmid42007400,
year = {2026},
author = {Ueda, M and Erskine, D and Thomas, A and Hamilton, C and Donaghy, PC},
title = {Association between angiotensin receptor blocker use and postmortem dementia pathology: analysis of the UK Brain Banks Network dataset.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001342},
pmid = {42007400},
issn = {2632-6140},
abstract = {BACKGROUND: Angiotensin receptor blockers (ARB) may be associated with a lower risk of a clinical dementia diagnosis. This study investigated the association between ARB use during life and postmortem dementia neuropathology, compared with angiotensin-converting enzyme inhibitors (ACEI) use.

METHOD: Cases with documented ACEI (n=257) or ARB (n=102) use, regardless of dementia pathology, were selected from the UK Brain Banks Network dataset. Pathology was categorised as either 'significant' pathology (Thal amyloid phase >3, Braak neurofibrillary tangle stage >3, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score of moderate/high density and Lewy body (LB) Braak >0 or cortical/limbic/neocortical LB pathology) or 'not significant'.

RESULTS: The ARB group was less likely to have Alzheimer's disease (AD) pathology compared with the ACEI group: Thal amyloid (adjusted OR (AOR) 0.59 (95% CI 0.36 to 0.97), p=0.038), Braak neurofibrillary tangle (AOR 0.61 (95% CI 0.38 to 0.98), p=0.041) and CERAD neuritic plaque (AOR 0.58 (95% CI 0.35 to 0.96), p=0.035). LB pathology did not differ significantly between ARB and ACEI groups, though use of either ACEI or ARB was associated with a lower likelihood of LB pathology (AOR 0.27 (95% CI 0.21 to 0.36), p<0.001).

CONCLUSION: ARB use is associated with a lower risk of AD pathology. The association between ARB/ACEI use and LB pathology requires further investigation.},
}

@article {pmid42007415,
year = {2025},
author = {Crenshaw, KH and Ortega, A and Curiel Cid, RE and Zheng, DD and Carrasquillo, MM and Crocco, E and Ramirez, S and Frydman, A and Remedios, S and Morales, YV and Vaillancourt, DE and Wang, WE and Garcia, DF and de Rivero Vaccari, JP and Ertekin-Taner, N and Kuchenbecker, L and Duara, R and Loewenstein, DA},
title = {Detecting Cognitive Impairment in African American Older Adults Using the LASSI-L and Plasma P-Tau217.},
journal = {Advances in Alzheimer's disease},
volume = {14},
number = {2},
pages = {23-37},
pmid = {42007415},
issn = {2169-2459},
support = {R01 AG077677/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) disproportionately affects Black/African American (B/AA) older adults, yet this group remains underrepresented in research. Traditional neuropsychological assessments, often developed on predominantly White populations, may not be reliable for B/AA individuals. The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) have been shown to effectively differentiate individuals with amnestic mild cognitive impairment (aMCI) from cognitively unimpaired (CU) individuals. This study examines the relationship between LASSI-L performance and plasma p-tau217 levels to explore early detection methods for AD in B/AA populations.

METHODS: Fifty-six older adults received clinical and cognitive evaluations and were deemed cognitively unimpaired (CU) and p-tau217 negative (n = 35) or met criteria for amnestic mild cognitive impairment (aMCI) and p-tau217 positive (n = 21). All participants were administered the LASSI-L to compare groups, but it was not used for group allocation to avoid circularity.

RESULTS: After adjusting for age and MMSE score, the aMCI p-tau217+ group performed significantly worse than the CU p-tau217- group on both free recall on List B (Free B1 Recall) and frPSI (correct responses on Cued B2). These differences remained statistically significant after covariate adjustment (p < 0.001). In addition, four other outcomes remained statistically significant following covariate adjustment: the aMCI p-tau217+ group exhibited a higher percentage of intrusion errors (PIE) on both Cued B1 and Cued B2, along with poorer performance on maximal learning ability (Cued A2) and PSI (correct responses on Cued B1). However, after applying the Bonferroni correction, only PIE on Cued B2 remained statistically significant among these measures. Notably, performance on LASSI-L Free B1 Recall and PIE for List Cued B2 were significant predictors distinguishing aMCI p-tau217+ from CU p-tau217- groups, with high sensitivity (80%) and specificity (91.7%). ROC analysis of these predictors yielded an area under the curve of 0.872 (SE = 0.055; p < 0.001), with a 95% confidence interval ranging from 0.765 to 0.979.

CONCLUSION: The study highlights the utility of the LASSI-L in conjunction with plasma biomarkers, particularly p-tau217, for early AD detection in B/AA older adults. The LASSI-L demonstrated strong sensitivity to cognitive impairment, effectively differentiating between CU and aMCI groups based on plasma p-tau217 levels. These findings suggest that combining cognitive assessments with plasma biomarkers can enhance early diagnosis and improve timely interventions, addressing health disparities in AD diagnosis and care.},
}

@article {pmid42007489,
year = {2026},
author = {Yang, F and Wang, F and Jiang, Y and Qian, D and Chen, L},
title = {Role of the WNT signalling pathway in physiological and pathological blood-brain barrier.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2657638},
doi = {10.1080/07853890.2026.2657638},
pmid = {42007489},
issn = {1365-2060},
mesh = {*Blood-Brain Barrier/pathology/metabolism/physiopathology/physiology ; Humans ; *Wnt Signaling Pathway/physiology ; Animals ; Induced Pluripotent Stem Cells ; Cell Differentiation ; Wnt Proteins/metabolism ; },
abstract = {BACKGROUND: The blood-brain barrier (BBB) is essential for maintaining central nervous system (CNS) homeostasis and protecting neural tissue. The wingless-type MMTV integration site family (WNT) signalling pathway has emerged as a key regulator of BBB development, maintenance, and repair. Dysregulation of this pathway is implicated in BBB dysfunction associated with various neurological disorders.

METHODS: We conducted a comprehensive review of recent literature integrating data from animal models, human induced pluripotent stem cell (iPSC)-derived BBB systems, and disease-specific mechanistic studies. The role of canonical and non-canonical WNT signalling in BBB formation, maturation, and pathological alteration was systematically analyzed.

RESULTS: WNT7a/b ligands activate β-catenin-dependent signalling to drive cerebral angiogenesis and BBB differentiation, with G protein‑coupled receptor 124 (GPR124), Reversion‑inducing cysteine‑rich protein with Kazal motifs (RECK), and SRY‑related HMG‑box transcription factor 17 (Sox17) identified as critical co-regulators. In the mature BBB, WNT activity is suppressed epigenetically to maintain barrier stability. In diseases such as ischaemic stroke, Alzheimer's disease, multiple sclerosis, and glioblastoma, WNT signalling is disrupted, leading to BBB breakdown. Pharmacological activation of WNT/β-catenin signalling (e.g. lithium, Glycogen synthase kinase 3β (GSK-3β) inhibitors and engineered WNT ligands) restores BBB integrity in preclinical models. Additionally, modulation of WNT signalling can enhance drug delivery across the BBB, offering therapeutic advantages in brain tumours and neurodegenerative diseases.

CONCLUSIONS: WNT signalling is a central molecular axis governing BBB integrity under both physiological and pathological conditions. Targeted modulation of this pathway represents a promising therapeutic strategy for restoring BBB function and improving CNS drug delivery. Further mechanistic and translational studies are warranted to advance clinical applications.},
}

*Blood-Brain Barrier/pathology/metabolism/physiopathology/physiology
Humans
*Wnt Signaling Pathway/physiology
Animals
Induced Pluripotent Stem Cells
Cell Differentiation
Wnt Proteins/metabolism

@article {pmid42007524,
year = {2026},
author = {Bao, N and Zhang, M and Tang, M and Shen, Z and Wang, S and Jiang, G},
title = {Ketogenic diet regulates Uch-L1(C) to improve cerebral energy metabolism and cognitive function in Alzheimer's disease mice.},
journal = {European journal of histochemistry : EJH},
volume = {70},
number = {2},
pages = {},
doi = {10.4081/ejh.2026.4548},
pmid = {42007524},
issn = {2038-8306},
mesh = {Animals ; *Alzheimer Disease/metabolism/diet therapy ; *Diet, Ketogenic ; *Energy Metabolism ; Mice ; *Ubiquitin Thiolesterase/metabolism ; Male ; *Cognition ; Hippocampus/metabolism ; *Brain/metabolism ; GTP Phosphohydrolases/metabolism ; Oxidative Stress ; Apoptosis ; },
abstract = {The ketogenic diet (KD), a high-fat, low-carbohydrate diet, can effectively regulate energy metabolism in the brain. The regulation of cerebral energy metabolism in patients with Alzheimer's disease (AD) has attracted the attention of researchers. Recent studies have shown that ubiquitin carboxyl terminal hydrolase L1 (Uch-L1) deficiency leads to neurodegeneration by increasing energy demand and endoplasmic reticulum stress. However, the effect of Uch-L1 on AD remains to be explored. This study first combined Uch-L1 with cerebral energy metabolism to explore its role in long-term KD in AD. We found that AD mice with long-term KD showed better spatial recognition and working memory. KD promoted Uch-L1(C) and Mfn2 expression by inhibiting oxidative stress in the hippocampus of mice, improved mitochondrial function, increased ATP content, and significantly reduced neuronal apoptosis. In conclusion, KD can increase Uch-L1(C) and Mfn2 expression in the brain, and improve cerebral energy metabolism and cognitive function in AD mice.},
}

Animals
*Alzheimer Disease/metabolism/diet therapy
*Diet, Ketogenic
*Energy Metabolism
Mice
*Ubiquitin Thiolesterase/metabolism
Male
*Cognition
Hippocampus/metabolism
*Brain/metabolism
GTP Phosphohydrolases/metabolism
Oxidative Stress
Apoptosis

@article {pmid42007542,
year = {2026},
author = {Cao, P and Zhang, J and Shen, Y and Xing, Z and Han, F and Chen, X and Jiang, N},
title = {MechMemDyn: Coupling Frustration Analysis with Membrane Dynamics to Target the TREM2-DAP12 Complex Interface.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.5c03239},
pmid = {42007542},
issn = {1549-960X},
abstract = {The transmembrane complex formed by TREM2 (Triggering Receptor Expressed on Myeloid cells 2) and DAP12 (DNAX-activating protein of 12 kDa) constitutes a pivotal therapeutic target for Alzheimer's disease. However, the intrinsic plasticity of its interface poses a formidable challenge for structure-based discovery of protein-protein interaction stabilizers (PPI stabilizers). Conventional approaches, ranging from static molecular docking to geometric deep learning, fail to capture the subtle interfacial energetics required for stabilizing this assembly, often leading to erroneous activity predictions. Here, we present MechMemDyn, a novel predictive framework that uniquely integrates protein frustration analysis with membrane-embedded molecular dynamics (MD) simulations. To our knowledge, this is the first systematic application of frustration analysis to rationalize PPI-stabilizing activity and guide ligand design. By mapping the local frustration landscape, we identify critical, minimally frustrated contact networks at the protein interface, which are essential for stabilizing the PPI. We demonstrate that the ability of a ligand to dampen distance fluctuations within these key networks, a metric rooted in thermodynamic rigor, correlates strongly with experimental potency. This method outperforms conventional static docking, AI-driven dynamic docking approaches, and standard molecular simulations, providing a more accurate and reproducible basis for cross-ligand comparison. This work not only resolves the intractability of the TREM2-DAP12 complex but also establishes a physics-driven paradigm for targeting dynamic transmembrane interfaces via frustration-optimized PPI stabilizers.},
}

@article {pmid42007885,
year = {2026},
author = {Zheng, S and Liu, Y and Zhong, B and Chu, H and Gong, Z and Zhao, B and Cheng, M and Liang, Z and Zhang, Y and Zhao, Q and Zhang, L},
title = {Orthogonal Ionic Liquid-Based Extraction Strategy Enables Amyloid-Specific Profiling of Aggregate Proteome.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23685},
doi = {10.1002/advs.202523685},
pmid = {42007885},
issn = {2198-3844},
support = {2024YFC3405403//National Key R&D Program of China/ ; 2021YFA1301501//National Key R&D Program of China/ ; 22322411//National Natural Science Foundation/ ; 22274150//National Natural Science Foundation/ ; 32088101//National Natural Science Foundation/ ; 22393931//National Natural Science Foundation/ ; DICP I202529 DICP I202413//Innovation program of science and research from the Dalian institute of chemical physics, Chinese Academy of sciences/ ; 2024RJ009//Dalian Science Foundation for Distinguished Young Scholars/ ; },
abstract = {Amyloid deposits, composed of insoluble cross-β-sheet fibrils, are pathological hallmarks of many neurodegenerative diseases. However, their structural heterogeneity and extreme insolubility hinder characterization of their molecular composition and deposition mechanisms. Here, an orthogonal ionic liquid-based extraction strategy (Orth-iEA) was developed to selectively enrich amyloid aggregates from complex biological samples. Systematic screening identified tetramethylguanidine tetrafluoroborate (TMGBF4) as a potent ionic liquid capable of disrupting hydrogen bonds within cross-β-sheet structures, thereby solubilizing amyloid aggregates. In contrast, 1-dodecyl-3-methylimidazolium chloride (C12ImCl) preferentially solubilized non-amyloid proteins through hydrophobic interactions. In combination, these two reagents constitute the orthogonal extraction system, enabling the highly selective enrichment of amyloid aggregates from complex biological samples while remaining compatible with downstream LC-MS/MS proteomic workflows after mild desalting. Application of Orth-iEA to hippocampal tissue from 12-month-old 3xTg Alzheimer's disease model mice identified numerous amyloid-associated proteins enriched in mitochondrial components, which was further confirmed by immunofluorescence co-localization analysis. Functional and network analyses converged on pathways involving protein transport, mitochondrial translation, intracellular signaling, and apoptosis, revealing previously unrecognized molecular links between amyloid pathology and Alzheimer's disease. Therefore, Orth-iEA provides a versatile chemical platform for selective isolation and molecular profiling of amyloid aggregates.},
}

@article {pmid42007924,
year = {2026},
author = {Maestri, S and Scalzo, D and Zobel, M and Besusso, D and Cattaneo, E},
title = {Towards AI-driven prediction of HTT CAG size in super-expanded human spiny projection neurons from Huntington disease donors.},
journal = {Journal of Huntington's disease},
volume = {},
number = {},
pages = {18796397261443137},
doi = {10.1177/18796397261443137},
pmid = {42007924},
issn = {1879-6400},
abstract = {Somatic instability (SI) of the CAG tract in HTT is a major driver of neurodegeneration of Spiny Projection Neurons (SPNs), the primary neuronal subtype affected in Huntington's disease (HD). SPNs can accumulate hundreds of CAG repeats during a patient's lifetime, and once the expansion exceeds ∼150 CAGs, they acquire distinct, cell-autonomous transcriptional alterations that ultimately contribute to degeneration. Here, we developed the "HD-Phase-Model", a mathematical framework designed to identify "super-expanded" SPNs without repeat sizing, by leveraging the only available single-nucleus HD post-mortem dataset that provides both transcriptional profile and matched HTT CAG sizes. After validating model performance on the test data, we applied it to independent single-nucleus datasets lacking CAG sizing information and across multiple brain regions. In all cases, the model consistently detected SPNs populations with convergent transcriptional dysregulation signatures indicative of extreme CAG expansion.Importantly, although the model was trained on caudate SPNs, we observed highly similar dysregulation patterns in putamen and accumbens, while no evidence of super-expansion was found in SPNs from Alzheimer's and Parkinson's disease donors.Together, these findings demonstrate that transcriptional profiles alone can serve as predictors of HTT CAG size, enabling systematic identification of super-expanded SPNs and providing insights into HD-specific neurodegenerative mechanisms.},
}

@article {pmid42008214,
year = {2026},
author = {Abuhassan, Q and Ardah, MT and Menon, SV and Maharana, L and Inbathamizh, L and Mukherjee, G and Sinha, A and Khodzhiyeva, S and , },
title = {Stage-dependent associations of plasma clusterin with reduced brain volume, tau pathology, and cognitive impairment across the Alzheimer's disease spectrum.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42008214},
issn = {2240-2993},
abstract = {Clusterin, a multifunctional glycoprotein involved in proteostasis, amyloid-β clearance, and neuroinflammation, has been proposed as a biomarker in Alzheimer's disease (AD), but its stage-specific links to brain structure, tau pathology, and cognition remain unclear. This study evaluated plasma clusterin across the AD spectrum, its associations with brain volumes and CSF tau/p-tau, and whether structural brain measures mediate its cognitive effects. Data from 333 participants (CN = 38, MCI = 207, AD = 88) were analyzed using FDR-corrected regression, Pearson correlations, and mediation analyses, adjusting for demographic factors and APOE ɛ4 status. Results showed that plasma clusterin was highest in mild cognitive impairment (MCI) compared to cognitively normal (CN) and AD, suggesting a peak during early neurodegeneration. In CN participants, higher clusterin was associated with lower whole-brain volume, but it was not significantly related to hippocampal volumes or tau/p-tau. In MCI, clusterin was modestly associated with reduced whole-brain volume and elevated CSF tau, while associations with hippocampal volumes and p-tau were nonsignificant. In AD, higher clusterin was significantly associated with smaller left and right hippocampal volumes, with a trend toward lower whole-brain volume; no significant associations with tau or p-tau were observed. Based on the mediation analysis, in CN participants, no significant mediation effects of brain volumes were observed between plasma clusterin and cognitive function. In the MCI group, higher plasma clusterin was associated with lower whole-brain volume, and this volumetric measure showed significant indirect effects linking plasma clusterin to cognitive performance, consistent with indirect-only (full mediation) patterns. This suggests an indirect association whereby higher clusterin may be linked to poorer cognitive function through its association with reduced global brain volume. Likewise, in the AD group, higher clusterin levels were associated with lower whole-brain and right hippocampal volumes. Both measures significantly mediated the relationship between clusterin and cognitive performance, indicating that higher clusterin may be linked to poorer cognitive function through its association with reductions in global and region-specific brain volumes. Future studies should clarify the temporal and mechanistic pathways linking clusterin to neurodegeneration to determine its value as a biomarker and therapeutic target.},
}

@article {pmid42008257,
year = {2026},
author = {Fowler, NR and Perkins, AJ and Gao, S and Bakas, T and Head, KJ and Higbie, A and Baucco, C and Callahan, CM and Williams-Farrelly, MM and Boustani, MA},
title = {Benefits and Harms of Dementia Screening for Family Members of Older Adults: A Randomized Clinical Trial.},
journal = {JAMA internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2026.0844},
pmid = {42008257},
issn = {2168-6114},
abstract = {IMPORTANCE: Early detection of Alzheimer disease and related dementias (ADRD) may influence outcomes for both patients and their family members, yet the risks and benefits of screening for family members are not established.

OBJECTIVE: To evaluate the benefits and risks of ADRD screening for family members of older adults screened in primary care (PC).

This multisite randomized clinical trial was conducted in 29 PC clinics from October 2018 to September 2023. Dyads of patients aged 65 years and older and a family member were randomized into 1 of 3 groups: screening only, screening plus referral for diagnostic follow-up, and no-screening control. Data were collected at baseline and at 6, 12, 18, and 24 months.

INTERVENTIONS: Cognitive screening was conducted in-person, by telephone, or secure video using the Mini-Cog, the Memory Impairment Screen Telephone version (MIS-T), or the MIS-T with the clock drawing test.

MEASURES: The primary outcome was family member health-related quality of life at 24 months measured using the Short Form Health Survey (SF-36) physical and mental component summary scores. Secondary outcomes included family member depressive and anxiety symptoms, caregiver preparedness, and caregiving self-efficacy, as well as patient health-related quality of life and depressive and anxiety symptoms.

RESULTS: A total of 1808 dyads completed baseline assessments. Mean (SD) patient age was 73.7 (5.7) years and 959 (53%) were female. Among family members, 1171 (64.8%) were spouses, 1224 (67.7%) were female, and mean [SD] age was 64.2 [12.9] years. Overall, 62 patients (5.1%) screened positive for cognitive impairment. Among dyads assigned to screen plus, 10 (35.7%) did not pursue diagnostic follow-up. There were no significant differences between the combined screening groups and no-screening group in SF-36 physical (24-month predicted difference, -0.21; 95% CI, -1.26-0.85) or mental (24-month predicted difference, 0.58; 95% CI, -0.18-1.33) component scores. No differences were observed in patient secondary outcomes at 24 months.

DISCUSSION: This randomized clinical trial found that ADRD screening in PC was not associated with improvement in family member health-related quality of life, caregiver preparedness, or caregiving self-efficacy. Screening was also not associated with increased family member depression or anxiety. Low rates of positive screening and high rates of refusal for follow-up diagnostic assessment may help explain these findings.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03300180.},
}

@article {pmid42008282,
year = {2026},
author = {Burns, JM and Woodward, JL and Morris, JK and Townley, RA},
title = {Reimagining Care Delivery for Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0801},
pmid = {42008282},
issn = {2168-6157},
}

@article {pmid42008377,
year = {2026},
author = {Siddiqui, A and Kathiresan, T and Opler, M and Cohen, A and Alber, J and Snyder, PJ and Vogel, AP},
title = {The utility of Speech and Language analytics for screening Alzheimer's Disease.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-26},
doi = {10.1159/000552094},
pmid = {42008377},
issn = {1660-2862},
abstract = {BACKGROUND: Effective screening and cohort enrichment remain major challenges in clinical trials for Alzheimer's disease (AD), where traditional diagnostic pathways rely on costly, invasive, and time-consuming procedures. Speech and language analysis has emerged as a scalable, low-burden approach for detecting subtle cognitive-linguistic and motor-speech changes that may appear early in the disease course.

SUMMARY: This review synthesizes current evidence on acoustic, prosodic, lexical, semantic, and syntactic speech features associated with AD and mild cognitive impairment (MCI) and evaluates their reported utility across a range of elicitation tasks including picture description, verbal fluency, narrative recall, spontaneous speech, and reading. Across studies, machine-learning models trained on speech and language features have reported consistent performance, although results vary substantially depending on task design, feature sets, and cohort characteristics. Task-dependent variability is evident, with picture description and verbal fluency tasks capturing lexical-semantic and timing markers, while narrative and spontaneous speech tasks capture impairments in coherence, information content, and prosody. Hybrid approaches integrating hand-crafted and machine-extracted features have also been explored to improve interpretability and model performance. Speech and language analytics may support digital pre-screening, cohort enrichment, and quality-assurance monitoring within clinical trials; however, their application depends on methodological considerations and validation across diverse settings.

KEY MESSAGES: Despite encouraging findings, several methodological challenges persist, including inter-individual variability, limited dataset sizes, differences in recording conditions, and limitations in automatic speech recognition performance in cognitively impaired populations. Continued development of standardized protocols, disorder-adapted speech models, and multimodal analytic pipelines is needed to support clinical translation. Collectively, current evidence suggests that speech and language features represent candidate digital markers that may improve screening efficiency and support clinical trial enrichment in AD, although further validation is required to establish their reliability and generalizability.},
}

@article {pmid42008415,
year = {2026},
author = {Ou, C and Chen, B and Deng, J and Long, H},
title = {Deciphering the molecular network of Trichostatin A in regulating Alzheimer's disease screening of core genes and mechanistic investigation based on multidimensional bioinformatics and molecular simulation.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0347532},
doi = {10.1371/journal.pone.0347532},
pmid = {42008415},
issn = {1932-6203},
mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism ; *Hydroxamic Acids/pharmacology/chemistry/therapeutic use ; Humans ; *Histone Deacetylase Inhibitors/pharmacology ; *Computational Biology/methods ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Gene Regulatory Networks/drug effects ; Machine Learning ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Histone deacetylases (HDACs) regulate neuroprotection; however, Trichostatin A (TSA), an HDAC inhibitor, lacks clear molecular mechanisms and core targets in Alzheimer's disease (AD), limiting clinical translation. This study aimed to decipher TSA's AD-regulating network, screen core genes, and support AD early diagnosis and multi-target therapies.

METHODS: TSA targets were computationally predicted. Five GEO AD datasets were analyzed for differential genes and core modules, and 130 machine learning algorithms were employed to identify core genes. Functional annotation, immune cell analysis, and single-cell expression profiling were conducted. Molecular docking and 100 ns molecular dynamics simulations verified TSA-protein interactions.

RESULTS: 949 potential TSA targets were identified, overlapping with AD differential genes and enriching key pathways such as GABAergic synapse and tau phosphorylation. Eight machine learning-identified core genes (EFNA1, GABRB2, GABARAPL1, EGR1, CDK5, KCNC2, MET, GRIA2) exhibited a distinct AD expression pattern: synergistic downregulation of protective genes and unique upregulation of pathological EFNA1. These genes are implicated in neurotransmission, synaptic plasticity, tau clearance, and immune-neural crosstalk. Molecular dynamics simulations suggested TSA may not stably bind these candidates, implying its regulation relies on epigenetic mechanisms via HDAC1-3/6 inhibition, potentially restoring gene network balance and disrupting neuroinflammation-neurodegeneration cycles. Complex regulatory modes and cell type-specific expression were also observed.

CONCLUSION: This study provides preliminary insights into TSA's putative mechanisms in AD intervention, highlighting the eight candidate core genes' potential diagnostic and therapeutic value as AD biomarkers, supporting TSA's multi-target therapy. All findings are computationally derived and require experimental verification.},
}

*Alzheimer Disease/genetics/drug therapy/metabolism
*Hydroxamic Acids/pharmacology/chemistry/therapeutic use
Humans
*Histone Deacetylase Inhibitors/pharmacology
*Computational Biology/methods
Molecular Docking Simulation
Molecular Dynamics Simulation
*Gene Regulatory Networks/drug effects
Machine Learning
Gene Expression Profiling

@article {pmid42008483,
year = {2026},
author = {Zhang, X and Wang, Z and Sun, M and Bao, Q and Chen, Z and Liu, Y and Wang, Z and Ye, F and Yang, Z and Du, X and Zhang, H and Mou, X and He, X and Li, D and Wu, K and Yao, J and Zhong, W and Xu, P and Yang, S and Zhao, L and Yin, Z and Liang, F},
title = {Acupuncture for amnestic mild cognitive impairment: Study protocol for a multicenter, single-blinded, long-term, randomized controlled trial.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346717},
doi = {10.1371/journal.pone.0346717},
pmid = {42008483},
issn = {1932-6203},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Single-Blind Method ; Aged ; Female ; Male ; Treatment Outcome ; *Amnesia/therapy ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), a common neurodegenerative disease affecting older adults, has garnered significant research interest over the past few years. While previous studies have suggested that acupuncture holds promise as a clinical intervention to improve cognitive function in patients with aMCI, the long-term effect of acupuncture treatment for aMCI remains unclear.

METHODS: This is a multicenter, single-blinded, randomized controlled trial (RCT) with a long-term follow-up.166 patients diagnosed with aMCI will be randomly divided into acupuncture group (AG) and sham acupuncture group (SA). The intervention will last for 12 weeks (2 sessions per week), follow-up for 48 weeks, and the study will last a total of 60 weeks. The primary outcomes are the changes in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score from baseline to week 12 and from baseline to week 60. Generalized estimating equations (GEE) will be used to assess the impact of the acupuncture intervention on outcome variables over time at baseline and weeks 12, 24, 48, and 60.

DISCUSSION: This protocol outlines a detailed procedure for a multicenter RCT designed to further evaluate the long-term effect of acupuncture in managing aMCI. We anticipate that the findings of this research will provide valuable insights and evidence-based recommendations for the clinical management of this patient population.

TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry on 28 May 2024 (Number: ChiCTR2400084932).},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods
Single-Blind Method
Aged
Female
Male
Treatment Outcome
*Amnesia/therapy
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Middle Aged
Aged, 80 and over

@article {pmid42008564,
year = {2026},
author = {Al-Anbari, E and Karshenas, H and Shoushtarian, B},
title = {Normalizing flow based neural processes for Alzheimer's disease progression prediction.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0345958},
doi = {10.1371/journal.pone.0345958},
pmid = {42008564},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Aged ; Male ; Female ; Neuroimaging ; },
abstract = {As one of the most common neurodegenerative diseases, Alzheimer's accounts for serious health problems worldwide. Accurate detection and prediction of this disease contribute to the health system for better prevention and interventions in the treatment plans. However, traditional models designed for prediction and classification face several challenges, including handling complex data, which neglects many data points for the diagnosis. To overcome this challenge, we propose a novel model based on the integration of Neural Processes (NPs) and Normalizing Flows (NFs). The dataset used for this study is the Alzheimer's Disease Prediction of Longitudinal Evolution (TADPOLE). We selected various features to build an efficient model, including cognitive, neuroimaging, genetic, and demographic data. which contains three classes: Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD. The proposed model is able to capture the temporal dependencies present in the complex distribution. The stochastic processes were modeled by NPs, while NF was able to transform the Gaussian distributions from simple to complex distributions, allowing them to model a wide range of data distributions. The prediction performance and robustness have been enhanced since this framework is able the adapt to every patient trajectory and generalizing across different populations. The model was compared with other models, such as SNP, deep geometric learning, Manifold DCNN, and other models. Our model (SNP-NF) made an improvement regarding mAUC, Precision, and Recall, approximately 3%,1%, and 0.7%, respectively from our previous model, which utilized only NP. These results demonstrate the capability of the proposed approach to provide early detection and personal treatment plans for patients suffering from this disease.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics
Disease Progression
Cognitive Dysfunction/diagnosis
Aged
Male
Female
Neuroimaging

@article {pmid42008601,
year = {2026},
author = {Alvi, AM and Siuly, S and De-Cola, MC and Wang, H},
title = {CDR-Net: A computerized framework to detect Alzheimer's diseases and mild cognitive impairment.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346576},
doi = {10.1371/journal.pone.0346576},
pmid = {42008601},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Electroencephalography/methods ; Aged ; Male ; Female ; Machine Learning ; *Diagnosis, Computer-Assisted/methods ; Aged, 80 and over ; *Neural Networks, Computer ; Brain/physiopathology/diagnostic imaging ; },
abstract = {Alzheimer's disease (AD) and mild cognitive impairment (MCI) are two dementia-related brain illnesses that are prevalent among elders in the twenty-first century. MCI is treated as the initial stage of AD, and once the illness reaches the AD stage, there is no escape from certain death. The accuracy and efficacy of current multiclass computer-based approaches to diagnose AD and MCI are constrained by traditional machine learning (ML) classifiers due to their shallow architecture. This makes it challenging to make a prompt and accurate diagnosis of AD and MCI. This research proposes a framework employing electroencephalography (EEG) to diagnose MCI, AD, and healthy subjects (HSs) to boost multiclass performance and efficacy. EEG is a portable, non-invasive, and affordable means to identify brain problems as compared to expensive and time-consuming techniques like computed tomography (CT) scans, positron emission tomography (PET), magnetic resonance imaging (MRI), and the mini-mental state examination (MMSE). To circumvent these issues, the Cognitive Decline Recognition Network (CDR-Net) architecture has been developed to identify MCI, AD, and healthy individuals using EEG data. The proposed architecture allows for the acquisition of EEG data, data preprocessing (down-sampling, noise cleaning, segmentation, and digital picture construction), feature extraction and classification using CDR-Net, as well as performance assessment and cross-validation stages. Our suggested CDR-Net architecture produced better multiclass accuracy, sensitivity, and specificity of 99.25%, 99.13%, and 99.32%, respectively. By using 10 folds and leave-one-out cross validations, stability, consistency, and data overfitting and underfitting concerns are addressed. This framework will serve as a foundation for future systems designed to detect multiple brain disorders.},
}

Humans
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Electroencephalography/methods
Aged
Male
Female
Machine Learning
*Diagnosis, Computer-Assisted/methods
Aged, 80 and over
*Neural Networks, Computer
Brain/physiopathology/diagnostic imaging

@article {pmid42008670,
year = {2026},
author = {Lindberg, M and Hu, J and Thacker, D and Sparr, E and Linse, S},
title = {The temperature dependence of amyloid β solubility reveals the hydrophobic effect as the main driving force for fibril formation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {17},
pages = {e2531916123},
doi = {10.1073/pnas.2531916123},
pmid = {42008670},
issn = {1091-6490},
support = {2015-00143//Vetenskapsrådet (VR)/ ; 2019-02397//Vetenskapsrådet (VR)/ ; AdG 101097824//EC | European Research Council (ERC)/ ; 2022-0059//Knut och Alice Wallenbergs Stiftelse (kawforskning)/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Solubility ; Hydrophobic and Hydrophilic Interactions ; Temperature ; Humans ; *Peptide Fragments/chemistry/metabolism ; Circular Dichroism ; *Amyloid/chemistry ; Thermodynamics ; Protein Aggregates ; Kinetics ; Alzheimer Disease/metabolism ; },
abstract = {The aggregation of amyloid proteins into fibrillar and oligomeric aggregates is linked to a number of neurodegenerative diseases. While the disease onset remains elusive in many cases, an understanding of the driving forces for the aggregation may help finding possible causes. While effects on amyloid formation kinetics are more commonly studied, gaining insights into these driving forces require a thermodynamic approach with equilibrium measurements. Here we investigate the temperature dependence of the solubility of the amyloid beta peptide, Aβ42, related to Alzheimer's disease, using high-performance liquid chromatography coupled to a mass spectrometer and circular dichroism spectroscopy. Samples of 8 to 50 μM Aβ42 were incubated for up to 168 h at pH 8.0 and moderate ionic strength at multiple temperatures in the range of 5 to 80 [°]C. The remaining monomer concentration was measured after 48 to 168 h, with little change in between suggesting that equilibrium is approached at 168 h. The lowest solubility of 20 ± 10 nM is found around body temperature, with higher solubility at both lower and higher temperatures. This nonmonotonic temperature dependence is indicative of the hydrophobic effect being a major driving force for the fibril formation of this peptide.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Solubility
Hydrophobic and Hydrophilic Interactions
Temperature
Humans
*Peptide Fragments/chemistry/metabolism
Circular Dichroism
*Amyloid/chemistry
Thermodynamics
Protein Aggregates
Kinetics
Alzheimer Disease/metabolism

@article {pmid42008697,
year = {2026},
author = {Xin, Y and Liu, D and Ma, Y and Zhang, Z and Chen, P and Wu, M and Li, Y and Chen, S and Yan, S and Song, G and Chen, L and Wang, Q and Geng, J and Sun, K},
title = {Simultaneous Profiling and Quantification of Tau and Its Phosphorylated Isomers Using Engineered FraC Nanopores.},
journal = {Nano letters},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.nanolett.6c00368},
pmid = {42008697},
issn = {1530-6992},
abstract = {Tau aggregation and hyperphosphorylation are key pathological hallmarks and early diagnostic biomarkers of Alzheimer's disease (AD). However, the simultaneous profiling and quantitative analysis of Tau and its phosphorylated isoforms remain technically challenging. Here, by introducing an acidic aspartate residue at the G6 site of FraC[G13F], we engineered a high-resolution FraC[G6DG13F] nanopore with enhanced temporal resolution for protonated polypeptide detection. Integrated with machine-learning algorithms, our nanopore-based workflow enabled the real-time identification of 12 tryptic peptides from native Tau (2N4R) protein with over 91.1% accuracy. Furthermore, positional phosphorylation isomers at either S400 or S402 of Tau (2N4R) were precisely resolved and quantified in mixed digestion samples, achieving classification accuracy exceeding 93% and sensitivity comparable to that of microgram-level mass spectrometry. This study demonstrates a promising advancement of global analysis of phosphorylated Tau in nanopore-based methods, highlighting its potential for high-resolution characterization and accurate quantification of proteins with PTMs.},
}

@article {pmid42008717,
year = {2026},
author = {Neltner, AM and Shahidehpour, RK and Hall, ME and Ning, X and Fister, S and Kang, H and Anderson, S and Jicha, GA and Lee, TL and Abner, EL and Fardo, DW and Nelson, PT},
title = {Locus coeruleus TDP-43 pathology in a community-based cohort: Clinical and pathological correlates.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag035},
pmid = {42008717},
issn = {1554-6578},
support = {P30 AG072946/GF/NIH HHS/United States ; R01 NS118584/GF/NIH HHS/United States ; RF1 AG082339/GF/NIH HHS/United States ; P01 AG078116/GF/NIH HHS/United States ; R01 AG076932/GF/NIH HHS/United States ; },
abstract = {The locus coeruleus (LC) is the source of norepinephrinergic innervation in the human brain. Locus coeruleus pathology has been linked to clinical conditions such as cognitive impairment and behavioral and psychiatric symptoms of dementia (BPSD). However, phosphorylated TDP-43 (pTDP-43) pathology in the LC has been understudied, particularly in the contexts of aging and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Here, a convenience sample (n = 134) of autopsied participants from the University of Kentucky Alzheimer's Disease Research Center community-based cohort was analyzed for LC pTDP-43 and phosphorylated tau (pTau) pathologies. Locus coeruleus pTDP-43 pathology was found in 28/134 (20.9%) brains and was generally sparse when present. Locus coeruleus pTDP-43 lesions typically appeared as round granular structures that measured ∼3-12 µm in diameter. Locus coeruleus pTDP-43 pathology was increased with aging and was imperfectly correlated with LATE-NC staging; it showed no correlation with cortical pTau pathology in ADNC or PART. In terms of clinical-pathological correlations, LC pTDP-43 pathology was associated with depressive symptoms but not with global cognition or with other BPSDs. Locus coeruleus pTau pathology was positively correlated with cortical pTau pathologic severity and with LATE-NC stages. In conclusion, LC pTDP-43 pathology is a common feature of brain aging, associated with LATE-NC.},
}

@article {pmid42008720,
year = {2026},
author = {Calderón-Garcidueñas, L and Nalbantoglu, OU and González-Maciel, A and Torres-Jardón, R},
title = {Alzheimer neuropathological change, α-synuclein and transactive response DNA-binding protein of 43 kDa expression in children and young adult brains from forensic autopsies: Value for early measurement of abnormal protein expression prevalence in neurodegenerative diseases.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag028},
pmid = {42008720},
issn = {1554-6578},
abstract = {Alzheimer disease (AD) neuropathologic change (ADNPC), Parkinson disease (PD) α-synuclein (α-Syn), and TAR DNA-binding protein 43 (TDP-43) pathology overlap in a continuum in fine particulate matter (PM2.5)-exposed Metropolitan Mexico City (MMC) children and young adult forensic autopsy brains. This report focuses on a forensic targeted immunohistochemistry protocol to assess ADNPC, α-Syn and TDP-43 in ≤40y subjects, and to define their relationship with cumulative PM2.5 (CPM) exposures. We proposed an early measurement of abnormal protein expression to evaluate neurodegenerative disease prevalence in exposed PM2.5 urban young populations. We studied 189 autopsies average age 26±10y, including 179 MMC ≤40y olds and 10 low pollution controls. Among MMC adults 18-40y, 11.3% exhibited ADNPC alone; 50% had ADNPC + PD, 32.0% had ADNPC + PD + TDP-43 and 6.7% had ADNPC + TDP-43 pathology. In 37 children (13.0±4.8y), 24.3% had ADNPC, 37.8% had ADNPC + PD, 32.4% had ADNPC + PD + TDP-43; 5.4% had ADNPC + TDP-43 pathology. The overlapping children's neuropathology was documented under low CPM. We suggest that measurements of abnormal protein expression to evaluate neurodegenerative disease in young PM2.5-exposed young urban populations in US autopsies will define the prevalence and overlap of early neurodegenerative biological markers. This information guide preventive medicine, health services, environmental PM2.5 emission control and early neuroprotection from potentially preventable air pollution-associated neurodegenerative diseases.},
}

@article {pmid42008766,
year = {2026},
author = {Ramalingam, SV and Soloman, VG and Ramesh, H and Bakthavatchalam, S and Ramesh, M and Ramachandran, K and Govindasamy, C and Al-Numair, KS and Vinayagam, R},
title = {Bioactive Zoochemicals From Portunus sanguinolentus Shells: A Sustainable Source of Acetylcholinesterase Inhibitors and Antimicrobial Agents.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {4},
pages = {e02610},
doi = {10.1002/cbdv.202502610},
pmid = {42008766},
issn = {1612-1880},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; *Acetylcholinesterase/metabolism ; Animals ; Molecular Docking Simulation ; *Brachyura/chemistry ; Microbial Sensitivity Tests ; Antioxidants/pharmacology/chemistry/isolation & purification ; *Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification ; Dose-Response Relationship, Drug ; Structure-Activity Relationship ; Molecular Structure ; },
abstract = {This study explores the therapeutic potential of methanol extracts from the shells of the marine crab Portunus sanguinolentus, with a focus on inhibiting acetylcholinesterase (AChE) to enhance acetylcholine (ACh) levels, an essential strategy in the management of Alzheimer's disease (AD). GC-MS analysis identified 18 distinct zoochemicals, predominantly fatty acid derivatives, and HPLC analysis confirmed the presence of n-Hexadecanoic acid, while FT-IR spectroscopy confirmed the presence of functional groups typical of polyphenols, alkaloids, and terpenoids. The extract exhibited notable antioxidant activity, with IC50 values of 62.08 µg/mL (DPPH) and 68.05 µg/mL (ABTS), both showing strong dose-dependent responses (R[2] = 0.90). AChE inhibition assays revealed dose-dependent effects with an IC50 of 161.49 µg/mL (R[2] = 0.943). Molecular docking studies further supported the bioactivity, indicating strong interactions between identified zoochemicals and key targets, including AChE (1EVE), Peroxiredoxin 5 (1HD2), Myeloperoxidase (1DNU), and MraY (5CKR). Additionally, the extract demonstrated significant antibacterial efficacy, confirmed through MIC, MBC, zone of inhibition assays, cytoplasmic leakage (DNA and protein), and in silico predictions. These findings suggest that the P. sanguinolentus shell methanol extract contains bioactive zoochemicals with promising AChE-inhibitory, antioxidant, and antibacterial activities. Importantly, the use of crab shells not only contribute to drug development for Alzheimer's disease but also offers a sustainable approach to marine biowaste valorization.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
*Acetylcholinesterase/metabolism
Animals
Molecular Docking Simulation
*Brachyura/chemistry
Microbial Sensitivity Tests
Antioxidants/pharmacology/chemistry/isolation & purification
*Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification
Dose-Response Relationship, Drug
Structure-Activity Relationship
Molecular Structure

@article {pmid42008868,
year = {2026},
author = {Liu, X and Xu, J and Lin, C and Gao, X and Xie, Y and Chen, X and Huang, Q and Ye, R and Shi, H and Zhang, L and Ye, ZC and Wu, C and Zha, D},
title = {Design, synthesis, and biological evaluation of pyranone-carbamate hybrids as selective butyrylcholinesterase inhibitors with anti-neuroinflammatory activity for Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {176},
number = {},
pages = {109887},
doi = {10.1016/j.bioorg.2026.109887},
pmid = {42008868},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which cholinergic dysfunction and chronic neuroinflammation jointly contribute to cognitive decline. To address these converging pathological features, a series of carbamate-pyranone hybrids (E1-E17) were designed using a pharmacophore hybridization strategy that integrates the cholinesterase-inhibitory carbamate motif of Rivastigmine with the anti-neuroinflammatory γ-pyranone scaffold derived from D30. Among these derivatives, E14 emerged as a promising hit compound. E14 inhibited lipopolysaccharide-induced nitric oxide production in BV2 microglial cells (IC50 = 9.76 ± 0.59 μM), while maintaining acceptable cytocompatibility. Enzymatic assays revealed that E14 selectively inhibited butyrylcholinesterase, with IC50 values of 15.59 ± 2.98 μM against eqBuChE and 38.65 ± 3.40 μM against hBuChE, while showing negligible activity against acetylcholinesterase, and kinetic analysis indicated a competitive inhibition mechanism. Consistent with its CNS-oriented design, E14 exhibited high passive blood-brain barrier permeability in a PAMPA-BBB assay (Pe = 11.87 × 10[-6] cm/s) and showed good acute tolerability in mice. In an oligomeric Aβ-induced cognitive impairment mouse model, E14 significantly improved recognition memory and spatial learning performance. Mechanistic investigations demonstrated that E14 attenuated hippocampal glial activation and neuroinflammation, suppressing the TLR4/p38 MAPK signaling pathway and modulating the IL-1β/C3-mediated microglia-astrocyte inflammatory axis. Network pharmacology analyses further suggested multitarget engagement across inflammation- and stress-related pathways relevant to AD pathology. Collectively, these findings identify E14 as a brain-penetrant, BuChE-selective dual-functional compound that integrates cholinesterase inhibition with anti-neuroinflammatory activity, supporting its further development as a multitarget-directed lead for AD intervention.},
}

@article {pmid42008955,
year = {2026},
author = {Yoshikawa, H and Yoshida, E and Matsumoto, T and Sugita, K and Kamiya, S and Ohgita, T and Kobuchi, S and Shimohama, S and Takata, K},
title = {Identification of daurioxoisoporphine D and moringamine I as blood-brain barrier-permeable natural inhibitors of amyloid-β aggregation and neuronal toxicity.},
journal = {Bioorganic & medicinal chemistry},
volume = {138},
number = {},
pages = {118664},
doi = {10.1016/j.bmc.2026.118664},
pmid = {42008955},
issn = {1464-3391},
abstract = {Early Alzheimer's disease (AD) is characterized by extracellular accumulation of amyloid-β (Aβ) peptides and degeneration of basal forebrain cholinergic neurons. Currently, acetylcholinesterase inhibitors and costly anti-Aβ antibodies are used in clinical practice; however, their therapeutic efficacy remains limited. Consequently, disease-modifying therapies that directly target AD pathogenesis and provide neuroprotection-preferably affordable, small-molecule compounds-are urgently needed. To identify seed compounds with potential for clinical translation, screening platforms that accurately recapitulate AD pathophysiology in human-based models are necessary. Therefore, in this study, we employed previously established human induced pluripotent stem cell-derived basal forebrain cholinergic neurons (hiBFChNs). The inhibitory activity against Aβ aggregation was initially evaluated for 129 natural compounds using the thioflavin T assay. Subsequently, the neuroprotective effects of the 65 selected compounds were assessed in human neuroblastoma SH-SY5Y cells and hiBFChNs using the WST-8 and lactate dehydrogenase assays as secondary and tertiary screening steps, respectively. Among these, 17 compounds demonstrated both inhibitory effects against Aβ aggregation and neuroprotective effects. Further evaluation of physicochemical properties relevant to brain penetration, together with confirmation of in vitro blood-brain barrier (BBB) permeability using a monkey BBB kit, identified daurioxoisoporphine D and moringamine I as promising seed compounds for AD drug development. Overall, these results indicate that a unified screening platform capable of seamlessly evaluating Aβ aggregation inhibition, neuroprotection, and brain permeability could facilitate the identification of small-molecule therapeutics that modify disease progression in AD.},
}

@article {pmid42008960,
year = {2026},
author = {Bhattacharya, K and Chanu, NR and Das, D and Khanal, P and Bhattacharjee, A},
title = {NeuroBACE-ML: A reliability-aware screening framework for high-throughput prioritization of potent BACE1 inhibitors.},
journal = {Journal of molecular graphics & modelling},
volume = {146},
number = {},
pages = {109415},
doi = {10.1016/j.jmgm.2026.109415},
pmid = {42008960},
issn = {1873-4243},
abstract = {Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in amyloid-β generation and remains an important target in Alzheimer's disease (AD) drug discovery. Here, we present NeuroBACE-ML, a reliability-aware screening framework for high-throughput prioritization of potent BACE1 inhibitors from small-molecule libraries. Human BACE1 bioactivity records were curated from ChEMBL and standardized on a pIC50 scale using a strict binary definition to reduce label ambiguity: active (IC50 ≤ 100 nM; pIC50 ≥ 7) and inactive (IC50 ≥ 1 μM; pIC50 ≤ 6), while excluding the intermediate grey zone (100-1000 nM; 6 < pIC50 < 7). Molecules were represented using Morgan fingerprints and the primary classifier was built using XGBoost with Optuna-based hyperparameter optimization. On the fixed random held-out test set, NeuroBACE-ML showed high discriminative performance, with AUROC = 0.986, AUPRC = 0.991, MCC = 0.868 and balanced accuracy = 0.943 at the deployed operating threshold of 0.70 (TN = 468, FP = 14, FN = 71, TP = 763). To strengthen reliability for prospective screening, the framework incorporates probability calibration, scaffold-aware robustness assessment, applicability-domain-aware decision support, abstention logic and ensemble uncertainty analysis. In addition, external validation on an independent non-overlapping BindingDB dataset supported generalizability beyond the ChEMBL-derived benchmark (AUROC = 0.969, AUPRC = 0.987, MCC = 0.790). While the framework is intended for early-stage candidate prioritization rather than direct clinical translation, it provides a practical and deployable tool for identifying high-confidence BACE1 inhibitor candidates for downstream medicinal chemistry and experimental follow-up. The exclusion of intermediate compounds may limit real-world applicability by simplifying borderline activity patterns that can occur in practical screening settings. NeuroBACE-ML is available as a web application at https://neurobace-ml.streamlit.app/with supporting code and deployment resources available via GitHub at https://github.com/kunal74/NeuroBACE-ML.},
}

@article {pmid42009011,
year = {2026},
author = {Powell, A and Chan, K and Shepherd, CE and Brodaty, H},
title = {Cognitive resilience in ageing: determinants and interventions.},
journal = {The Lancet. Neurology},
volume = {25},
number = {5},
pages = {492-505},
doi = {10.1016/S1474-4422(26)00027-X},
pmid = {42009011},
issn = {1474-4465},
mesh = {Humans ; *Aging/psychology/physiology ; *Resilience, Psychological ; *Cognition/physiology ; *Cognitive Reserve/physiology ; },
abstract = {Understanding the factors that contribute to the preservation of cognitive abilities into advanced age despite brain injury or disease is a key goal of ageing research. Up until the last two decades, the extent of brain pathology could only be fully appreciated at autopsy. Advances in laboratory and imaging biomarkers now mean that cognitive function can be understood in the context of markers of brain injury and specific pathologies (eg, Alzheimer's disease, Lewy body disease, and cerebrovascular disease). Knowledge on the characteristics of individuals displaying cognitive resilience and its social determinants across the lifespan can inform strategies to enhance resilience at individual and population levels. There is some evidence of the effectiveness of interventions to improve cognitive functioning from high-income countries, supported by biomarker data. Looking ahead, translation of cognitive resilience research to low-income and middle-income countries-the regions with the fastest growth in dementia burden-will require addressing key challenges and seizing opportunities.},
}

Humans
*Aging/psychology/physiology
*Resilience, Psychological
*Cognition/physiology
*Cognitive Reserve/physiology

@article {pmid42009141,
year = {2026},
author = {Liu, Y and Jiang, Y and Zhao, Z and Zhang, H and Li, D and Chai, G and Zhao, P and Xu, B and Jin, Z and Qiu, F and Chen, D and Zhu, E and Shao, W and Zhu, A and Xu, R and Gui, S and Liu, Y and Chen, J and Hu, R and Lu, H},
title = {A Functional Deep Cervical Lymphovenous Anastomosis Model in APP/PS1 Mice Augmenting Cerebral Lymphatic Drainage.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110779},
doi = {10.1016/j.jneumeth.2026.110779},
pmid = {42009141},
issn = {1872-678X},
abstract = {BACKGROUND: Deep cervical lymphatics constitute the final pathway for cerebral lymphatic drainage into the circulatory system. Dysfunction in this pathway inevitably impairs the clearance of cerebral metabolic waste. Recent clinical study has reported the efficacy of deep cervical lymphovenous anastomosis (dcLVA) in Alzheimer's disease (AD) patients. However, the lack of a mouse animal model for LVA has hindered mechanistic research.

NEW METHOD: To address this gap, we established a dcLVA model in APP/PS1 mice. Ten-month-old male APP/PS1 transgenic mice and wild-type (WT) littermates underwent side-to-side anastomosis between deep cervical lymph node and external jugular vein using supermicrosurgical techniques. Indocyanine green (ICG) was injected into the cisterna magna for evaluating cerebrospinal lymphatic drainage via near-infrared fluorescence tracking. Fluorescence intensity of deep cervical lymph node was dynamically recorded at 10min, 30min, 1h, 2h, 3h, and 6h post-ICG injection.

RESULTS: Results revealed significantly impaired ICG drainage in AD mice compared to WT littermates. Notably, dcLVA enhanced ICG drainage from subarachnoid space of cisterna magna in AD mice.

This study is the first to establish a functional LVA model in AD mouse, demonstrating its ability to augment cerebral lymphatic drainage.

CONCLUSIONS: Our findings provide a novel platform for future study to explore the effect and underlying mechanisms of LVA on AD and other neurodegenerative disorders associated with impaired lymphatic function.},
}

@article {pmid42009326,
year = {2026},
author = {Garg, A and Shaw, R},
title = {SSiamese Capsule Network (SNNCap) : Cognitive Analysis for Alzheimer's Disease Classification from MRI Data.},
journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TIP.2026.3683547},
pmid = {42009326},
issn = {1941-0042},
abstract = {Alzheimer's Disease (AD) detection is essential for timely treatment and better patient care. Magnetic Resonance Imaging (MRI) is a technique in which radio waves and magnetic fields are used to capture high-resolution, multi-dimensional representations of brain structures. This high-resolution imaging capability makes MRI a key tool for diagnosing neurological disorders such as Alzheimer's disease. However, the problem is to correctly classify the fresh MRI scans of patients. Researchers have proposed a deep learning-based method for Alzheimer's disease diagnosis using a Siamese Convolutional Neural Network (SCNN) with three ResNet-34 branches trained on structural MRI data. However, this method relies solely on ResNet34 for feature extraction which struggles to preserve spatial relationship due to pooling operations, causing loss of positional information. Other researchers have explored methods like attention mechanisms and 3D convolutional networks to capture spatial dependencies. However, these methods underperform by missing brain complexity or needing high resources without consistent accuracy. In this study, we propose a cognitively inspired approach for classifying MRI images as Non Demented, Very Mild Demented, Mild Demented and Moderate Demented using Siamese Capsule Network (SNNCap). SNNCap uses ResNet-18 for feature extraction and capsule layers to preserve spatial and part-whole relationships in the images. It compares a test image against a few known reference examples per class. This reference-based validation closely mimics cognitive reasoning, improving the system's generaliz-ability. The model achieves strong results on unseen data and demonstrates its effectiveness through classification reports and confusion matrices.},
}

@article {pmid42009653,
year = {2026},
author = {He, Y and Du, Y and Liu, D and Che, P and Wang, Y and Li, J and Wang, C and Zhang, N},
title = {Diagnostic performance of plasma p-tau217 levels measured with different assays for Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04043-0},
pmid = {42009653},
issn = {2158-3188},
abstract = {Plasma tau phosphorylated at threonine 217 (p-tau217) has been recommended as a biomarker for the diagnosis of Alzheimer's disease (AD). We evaluated the diagnostic and differential performance of plasma p-tau217 levels measured with three novel assays in a Chinese population. A total of 233 participants were recruited, including 39 cognitively unimpaired controls (CUCs), 28 individuals with mild cognitive impairment (MCI) due to AD, 57 individuals with AD dementia (ADD), 70 individuals with subcortical ischemic vascular dementia (SIVD), and 39 individuals with frontotemporal lobar degeneration (FTLD). Plasma p-tau217 levels were measured using one assay based on single-molecule techniques (DiSMS), one assay based on digital ELISA (LyMedivh™ AXL), and one assay based on flow cytometry (CBA), as well as a reference assay (ALZpath Simoa). Group differences in plasma p-tau217 levels were assessed using analysis of covariance, and the diagnostic and differential performance of the assays was evaluated via receiver operating characteristic analysis. Partial correlation analysis was used to examine the correlations between the measurements of the three novel assays and those of the reference assay. We found that plasma p-tau217 levels measured with all three novel assays were higher in the ADD group than in the CUC, SIVD, and FTLD groups (all p < 0.05) and effectively discriminated ADD patients from both CUCs and non-AD dementia patients. The diagnostic and differential performances did not significantly differ among the three assays (all p > 0.05). Both the DiSMS and LyMedivh™ AXL assays also revealed elevated plasma p-tau217 levels in the MCI group compared to the CUC group. Moreover, the measurements of the three novel assays demonstrated significant correlations with the ALZpath Simoa measurements (p < 0.01). When using their optimal cutoff values, both the DiSMS and LyMedivh™ AXL assays yielded a specificity of 100% and a sensitivity of 94.4%, and the CBA assay showed a specificity of 100% and a sensitivity of 88.9%. In conclusion, our study demonstrated the diagnostic and differential abilities of plasma p-tau 217 levels measured with three novel assays that can serve as potential alternatives to the currently available testing methods for AD diagnosis.},
}

@article {pmid42009666,
year = {2026},
author = {Moustafa, SA and Mowafi, S and Fawi, G and Othman, M and Heikal, S and Mohamed, AS and Habib, H and Hassan, OA and Meghaed, F and Youssef, AS and Ali, EM and Moustafa, R and Mohamed, M and Moustafa, M and Sweilam, J and Wahdan, M and Ezzeldin, S and Shebl, N and Khella, K and Tantawi, L and Mahmoud, F and Gaballah, Z and Zaki, F and Qansuwa, E and El Taras, M and Sayed, S and El Sayed, M and Srour, I and El Sayed Moustafa, S and Sameer, S and Gad, ES and Sweilam, M and Rizig, M and Meier, I and Narayan, V and Salama, M},
title = {Cohort profile Davos Alzheimer's Collaborative DAC Egypt Cohort.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42009666},
issn = {2731-6068},
abstract = {The Davos Alzheimer's Collaborative (DAC) Egypt Cohort (DAC-Egypt) is a newly established longitudinal study of cognitive aging in a community-based convenience sample of older Egyptian adults. The cohort's purpose is to characterize trajectories of cognitive decline and dementia risk factors in an understudied population, filling a critical gap in aging research in the Middle East. Participants (n = 1,530) aged 55 and above were recruited via regionally diverse convenience sampling, with detailed baseline data collected on demographics, health status, lifestyle, and cognitive function. Cognitive assessments included both traditional neuropsychological testing and innovative digital tools (digital voice/speech & olfactory-sensory assessments) to enable comprehensive monitoring. Key preliminary findings indicated a high prevalence of chronic diseases and notable socioeconomic disparities in cognitive performance among older Egyptians. Blood samples were collected from 98% of participants, and dried blood spot (DBS) cards were obtained for 88% of participants to facilitate future biomarker and genetic research. This study seeks to enrich the scientific field of dementia and Alzheimer's disease and related disorders (ADRD) for early detection and intervention strategies for cognitive health in aging populations.},
}

@article {pmid42009747,
year = {2026},
author = {Chen, P and Fan, M and Lin, H and Chen, Z and Zhang, Q and Cheng, Y and Xu, J},
title = {Identification of small ubiquitin-related modifier (SUMO)-related genes-based biomarkers in Alzheimer's disease based on bioinformatics analysis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49884-3},
pmid = {42009747},
issn = {2045-2322},
support = {2025J011378//Research on Self-Assembled Nano-Biosensors for the Early Diagnosis of Alzheimer's Disease/ ; 2023J011519//Natural Science Foundation of Fujian Province, China/ ; 2024ZY04//Intramural Research Project of Fuzhou Second General Hospital, China/ ; },
abstract = {To investigate the role of small ubiquitin-like modification (SUMO) in Alzheimer's disease (AD) and its pathogenesis, this study employed bioinformatics methods to identify diagnostic biomarkers for AD based on SUMO-related genes (SRGs). It further conducted preliminary explorations into their role in AD pathogenesis and potential therapeutic targets. Datasets related to AD (GSE140831, GSE63060), a dementia dataset (GSE140830), and 189 SRGs were retrieved from public databases. Candidate genes were identified by intersecting differentially expressed genes (DEGs) with SRGs. A protein-protein interaction (PPI) network was constructed to select the top 15 core genes, and the support vector machine-recursive feature elimination (SVM-RFE), least absolute shrinkage and selection operator (LASSO) and boruta random forest (Boruta-RF) identified feature genes. Validation was done using the GSE140831 and GSE63060 datasets, and the nomogram model was assessed by receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis (GSEA) and other analyses were performed. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used for further validation. Overlapping 189 SRGs and 12,853 DEGs identified 107 candidate genes. Six overlapping genes were selected. CREBBP, PIAS1, and TRIM28 were confirmed as AD biomarkers due to their increased expression in AD and strong ROC performance. GSEA highlighted their involvement in pathways such as olfactory transduction, lysosome, and spliceosome. Immune infiltration analysis suggested immune cell involvement in AD progression. Additionally, 21 potential drugs for AD therapy were predicted. RT-qPCR confirmed the over-expression of CREBBP and TRIM28 in AD samples, consistent with dataset trends. CREBBP, PIAS1, and TRIM28 were identified as SRG-based biomarkers for AD diagnosis, providing new insights into AD pathogenesis.},
}

@article {pmid42009901,
year = {2026},
author = {Söylemez, DÖ and Unur, E and Sağır, D},
title = {Protective effects of curcumin and resveratrol on neurodegeneration and cognitive dysfunction in a streptozotocin-induced alzheimer rat model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-48216-9},
pmid = {42009901},
issn = {2045-2322},
support = {TDK-2021-11068//Erciyes University Scientific Research Projects Unit/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by memory loss, cognitive decline, and behavioral disturbances. Given the limited efficacy of current treatments, there is an urgent need for new neuroprotective strategies. In this study, the therapeutic potential of curcumin and resveratrol was evaluated in a rat AD model induced by intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg). Subsequent to model induction, rats were administered curcumin, resveratrol, or a combination of both. The behavioral analyses, which included the Morris water maze, open field, and passive avoidance tests, revealed that both compounds significantly improved learning and memory performance. The histological and immunohistochemical findings demonstrated a decrease in caspase-3 and GFAP immunoreactivity, suggesting reduced neuronal apoptosis and astrocyte activation. The behavioral analyses, which included the Morris water maze, open field, and passive avoidance tests, revealed that both compounds significantly improved learning and memory performance. The histological and immunohistochemical findings demonstrated a decrease in caspase-3 and GFAP immunoreactivity, suggesting reduced neuronal apoptosis and astrocyte activation. Biochemical results showed an increase in total antioxidant status (TAS) and superoxide dismutase (SOD) activity, along with a decrease in total oxidative status (TOS) and TNF-α levels. Stereological evaluation also confirmed partial restoration of hippocampal volume. While curcumin and resveratrol exhibited potent neuroprotective effects when used separately, no synergistic interaction was observed when used in combination. These findings suggest that curcumin and resveratrol may serve as promising therapeutic agents for reducing oxidative stress, neuroinflammation, and neuronal degeneration associated with Alzheimer's disease.},
}

@article {pmid42009978,
year = {2026},
author = {Wang, L and Venkatesh, S and Morris, M and Li, M and Srivastava, R and Visweswaran, S and Lopez, OL and Xia, Z and Cai, T},
title = {Stratification of Alzheimer's disease patients using knowledge-guided unsupervised latent factor clustering with electronic health record data.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01511-y},
pmid = {42009978},
issn = {2730-664X},
abstract = {BACKGROUND: Prognostication for people with Alzheimer's disease (AD) at the point of care could improve clinical management.

METHODS: In this retrospective cohort study using the electronic health record (EHR) data from a large healthcare system (2011-2022), we applied an unsupervised latent factor clustering approach guided by knowledge graph embeddings to stratify AD patients into two groups at diagnosis (baseline) using clinical features in the two years preceding diagnosis. We prognosticated the risk of AD-related outcomes (nursing home admission and mortality) for the clusters in survival analyses adjusted for baseline confounders (age, gender, race, ethnicity, healthcare utilization, and comorbidities). To reflect real-world evolution in clinical trajectories, we updated patient stratification for patients remaining at risk one year post-diagnosis and repeated prognostication.

RESULTS: We stratify 16,411 AD patients into two groups at baseline (41% Group 1, 59% Group 2). Baseline Group 2 has a significantly lower risk of nursing home admission (HR [95% CI] = 0.804 [0.765, 0.844], p < .001) but comparable mortality risk to baseline Group 1 (HR [95% CI] = 1.008 [0.963, 1.056], p = 0.733). We re-stratify the 12,606 patients remaining at risk one year post-diagnosis (46% Group 1, 54% Group 2). Consistent with baseline, the updated Group 2 has a lower risk of nursing home admission (HR [95% CI] = 0.815 [0.766, 0.868], p < .001) but comparable mortality risk (HR [95% CI] = 0.977 [0.922, 1.035], p = .430) to Group 1.

CONCLUSIONS: Patient stratification enables outcome prognosis for AD patients. While baseline prognostication can guide early treatment and tailored management, dynamic prognostication may inform more timely interventions to improve long-term outcomes.},
}

@article {pmid42009995,
year = {2026},
author = {Tan, JY and Retinasamy, T and Lee, VLL and Radhakrishnan, AK and Yeong, KY},
title = {Exploring the role of tocotrienol-rich fraction (TRF) in ameliorating neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42009995},
issn = {1568-5608},
abstract = {Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.},
}

@article {pmid42010082,
year = {2026},
author = {Guo, J and Yang, Z and Luo, S and Li, C and Xu, S},
title = {Alzheimer's disease: disrupted communication between the endoplasmic reticulum and mitochondria.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42010082},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Endoplasmic Reticulum/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Endoplasmic Reticulum Stress/physiology ; },
abstract = {Alzheimer's disease (AD) remains a major, intractable neurodegenerative disorder and a serious threat to human health, characterized by a protracted clinical course, gradual progression, and irreversible cognitive decline. The current therapeutic landscape is characterized by a lack of disease-modifying agents, making the pursuit of early, effective interventions a global priority. Endoplasmic reticulum-mitochondria contact sites (ERMCs), also termed mitochondria-associated ER membranes (MAMs), constitute critical platforms for interorganellar communication, enabling material exchange and signal transduction. Key functions regulated at these junctions include calcium (Ca[2+]) homeostasis, mitochondrial dynamics, and lipid synthesis/transfer. Growing evidence implicates dysregulated ERMCs in the pathogenesis of neurodegenerative diseases, including AD and Parkinson's disease (PD). Recent advances in understanding the physiological and pathological roles of ERMCs have further illuminated their multifaceted contribution to AD, spanning amyloid-β (Aβ) production, Ca[2+] signaling, energy and lipid metabolism, mitochondrial integrity, and endoplasmic reticulum stress (ERs). This review synthesizes current knowledge on ERMCs as a pivotal communication hub in AD and underscores their promising potential as targets for novel therapeutic strategies. Deeper insights into this axis may inform future approaches to improve clinical outcomes.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Endoplasmic Reticulum/metabolism/pathology
*Mitochondria/metabolism/pathology
Animals
Endoplasmic Reticulum Stress/physiology

@article {pmid42010230,
year = {2026},
author = {Liu, Y and Kunutsor, SK},
title = {Brain, benefit, or burden? Revisiting statins and cognitive function in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42010230},
issn = {2509-2723},
abstract = {Statins are among the most widely prescribed medications for the prevention and treatment of cardiovascular disease, particularly in older adults. However, concerns regarding their potential adverse cognitive effects, including memory loss and dementia, have generated substantial debate and regulatory attention. This narrative review critically appraises current evidence on the relationship between statin use and cognitive outcomes in older adults, exploring both potential risks and benefits. We synthesized findings from randomized controlled trials (RCTs), observational cohort studies, meta-analyses, and Mendelian randomization studies. We also examined biological mechanisms, subgroup differences by statin type, and clinical considerations specific to older populations. Most RCTs have not demonstrated a harmful effect of statins on cognition, while observational studies have shown mixed results, including possible protective associations. Mechanistically, statins may exert both neuroprotective and neurotoxic effects, depending on their type, dose, and ability to cross the blood-brain barrier. Mendelian randomization analyses, including those involving over 100,000 individuals from the Danish general population, have largely found no causal effect of genetically proxied statin targets on dementia or neurodegenerative diseases. Importantly, older adults remain underrepresented in trials with cognitive outcomes, and real-world evidence is limited by confounding. Two large-scale randomized trials, PREVENTABLE and STAREE, are currently underway and poised to provide definitive evidence regarding the cognitive effects of statins in older populations. Current evidence does not support discontinuing statin therapy in older adults based solely on concerns about cognitive decline. Instead, decisions should be individualized, weighing cardiovascular benefit against cognitive risk, particularly in those with pre-existing cognitive impairment, polypharmacy, or frailty. Future research should prioritize cognition as a primary outcome in studies involving older populations.},
}

@article {pmid42010343,
year = {2026},
author = {Coomans, EM and Smith, R and Pawlik, D and Oliveira Hauer, K and Palmqvist, S and Stomrud, E and Mattsson-Carlgren, N and Tremblay, C and Serrano, GE and Beach, TG and Rozemuller, AJ and Pijnenburg, Y and van de Giessen, E and Kotari, V and Pontecorvo, M and Shcherbinin, S and Hansson, O and Ossenkoppele, R},
title = {Neuropathological correlates of age and sex differences in 18F-flortaucipir PET.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag136},
pmid = {42010343},
issn = {1460-2156},
abstract = {Among amyloid-positive individuals with symptomatic Alzheimer's disease, older age and male sex have been associated with a lower prevalence of Tau-PET-positivity. Whether Tau-PET-negative older and/or male individuals truly do not harbor widespread tau pathology or whether tangle density is below the PET-detection threshold remains unknown. Therefore, we aimed to investigate the neuropathological correlates of age- and sex-differences in Tau-PET in independent PET-only, autopsy-only, and PET-to-autopsy cohorts. In the PET-only cohort, we included amyloid-β-positive participants with MCI or dementia who underwent [18F]flortaucipir-PET (n=672). In the autopsy-only cohort, we included participants with moderate-to-frequent CERAD scores and MCI or dementia with available data on Braak stage and tangle density (n=945). In the PET-to-autopsy cohort, we included participants who underwent antemortem Tau-PET and had undergone a postmortem assessment of Braak staging (n=85) (median PET-to-post-mortem-interval: 2.6 months). A subset additionally had tangle density data available (n=63). Tau-PET SUVr was calculated in a temporal meta-region, and Tau-PET-positivity was defined using a predefined threshold of 1.36 SUVr. Autopsy cases were categorized as Braak 0-IV versus Braak V-VI. In PET-only-analyses (age: 71.9±8.2, 52.8% male), older age and male sex were associated with a lower prevalence of Tau-PET-positivity and lower Tau-PET SUVr (all p<0.05). In autopsy-only-analyses (age: 82.7±7.9, 54.6% male), older age and male sex were associated with a lower prevalence of Braak-V/VI neuropathology (both p<0.05). Among Braak-V/VI autopsy cases (n=598), older age was associated with lower tangle density (β=-0.38, p<0.001). In PET-to-autopsy-analyses (age: 81.7±9.2, 52.9% male), Tau-PET showed excellent specificity for detecting Braak-V/VI neuropathology (100% across age-stratified and sex-stratified models), while the sensitivity decreased at older age (<83y: 92% [95% confidence interval: 80%-100%] vs ≥83y: 42% [23%-62%]) and in males (females: 85% [69%-96%] vs males: 48% [28%-68%]). Older and male participants with Braak-V/VI neuropathology showed both lower Tau-PET SUVr (age: β=-0.46, p=0.003; sex: β=-0.97, p=0.001), and in the same individuals, older participants showed trend-level lower tangle density (β=-0.31, p=0.053). The lack of age/sex-interactions indicate that the relationship between Tau-PET and tangle density is consistent across ages and sexes. Comprehensive and independent PET, autopsy, and PET-to-autopsy analyses demonstrate that the associations of older age and male sex with lower [18F]flortaucipir-PET uptake and positivity rates can be explained by lower tangle densities. [18F]flortaucipir-PET SUVr thus closely reflects tangle density, which accounts for the lower sensitivity of [18F]flortaucipir-PET for detecting low-density Braak-V/VI tau pathology in older individuals and males.},
}

@article {pmid42010371,
year = {2026},
author = {Malek-Ahmadi, M and Perez, SE and He, B and Rogalski, E and Counts, SE and Ikonomovic, MD and Abrahamson, EE and Ginsberg, SD and Alldred, MJ and Serrano, GE and Belden, CM and Atri, A and Mufson, EJ},
title = {Psychometric criteria for superior cognitive performance in very old adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435166},
doi = {10.1177/13872877261435166},
pmid = {42010371},
issn = {1875-8908},
abstract = {BackgroundThe cellular mechanisms that promote the maintenance of cognitive abilities in very old people designated as successful agers remain under-investigated. Here, we report an episodic memory performance-based criteria that differentiates superior cognitive function from normative cognitive function in adults aged 80 and older.ObjectiveUsing this new criteria, we demonstrate how neuropathological and neurobiological underpinnings of superior cognitive performance can be investigated.MethodsThe most recent verbal episodic memory WMS-R Logical Memory Delayed Recall (LM-DR) score was derived from 144 participants with no cognitive impairment (NCI) 80 years or older participants from the Rush Religious Orders Study classified with Superior Cognitive Performance (SCP, LM-DR ≥ 14) or Normal Cognitive Performance (NCP, LM-DR 13 ≥ 7). Both groups were compared on neuropathological measures for neuritic plaque (NP), diffuse plaque (DP), and neurofibrillary tangle (NFT) load.ResultsNP (p = 0.44), DP (p = 0.27), and NFT (p = 0.28) burden did not differ between SCP and NCP cases. LM-DR scores did not correlate with NP (r = -0.08, p = 0.32), DP (r = -0.14, p = 0.07), or NFT (r = -0.12, p = 0.13) load. Biochemical analysis revealed significantly higher levels of heat-shock protein HSPB6 in SCP compared to NCP (p < 0.001).ConclusionsHeat shock protein differences were observed between NCP and SCP groups. This suggests that our proposed criteria for SCP can help identify neurobiological mechanisms of successful cognitive aging. Our SCP criteria are also concordant with the SuperAger criteria which supports the generalizability of the SCP criteria to other datasets.},
}

@article {pmid42010462,
year = {2026},
author = {Polu, PR},
title = {AI-Driven Chemometrics for Multi-omics Data Integration: Advances, Challenges, and Future Directions.},
journal = {Critical reviews in analytical chemistry},
volume = {},
number = {},
pages = {1-36},
doi = {10.1080/10408347.2026.2657553},
pmid = {42010462},
issn = {1547-6510},
abstract = {The convergence of artificial intelligence and chemometrics has revolutionized multi-omics data integration, enabling unprecedented insights into complex biological systems. This critical review examines AI-driven approaches for integrating genomics, proteomics, metabolomics, and other omics layers, emphasizing developments from 2020 to 2025. We explore fundamental multi-omics challenges including batch effects, high dimensionality, and structural heterogeneity, evaluating how classical chemometric methods have evolved into sophisticated deep learning architectures. Convolutional neural networks, autoencoders, variational autoencoders, and graph neural networks demonstrate remarkable capabilities for non-linear feature extraction and data fusion. Explainable AI frameworks including SHAP and LIME address interpretability concerns critical for analytical chemistry. We review vertical and horizontal integration strategies, highlighting transformer-based attention mechanisms and biological network-informed architectures. Clinical applications in Alzheimer's disease, obesity, and cancer demonstrate 20%-30% performance improvements over traditional approaches. Emerging hyphenated techniques coupling microfluidics with mass spectrometry enable miniaturized analyses. Persistent challenges include computational scalability, overfitting mitigation, regulatory validation gaps, and interdisciplinary collaboration barriers. Future directions encompass federated learning for privacy-preserving analyses, quantum computing applications, and single-cell spatial multi-omics at subcellular resolution. This assessment provides analytical chemists with critical evaluation of available tools, benchmarking strategies, and roadmaps for advancing precision medicine and analytical applications.},
}

@article {pmid42010634,
year = {2026},
author = {Castilla-Silgado, J and Perez-Oliveira, S and Pinto-Hernandez, P and Fernandez-Sanjurjo, M and Corte-Torres, MD and Fernandez-Alvarez, O and Iglesias-Gutierrez, E and Menendez-Gonzalez, M and Alvarez, V and Tomas-Zapico, C},
title = {Connecting HTT intermediate alleles and microRNA dysregulation to enhanced tauopathy in late-onset Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02039-y},
pmid = {42010634},
issn = {1758-9193},
support = {AC20/00017//Instituto de Salud Carlos III/ ; AC20/00017//Instituto de Salud Carlos III/ ; AYUD/2021/5134//Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología/ ; },
}

@article {pmid42010706,
year = {2026},
author = {Chen, Z and Liu, Y and Wang, H and Liu, K and Li, Y and Hu, X and Li, R and Sun, L},
title = {Literature-derived serum miRNA signatures associated with cognitive decline in Alzheimer's disease: integrated analysis and machine learning-based diagnostic modeling.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02048-x},
pmid = {42010706},
issn = {1758-9193},
support = {XYZX0301-12//Capacity Building Project of Xiyuan Hospital, China Academy of Chinese Medical Sciences/ ; },
}

@article {pmid42010774,
year = {2026},
author = {Jin, Y and Topaloudi, A and Drineas, P and Paschou, P},
title = {Risk factors underlying brain structure change rate in cognitive decline: Results from genomewide and phenomewide investigations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71411},
doi = {10.1002/alz.71411},
pmid = {42010774},
issn = {1552-5279},
support = {2006929//Purdue Institute for Drug Discovery/ ; 1715202//Purdue Institute for Drug Discovery/ ; },
mesh = {Humans ; Genome-Wide Association Study ; *Cognitive Dysfunction/genetics/pathology ; *Brain/pathology/diagnostic imaging ; Male ; Risk Factors ; Female ; Aged ; Mendelian Randomization Analysis ; Longitudinal Studies ; Magnetic Resonance Imaging ; Polymorphism, Single Nucleotide ; Apolipoproteins E/genetics ; Atrophy ; Middle Aged ; Genetic Predisposition to Disease ; Aged, 80 and over ; Phenotype ; },
abstract = {INTRODUCTION: The genetic and clinical factors influencing the rate of brain structure change in cognitive decline remain poorly understood. This study aimed to identify genetic variants and risk factors contributing to these changes and explore potential causal relationships.

METHODS: We analyzed data from 2036 individuals across three longitudinal cohorts to assess change rates in 17 brain regions associated with cognitive decline. Genome-wide association studies (GWASs) were followed by phenome-wide association studies (PheWASs), Mendelian randomization (MR), and independent replication.

RESULTS: We identified loci associated with brain structure change, including known Alzheimer's disease genes (apolipoprotein E, APOC1) and novel signals (BEAN1, SDHC). PheWAS and MR analyses in large biobanks suggested potential causal links between brain atrophy and anemia-related traits as well as type 2 diabetes.

DISCUSSION: Our findings highlight genetic contributors and clinical traits associated with brain structure change in cognitive decline. Larger studies with broader cognitive assessments are needed to validate these findings.},
}

Humans
Genome-Wide Association Study
*Cognitive Dysfunction/genetics/pathology
*Brain/pathology/diagnostic imaging
Male
Risk Factors
Female
Aged
Mendelian Randomization Analysis
Longitudinal Studies
Magnetic Resonance Imaging
Polymorphism, Single Nucleotide
Apolipoproteins E/genetics
Atrophy
Middle Aged
Genetic Predisposition to Disease
Aged, 80 and over
Phenotype