@article {pmid42982748,
year = {2026},
author = {Syrjanen, JA and Figdore, DJ and Griswold, ME and Wiste, HJ and Dierkhising, RA and Kremers, WK and Lachner, C and Graff-Radford, NR and Day, GS and Graff-Radford, J and Jack, CR and Knopman, DS and Petersen, RC and Bornhorst, JA and Algeciras-Schimnich, A and , },
title = {Validation of plasma biomarker immunoassay-based models for predicting brain amyloid positivity in cognitively impaired individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {42982748},
issn = {1552-5279},
support = {//The Carl Angus DeSantis Foundation/ ; /AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health (FNIH)/ ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //Biogen/ ; //CereSpir, Inc./ ; //Cogstate; Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun/ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd/ ; //Janssen Alzheimer Immunotherapy Research and Development LLC/ ; //Johnson & Johnson Pharmaceutical Research and Development LLC./ ; //Lumosity/ ; //Merck & Co. Inc./ ; //Meso Scale Diagnostics LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Piramal Imaging/ ; //Servier/ ; //Takeda Pharmaceutical Company/ ; //Transition Therapeutics/ ; },
mesh = {Humans ; Female ; *Amyloid beta-Peptides/blood ; Biomarkers/blood ; *tau Proteins/blood ; Immunoassay/methods ; Male ; Aged ; *Peptide Fragments/blood ; *Brain/metabolism/diagnostic imaging ; *Alzheimer Disease/blood ; *Cognitive Dysfunction/blood ; Aged, 80 and over ; Predictive Value of Tests ; Logistic Models ; },
abstract = {INTRODUCTION: Combining Alzheimer's disease blood biomarkers may improve prediction of amyloid positivity (A+) compared with single biomarkers.

METHODS: Logistic regression models using plasma phosphorylated tau 217 (p-tau217), amyloid beta (Aβ) 42, and Aβ40 were developed in cognitively impaired (CI) participants from Mayo Clinic Rochester (MCR) and validated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Mayo Clinic Florida (MCF) cohorts. Performance was measured by area under the curve (AUC) and Probability of Amyloid Positivity Score (PAPS).

RESULTS: Plasma p-tau217 alone showed high AUC (95% confidence intervals) across cohorts MCR, 0.928 (0.900-0.953); ADNI, 0.938 (0.915-0.959); MCF, 0.935 (0.893-0.970). Adding Aβ42 to regression models yielded marginal model improvement MCR, 0.940 (0.915-0.963); ADNI, 0.945 (0.922-0.965); MCF, 0.960 (0.925-0.986). Utilization of two cutpoints (≥ 90% sensitivity and specificity), yielded ≤ 10% intermediate results for p-tau217, and ≤ 8% for p-tau217+Aβ42. Addition of Aβ40 did not improve models' performance.

DISCUSSION: An immunoassay-based p-tau217 PAPS model accurately predicted amyloid positivity across independent CI cohorts and achieved confirmatory-test performance with two cutpoints. The added value of Aβ42 was modest and cohort dependent, supporting the potential of use of p-tau217-based PAPS in clinical workflows.},
}

Humans
Female
*Amyloid beta-Peptides/blood
Biomarkers/blood
*tau Proteins/blood
Immunoassay/methods
Male
Aged
*Peptide Fragments/blood
*Brain/metabolism/diagnostic imaging
*Alzheimer Disease/blood
*Cognitive Dysfunction/blood
Aged, 80 and over
Predictive Value of Tests
Logistic Models

@article {pmid42982755,
year = {2026},
author = {Van Egroo, M and Patsyuk, Y and Baillet, M and Vogt, NM and Lim, ASP and Ashton, NJ and Janelidze, S and Blennow, K and Hansson, O and Zetterberg, H and Jacobs, HIL},
title = {Locus coeruleus microstructural integrity and sleep disruption in the context of Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {42982755},
issn = {1552-5279},
support = {//Centre for Integrative Neuroscience at Maastricht University/ ; R01AG082006//Foundation for the National Institutes of Health/ ; R01AG062559//Foundation for the National Institutes of Health/ ; R01AG068062//Foundation for the National Institutes of Health/ ; UKDRI-1003//UK Dementia Research Institute/ ; //UCLH Biomedical Research Centre/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; 860197-MIRIADE//H2020 Marie Skłodowska-Curie Actions/ ; FO2022-0270//Stiftelsen för Gamla Tjänarinnor/ ; //Familjen Erling-Perssons Stiftelse/ ; //Olav Thon Stiftelsen/ ; //Bluefield Project/ ; ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 101053962//Horizon Europe Research and Innovation Programme/ ; //Swedish federal government/ ; 2020-0314//Regionalt Forskningsstöd/ ; 2020-O000028//Skåne University Hospital Foundation/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; //Cure Alzheimer's Fund/ ; 1280/20//Parkinsonfonden/ ; FO2021-0293//Swedish Brain Foundation/ ; FO2022-0270//Swedish Brain Foundation/ ; //Strategic Research Area Multipark/ ; 2015.0125//Marianne and Marcus Wallenberg Foundation/ ; 2017-0383//Knut och Alice Wallenbergs Stiftelse/ ; //Swedish state under the agreement between the Swedish government and the County Councils/ ; FO2021-0293//Hjärnfonden/ ; FO2022-0270//Hjärnfonden/ ; FO2024-0048-TK-130//Hjärnfonden/ ; FO2024-0048-HK-24//Hjärnfonden/ ; 2022-00732//Swedish Research Council/ ; 2016-00906//Swedish Research Council/ ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; AF-1032702//Swedish Alzheimer Foundation/ ; AF-994551//Swedish Alzheimer Foundation/ ; AF-939932//Swedish Alzheimer Foundation/ ; 101109451-ADEEPSLEEP//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; A20211016F//BrightFocus Foundation/ ; AARF-23-1145963/ALZ/Alzheimer's Association/United States ; AARG-22-920434/ALZ/Alzheimer's Association/United States ; WE.03-2019-02//Alzheimer Nederland/ ; },
mesh = {Humans ; *Locus Coeruleus/pathology/diagnostic imaging ; *Alzheimer Disease/pathology/complications/diagnostic imaging/physiopathology ; Female ; Male ; Aged ; Actigraphy ; tau Proteins/blood ; Electroencephalography ; *Sleep Wake Disorders/pathology/etiology/diagnostic imaging/physiopathology ; Magnetic Resonance Imaging ; Biomarkers/blood ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; },
abstract = {INTRODUCTION: The locus coeruleus (LC) is among the first sites of tau pathology in Alzheimer's disease (AD) and plays a key role in sleep-wake regulation. However, evidence linking LC integrity to objective sleep measures in the context of emerging AD pathology remains limited.

METHODS: Thirty-nine cognitively unimpaired older adults underwent dedicated LC and neurite orientation dispersion and density imaging at 7T magnetic resonance imaging, actigraphy, and quantification of plasma AD-related biomarkers. A subsample of 20 individuals also completed at-home sleep electroencephalogram (EEG) recordings.

RESULTS: Lower LC orientation dispersion index, indicating lower complexity in the arborization of LC neurites, was associated with actigraphy- and EEG-derived measures of shorter and more fragmented sleep. These associations were exacerbated at elevated plasma phosphorylated tau 217 and glial fibrillary acidic protein concentrations.

DISCUSSION: Our findings provide in vivo evidence of the LC's involvement in sleep disruption, and they highlight LC microstructure as a potential marker for identifying individuals at risk for AD-related sleep disturbances.},
}

Humans
*Locus Coeruleus/pathology/diagnostic imaging
*Alzheimer Disease/pathology/complications/diagnostic imaging/physiopathology
Female
Male
Aged
Actigraphy
tau Proteins/blood
Electroencephalography
*Sleep Wake Disorders/pathology/etiology/diagnostic imaging/physiopathology
Magnetic Resonance Imaging
Biomarkers/blood
Aged, 80 and over
Glial Fibrillary Acidic Protein/blood

@article {pmid42982757,
year = {2026},
author = {Gupta, S and Morrill, V and Groechel, RC and Kucharska-Newton, A and Mosley, TH and Lutsey, PL and Meza, E and Gottesman, RF},
title = {Intergenerational educational attainment and risk for incident dementia in a U.S. community-based cohort study: Findings from the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500432},
doi = {10.1177/13872877261500432},
pmid = {42982757},
issn = {1875-8908},
abstract = {BackgroundIndividuals with higher educational attainment have a lower risk for dementia, including Alzheimer's disease, but it is less clear how the educational attainment of an individual's parents may influence dementia risk, particularly in diverse populations.ObjectiveThis study examined whether intergenerational educational attainment for two adjacent generations was associated with incident dementia risk.MethodsIndividuals from the Atherosclerosis Risk in Communities study were asked about their own educational level (at study baseline, 1987-1989; ages 44-66 years) and, several years later, that of each parent. Dementia status was ascertained from baseline through 2020 using expert committee diagnoses from in-person and telephonic neuropsychological assessments, informant interviews, hospitalization codes, and death certificates. Individuals without dementia at baseline, and with non-missing covariates/ educational history, were included. Educational level was classified (for individuals and the highest-educated parent) as less than high school, completed high school or GED, or more than high school. Cox proportional-hazard models were used to evaluate the association between intergenerational educational attainment and incident dementia risk.ResultsAmong 10,626 individuals (21.8% Black; 55.9% female), models showed that high parental education level and individual education level were each significantly and independently associated with a lower hazard of dementia, although associations were strongest and most consistent for individual education. Individuals whose educational attainment surpassed that of their parents, compared to those with comparable levels, exhibited a significantly lower dementia risk.ConclusionsAn individual's own educational attainment may exert a more significant influence in lowering dementia risk, even when parental education is considered.},
}

@article {pmid42982811,
year = {2026},
author = {Kilian, L and Bengelsdorff, V and Just, J and Stork, S and Galanis, C and Banicevic, M and Amrein, I and Back, M and Jungenitz, T and Fellenz, M and von Engelhardt, J and Deller, T and Wolfer, DP and Vlachos, A and Korte, M and Müller, UC},
title = {Physiological APP processing is required for synaptic plasticity and cognition.},
journal = {Cell death & disease},
volume = {17},
number = {1},
pages = {},
pmid = {42982811},
issn = {2041-4889},
support = {MU 1457/17-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; MU 1457/15-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; CRC/TRR 167/3 2025, - 259373024, B14//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; KO 1674/28-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
mesh = {Animals ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Cognition/physiology ; *Neuronal Plasticity/physiology ; Long-Term Potentiation/physiology ; Hippocampus/metabolism ; Mice ; Amyloid Precursor Protein Secretases/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Synapses/metabolism ; },
abstract = {While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer's disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin mice (termed APPΔS622) lack APPsα, APPβ, and Aβ production and show only minimal soluble APPs shedding. These APPΔS622 mice provide a unique model to distinguish between functions mediated by unprocessed cell surface APP involved in synaptic adhesion or by proteolytic fragments. Strikingly, APPΔS622 mice exhibit pronounced impairments in both long-term potentiation (LTP) and homeostatic forms of synaptic plasticity. Extracellular field recordings revealed significant deficits in hippocampal LTP, associated with a reduced density of mature spines and reduced spine head size. LTP deficits could be restored by APPsα application, suggesting a requirement for non-amyloidogenic APP processing for LTP. In addition, APPΔS622 mice lacking endogenous Aβ displayed a lack of homeostatic synaptic scaling in response to network impairment that could be specifically rescued by exogenous Aβ. Importantly, these deficits in different forms of synaptic plasticity also led to impairments in cognitive behavior. In summary, our findings reveal an essential role of physiological APP processing products to differentially regulate complementary forms of synaptic plasticity that are critical for network stability, normal brain function and cognition.},
}

Animals
*Amyloid beta-Protein Precursor/metabolism/genetics
*Cognition/physiology
*Neuronal Plasticity/physiology
Long-Term Potentiation/physiology
Hippocampus/metabolism
Mice
Amyloid Precursor Protein Secretases/metabolism/genetics
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Synapses/metabolism

@article {pmid42982855,
year = {2026},
author = {Chen, K and Chen, Y and Ren, Y and Wang, Z and Huang, Y and Pan, M and Li, Z and Casey, MC and Qiao, W and Shi, J and Kong, D and Xhafkollari, G and Santhakumar, H and Wetmore, AM and Thompson, EA and Wang, X and Dickson, DW and Holtzman, DM and Bu, G and Han, X and Peng, J and Zhao, N},
title = {APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42982855},
issn = {2041-1723},
support = {U19AG069701//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; *Apolipoprotein E4/metabolism/genetics ; Disease Models, Animal ; *Apolipoprotein E2/genetics/metabolism ; Mice ; Brain/metabolism/pathology ; Mice, Transgenic ; Microglia/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Apolipoprotein E3/genetics/metabolism ; Plaque, Amyloid/pathology/metabolism ; Male ; Female ; Humans ; Alleles ; Myelin Basic Protein/metabolism ; Heterozygote ; Proteomics ; },
abstract = {The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD), influencing amyloid-β (Aβ) aggregation, clearance, and glial function. While APOE4 promotes Aβ pathology and APOE2 is protective, how these opposing alleles interact in the heterozygous APOE2/4 state remains unknown. Here, using littermate-controlled heterozygous APOE mice (APOE2/3, APOE3/4, and APOE2/4) alongside APOE3/3 controls crossed with 5xFAD mice, we show that APOE3/4 mice exhibit increased Aβ deposition, maladaptive microglial activation, and reduced microglial interactions with plaques. These changes were attenuated in APOE2/4 mice, accompanied by a brain proteomic profile more similar to those of APOE3/3 and APOE2/3 mice. Increased myelin basic protein (MBP) abundance was observed in APOE2/3 but not APOE2/4 mice. Plasma lipidomics revealed shared alterations in APOE3/4 and APOE2/4 mice, with distinct signatures in APOE2/3 mice. These findings define allele interaction-dependent effects of APOE on brain and systemic phenotypes and provide a framework for understanding the biological consequences of the APOE2/4 genotype.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics
*Apolipoprotein E4/metabolism/genetics
Disease Models, Animal
*Apolipoprotein E2/genetics/metabolism
Mice
Brain/metabolism/pathology
Mice, Transgenic
Microglia/metabolism/pathology
Amyloid beta-Peptides/metabolism
Apolipoprotein E3/genetics/metabolism
Plaque, Amyloid/pathology/metabolism
Male
Female
Humans
Alleles
Myelin Basic Protein/metabolism
Heterozygote
Proteomics

@article {pmid42982982,
year = {2026},
author = {Nakamura, K and Sekijima, Y},
title = {Clinical genetics and genetic counseling in the era of disease-modifying therapies for dementia: lessons from Japan.},
journal = {Journal of human genetics},
volume = {},
number = {},
pages = {},
pmid = {42982982},
issn = {1435-232X},
support = {JP23dk0207066h0001, JP24dk0207066h0002, JP25dk0207066h0003, and　JP26dk0207081h0001.//Japan Agency for Medical Research and Development (AMED)/ ; JP23dk0207066h0001, JP24dk0207066h0002, JP25dk0207066h0003, and　JP26dk0207081h0001.//Japan Agency for Medical Research and Development (AMED)/ ; },
abstract = {Recent advances in hereditary dementia research have clarified its molecular pathogenesis and clinical applications, with several advances already reaching implementation. The late 2023 introduction of anti-amyloid β therapies for Alzheimer's disease (AD) in Japan marked the beginning of a transformative era, though amyloid-related imaging abnormalities (ARIA) remain a notable adverse effect. Because APOE genotype, and ε4 dose in particular, is a major determinant of ARIA, genotyping is now embedded in pretreatment assessment. This review examines how one national health system has incorporated these advances and distinguishes between two frequently conflated domains: real-world clinical practice and clinical research. Practically, we describe the Guidelines for the Appropriate Use of APOE Genetic Testing in Dementia, established in 2025 and revised in 2026 following national health insurance approval, which position APOE testing as a pharmacogenetic tool governing monitoring intensity rather than treatment eligibility. We consider what the lower ε4 allele frequency in Japan implies, now that per-genotype effect estimates have been revised to values comparable to those in European-ancestry populations, and we set out the counseling required when a pharmacogenetic result carries risk information for untested relatives. On the research side, we describe the Hereditary Dementia Trial Ready Cohort, a national registry spanning 21 causative genes, and explain why its scope diverges from that of autosomal dominant AD-focused international initiatives such as DIAN. We conclude that features of the Japanese experience are most likely to be transferred to other healthcare systems.},
}

@article {pmid42983214,
year = {2026},
author = {Vidal-Palencia, L and González-Parra, JA and Ramon-Duaso, C and Busquets-Garcia, A},
title = {Sex-Dependent Effects of Chronic Cannabinoid Treatment on Repetitive Behaviors and Amyloid Burden in APP/PS1 Mice.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X486537260911115437},
pmid = {42983214},
issn = {1875-6190},
abstract = {INTRODUCTION/OBJECTIVE: The endocannabinoid system has been linked to the pathophysiology of Alzheimer's Disease (AD), which is accompanied by both neuropathological and behavioral alterations. However, the contribution of this system to these specific processes remains incompletely understood. Here, we investigated the effects of ACEA, a selective agonist of type-1 cannabinoid receptors (CB1R), on repetitive behaviors and amyloid load in the APP/PS1 mouse model of AD.

METHODS: ACEA for 21 days at 3 months of age, a presymptomatic stage, was administered in male and female APP/PS1 mice and evaluated using non-cognitive behavioral tasks, amyloid load, and CB1R expression.

RESULTS: By using two complementary behavioral paradigms, the splash test and the marble-burying test, we assessed the impact of cannabinoid treatment on male and female mice, revealing sex-dependent differences in repetitive behaviors. Molecular analyses further demonstrated that ACEA also modulates amyloid burden and CB1R expression, considering brain-region- and sex-specific parameters. Additionally, the study characterized distinct amyloid plaque types, offering new insights into the relationship between cannabinoid signaling and AD neuropathology.

DISCUSSION: The present findings demonstrate that cannabinoid-based interventions can influence both behavioral outcomes and molecular alterations associated with AD. Importantly, the observed effects appear to depend on biological sex and specific brain regions, emphasizing the need to consider these variables when designing cannabinoid-based therapeutic strategies for AD.

CONCLUSION: Collectively, the study's findings highlight a modulatory role of cannabinoid drugs in both behavioral and molecular aspects of AD, supporting their potential relevance as therapeutic targets tailored to sex and brain region.},
}

@article {pmid42983220,
year = {2026},
author = {Kalidas, N and Panerai, RB and Beishon, L},
title = {Directional Sensitivity of Dynamic Cerebral Autoregulation in Alzheimer's Disease and Mild Cognitive Impairment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050490972261015102304},
pmid = {42983220},
issn = {1875-5828},
abstract = {INTRODUCTION: Directional sensitivity of dynamic cerebral autoregulation refers to greater efficiency in counteracting increases in mean arterial pressure than decreases in it, thereby protecting the brain against hypertensive surges. Directional sensitivity may be affected in Alzheimer's disease and mild cognitive impairment.

METHODS: This retrospective study analysed data from healthy controls (n=30) and individuals with Alzheimer's disease (n=35) and mild cognitive impairment (n=22). Continuous cerebral blood velocity (CBv) and beat-to-beat mean arterial pressure were recorded during 5 minutes of rest. CBv responses to spontaneous mean arterial increases (MAP+D) and decreases (MAP-D) were assessed over 15 s (T1: 0-5s, T2: 5-10s, T3: 10-15s). The primary outcome explored directional sensitivity strength, quantified as the difference in CBv responses (ΔT1, ΔT2, ΔT3) and autoregulatory index (ΔARI) between MAP+D and MAP-D. The secondary outcome examined the separate autoregulatory response during positive and negative MAP derivatives.

RESULTS: Diagnosis was not significantly associated with any of the primary DSCA strength measures. However, diagnosis was significantly associated with ARI during MAP+D (p=0.030). Healthy controls showed significantly higher autoregulatory efficiency in response to MAP+D compared to individuals with mild cognitive impairment (p=0.003).

DISCUSSION: Although DSCA strength did not differ between diagnostic groups, individuals with early cognitive impairment showed alterations in autoregulatory efficiency during spontaneous BP rises that might reflect selective impairment of myogenic (vasoconstrictive) dCA pathways.

CONCLUSION: These findings suggest altered dynamic cerebral autoregulatory efficiency in response to increases in mean arterial pressure in mild cognitive impairment, despite preserved directional sensitivity strength.},
}

@article {pmid42983236,
year = {2026},
author = {Verma, AK and Singh, R},
title = {Neuroinflammatory Biomarkers in Neurodegenerative Disease Diagnosis and Progression.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026491877261022114319},
pmid = {42983236},
issn = {1875-5739},
abstract = {Neuroinflammatory markers are now key tools for diagnosing and monitoring neurodegenerative diseases. These biomarkers are associated with the activation of the immune system in the central nervous system, which is associated with the disease process. This review highlights some selected aspects of the neuroinflammatory markers, cytokines, chemokines, and markers of glial activation, and their role in diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Recent innovations in molecular and imaging technology have led to better identification and measurement of neuroinflammatory biomarkers in CSF, blood, and brain tissue. These approaches allow noninvasive monitoring and assist in the integration of biomarker profiles coupled with clinical evaluation for better diagnostic accuracy and patient stratification. Fluctuations in neuroinflammatory markers are associated with disease activity and cognitive impairment, which suggest these markers as potential early diagnostic and prognostic indicators. Using a biomarker profile in addition to clinical information helps better distinguish among neurodegenerative disorders and monitor therapeutic outcomes. Although promising, challenges remain in standardising biomarker measurement and interpreting biomarker specificity, given overlapping inflammatory pathways between diseases. There is ongoing research to confirm biomarker panels that can reliably differentiate between neurodegenerative disorders and track treatment effects. Decoding the multifaceted crosstalk between neuroinflammation and neurodegeneration is essential for developing targeted therapies that modulate immune processes and slow disease progression. Neuroinflammatory biomarkers are useful diagnostic and prognostic tools that can aid in the clinical management and the development of new treatment strategies in neurodegenerative disorders.},
}

@article {pmid42983238,
year = {2026},
author = {An, X and Cao, M and Yi, Z and Wang, Y and Yu, W and Ren, Z},
title = {Multi-Omics Machine Learning Framework Identifies CAPS, NUBPL, and RRBP1 as Hubs Linking Neuroinflammation and Mitophagy in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050516863261020114159},
pmid = {42983238},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and the accumulation of amyloid-beta plaques and hyperphosphorylated tau protein. The role of mitophagy in AD pathogenesis is not well understood. This study explores how mitophagy-related genes affect AD progression through transcriptomic analysis, machine learning, and immune profiling.

MATERIALS AND METHODS: Post-mortem transcriptomic data from the middle temporal gyrus (training dataset GSE132903, 97 AD cases and 98 controls) were analyzed. A total of 552 Differentially Expressed genes (DEGs) were identified using stringent criteria (unadjusted p-value < 0.05, |log2FC| > 0.5). Weighted Gene Co-expression Network Analysis (WGCNA) was performed to identify gene modules associated with mitophagy.

RESULTS: Three diagnostic biomarkers were identified and validated using LASSO, Random Forest, and XGBoost: CAPS (AUC = 0.83), NUBPL (AUC = 0.756), and RRBP1 (AUC = 0.78). CIBERSORT analysis revealed a distinct neuroinflammatory profile in AD, characterized by M1 macrophage polarization and CD4+ T cell depletion. Gene Set Enrichment Analysis (GSEA) showed that these biomarkers were associated with metabolic pathways, suggesting a role for metabolicepigenetic interactions in AD progression.

DISCUSSION: The integration of differential expression analysis, WGCNA, and three machine learning algorithms consistently identified CAPS, NUBPL, and RRBP1 as robust diagnostic candidates, which were independently validated in an external cohort. These findings suggest that mitophagyrelated genes may contribute to AD through mechanisms involving neuroinflammation and metabolic pathways. Nevertheless, the generalizability of these biomarkers across demographics necessitates validation in larger, more diverse cohorts.

CONCLUSION: Our findings indicate that these mitophagy-related genes may serve as biomarkers for AD. A nomogram model incorporating these biomarkers showed promising diagnostic performance (training AUC = 0.834; validation with GSE29378: AUC = 0.716). In summary, our research suggests that mitophagy-related genes play a role in AD through immune and metabolic pathways. Understanding these mechanisms could lead to new approaches for the diagnosis and treatment of AD.},
}

@article {pmid42983254,
year = {2026},
author = {Du, L and Liu, T},
title = {Dementia Risk Across Profiles of Subjective Memory Complaints and Slow Gait: Disentangling Cognitive and Motor Contributions.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050523575261016074856},
pmid = {42983254},
issn = {1875-5828},
abstract = {INTRODUCTION: This study aimed to examine incident dementia and/or Alzheimer's Disease (AD) risk across profiles defined by Subjective Memory Complaints (SMC) and slow gait, and to further assess the component-specific contributions of these two markers.

METHODS: Data were retrieved from two national cohorts: the English Longitudinal Study of Ageing (ELSA) and the Health and Retirement Study (HRS). Participants were classified into four profiles: normal, SMC only, slow gait only, and Motoric Cognitive Risk syndrome (MCR), defined as the coexistence of SMC and slow gait. Cox models were used to assess profile-based associations with incident dementia and/or AD. Component-based models further examined SMC presence and slow gait presence in separate and mutually adjusted Cox models, with interaction assessed on both multiplicative and HR-based additive scales. Kaplan-Meier curves, Restricted Cubic Splines (RCS), subgroup analyses, and sensitivity analyses were used to evaluate survival patterns, dose-response associations, heterogeneity, and robustness.

RESULTS: In fully adjusted profile-based models, MCR showed the highest hazard in both cohorts. SMC only was associated with increased risk in ELSA (HR = 2.21, 95% CI: 1.65-2.97) and HRS (HR = 1.89, 95% CI: 1.45-2.46), whereas slow gait only was associated with increased risk in HRS but not in ELSA. Component-based analyses showed that SMC presence remained associated with increased risk after mutual adjustment in both cohorts, whereas the association for slow gait presence was less consistent across cohorts. Neither the multiplicative nor the HR-based additive interaction analyses provided clear evidence of interaction between SMC and slow gait.

DISCUSSION: The risk signal captured by MCR appeared heterogeneous rather than uniform. SMC showed a more consistent association than slow gait, supporting a component-informed interpretation of dementia risk.

CONCLUSION: SMC and slow gait showed different patterns of association with subsequent dementia and/or AD, with more consistent evidence for SMC. Their incremental predictive value and clinical utility require further validation in dedicated prospective prediction studies.},
}

@article {pmid42983255,
year = {2026},
author = {Wilczyński, K},
title = {AI-Assisted Cross-Dataset Prioritization of Circulating microRNA Candidates for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050513173261019105444},
pmid = {42983255},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Reproducibility of circulating microRNA biomarkers in Alzheimer's disease remains limited because public studies vary across platforms, biofluids, cohort structures, and analytical methods. Direct cross-platform pooling can create apparent agreement while obscuring biological and pre-analytical heterogeneity. To develop a transparent, conservative workflow for prioritizing circulating microRNA candidates for Alzheimer's disease across public datasets without raw cross-platform pooling.

MATERIALS AND METHODS: AIM-AD used HMDD v4.0 as an Alzheimer's-focused candidate layer and evaluated retained candidates across two plasma AD-versus-control GEO datasets: GSE305625 (targeted qPCR; 71 AD, 74 controls) and GSE215789 (small RNA sequencing; 23 AD, 21 controls). GSE120584 serum AD-versus-control data (microarray; 1021 AD, 288 controls) were used only as contextual serum evidence. Direction, within-dataset support, serum status, and cautionary modifiers were integrated through documented rule-based prioritization.

RESULTS: Of 50 harmonized plasma-overlap candidates, 34 (68.0%) had concordant plasma directions: 29 were lower in AD, and 5 were higher in AD; 16 were discordant. Rule-based prioritization retained 0 candidates in Priority 1, 18 in Priority 2, 1 in Watchlist, and 31 in Deprioritize. Fourteen candidates had q ≤ 0.10 in GSE305625; none reached raw p ≤ 0.10 or q ≤ 0.10 in GSE215789. The output is therefore a hypothesis-generating shortlist, not independent validation.

DISCUSSION: The prioritization framework deliberately treats AIM-AD as a pre-validation shortlisting workflow rather than a diagnostic classifier, emphasizing cross-dataset plasma-direction concordance, source-aware interpretation, and conservative handling of biofluid and platform heterogeneity.

CONCLUSION: A transparent AI-assisted workflow can document harmonization, execute authordefined rules, and prioritize a heterogeneous public microRNA evidence set. The resulting shortlist is hypothesis-generating and requires independent tissue- and cell-level validation, as well as prospective clinical validation.},
}

@article {pmid42983265,
year = {2026},
author = {Zou, Y and Gong, C and Pan, C},
title = {Neuroprotective Effects of Natural Products: Innovative Therapeutic Strategies for Preventing the Progression of Neurodegenerative Diseases.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575538032261020064508},
pmid = {42983265},
issn = {1875-5607},
abstract = {Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are serious conditions characterized by progressive neuronal degeneration, which leads to cognitive decline, motor dysfunction, and other neurological problems, severely impairing daily activities and quality of life. These diseases involve multiple biological pathways, including oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein folding. Given the multifactorial nature of neurodegenerative diseases, neuroprotective approaches targeting multiple mechanisms hold great promise for prevention and treatment. Natural products derived from plants, microorganisms, and marine organisms are renowned for their excellent antioxidant and anti-inflammatory activities and show great potential in preventing neurodegenerative diseases. Unlike synthetic compounds, these naturally sourced bioactive compounds offer a variety of therapeutic targets due to their diverse structures and biological activities. This review provides a systematic overview of 125 newly identified neuroprotective natural products derived from plants, microorganisms, and marine organisms in 2025, with a comprehensive summary of their origins, chemical architectures, and biological activities. These collected natural products are categorized into seven classes based on their structural features: terpenoids (42.4%, 53/125), alkaloids (19.2%, 24/125), glycosides (10.4%, 13/125), lignans (9.6%, 12/125), phenols (6.4%, 8/125), flavonoids (6.4%, 8/125), and other miscellaneous compounds (5.6%, 7/125). Accumulating evidence indicates that natural products hold great promising potential for preventing and slowing the progression of neurodegenerative disorders.},
}

@article {pmid42983391,
year = {2026},
author = {Liu, X and Liu, D and Gao, Y and Yan, S and Liu, H and Yang, X},
title = {Effects of the extract of Ginkgo biloba L. on inflammatory response and mitochondrial dynamics in microglia in Alzheimer's disease.},
journal = {BMC complementary medicine and therapies},
volume = {26},
number = {1},
pages = {},
pmid = {42983391},
issn = {2662-7671},
support = {82204826//The National Natural Science Foundation of China (NSFC)/ ; 82174184//The National Natural Science Foundation of China (NSFC)/ ; BJZYQN-2023-18//Beijing Traditional Chinese Medicine Science and Technology Development Fund Project/ ; },
mesh = {*Ginkgo biloba ; *Mitochondrial Dynamics/drug effects ; *Alzheimer Disease/drug therapy ; Animals ; *Plant Extracts/pharmacology ; *Microglia/drug effects ; Mice ; Ginkgo Extract ; Amyloid beta-Peptides ; Oxidative Stress/drug effects ; Inflammation/drug therapy ; Cell Line ; Mitochondria/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that lacks disease-modifying therapies. This study investigated the effects of Extract of Ginkgo biloba L. (EGb) on mitochondrial fission machinery and inflammatory responses in an Aβ1-42-stimulated BV2 microglial model.

METHODS: The chemical profile of EGb was qualitatively analyzed using HPLC-MS. BV2 microglial cells were exposed to Aβ1-42. Mitochondrial morphology was observed using high-resolution microscopy; DRP1-MFF and DRP1-FIS1 associations were assessed by co-immunoprecipitation (Co-IP); dynamin-related protein 1 (DRP1), mitochondrial fission 1 protein (FIS1) and mitochondrial fission factor (MFF) were evaluated using image-based phenotypic metrics and Western blotting; interleukin-1 beta (IL-1β) levels were measured by ELISA; p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) were assessed via high-content screening; mitochondrial membrane potential (ΔΨm), oxidative stress and apoptosis-associated changes were detected by fluorescence and spectrophotometry.

RESULTS: Fifty-eight compounds, including ginkgolides, flavonoids and phenolic acids, were tentatively identified. EGb alleviated Aβ1-42-induced mitochondrial structural abnormalities, increased MFF expression, and decreased DRP1 and FIS1 expression. Co-IP analysis indicated the association of DRP1 with MFF and FIS1. EGb also reduced IL-1β release and altered the expression levels of p38, JNK, and ERK, while mitigating ΔΨm loss, alleviating oxidative stress-related changes, and partially reducing apoptosis-associated TUNEL staining.

CONCLUSIONS: EGb attenuated Aβ1-42-induced injury and modulated mitochondrial fission-related changes in BV2 microglial cells, suggesting a cellular-level protective effect in AD-related microglial dysfunction.},
}

*Ginkgo biloba
*Mitochondrial Dynamics/drug effects
*Alzheimer Disease/drug therapy
Animals
*Plant Extracts/pharmacology
*Microglia/drug effects
Mice
Ginkgo Extract
Amyloid beta-Peptides
Oxidative Stress/drug effects
Inflammation/drug therapy
Cell Line
Mitochondria/drug effects

@article {pmid42983435,
year = {2026},
author = {Dubey, AR and Kumar, S and Singh, R},
title = {Lysosomal alkalinization: a convergent mechanism in lysosomal storage disorders and classical neurodegenerative diseases.},
journal = {Cell communication and signaling : CCS},
volume = {24},
number = {1},
pages = {},
pmid = {42983435},
issn = {1478-811X},
mesh = {*Lysosomes/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Lysosomal Storage Diseases/metabolism/pathology ; Hydrogen-Ion Concentration ; Animals ; },
abstract = {Lysosomes are important cellular organelles involved in the recycling of biomolecules in the cell. The acidic intraluminal pH of the lysosome is necessary for the functioning of various hydrolytic enzymes involved in the recycling of biomolecules. Elevated lysosomal pH has been consistently documented in pathological conditions associated with progressive neurodegeneration, including several classical neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease) and lysosomal storage disorders or LSDs (e.g., Gaucher disease, CLN3 disease). This review focuses on the molecular mechanisms of lysosomal pH regulation, describing the critical roles of vacuolar ATPases and ion channels in maintaining lysosomal pH homeostasis. Further, we highlight how defective acidification of the lysosome can promote common cellular defects linked with both classical neurodegeneration and LSDs. The review also draws a parallel between the pathological consequences of experimentally-induced lysosomal alkalinization and two complex classes of disorders: classical neurodegeneration and LSDs. This comparison raises the possibility that lysosomal pH is one of the multiple shared contributing mechanisms for both conditions and, therefore, a conceivable therapeutic target of classical neurodegeneration and LSDs.},
}

*Lysosomes/metabolism
Humans
*Neurodegenerative Diseases/metabolism/pathology
*Lysosomal Storage Diseases/metabolism/pathology
Hydrogen-Ion Concentration
Animals

@article {pmid42983447,
year = {2026},
author = {Cheng, J and Zhang, C and He, Y and Lan, X and Zheng, Y and Han, J and Li, J and Zhao, Y and Zhang, B and Feng, S and Cheng, F and Wang, Q and Li, C and Wang, X},
title = {Regulatory cell death of microglia in common cerebrovascular diseases: mechanism, heterogeneity and therapeutic significance.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42983447},
issn = {1479-5876},
mesh = {Humans ; *Microglia/pathology ; *Cell Death ; Animals ; *Cerebrovascular Disorders/pathology/therapy ; Inflammation/pathology ; },
abstract = {Cognitive impairment encompasses a range of clinical syndromes resulting from various brain disorders. Among these, Alzheimer's disease and related dementias, Parkinson's disease, and stroke represent the most prevalent and significant cerebrovascular conditions that impact cognitive function and lead to neurodegenerative damage. Microglia, serving as the principal immune regulators within brain tissue, exhibit diverse phenotypes, including M1 and M2, in response to inflammatory environments, thereby collectively contributing to the restoration of homeostasis. However, under sustained stimulation, microglia undergo cell death and release inflammatory factors through different mechanisms of cell death, thereby influencing the prognosis of cerebrovascular diseases. Although there is a growing recognition of the regulatory role of microglial phenotypic transformation in the progression of cerebrovascular diseases, research remains insufficient regarding the developmental processes of these diseases following the death of microglial cells with varying phenotypes. This article centres on cerebrovascular disease-induced cognitive impairment as its primary focus. It provides a comprehensive review of common acute cerebrovascular diseases, such as ischemic stroke, alongside neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, and vascular dementia. The discussion extends to the common phenotypes of microglia and their impact on cerebrovascular diseases. Additionally, the article explores how inflammatory cell death mechanisms of microglia, namely necroptosis, pyroptosis, ferroptosis, and autophagy, regulate disease progression, thereby providing insights for future research on the role of microglia in cerebrovascular pathology.},
}

Humans
*Microglia/pathology
*Cell Death
Animals
*Cerebrovascular Disorders/pathology/therapy
Inflammation/pathology

@article {pmid42983581,
year = {2026},
author = {Shi, X and Kong, H and Chen, W and Lin, L and Yuan, K and Su, F and Wang, Y and Zhang, Y and Zhou, J and Zhou, X and Ashford, CB and Li, F and Ashford, JW and Bergeron, MF and Pei, Z and Zheng, Y and Xian, W},
title = {MemTrax as a scalable digital triage tool for mild cognitive impairment screening: primary validation in Alzheimer's disease and exploratory analysis in Parkinson's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42983581},
issn = {1758-9193},
support = {(No. 2022YFA1104904)//National Key Research and Development Program of China/ ; No. 82271266//the National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; Male ; *Alzheimer Disease/diagnosis/psychology ; Aged ; *Parkinson Disease/diagnosis/complications/psychology ; Female ; Cross-Sectional Studies ; *Neuropsychological Tests ; Mental Status and Dementia Tests ; *Triage/methods ; Middle Aged ; ROC Curve ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) pose escalating global health challenges, with early detection of mild cognitive impairment (MCI) being critical for timely intervention. The 2023 Delphi consensus highlights the need for scalable tools suitable for primary care. This study aimed to validate the MemTrax as a rapid memory-focused triage tool against consensus-recommended cognitive assessments, including the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), for detecting MCI due to Alzheimer's disease (AD-MCI) as the primary objective, and to explore its performance in MCI due to Parkinson's disease (PD-MCI) as an exploratory aim, evaluating its utility as a rapid, accessible digital tool.

METHODS: We conducted a cross-sectional study enrolling 222 participants: 74 with AD-MCI, 73 healthy controls (HCs; primary cohort); 42 PD patients with normal cognition (PD-NC), 33 with PD-MCI (exploratory cohort). All participants underwent MMSE, MoCA and MemTrax testing. Diagnostic accuracy, optimal cut‑offs, and correlations between MemTrax parameters (percent correct [MTx‑%C], reaction time [MTx‑RT], composite score [MTx‑Cp]) and standard cognitive measures were evaluated.

RESULTS: In the primary AD cohort, MTx-%C showed an area under the curve (AUC) of 0.876 (95% CI: 0.813-0.926) for discriminating AD-MCI from HCs, comparable to MoCA (AUC = 0.879) and MMSE (AUC = 0.916). At a cut-off of ≤ 80%, MTx-%C achieved a sensitivity of 70.3% and specificity of 90.4%. In the exploratory PD cohort, MTx-%C (AUC = 0.808) showed similar discrimination to MMSE (AUC = 0.694) in differentiating PD-MCI from PD-NC (DeLong's test, p = 0.142). Multivariate analysis of MTx-%C, MTx-RT, and MTx-Cp demonstrated significant separation between MCI and cognitively normal groups in both the AD and PD cohorts. MTx-%C showed significant correlations with MMSE in AD (r = 0.709) and PD (r = 0.340), and with MoCA in AD (r = 0.601) and PD (r = 0.608). MemTrax metrics correlated significantly with distinct domain-level associations reflecting disease-specific cognitive profiles.

CONCLUSIONS: MemTrax demonstrates good diagnostic accuracy comparable to established cognitive screening tools for AD-MCI (primary cohort), supporting its use as a rapid, scalable, and culturally neutral digital memory-focused triage tool. Exploratory findings in PD-MCI are promising but require confirmatory studies. Its brevity and automation support practical implementation in primary care and community settings, potentially facilitating earlier detection and stratification of cognitive impairment.},
}

Humans
*Cognitive Dysfunction/diagnosis
Male
*Alzheimer Disease/diagnosis/psychology
Aged
*Parkinson Disease/diagnosis/complications/psychology
Female
Cross-Sectional Studies
*Neuropsychological Tests
Mental Status and Dementia Tests
*Triage/methods
Middle Aged
ROC Curve

@article {pmid42983584,
year = {2026},
author = {Xiong, M and Huang, Y and Jiang, H and Zhang, Z},
title = {Brain clearance of protein aggregates in degenerative diseases: the role of microglia and astrocytes.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42983584},
issn = {2047-9158},
support = {82501688//National Natural Science Foundation of China/ ; 82525025//National Natural Science Foundation of China/ ; 2025AFB243//Natural Science Foundation of Hubei Province/ ; },
mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Microglia/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Protein Aggregates/physiology ; *Protein Aggregation, Pathological/metabolism/pathology ; Phagocytosis/physiology ; Proteotoxic Stress ; },
abstract = {Protein aggregation and impaired clearance constitute central pathological hallmarks of numerous neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Misfolded proteins, both extracellular and intracellular, disrupt proteostasis and contribute to synaptic dysfunction, neuroinflammation, and neuronal loss. Within the central nervous system, glial cells serve as the primary mediators of pathological protein clearance. Microglia detect, phagocytose, and degrade aggregated proteins. However, under chronic pathological stress, microglial function turns from clearing pathological proteins to paradoxically facilitating their spread. Astrocytes, which provide metabolic and homeostatic support for neurons, also participate in the clearance of aggregates through phagocytosis and glymphatic drainage. Critically, crosstalk between astrocytes and microglia enhances the clearance: microglia can recruit and process aggregates internalized by astrocytes, while astrocyte-derived signals modulate the microglial phagocytic activity. Aging, genetic risk factors, or sustained neuroinflammation may reduce the efficiency of glial removal of aggregates and accelerate disease progression. Understanding the cellular and molecular underpinnings of microglial and astrocytic clearance pathways is essential for developing therapies aimed at restoring proteostasis and mitigating neurodegeneration.},
}

Humans
*Astrocytes/metabolism/pathology
*Microglia/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Protein Aggregates/physiology
*Protein Aggregation, Pathological/metabolism/pathology
Phagocytosis/physiology
Proteotoxic Stress

@article {pmid42983790,
year = {2026},
author = {Melville, M and Valacsay, D and Nissen, JF and Zokaei, N and Mainstone-Cotton, L and Spector, A},
title = {Post-diagnostic support for dementia in the UK: mapping access, delivery and gaps in provision.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {42983790},
issn = {1472-6963},
mesh = {Humans ; *Dementia/therapy/diagnosis ; United Kingdom ; *Health Services Accessibility ; Surveys and Questionnaires ; *Cognitive Behavioral Therapy ; State Medicine ; },
abstract = {BACKGROUND: Dementia is a progressive condition affecting approximately 982,000 people in the UK, with substantial implications for people living with dementia, carers, and healthcare systems. Effective post-diagnostic support is essential for managing symptoms and maintaining quality of life, yet services remain inconsistent, fragmented, and highly variable across regions, particularly in rural and underserved areas. Cognitive Stimulation Therapy (CST) is the only non-pharmacological intervention recommended by the National Institute for Health and Care Excellence (NICE) to improve cognition, independence and wellbeing in people with dementia. However, a 2020 survey indicated substantial variation in its availability and delivery.

OBJECTIVES: To investigate the availability, delivery, and challenges of post-diagnostic support for dementia in the UK, with a particular emphasis on CST.

METHODS: An online survey with a mix of open and closed questions was conducted between August and December 2024 among healthcare professionals working in NHS Trusts, memory clinics, care-homes, non-profit organisations and dementia services across the UK. The questionnaire collected information on post-diagnostic dementia support, including the availability and delivery of CST, psychological support, staffing, service integration and perceived barriers to service provision. Quantitative data were summarised descriptively, and free-text responses were analysed using descriptive content analysis.

RESULTS: 129 responses were received from staff across 71 distinct services across the UK, including 45 of the 202 NHS Trusts and third-sector dementia organisations (e.g. the Alzheimer's Society). All available data, including partial responses, were included in the analysis. Respondents reported variation in the availability of post-diagnostic support across UK dementia services. 65.5% (55/84) reported that their organisation delivered CST. Of those, 58.5% (24/41) reported running only a single CST group programme at a time. Reported waiting times for post-diagnostic support varied widely, with a mean of 13.7 weeks and a range from 2 to 100 weeks. Overall, the findings highlight reported delays in access to post-diagnostic support, variation in the availability of CST, and persistent challenges related to staffing capacity and funding constraints.

CONCLUSION: These findings suggest substantial variation in the reported availability and delivery of post-diagnostic support across UK dementia services. There is an urgent need for increased funding, workforce expansion, and clearer national standards for post-diagnostic dementia care to ensure that people living with dementia can access timely, evidence-based support that helps them maintain independence, manage symptoms, and sustain quality of life following diagnosis.},
}

Humans
*Dementia/therapy/diagnosis
United Kingdom
*Health Services Accessibility
Surveys and Questionnaires
*Cognitive Behavioral Therapy
State Medicine

@article {pmid42983912,
year = {2026},
author = {Loveless, J and Pilcher, L and Bolton, CJ and Guan, DX and Imo, U and Ngubo, CGA and McAteer, MB and Urquhart, O and Rangarajan, SK and Kim, LS and Sako, K and Tang, B and Yakoub, Y and Machado, LS and Ko, F and Rentz, D and Pahlke, S and Mahinrad, S and Snyder, H and Tampi, MP},
title = {Evaluating the accuracy of brief cognitive assessments for the early detection of cognitive impairment in adults across primary and specialty care settings: A systematic review and meta-analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {42983912},
issn = {1552-5279},
support = {/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Primary Health Care ; *Cognitive Dysfunction/diagnosis ; Early Diagnosis ; *Neuropsychological Tests/standards ; Dementia/diagnosis ; *Mental Status and Dementia Tests ; },
abstract = {BACKGROUND: This systematic review and meta-analysis aimed to assess the accuracy of brief (i.e., ≤15 minutes), freely available cognitive tests for the early detection of cognitive impairment (including mild cognitive impairment and dementia) in adults 55 years and older in primary and specialty care.

METHODS: A systematic search of MEDLINE, Embase, and Cochrane Library databases was conducted to identify studies published between January 1999 and August 2024 that evaluated the accuracy of brief, freely available cognitive tests for early detection of cognitive impairment. The tests included 5-Cog, Eight-item Informant Interview to Differentiate Aging and Dementia (AD8), General Practitioner assessment of Cognition (GPCOG), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Mini-Cog, Memory Impairment Screen (MIS), Montreal Cognitive Assessment (MoCA), Quick Dementia Rating System (QDRS), Rowland Universal Dementia Assessment Scale (RUDAS), and Saint Louis University Mental Status (SLUMS). Though widely used, the Mini-Mental State Examination did not meet eligibility criteria and was not considered. Accuracy measures were extracted from eligible studies and pooled where possible. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2, and certainty of evidence was assigned according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

RESULTS: Forty-seven studies evaluating 10 index tests, including short versions of IQCODE and MoCA, were included. Test accuracy varied widely among tests and data pooling was not possible for most analyses. Studies conducted in both primary and specialty care were identified for AD8, Mini-Cog, MIS, MoCA, QDRS, Short IQCODE, and SLUMS, while evidence for IQCODE, short MoCA, and RUDAS was limited to a single setting. No studies meeting eligibility criteria were found for 5-Cog and GPCOG. Across all tests, in primary care, sensitivity ranged from 0.17 to 0.98, and specificity ranged from 0.10 to 0.98. Across all tests and assuming the same prevalence in specialty care, sensitivity ranged from 0.73 to 0.97, and specificity ranged from 0.45 to 0.90.

CONCLUSION: This systematic review provides a synthesis of the evidence on the accuracy of brief, freely available cognitive assessment tools for the early detection of cognitive impairment in primary and specialty care. Results from primary care settings informed the development of evidence-based recommendations presented in the accompanying clinical practice guideline on the use of brief cognitive tests in primary care.},
}

Humans
Primary Health Care
*Cognitive Dysfunction/diagnosis
Early Diagnosis
*Neuropsychological Tests/standards
Dementia/diagnosis
*Mental Status and Dementia Tests

@article {pmid42983921,
year = {2026},
author = {Uludag, K},
title = {Designing Memory into the Medicine Box: A Call for Smarter Adherence Tools in Alzheimer's Care.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050485058261023050143},
pmid = {42983921},
issn = {1875-5828},
abstract = {Medication non-adherence is common among people with Alzheimer's disease (AD). In the study, it is argued that the pill container should be redesigned as a cognitive-support device rather than a passive holder for medication, and the cognitive, equity, and implementation considerations that this position raises are outlined. The study proposes matching tool complexity to disease stage and an individual's broader cognitive profile may support adherence: connected reminder devices where executive, sensory, and technological capacities allow, and simpler, high-cue designs where these capacities are more limited. The study emphasizes that personalization should apply to the medication-management interface. We conclude that redesigning the medicine box as an active therapeutic interface is a plausible, low-risk complement to pharmacological care that warrants comparative evaluation.},
}

@article {pmid42983922,
year = {2026},
author = {Chen, C and Bhargava, V and Su, Y and Reiman, E and Chen, K},
title = {Reassessing the Amyloid-Neurodegeneration Relationship: Integrating Demographic and Amyloid PET Measures to Estimate AD-Related Glucose Hypometabolism.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050521219261021073341},
pmid = {42983922},
issn = {1875-5828},
abstract = {INTRODUCTION: The relationship between amyloid deposition and neurodegeneration in Alzheimer's Disease (AD) remains incompletely understood. Previous studies have indicated that using a cerebral white matter reference region for amyloid PET Standardized Uptake Value Ratio (SUVR) calculation strengthens the association compared with the commonly used cerebellar reference region. This study examined whether amyloid PET measures, when integrated with demographic information, can further enhance the estimate of the AD-related glucose hypometabolism, measured by the FDG-PET Hypometabolic Convergence Index (HCI), and whether this relationship is stronger when amyloid burden is quantified using a cerebral white matter reference region rather than a cerebellar reference region.

MATERIALS AND METHODS: Baseline ADNI data from 1,133 participants, including cognitively unimpaired individuals, participants with mild cognitive impairment, and patients with AD, were analyzed. HCI was used as the outcome measure of AD-related glucose hypometabolism. Predictors included age, sex, education, and amyloid PET mean cortical SUVR calculated using either a cerebellar reference region (mcSUVRcb), a cerebral white matter reference region (mcSUVRwm), or both. Six modeling approaches, partial least squares, regression tree, elastic net, k-nearest neighbors, random forest, and support vector machine, were evaluated using training and independent testing datasets. Model performance was evaluated on independent testing data using complementary measures of estimation accuracy and explained variance.

RESULTS: Across the full cohort and within diagnostic subgroups, adding amyloid PET measures to demographic variables improved estimation of HCI. Models including mcSUVRwm consistently estimated HCI more accurately and explained more variance than corresponding models including mcSUVRcb alone. Models including both amyloid PET measures achieved the best or near-best performance, suggesting that cerebellar- and white-matter-referenced SUVRs may contain complementary information.

DISCUSSION: Because the analyses were cross-sectional and did not include tau PET, these findings should be interpreted as association-based estimation rather than evidence for a direct amyloidmediated neurodegenerative pathway.

CONCLUSION: Amyloid PET improves cross-sectional estimation of AD-related glucose hypometabolism beyond demographic covariates, particularly when amyloid burden is quantified using a cerebral white matter reference region.},
}

@article {pmid42983936,
year = {2026},
author = {Mehra, A and Mittal, A},
title = {Phytochemicals in Alzheimer's disease: Mechanistic Insights, Targets, and Future Directions.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575501602261023054129},
pmid = {42983936},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment, cognitive decline, and behavioral alterations. It is the most common form of dementia among older adults and represents a major global health, social, and economic burden. Current pharmacological interventions primarily provide symptomatic relief and have limited efficacy in preventing or reversing the underlying disease pathology, highlighting the need for alternative and innovative therapeutic approaches. Natural compounds with neuroprotective properties have demonstrated considerable potential for targeting multiple pathological mechanisms associated with AD. Phytochemicals, including polyphenols, alkaloids, terpenoids, flavonoids, and other bioactive constituents widely found in fruits, vegetables, herbs, and medicinal plants, exhibit diverse and complementary mechanisms of action. These include inhibition of acetylcholinesterase (AChE), suppression of amyloid-β aggregation, antioxidant and anti-inflammatory activities, and modulation of key signaling pathways involved in neuronal survival and synaptic plasticity. Ginsenosides derived from ginseng, resveratrol from grapes, curcumin from turmeric, and epigallocatechin gallate (EGCG) from green tea are among the most extensively studied phytochemicals and have demonstrated promising neuroprotective effects in numerous preclinical models. These compounds may exert multitarget effects against several pathological hallmarks of AD, offering potential advantages over conventional pharmacological approaches that primarily target individual disease mechanisms. This review provides a comprehensive overview of the therapeutic potential and mechanisms of action of major phytochemicals, with particular emphasis on their prospective applications in the development of novel therapeutic agents and evidence-based preventive strategies for AD.},
}

@article {pmid42984124,
year = {2026},
author = {Ding, L and Yu, W and Chen, Y and Wang, H and Li, S and Li, H and Shu, T and Huang, X and Yang, Y and Liu, R and Liu, X and Ai, Z and Guo, X and Chen, J and Qu, Q},
title = {Intrathecal Transplantation of Human Umbilical Cord-Derived MSCs Outperforms Intravenous Administration in Attenuating Pathology and Cognitive Deficits in Alzheimer's Disease Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {11},
pages = {},
pmid = {42984124},
issn = {1755-5949},
support = {ZY2019M047//the Health Commission of Hubei Province Scientific Research Project/ ; 2020K52//the Science and Technology Research and Development Project Plan of Shiyan City/ ; GXB2023004//the Stem Cell Research Fund of Taihe Hospital/ ; ZY2023Q049//the Health Commission of Hubei Province Traditional Chinese Medicine Research Project for Youths/ ; 2023AFB336//Natural Science Foundation of Hubei Province/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/therapy/genetics ; Humans ; *Mesenchymal Stem Cell Transplantation/methods ; Mice, Transgenic ; Mice ; Injections, Spinal ; Disease Models, Animal ; Umbilical Cord/cytology ; Administration, Intravenous ; Maze Learning/physiology ; *Cognitive Dysfunction/therapy/pathology ; Mesenchymal Stem Cells ; Male ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {BACKGROUND: Mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for Alzheimer's disease (AD), owing to their neuroprotective, anti-inflammatory, and immunomodulatory properties. However, the optimal delivery route for maximizing therapeutic efficacy within the central nervous system remains unclear. This study aimed to directly compare the therapeutic effects of intravenous versus intrathecal transplantation of human umbilical cord-derived mesenchymal stem cells (HUCMSCs) in a transgenic AD mouse model (5xFAD).

METHODS: HUCMSCs were isolated, characterized, and administered to 5xFAD mice via intravenous or intrathecal routes. Cognitive function was assessed using the Morris water maze. Amyloid plaque burden, microglial activation, microglial barrier integrity, and axonal dystrophy were evaluated through immunofluorescence and confocal microscopy. The expression of TREM2, DAP12, and Syk was analyzed to elucidate underlying molecular mechanisms.

RESULTS: Intrathecal transplantation of HUCMSCs significantly improved spatial learning and memory in 5xFAD mice compared to intravenous delivery. HUCMSC treatment substantially reduced amyloid plaque burden and axonal dystrophy, while promoting microglial activation and enhancing the protective function of the microglial barrier. Additionally, HUCMSC administration upregulated TREM2, DAP12, and Syk expression, with intrathecal delivery inducing more robust activation of these microglial signaling pathways than intravenous infusion.

CONCLUSIONS: HUCMSC transplantation alleviates cognitive deficits and modulates key pathological and molecular features of AD in the 5xFAD mouse model, with intrathecal administration demonstrating superior therapeutic efficacy compared to intravenous delivery. These findings underscore the critical importance of optimizing cell delivery routes to enhance the clinical potential of stem cell-based interventions for AD.},
}

Animals
*Alzheimer Disease/pathology/therapy/genetics
Humans
*Mesenchymal Stem Cell Transplantation/methods
Mice, Transgenic
Mice
Injections, Spinal
Disease Models, Animal
Umbilical Cord/cytology
Administration, Intravenous
Maze Learning/physiology
*Cognitive Dysfunction/therapy/pathology
Mesenchymal Stem Cells
Male
Amyloid beta-Protein Precursor/genetics

@article {pmid42984186,
year = {2026},
author = {Jha, P and Saxena, S},
title = {Virtual screening and molecular docking of flavonoid compounds as BACE-1 inhibitors for Alzheimer's Disease: identification of Betagarin as a promising nutraceutical lead candidate.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/14786419.2026.2754300},
pmid = {42984186},
issn = {1478-6427},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder accounting for 60-70% of dementia cases globally, with the β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) representing one of the most intensively studied therapeutic targets due to its rate-limiting role in amyloid-β (Aβ) peptide production. Despite decades of drug discovery efforts, no approved BACE-1 inhibitor has successfully demonstrated both efficacy and safety in large-scale clinical trials, largely owing to off-target toxicity and poor blood-brain barrier (BBB) permeability. This study presents a multi-tiered structure-based virtual screening of 1,870 flavonoid compounds against the catalytic domain of BACE-1 (PDB ID: 2ZJN) using AutoDock Vina. Ligand preparation was performed with Open Babel v3.1.1, and docking was executed within a 30 × 30 × 30 Å grid box centred on the catalytic aspartyl dyad (Asp32 and Asp228). Drug-likeness was evaluated using Lipinski's Rule of Five, and in silico toxicity was assessed via the OSIRIS Property Explorer across four risk categories. Betagarin, a natural flavonoid constituent of Beta vulgaris (beetroot), was selected as the primary lead candidate, demonstrating a binding affinity of -9.3 kcal/mol, zero Lipinski violations, a molecular weight of 328.316 Da, a LogP of 3.139, and uniformly low-risk toxicological predictions. These results collectively support Betagarin as a compelling nutraceutical-derived BACE-1 inhibitor with a favourable pharmacokinetic and safety profile. Future in vitro enzymatic assays and in vivo validation studies are warranted to confirm inhibitory efficacy and advance this compound towards preclinical development.},
}

@article {pmid42984363,
year = {2026},
author = {Traversa, G},
title = {[Alzheimer's Disease: When the evidence does not justify reimbursement for a drug].},
journal = {Epidemiologia e prevenzione},
volume = {50},
number = {4-5},
pages = {361-364},
doi = {10.19191/EP26.4-5.104},
pmid = {42984363},
issn = {1120-9763},
}

@article {pmid42984379,
year = {2026},
author = {Defrancesco, AD and Wang, B and Yi, C and Oliver, BG and Chen, H},
title = {Mechanistic understanding of the role of the lung-brain axis in the pathogenesis of PM2.5-induced Alzheimer's disease.},
journal = {Clinical science (London, England : 1979)},
volume = {140},
number = {11},
pages = {2611-2635},
doi = {10.1042/CS20262109},
pmid = {42984379},
issn = {1470-8736},
support = {//Australian Government Research Training Program scholarship/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/chemically induced/pathology/physiopathology/etiology ; *Particulate Matter/adverse effects/toxicity ; *Brain/metabolism/pathology/physiopathology/drug effects ; Animals ; *Lung/metabolism/physiopathology/drug effects/pathology ; *Air Pollutants/adverse effects ; Signal Transduction ; Environmental Exposure/adverse effects ; Oxidative Stress ; },
abstract = {Air pollution, particularly fine particulate matter (PM2.5), has emerged as an important yet under-recognised environmental contributor to cognitive decline and Alzheimer's disease (AD) across the life course. Although epidemiological studies consistently associate long-term PM2.5 exposure with impaired cognition, from reduced neurodevelopmental performance in children to accelerated neurodegeneration in older adults, the biological mechanisms linking inhaled particles to AD-related brain pathology remain incompletely defined. In the present review, we synthesise current epidemiological and experimental evidence to position the lung-brain axis as a central mechanistic framework through which PM2.5 may influence brain aging and AD pathogenesis. Rather than acting solely through direct particle entry into the brain, PM2.5-induced pulmonary injury initiates systemic signalling cascades, including inflammatory mediators, oxidative stress, blood-brain barrier disruption, and extracellular vesicle-mediated intercellular communication, which together propagate disease signals from the lung to the brain. We further examine how these pathways intersect with core AD-related processes, including amyloid-β accumulation, tau pathology, impaired protein clearance, maladaptive microglial responses, and autophagy-lysosomal dysfunction. We also discuss important modifiers of susceptibility and heterogeneity in reported associations, including pollutant composition, co-exposure to other air pollutants, sex, APOE genotype, and epigenetic reprogramming. Overall, the present review proposes an integrated multi-organ model of PM2.5 neurotoxicity that aligns environmental exposure with key mechanisms of AD pathogenesis and highlights priorities for strengthening causal inference and future translational research.},
}

Humans
*Alzheimer Disease/metabolism/chemically induced/pathology/physiopathology/etiology
*Particulate Matter/adverse effects/toxicity
*Brain/metabolism/pathology/physiopathology/drug effects
Animals
*Lung/metabolism/physiopathology/drug effects/pathology
*Air Pollutants/adverse effects
Signal Transduction
Environmental Exposure/adverse effects
Oxidative Stress

@article {pmid42984381,
year = {2026},
author = {Phanrang, PT and Upadhyaya, J and Chandra, AK and Mitra, S},
title = {Molecular Insights on the Reduction-Dependent Electronic Modulation of Graphene Oxide Surface Toward Reactivity and Acetylcholinesterase Inhibition of Alzheimer's Drugs.},
journal = {Chemphyschem : a European journal of chemical physics and physical chemistry},
volume = {27},
number = {21},
pages = {},
doi = {10.1002/cphc.70616},
pmid = {42984381},
issn = {1439-7641},
support = {CRS/2023-24/03/1211//UGC-DAE Consortium for Scientific Research, University Grants Commission/ ; 09/0347(24914)/2025-EMR-I//Council of Scientific and Industrial Research, India/ ; },
mesh = {*Graphite/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology ; *Acetylcholinesterase/metabolism/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Molecular Dynamics Simulation ; Surface Properties ; Oxidation-Reduction ; *Alkaloids/chemistry/pharmacology ; *Sesquiterpenes/chemistry/pharmacology ; *Tacrine/chemistry/pharmacology ; Humans ; },
abstract = {Assessing the chemistry of drug molecules at nanointerfaces offers opportunities for designing advanced therapeutic materials. The systematic reduction of oxygen-containing functional groups on graphene oxide (GO) surface from 49% to 19% significantly enhances acetylcholinesterase (AChE) inhibition activity of Alzheimer's disease drugs, huperzine A (HUP) and tacrine (TAC) by 10.44% and 27.87%, respectively. Molecular dynamics simulations combined with protein tunnel analysis reveal that shrinking of "bottleneck radius" in the AChE active site gorge due to adsorption on reduced GO surface promotes enhanced AChE inhibition. Additionally, significant increase in antioxidant activity of HUP and TAC (6.94% and 8.81%, respectively). The results are also consistent for the benchmark phenolic and nonphenolic model antioxidant systems represented by gallic acid and α-terpinene, respectively. Notably, highly reduced GO induces a SOMO-HOMO inversion, indicating an extensive electronic reorganization at the interface that leads to the stability of surface-bound radical species. These results establish a direct correlation between the extent of GO surface reduction, electronic structure, and molecular reactivity, providing a mechanistic framework for tuning nano-bio interactions. Looking from the broader perspective, this work offers a rational basis for the design of multifunctional GO-based nanomaterials for applications in catalysis, radical chemistry, and neurotherapeutics.},
}

*Graphite/chemistry/pharmacology
*Cholinesterase Inhibitors/chemistry/pharmacology
*Acetylcholinesterase/metabolism/chemistry
*Alzheimer Disease/drug therapy/metabolism
Molecular Dynamics Simulation
Surface Properties
Oxidation-Reduction
*Alkaloids/chemistry/pharmacology
*Sesquiterpenes/chemistry/pharmacology
*Tacrine/chemistry/pharmacology
Humans

@article {pmid42984463,
year = {2026},
author = {Huang, S and Lv, Q and Chen, L and Zhou, C and Liao, Y and Pan, R},
title = {Systems Pharmacology and Molecular Docking-Based Investigation of the Molecular Mechanism of Astilbin in the Treatment of Alzheimer's Disease.},
journal = {Biomedical chromatography : BMC},
volume = {40},
number = {12},
pages = {},
doi = {10.1002/bmc.70655},
pmid = {42984463},
issn = {1099-0801},
support = {S202310412007//Jiangxi University of Traditional Chinese Medicine Students Innovation and Entrepreneurship Training Program/ ; },
mesh = {*Molecular Docking Simulation ; *Flavonols/chemistry/pharmacology/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Network Pharmacology ; Protein Interaction Maps/drug effects ; },
abstract = {This study combined systems pharmacology and computational biology to systematically investigate the multi-target mechanisms and network features of Astilbin, a natural flavonoid glycoside, in Alzheimer's disease (AD) intervention. We collected potential targets of astilbin and AD-associated genes from PharmGKB, GeneCards, and OMIM databases and screened their intersecting targets. A PPI network was built via STRING, and hub genes were screened by topological analysis in Cytoscape. GO and KEGG enrichment analyses were performed, followed by molecular docking to assess binding affinity between Astilbin and core targets. In total, 250 overlapping targets were identified. Enrichment showed these targets participate in hormone/lipid responses, carboxylic acid metabolism and kinase activities. KEGG revealed Astilbin acts via PI3K-Akt, MAPK and lipid metabolism pathways. Molecular docking verified that Astilbin exhibits low binding energy toward the core targets of Alzheimer's disease, implying a possible role in modulating neural signaling and ameliorating AD-related pathological processes. Collectively, Astilbin may contribute to AD intervention through a multi-target, multi-pathway network involving neural signaling, metabolism, inflammation, and cerebrovascular protection. This study clarifies the pharmacological mechanism of Astilbin and provides theoretical support for the development of natural product-based therapeutic agents for neurodegenerative diseases.},
}

*Molecular Docking Simulation
*Flavonols/chemistry/pharmacology/metabolism
*Alzheimer Disease/drug therapy/metabolism
Humans
Network Pharmacology
Protein Interaction Maps/drug effects

@article {pmid42984689,
year = {2026},
author = {Liu, H and Liu, X and Ji, H and Xiao, A and Liu, Y},
title = {Disease-context dependence of periventricular diffusivity and DTI-ALPS in asymptomatic moyamoya disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1927018},
pmid = {42984689},
issn = {1664-2295},
mesh = {Humans ; Female ; *Moyamoya Disease/diagnostic imaging/psychology/complications ; *Diffusion Tensor Imaging ; Male ; Middle Aged ; *Glymphatic System/diagnostic imaging ; White Matter/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; },
abstract = {Asymptomatic moyamoya disease, chronic cerebral hypoperfusion, periventricular diffusivity (PVeD), and diffusion tensor image analysis along the perivascular space (DTI-ALPS) are relevant to the study of brain fluid transport and vascular cognitive impairment. PVeD has recently been proposed as a diffusion MRI marker related to amyloid burden and cognition in the Alzheimer's disease continuum, but whether this marker has similar cognitive relevance in chronic hypoperfusion remains unclear. We studied 59 patients with asymptomatic moyamoya disease who had complete demographic, cognitive, diffusion MRI-derived imaging, white matter hyperintensity (WMH), and bilateral Suzuki staging data. Age, sex, MoCA, MMSE, bilateral and mean ALPS indices, and bilateral and mean PVeD indices were analyzed using Spearman correlation, age- and sex-adjusted partial correlation, and multivariable linear regression. False discovery rate (FDR) correction was applied to the correlation analyses. After age- and sex adjustment and FDR correction, five of the six ALPS-cognition partial correlations remained significant (mean, left, and right ALPS with MoCA; mean and left ALPS with MMSE), whereas none of the six PVeD-cognition partial correlations survived FDR correction. In sensitivity models additionally adjusted for WMH burden and maximum hemispheric Suzuki stage, mean ALPS remained associated with MoCA, whereas its association with MMSE was attenuated; mean PVeD was not associated with either cognitive score. These cross-sectional findings suggest that the cognitive relevance of diffusion-based brain fluid markers may vary according to the underlying disease context, structural white matter injury, and angiographic disease severity, and support further longitudinal validation in vascular populations.},
}

Humans
Female
*Moyamoya Disease/diagnostic imaging/psychology/complications
*Diffusion Tensor Imaging
Male
Middle Aged
*Glymphatic System/diagnostic imaging
White Matter/diagnostic imaging
Diffusion Magnetic Resonance Imaging

@article {pmid42984863,
year = {2026},
author = {Griñán-Ferré, C and Hussain, F and Bellver-Sanchis, A and Pérez-Salvador, N and Valle, Y and Ortuño-Sahagún, D and Arias-Carrión, O},
title = {From developmental divergence to degenerative vulnerability: convergent molecular mechanisms linking autism spectrum disorder and Alzheimer's disease.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1963972},
pmid = {42984863},
issn = {1662-5099},
abstract = {Neurodevelopmental disorders (NDDs) and neurodegenerative diseases (NDEs) have long been regarded as temporally and mechanistically distinct: NDDs such as autism spectrum disorder (ASD), Fragile X syndrome, Prader-Willi syndrome, and Phelan-McDermid syndrome arise during critical periods of brain maturation, whereas NDEs such as Alzheimer's disease (AD) manifest later with progressive neuronal loss, protein aggregation, and cognitive decline. Accumulating genetic, molecular, cellular, and epidemiological data now suggests substantial overlaps, indicating that diverse genetic and environmental insults converge on a limited set of shared biological pathways across the lifespan. Large-scale genomic analyses have identified at least 148 genes shared between ASD and AD, but this overlap should be understood as a shared regulatory architecture rather than evidence of a common causal pathway. About half of these genes are linked to the mTOR signaling pathway, which regulates protein synthesis, autophagy, and synaptic homeostasis. Epidemiological studies indicate an increased occurrence of early-onset dementia among adults with ASD, although available studies do not establish that this association is specific to Alzheimer's disease or to idiopathic ASD. Both conditions involve dysregulation of synaptic scaffolding (e.g., SHANK3), epigenetic regulation (including G9a/EHMT2-mediated H3K9 methylation), complement-dependent synaptic pruning, mitochondrial and metabolic homeostasis, neuro-inflammation, and glymphatic clearance. We propose a unifying framework, presented as a testable hypothesis rather than an established mechanism, in which NDDs and NDEs represent distinct temporal manifestations within a shared evolutionary trade-off landscape balancing developmental connectivity, metabolic cost, and long-term proteostatic resilience. Within this landscape, convergent nodes-mTOR-autophagy, G9a/EHMT2-mediated chromatin regulation, complement-mediated pruning, and glymphatic function-may contribute to differences in early circuit formation and have been proposed as potential sources of later vulnerability. The APP-FMRP-mGluR5 axis further illustrates molecular convergence between monogenic NDDs and pathways relevant to AD. This review uses ASD and AD as paradigmatic examples to illustrate how heterochronic disruptions in synaptic maturation and proteostasis may create a lifespan continuum from atypical neurodevelopment to accelerated degeneration, while explicitly noting that this framework remains a testable hypothesis and does not establish a causal progression from ASD to AD. Recognizing these shared nodes opens avenues for transdiagnostic biomarkers, longitudinal risk stratification, and multitarget therapies-including epigenetic modulators, mTOR regulators, and glymphatic enhancers-that may benefit both ends of the continuum.},
}

@article {pmid42984925,
year = {2026},
author = {López-Sánchez, N and Rábano, A and Frade, JM},
title = {Specific enrichment of somatic single nucleotide variants in Alzheimer-associated tetraploid neurons.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1929505},
pmid = {42984925},
issn = {1662-5099},
abstract = {An early pathological process observed in the brains of patients with Alzheimer's disease (AD) is the reactivation of the cell cycle in neurons, followed by somatic neuronal tetraploidization (NT). NT increases with age, and aging has been shown to correlate with the accumulation of DNA somatic mutations in neurons. In this study, we evaluated the presence of somatic mutations, including single nucleotide variants (SNVs) and short insertions or deletions (INDELs), in genomic DNA from tetraploid neurons obtained from the parietal cortex of patients with AD, as compared with diploid neurons from control individuals and patients with AD. Here we show that, in contrast to somatic INDELs, somatic SNVs (sSNVs) are significantly increased in the exome of tetraploid neurons, with elevated levels of T to C (A to G) transitions, a type of mutation associated with oxidative stress. This finding correlates with the overrepresentation of sSNVs in genes involved in the oxidative stress response and DNA repair, with DNA repair genes showing significantly enhanced molecular pathogenicity scores (MPS). Moreover, sSNVs affecting cancer- and senescence-related genes show a greater MPS than those from a random sample of genes. We propose a model in which neuronal tetraploidy may be stochastically triggered in neurons with mutated DNA repair genes under oxidative stress, potentially exacerbating oxidative DNA damage. This could facilitate cell cycle progression, followed by tetraploidization and senescence in the affected neurons, a process that may contribute to the pathogenesis of AD.},
}

@article {pmid42985442,
year = {2026},
author = {Legault, EM and Izabal Gamez, JP and Drouin-Ouellet, J},
title = {Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1903701},
pmid = {42985442},
issn = {1663-4365},
abstract = {INTRODUCTION: In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). In neurons, the effect of aging on intrinsic molecular processes, and how they tie to age-related neurodegeneration remains unclear. Animal studies have shown that mitochondrial function decline, autophagy impairment and defective elimination of damaged mitochondria by mitophagy are all central features of neuronal aging. However, very few studies have investigated such events in human neurons, due to a lack of models showing aging features. Therefore, there is a crucial need for a better understanding of the effect of aging on neuronal health.

METHODS: Here, we use direct neuronal reprogramming, which maintains signatures of cellular aging, to study the effect of aging on mitochondrial health and mitophagy in human neurons derived from healthy donors ranging from 11 to 91 years old. We use confocal imaging to assess colocalization of mitochondria with autophagic structures following mitophagy induction.

RESULTS: We show age-related mitochondrial impairment in neurites of induced neurons (iNs) derived from older donors. Additionally, in these neurites, we show an accumulation of mitochondria targeted for degradation in autophagosomes and LAMP1-positive lysosomal vesicles following mitophagy induction. These impairments culminate into incomplete elimination of damaged mitochondria, despite preserved activity of the lysosomal enzymes assessed.

CONCLUSION: This study shows for the first time age-related mitophagy impairment in human neurons, and confirms findings of age-related mitochondrial impairments in human neurons. By doing so, this study paves the way for more in-depth mechanistic studies that would allow for the identification of therapeutic targets for anti-aging treatment and in the context of age-associated neurodegenerative diseases.},
}

@article {pmid42985466,
year = {2026},
author = {Fu, G and Pan, M and Sun, Q and Yue, G and Lei, T},
title = {Alzheimer's Disease: Mechanisms and Therapeutic Advances.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71093},
pmid = {42985466},
issn = {2688-2663},
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative condition accompanied by widespread central nervous system damage and complex networked pathogenesis spanning molecular, cellular, and systemic dimensions. Existing studies tend to focus on individual pathological cascades or monotherapeutic approaches, while overlooking the intrinsic crosstalk among protein pathology, neuroinflammation, metabolic dysfunction, and gut-brain axis imbalance, with insufficient systematic integration of nonpharmacological strategies and multifunctional nanoplatforms. Driven by intertwined molecular aberrations, glial dysregulation and systemic metabolic disorders, AD presents profound pathological complexity. Correspondingly, multitarget pharmacotherapy integrated with hierarchical nonpharmacological and nanotherapeutic interventions has achieved substantial progress, exerting synergistic effects on alleviating AD pathological cascades and optimizing overall therapeutic regimens. We comprehensively review current evidence to delineate the mechanistic landscape of AD and update therapeutic advances, including pharmacological agents, multimodal nonpharmacological interventions, and brain-targeted nanosystems for blood-brain barrier penetration, protein modulation, microenvironment remodeling, and gene editing delivery. This study underscores major research limitations and translational obstacles in therapeutic efficacy, biosafety, and nanomedicine applications. This work emphasizes biomarker-based early stratification and staged combined interventions, providing novel integrated insights into AD pathogenesis and prospective targeted therapeutic development.},
}

@article {pmid42985795,
year = {2026},
author = {Lu, B and Chen, YR and Li, RX and Zhang, MK and Yan, SZ and Chen, GQ and Wang, JH and Chai, WH and Castellanos, FX and Thompson, PM and Lu, J and Han, Y and Yan, CG},
title = {Deep Learning for AD Risk Screening and Progression Prediction.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {42985795},
issn = {2198-3844},
support = {2022ZD0211800//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 2021ZD0200600//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 82572192//National Natural Science Foundation of China/ ; 82327809//National Natural Science Foundation of China/ ; 2025HZGF02//Construction Fund of Key Medical Disciplines of Hangzhou/ ; E3CX1425CX//Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences/ ; 20230484465//Beijing Nova Program of Science and Technology/ ; J230040//Beijing Natural Science Foundation/ ; //the Qiantang Scholars Program/ ; },
abstract = {The rise of Alzheimer's disease (AD) immunotherapies underscores the need for accessible, time-efficient biomarkers for early diagnosis. MRI-based deep learning shows promise in this regard, yet few models have undergone comprehensive clinical validation. Using the SILCODE cohort (722 Chinese participants, 1,105 scans), we test the transportability of our classifier (pretrained on Western samples) to an independent Chinese cohort without retraining. The associations between risk scores and disease progression, cognitive performance, and plasma biomarkers are examined. In addition, an interpretable framework is developed to generate individualized brain risk maps and identify subtypes. The model classifies AD with an AUC of 0.913 and 95.2% sensitivity, identifying 90.5% of high-risk individuals 2-3 years before clinical diagnosis. Risk scores correlate significantly with cognitive and plasma indices, particularly p-tau 217. Brain risk maps reveal AD subtypes, including a subgroup with rapid cognitive decline. These findings establish a population-robust, clinically relevant MRI-based model for early AD detection and risk stratification.},
}

@article {pmid42985910,
year = {2026},
author = {Neale, ZE and Cooke, ME and Cárcamo, J and Trabilsy, M and Barr, PB and Chatzinakos, C and Furhang, R and Chorlian, DB and Kuang, W and Pandey, G and Goate, AM and Porjesz, B and Amstadter, AB and Meyers, JL},
title = {Childhood Trauma and APOEε4 Are Associated With Patterns of Developmental Frontal Alpha Connectivity, Posttraumatic Stress, and Alcohol-Related Outcomes.},
journal = {Genes, brain, and behavior},
volume = {25},
number = {6},
pages = {},
pmid = {42985910},
issn = {1601-183X},
support = {U10AA008401/AA/NIAAA NIH HHS/United States ; R01AA030010/AA/NIAAA NIH HHS/United States ; 3R01AA030010-02S1/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; *Stress Disorders, Post-Traumatic/genetics/physiopathology ; *Apolipoprotein E4/genetics ; Male ; *Alcoholism/genetics/physiopathology ; Adolescent ; Young Adult ; Longitudinal Studies ; Alpha Rhythm ; Adult ; *Frontal Lobe/physiopathology/growth & development ; },
abstract = {Childhood trauma affects neurodevelopment and lifelong risk for posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). Changes in brain structures and function are observed in young carriers of APOEε4, the genetic factor most associated with Alzheimer's disease. Longitudinal studies of APOEε4, childhood trauma, and neural connectivity in adolescence have not been explored. We studied 837 trauma-exposed participants (53% female) from the Collaborative Study on the Genetics of Alcoholism prospective sample, using latent growth curve models to assess associations of childhood trauma and APOEε4 on repeated measures of frontal alpha EEG coherence (EEGc) throughout adolescence and young adulthood. Young adult AUD and PTSD symptoms were also examined. Results indicate childhood sexual assaultive trauma (CSAT) and APOEε4 are linked to neural connectivity, with effects differing by brain region and direction. CSAT was associated with a higher EEGc baseline but less growth in three EEGc pairs, while APOEε4 associated with lower left frontocentral (LFC) EEGc baseline and higher slope. EEGc patterns and symptoms of PTSD and AUD were robustly associated. A significant interaction between CSAT-by-APOEε4 interaction also emerged, such that among APOEε4 carriers, childhood sexual assaultive trauma was associated with higher baseline PFI and diminished growth in PFI and LFC EEGc. No significant direct links between APOEε4 and PTSD or AUD were observed. Findings highlight how EEGc may help explain connections between genetics, trauma, and psychopathology, guiding at-risk group identification and informing prevention strategies.},
}

Humans
Female
*Stress Disorders, Post-Traumatic/genetics/physiopathology
*Apolipoprotein E4/genetics
Male
*Alcoholism/genetics/physiopathology
Adolescent
Young Adult
Longitudinal Studies
Alpha Rhythm
Adult
*Frontal Lobe/physiopathology/growth & development

@article {pmid42985920,
year = {2026},
author = {Dong, S and Zhao, S and Deng, J and Zhang, L and Sun, J},
title = {CRISPR-Cas Assays for Protein Detection: Strategies and Clinical Applications.},
journal = {Small methods},
volume = {},
number = {},
pages = {},
doi = {10.1002/smtd.71186},
pmid = {42985920},
issn = {2366-9608},
support = {2021YFA0909400//National Key R&D Program of China/ ; 2025YFF0518300//National Key R&D Program of China/ ; 22227805//National Natural Science Foundation of China/ ; 22534001//National Natural Science Foundation of China/ ; 22574035//National Natural Science Foundation of China/ ; YSBR-036//CAS Project for Young Scientists in Basic Research/ ; XDA0580000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 2025M780886//China Postdoctoral Science Foundation/ ; 20250673//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; },
abstract = {Measurement of protein biomarkers with high accuracy is critical for disease diagnostics and prognostic monitoring. However, conventional analytical platforms for protein detection suffer from insufficient sensitivity for low-abundance targets and require time-consuming, multi-step workflows. The CRISPR-Cas system is emerging as a powerful tool for protein analysis, with advantages including high programmability, excellent sensitivity, and compatibility with diverse readouts. This review presents a systematic overview of recent advances in CRISPR-based protein assays. We first summarize the design principles of aptamer-, antibody-, and enzyme-mediated systems that convert protein recognition events into CRISPR-activatable nucleic acid signals. We next examine the signal amplification and readout strategies, such as direct CRISPR activation, enzyme-mediated nucleic acid amplification, and enzyme-free DNA nanotechnology, along with colorimetric, fluorescent, or electrochemical signal outputs. We also review applications of these assays in infectious diseases, cancer, and Alzheimer's disease. Finally, we discuss challenges and perspectives for next-generation CRISPR-based protein detection platforms in clinical translation.},
}

@article {pmid42985938,
year = {2026},
author = {Teplow, DB and Raskatov, JA},
title = {On the Need to Revise the Amyloid Cascade Hypothesis.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {27},
number = {21},
pages = {},
pmid = {42985938},
issn = {1439-7633},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism/chemistry ; *Alzheimer Disease/metabolism/pathology ; *Amyloid/metabolism ; Animals ; Amyloid beta-Protein Precursor/metabolism ; },
abstract = {Seven million people in the USA are estimated to suffer from Alzheimer's disease (AD), a number expected to double by 2050. Patient care costs >$350 billion/year now but will exceed $1 trillion by 2050, bankrupting our economy. Tremendous progress in understanding and treating AD has been made over the past 4 decades, yet, after >400 clinical trials, no efficacious AD treatments exist. The amyloid cascade hypothesis (ACH), the leading disease model, holds that amyloid β (Aβ) initiates a cascade leading to disease. Alternative processing cleaves APP in the middle of Aβ, producing the C-terminal fragment, p3. Simply put, if the ACH is true, no Aβ means no disease because p3 is believed soluble, non-amyloidogenic, and nontoxic. However, recent studies have shown this to be untrue. In fact, p3 is more amyloidogenic than Aβ, and is neurotoxic. It also forms mixed aggregates with Aβ that have distinct structures and neurotoxicities. ACH has led the AD field to largely ignore these facts. Here, we provide an integrated perspective on how this has come about and urge expansion of the ACH to consider the possible roles of p3 in AD and to refer to it as Amyloid α (Aα), to better reflect its nature.},
}

Humans
*Amyloid beta-Peptides/metabolism/chemistry
*Alzheimer Disease/metabolism/pathology
*Amyloid/metabolism
Animals
Amyloid beta-Protein Precursor/metabolism

@article {pmid42986084,
year = {2026},
author = {Zhang, Y and Wu, Y and Zhang, S and Zhang, L and Li, X},
title = {Hesperetin Inhibits Aβ Early Aggregation by Disrupting the Continuity of the β-Sheet Structure.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {44},
pages = {11788-11798},
doi = {10.1021/acs.jpcb.6c06062},
pmid = {42986084},
issn = {1520-5207},
support = {12304255//National Natural Science Foundation of China/ ; 12574231//National Natural Science Foundation of China/ ; T2425029//National Natural Science Foundation of China/ ; xxj032025070//Fundamental Research Funds for the Central Universities/ ; 25JSQ019//Shaanxi Province/ ; },
mesh = {*Hesperidin/pharmacology/chemistry ; *Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors ; Molecular Dynamics Simulation ; Protein Conformation, beta-Strand/drug effects ; *Protein Aggregates/drug effects ; Humans ; Hydrogen Bonding ; },
abstract = {The misfolding and pathological aggregation of amyloid-β (Aβ) into insoluble amyloid deposits are closely associated with Alzheimer's disease (AD). Inhibiting early Aβ assembly is a critical strategy for the development of antiamyloid therapeutics. Hesperetin (HST), a natural flavanone abundant in citrus fruits, has been reported to inhibit Aβ fibrillogenesis and reduce Aβ-associated cytotoxicity. However, the molecular mechanism underlying HST-mediated inhibition of Aβ aggregation remains unclear. In particular, whether HST acts through mechanisms similar to other natural compounds or employs a distinct inhibitory strategy is yet to be determined. Here, we employed replica exchange molecular dynamics (REMD) simulations to investigate how HST modulates Aβ early aggregation and β-sheet assembly at the atomic level. The results demonstrate that HST disrupts the continuity of β-sheet structures within Aβ dimers, as evidenced by restricted β-strand extension. Mechanistically, HST preferentially interacts with aggregation-prone regions of Aβ through a synergistic interaction network of hydrogen-bonding, hydrophobic, π-π stacking, and cation-π interactions. Notably, HST-mediated hydrogen bonding with the Aβ backbone perturbs the local hydrogen-bonding environment required for β-sheet extension, while cooperative nonpolar and aromatic interactions further stabilize HST-bound conformations and weaken intra- and intermolecular interaction networks involved in Aβ self-assembly. Collectively, these findings reveal a specific mechanism by which HST regulates Aβ aggregation through disruption of β-sheet continuity, which provides atomic-level insights into the antiamyloid activity of natural flavanones.},
}

*Hesperidin/pharmacology/chemistry
*Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors
Molecular Dynamics Simulation
Protein Conformation, beta-Strand/drug effects
*Protein Aggregates/drug effects
Humans
Hydrogen Bonding

@article {pmid42986125,
year = {2026},
author = {Safari Moughadam, M and Yaghoubi, A and Cheragh Birjandi, S and Tavakoli, M},
title = {Effects of high-intensity interval and moderate-intensity continuous training on neuroinflammatory and amyloidogenic pathways in an STZ-induced AD-like model.},
journal = {Archives of physiology and biochemistry},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13813455.2026.2755767},
pmid = {42986125},
issn = {1744-4160},
abstract = {CONTEXT: Alzheimer's disease (AD) involves amyloid-beta 42 (Aβ1-42) accumulation, neuroinflammation, and cognitive decline.

OBJECTIVE: To compare high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) effects on hippocampal Aβ1-42, β-secretase 1 (BACE1), nuclear factor kappa B (NF-κB), and memory in streptozotocin (STZ)-induced AD-like rats.

MATERIALS AND METHODS: 35 male Wistar rats (n = 7/group): healthy control, Sham, AD control, AD + HIIT, AD + MICT. STZ was injected intracerebroventricularly. After eight weeks of training, memory (passive avoidance) and hippocampal markers (ELISA) were assessed.

RESULTS: Versus AD control, HIIT and MICT improved memory and lowered Aβ1-42 and NF-κB (all p ≤ 0.01). HIIT also lowered BACE1 (p < 0.001); MICT did not (p = 0.163). HIIT surpassed MICT only in memory (p = 0.006).

DISCUSSION AND CONCLUSION: Both exercise modes attenuated amyloidogenic and neuroinflammatory markers and improved memory; HIIT had a behavioral advantage.},
}

@article {pmid42986457,
year = {2026},
author = {Karimi, A and Hoveizi, E and Khajehpour, L and Ghotbeddin, Z},
title = {Behavioral, biochemical, histological, and electrophysiological changes following intracerebral injection of bone marrow stem cell-derived exosomes in male rat models of Alzheimer's disease.},
journal = {Experimental brain research},
volume = {245},
number = {1},
pages = {},
pmid = {42986457},
issn = {1432-1106},
support = {SCU.SB1403.12464//Shahid Chamran University of Ahvaz/ ; },
mesh = {Animals ; Male ; *Alzheimer Disease/therapy/pathology/physiopathology/metabolism ; *Exosomes/transplantation ; Disease Models, Animal ; Rats ; Brain-Derived Neurotrophic Factor/metabolism ; Rats, Sprague-Dawley ; Avoidance Learning/physiology ; Hippocampus/metabolism ; Bone Marrow Cells ; Injections, Intraventricular ; Electroencephalography ; },
abstract = {Recently, researchers have been exploring how exosomes can help treat neurodegenerative diseases, such as Alzheimer's disease (AD), has attracted considerable attention. This study aimed to investigate behavioral, biochemical, histological, and electrophysiological changes following the administration of bone marrow stem cell-derived exosomes (Exo-BMSCs) in AD model rats. Animals were divided into control, Lesion (Lesion, Lesion + saline), and treatment (Lesion + BMSCs, Lesion + Exo-BMSCs) groups. BMSCs were extracted from the bone marrow of newborn rats. Exosomes were extracted from the BMSCs culture medium using a chemical kit. Saline, BMSCs, and Exo-BMSCs were injected bilaterally into the nucleus of Meynert (NBM) one week after electrical lesion. 28 days after injection, behavioral, electrophysiological, and histological changes, as well as ACh and BDNF expression levels in the hippocampus, were evaluated. Electrical lesion of the NBM caused a significant decrease in passive avoidance memory retrieval, a significant decrease in ACh and BDNF levels, changes in EEG wave frequencies in the hippocampus, and histological changes in the NBM, similar to those observed in AD. On the other hand, injection of BMSCs and Exo-BMSCs into the NBM significantly improved passive avoidance memory, an increase in BDNF levels, an increase in power of gamma waves, and improved histological changes compared to the Lesion groups. The increase in power of gamma waves was significant only in the Exo-BMSC-treated group. Injection of BMSCs and Exo-BMSCs into the NBM can significantly improve disease symptoms. This improvement was more pronounced in the Exo-BMSCs-treated group. The concurrent increase in BDNF suggests that this neurotrophin contributes to the observed effects.},
}

Animals
Male
*Alzheimer Disease/therapy/pathology/physiopathology/metabolism
*Exosomes/transplantation
Disease Models, Animal
Rats
Brain-Derived Neurotrophic Factor/metabolism
Rats, Sprague-Dawley
Avoidance Learning/physiology
Hippocampus/metabolism
Bone Marrow Cells
Injections, Intraventricular
Electroencephalography

@article {pmid42986483,
year = {2026},
author = {da Silva Lima, B and Dos Santos, YTP and Farias, GC and de Lima Souza, EFR and de Lima, PDL and Quaresma, JAS and da Costa Vasconcelos, PF and de Sousa, JR},
title = {Astrocytic endoplasmic reticulum stress as an amplifier of neuroinflammation and neurodegeneration in Alzheimer's disease: a narrative review.},
journal = {Immunologic research},
volume = {74},
number = {1},
pages = {},
pmid = {42986483},
issn = {1559-0755},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/pathology ; Animals ; *Astrocytes/metabolism/immunology ; *Endoplasmic Reticulum Stress ; *Neuroinflammatory Diseases/immunology/metabolism ; Unfolded Protein Response ; Signal Transduction ; eIF-2 Kinase/metabolism ; Mitochondria/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Endoribonucleases/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multicellular neuroimmune disorder in which proteostatic failure, metabolic dysfunction, and sustained glial activation interact to accelerate synaptic loss. This narrative review examines endoplasmic reticulum (ER) stress in astrocytes as a mechanistic link among the unfolded protein response (UPR), neuroinflammation, mitochondrial dysfunction, and neurodegeneration. The three canonical UPR branches, mediated by protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), initially reduce protein-folding burden and reinforce ER quality control. When stress persists and adaptive capacity becomes insufficient, sustained PERK and IRE1 signaling may favor apoptosis, inflammatory transcriptional programs, cytokine production, calcium dyshomeostasis, and oxidative injury, whereas ATF6 remains predominantly associated with proteostatic reinforcement in a context-dependent manner. In astrocytes, persistent UPR activation may impair neuronal metabolic support, synaptogenic signaling, and astrocytic contributions to neurovascular homeostasis while promoting complement component 3 (C3) expression and bidirectional inflammatory crosstalk with microglia. ER-mitochondria contact sites further integrate calcium transfer, reactive oxygen species generation, bioenergetic failure, and intrinsic apoptotic signaling. Experimental evidence therefore supports a self-reinforcing neuroglial circuit in which astrocytic ER stress is proposed to function as an amplifier rather than merely a consequence of AD pathology. Therapeutic strategies targeting UPR signaling, chemical chaperones, extracellular vesicles, gene modulation, and cell-selective delivery systems remain under investigation, and their translation will require temporally controlled, cell-type-specific, and safety-conscious modulation of stress responses.},
}

Humans
*Alzheimer Disease/immunology/metabolism/pathology
Animals
*Astrocytes/metabolism/immunology
*Endoplasmic Reticulum Stress
*Neuroinflammatory Diseases/immunology/metabolism
Unfolded Protein Response
Signal Transduction
eIF-2 Kinase/metabolism
Mitochondria/metabolism
Protein Serine-Threonine Kinases/metabolism
Endoribonucleases/metabolism

@article {pmid42986540,
year = {2026},
author = {Rakshit, D and Mishra, A},
title = {7-Hydroxyflavone Attenuates Amyloid-β-Induced Alzheimer's Disease-Like Pathology Through Modulation of ROS/NLRP3 Inflammasome Signaling.},
journal = {Neurochemical research},
volume = {51},
number = {6},
pages = {},
pmid = {42986540},
issn = {1573-6903},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Alzheimer Disease/drug therapy/metabolism/chemically induced/pathology ; *Amyloid beta-Peptides/toxicity ; *Inflammasomes/metabolism/drug effects ; Mice ; *Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/physiology ; Male ; Peptide Fragments/toxicity ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Flavones/therapeutic use/pharmacology ; *Flavonoids/therapeutic use ; },
abstract = {Alzheimer's disease (AD), the widely recognised neurodegenerative disease with no proper cure to date, is typified by memory decline. Apart from the amyloid hypothesis and cholinergic dysfunction, neuroinflammation is also a key factor behind AD. 7-Hydroxyflavone (7HF), a flavonoid, possesses antioxidant, anti-inflammatory, and neuroprotective activities and remains unexplored in AD. Thus, in our study, we aimed to investigate the efficacy of 7HF against amyloid beta (Aβ)-induced AD in mice. Target acquisition for AD- and 7HF-related targets was performed, and gene ontology enrichment analysis was conducted using network pharmacology. 7HF was docked with AChE and NLRP3 proteins. The effect of 7HF was evaluated on Aβ-induced cytotoxicity, AChE activity and proinflammatory cytokines in Neuro2a (N2a) cells. Aβ1-42 was injected intracerebroventricularly in mice to induce AD, and mice were treated with 7HF (5, 10 & 20 mg/kg/day; p.o.) for 28 days. Behavioural assessments were performed during the last week of the study, followed by sacrifice and brain collection for further biochemical, molecular, and histological evaluations. 7HF shared targets with AD and exhibited a highly interconnected protein-protein network, with enriched ontology parameters linked to neuronal function. 7HF showed good binding affinity with AChE and NLRP3 proteins. It reduced Aβ-induced cytotoxicity, AChE activity, and proinflammatory cytokine levels in N2a cells. Treatment with 7HF improved the Aβ-induced memory deficits in mice. It also reduced pro-oxidant and AChE activity, as well as the molecular levels of NLRP3, ASC, cleaved caspase-1, and pro-inflammatory cytokines in the Aβ-induced mouse brain. Amyloid-associated structures in the Aβ-induced mouse brain were also reduced by 7HF intervention. These observations suggest that 7HF might have ameliorated AD-like pathology by reducing AChE activity, ROS levels, NLRP3-related neuroinflammatory markers, ultrastructural changes, and amyloid burden in Aβ-induced mice.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Alzheimer Disease/drug therapy/metabolism/chemically induced/pathology
*Amyloid beta-Peptides/toxicity
*Inflammasomes/metabolism/drug effects
Mice
*Reactive Oxygen Species/metabolism
Signal Transduction/drug effects/physiology
Male
Peptide Fragments/toxicity
*Neuroprotective Agents/therapeutic use/pharmacology
*Flavones/therapeutic use/pharmacology
*Flavonoids/therapeutic use

@article {pmid42986604,
year = {2026},
author = {Harather, S and Lehrner, J},
title = {No association between five-factor personality model and 5-year all-cause mortality in patients with subjective cognitive decline and mild cognitive impairment.},
journal = {Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater},
volume = {},
number = {},
pages = {},
pmid = {42986604},
issn = {2194-1327},
abstract = {BACKGROUND: Alzheimer's disease is the most common form of dementia and is preceded by prodromal stages including subjective cognitive decline (SCD), non-amnestic mild cognitive impairment (naMCI), and amnestic mild cognitive impairment (aMCI). While associations between personality traits and cognitive decline have been reported, their impact on mortality in these early disease stages remains unclear.

OBJECTIVES: This study aimed to investigate whether personality traits differ between patients with SCD, naMCI, and aMCI and whether these traits influence 5‑year all-cause mortality.

METHODS: In this retrospective single-center study, data from 353 patients aged 50 and older diagnosed with SCD (n = 72), naMCI (n = 156), or aMCI (n = 125) were analyzed. Personality traits were assessed using the Big Five Plus One (B5PO) questionnaire. Survival probabilities were estimated using Kaplan-Meier analysis, group differences were assessed by log-rank test, and the impact of personality traits on mortality was examined using Cox proportional hazards model.

RESULTS: The overall 5‑year survival probability was 87.1%. No significant differences in all-cause survival were observed between diagnostic subgroups (p = 0.629). No significant differences in personality traits were found between SCD, naMCI, and aMCI patients. Personality traits assessed by the B5PO showed no significant association with mortality. Apart from personality traits, exploratory analyses suggested that certain cognitive performance measures, namely, selective attention, were associated with survival probability, whereas higher age was associated with increased mortality risk.

CONCLUSION: Personality traits according to the B5PO do not appear to significantly influence mortality or differ between the subgroups of early cognitive impairment. Further studies with larger cohorts are necessary to clarify potential associations between personality, cognition, and long-term outcomes.},
}

@article {pmid42986663,
year = {2026},
author = {Mondal, S and Das Sharma, A and Mandal, SK and Saha, I and Cuspoca, AF and Montaña, MP and Mendez, YR and Dhiman, AK and Nguyen, TL and Shaikh, AR and Aich, P},
title = {Beyond blood: a narrative review of advancements in saliva-based diagnostics.},
journal = {Expert review of molecular diagnostics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737159.2026.2760897},
pmid = {42986663},
issn = {1744-8352},
abstract = {INTRODUCTION: Human whole saliva is an accessible, noninvasive biofluid reflecting systemic and oral physiology, offering a viable alternative to invasive venipuncture and its associated pre-analytical vulnerabilities (e.g. ex vivo glycolysis).

AREAS COVERED: This narrative review synthesizes salivary biomarkers across major clinical domains, focusing on glycemic control (glucose, 1,5-anhydroglucitol, α2-macroglobulin), cardiovascular risk indices (cTnI, hs-CRP, sAA), critical care and sepsis surveillance (IL-10, acute-phase proteins), endocrinology (free steroid hormones), infectious diseases (HIV, HCV, SARS-CoV-2), oncological liquid biopsy (exosomal miRNAs, ctDNA), and neurodegenerative disorders such as Alzheimer's disease (Aβ42, p-tau181, lactoferrin). Analytical modalities - ranging from high-sensitivity immunoassays to wearable electrochemical biosensors and mass spectrometry - are critically evaluated. Furthermore, this review delineates regulatory-cleared diagnostic platforms (FDA PMA/510(k), EUA, CE-IVD, and SAMHSA-certified panels for viral antibodies, late-night salivary cortisol, and toxicology) from emerging discovery-phase panels.

EXPERT OPINION: Widespread clinical translation remains constrained by unstandardized collection protocols, oral matrix interference, and a lack of normative reference intervals. Transitioning salivary testing into mainstream diagnostics requires three priorities: (1) universal sampling standardization incorporating flow-rate normalization, (2) engineering matrix-matched biosensors tailored for sub-picomolar detection, and (3) rigorous multicenter prospective trials to validate definitive clinical cutoffs, dynamic blood-saliva correlation kinetics, and digital point-of-care integration.},
}

@article {pmid42986694,
year = {2026},
author = {Deng, YS and Wang, WP and Wang, F and Ma, GM and Lin, JF and Yan, CX and Zhou, YL and Wang, LY and Gong, XQ and Sun, L and Zhao, J and Pei, G and Zhang, L and Wang, WY},
title = {A human gut-BBB-brain microphysiological model for studying Alzheimer's disease.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6lc00630b},
pmid = {42986694},
issn = {1473-0189},
abstract = {The gut-brain axis (GBA) has emerged as a crucial contributor to neurodegenerative diseases, with growing evidence implicating gut-derived metabolic and signaling alterations in Alzheimer's disease (AD). However, the lack of human-relevant in vitro models limits our ability to explore the mechanisms of this axis effectively. To address this limitation, we developed a human induced pluripotent stem cell (iPSC)-derived gut-blood-brain barrier (BBB)-brain microphysiological system that enables systematic investigation of gut-brain interactions in AD under controlled conditions. Using this platform, we showed that communication between gut and brain compartments was associated with increased expression of neuronal and glial markers, as well as phenotypes indicative of enhanced maturation-associated molecular features. Integrating gut and brain compartments also revealed disease-associated molecular and cellular alterations not observed in brain organoids alone. Importantly, exposure of healthy brain organoids to signals from AD patient-derived gut organoids induced changes in neuronal and glial phenotypes, indicating that gut-derived factors may contribute to brain dysfunction in AD. Collectively, our findings establish a human iPSC-derived gut-BBB-brain platform for studying brain organoid responses under combined intestinal and BBB co-culture conditions and provide an experimental framework for exploratory studies of AD-associated inter-organ influences.},
}

@article {pmid42986928,
year = {2026},
author = {Lai, J and Chen, J and Huang, H and Liu, J and Zou, Z and Liu, J and Lin, Z and Hong, G},
title = {An Electrochemiluminescence Biosensing Platform Based on a Hydrogel-AAO Nanochannel Membrane for GFAP Detection.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.6c03340},
pmid = {42986928},
issn = {2379-3694},
support = {82171474//National Natural Science Foundation of China/ ; 82204328//National Natural Science Foundation of China/ ; 82371200//National Natural Science Foundation of China/ ; 82571357//National Natural Science Foundation of China/ ; 2023J011620//Natural Science Foundation of Fujian Province/ ; },
abstract = {Electrochemiluminescence (ECL) biosensors are widely used for ultrasensitive bioanalysis; however, their practical application is often limited by insufficient interface stability under complex detection conditions. Herein, an integrated hydrogel-AAO membrane (HAM) as a novel composite ion-exchange membrane is developed for constructing stable ECL biosensing interfaces. In the HAM architecture, the agarose hydrogel provides a three-dimensional, biocompatible matrix for antibody immobilization and target recognition, while the highly ordered AAO nanochannels serve as an efficient ion-transport and signal transduction pathway. The composite membrane enables effective coupling between interfacial biorecognition events and ECL signal modulation while physically separating the recognition layer from the ECL reaction region. Using glial fibrillary acidic protein (GFAP), a clinically relevant biomarker for Alzheimer's disease, as the model analyte, the proposed sensor achieved a detection limit of 191.6 fg/mL with a linear range from 1 pg/mL to 100 ng/mL. The sensor further demonstrated reliable quantification of GFAP in human serum samples, showing good agreement with a commercial ELISA kit. This work establishes the HAM as a versatile composite ion-exchange membrane for ECL biosensing and provides a general design framework for developing stable and sensitive ECL biosensors for clinical analysis.},
}

@article {pmid42986976,
year = {2026},
author = {Börchers, S and Mazzini, G and Zetterberg, H and Clemmensen, C},
title = {Obesity pharmacotherapies and cognition.},
journal = {Science (New York, N.Y.)},
volume = {394},
number = {6824},
pages = {633-640},
doi = {10.1126/science.aek9987},
pmid = {42986976},
issn = {1095-9203},
mesh = {Humans ; *Obesity/drug therapy/metabolism ; *Cognition/drug effects ; *Diabetes Mellitus, Type 2/drug therapy ; Animals ; Islet Amyloid Polypeptide/metabolism ; Brain/drug effects/metabolism ; Glucagon-Like Peptide 1/metabolism/therapeutic use ; Alzheimer Disease/drug therapy ; Gastric Inhibitory Polypeptide/metabolism ; Glucagon/metabolism ; *Anti-Obesity Agents/therapeutic use ; Cognitive Enhancement ; Glucagon-Like Peptide-1 Receptor/metabolism ; Hypoglycemic Agents/therapeutic use ; },
abstract = {Pharmacotherapies for obesity and type 2 diabetes are increasingly being evaluated for their effects on cognition and brain health. Evidence from preclinical models, observational cohorts, and clinical trials has intensified interest, but findings remain mixed. A central challenge is to determine whether potential cognitive effects arise from direct actions on neural circuits, indirect consequences of improved cardiometabolic health, or both. This Review examines the evidence across cardiometabolic disease, aging, and Alzheimer's disease, focusing on glucagon-like peptide-1 (GLP-1)-based therapies and combination approaches that engage glucose-dependent insulinotropic polypeptide, glucagon, and amylin pathways. We assess how receptor pharmacology, brain exposure, metabolic context, and disease stage shape cognitive outcomes and discuss how mechanistic clarity could guide therapies aimed at preserving or improving cognition.},
}

Humans
*Obesity/drug therapy/metabolism
*Cognition/drug effects
*Diabetes Mellitus, Type 2/drug therapy
Animals
Islet Amyloid Polypeptide/metabolism
Brain/drug effects/metabolism
Glucagon-Like Peptide 1/metabolism/therapeutic use
Alzheimer Disease/drug therapy
Gastric Inhibitory Polypeptide/metabolism
Glucagon/metabolism
*Anti-Obesity Agents/therapeutic use
Cognitive Enhancement
Glucagon-Like Peptide-1 Receptor/metabolism
Hypoglycemic Agents/therapeutic use

@article {pmid42987188,
year = {2026},
author = {Goswami, S and Fabris, GSL and Mondal, D and de Oliveira, RB and Chakraborty, A and Yadav, TP and Mukhopadhyay, NK and Ray, SK and Galvão, DS and Tiwary, CS},
title = {Plasmonic Mediated Atomically Thin Aluminum Quasicrystal for Dopamine Sensing.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {},
doi = {10.1002/smll.76555},
pmid = {42987188},
issn = {1613-6829},
support = {FA2386-21-1-4014//AOARD/ ; //DST/ ; //Naval Research Board, DRDO, Ministry of Textiles, Government of India/ ; 2024/03413-9//São Paulo Research Foundation (FAPESP)/ ; 2013/08293-7//FAPESP/CEPID/ ; 2019/17874-0//Coaraci Supercomputer Center for computer time/ ; },
abstract = {Dopamine levels are linked to neurological illnesses like Parkinson's and Alzheimer's. Thus, reliable and sensitive detection of dopamine is crucial for early diagnosis and surveillance of neurodegenerative diseases. Non-noble-metal-based nanomaterials are ideal for light-mediated sensing of organic molecules. Among these, two-dimensional (2D) quasicrystal (QC) structures consisting of five elements (Al70Co10Fe5Ni10Cu5 (2D Al QC)) provide active sites due to their high surface-to-volume ratio, making them excellent for organic chemical sensing. Here, we propose a simple, label-free, spatial self-phase-modulation (SSPM)-based sensing method in liquid form. SSPM-based time evolution of the diffraction pattern for varied mixing levels of a 1100 ppb dopamine solution shows a shift in the SPR-activated 2D Al QC nanostructure solution. The 1100 ppb solution shows a different dN/dI value, indicating a change in sensitivity to the nonlinear refractive index and time constant. SSPM is used to demonstrate dopamine-sensing methods and to perform qualitative and quantitative evaluations. The SSPM-based sensing has been further compared with other optical sensing methods, such as Raman Spectroscopy, UV-vis Spectroscopy, and FTIR Spectroscopy. The experimental observations are also explained using DFTB-based simulations.The current SSPM method can be used for rapid, large-scale medical diagnostics.},
}

@article {pmid42987245,
year = {2026},
author = {Matos Silva, C and Justo, AFO and Ribeiro Paes, V and Grinberg, LT and Pasqualucci, CA and Ferriolli, E and Nitrini, R and Nelson, PT and Paraizo Leite, RE and Suemoto, CK},
title = {Association of LATE-NC With Neuropathologic Lesions and Cognitive Abilities: A Population-Based Autopsy Study.},
journal = {Neurology},
volume = {107},
number = {11},
pages = {e218694},
doi = {10.1212/WNL.0000000000218694},
pmid = {42987245},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Cross-Sectional Studies ; Aged ; Autopsy ; Brazil/epidemiology ; Aged, 80 and over ; *Brain/pathology ; Hippocampal Sclerosis ; Alzheimer Disease/pathology ; *TDP-43 Proteinopathies/pathology/psychology ; *Cognition ; *Aging/pathology ; Middle Aged ; Dementia ; },
abstract = {BACKGROUND AND OBJECTIVES: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common finding in aging brains. However, most previous studies were limited to ethnoracially homogeneous cohorts from high-income countries. The objective of this study was to investigate the associations between LATE-NC, cognitive performance, and coexisting neuropathologic lesions in a large, ethnoracially and socioeconomically diverse sample from Brazil.

METHODS: This cross-sectional study analyzed data from the Biobank for Aging Studies, a Brazilian population-based autopsy study based at the University of São Paulo. The study included a consecutive series of autopsies performed between 2004 and 2024. Inclusion criteria required participants to be at least 18 years old with a knowledgeable informant. LATE-NC, Alzheimer disease neuropathologic change (ADNC), Lewy body pathology (LBP), lacunar infarcts, small vessel disease, cerebral amyloid angiopathy, and hippocampal sclerosis were assessed following international criteria. Cognitive abilities were evaluated with the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB). Logistic and linear regression models were applied to examine associations of LATE-NC with comorbid neuropathologies and cognitive outcomes, with adjustments for sociodemographic, clinical, and neuropathologic covariates.

RESULTS: The sample comprised 1,860 participants (mean age = 72.6 ± 14.2 years; 49.1% female; 62.2% White; 35.4% Black). LATE-NC was present in 7.4% of participants (stage 1: 3.0%; stage 2: 4.0%; stage 3: 0.4%). After adjustment for sociodemographic, clinical, and other neuropathologic covariates, LATE-NC (stages 2-3) was associated with hippocampal sclerosis (OR = 14.95; 95% CI 7.42-30.27; p < 0.001), advanced Braak NFT stages (OR = 2.23; 95% CI 1.32-3.83; p = 0.003), and LBP (OR = 1.89; 95% CI 1.02-3.37; p = 0.036). Factoring in other pathologies, LATE-NC was associated with the CDR-SOB score (β = 4.06; 95% CI 2.95-5.18; p < 0.001), demonstrating a consistent association with cognition, similar to the one observed for moderate/severe ADNC (β = 3.78; 95% CI 3.14-4.42; p < 0.001) in the same sample.

DISCUSSION: LATE-NC was prevalent and associated with cognitive impairment in this ethnoracially and socioeconomically diverse sample. The cross-sectional design limits causal inference, and some estimates had wide confidence intervals due to the small number of advanced-stage cases.},
}

Humans
Female
Male
Cross-Sectional Studies
Aged
Autopsy
Brazil/epidemiology
Aged, 80 and over
*Brain/pathology
Hippocampal Sclerosis
Alzheimer Disease/pathology
*TDP-43 Proteinopathies/pathology/psychology
*Cognition
*Aging/pathology
Middle Aged
Dementia

@article {pmid42987276,
year = {2026},
author = {},
title = {Statement of Retraction: Magnolol attenuates the locomotor impairment, cognitive deficit, and neuroinflammation in Alzheimer's disease mice with brain insulin resistance via up-regulating miR-200c.},
journal = {Bioengineered},
volume = {17},
number = {1},
pages = {2745454},
doi = {10.1080/21655979.2026.2745454},
pmid = {42987276},
issn = {2165-5987},
}

@article {pmid42987521,
year = {2026},
author = {Yuan, W and Jin, Q and Rong, R and Wang, X and Wang, X and Wang, X},
title = {A versatile multi-dimensional ratiometric sensor exploiting material-interface properties for t-Tau protein detection in human serum.},
journal = {Talanta},
volume = {314},
number = {},
pages = {130895},
doi = {10.1016/j.talanta.2026.130895},
pmid = {42987521},
issn = {1873-3573},
abstract = {Ratiometric sensor provides self-calibration for enhanced reliability, but conventional single-ratio designs are validated only under fixed instrumental conditions, making their reliability environment-dependent and inherently non-transferable to other analytical scenarios. Herein, we exploited the physical, chemical and interfacial changes inherent to sensor fabrication to extract multiple orthogonal signals from a single interface, constructing a versatile multi-dimensional ratiometric sensor that simultaneously enhanced accuracy and scenario adaptability. As proof of concept, this sensor was applied to detect total tau protein (t-Tau), a key Alzheimer's disease (AD) biomarker. Electrospun Fe-MOF/polyacrylonitrile nanofibers on a glassy carbon electrode served as the substrate, providing a stable redox peak current (Ip) and a photothermal temperature signal (T) as intrinsic references. Target recognition triggered a catalytic hairpin assembly that released a Ru-MOF-labeled probe, generating dynamic electrochemiluminescence (IECL) and charge-transfer resistance (Rct) responses. After blank correction, the dynamic signals were integrated with the two references to yield five independent ratiometric outputs (ΔRct/Ip, ΔRct/ΔT, ΔRct/ΔIECL, ΔIECL/ΔT, ΔIECL/Ip), all exhibiting detection limits (3.4-4.1 fg mL[-1]) three orders of magnitude below the AD diagnostic threshold (21.3 pg mL[-1]). This demonstrated each ratio as an independently valid strategy for flexible deployment across varied scenarios. Receiver operating characteristic (ROC) analysis confirmed robust discriminatory power across all five ratios (area under the ROC curve 0.80-0.95), enabling both mutual cross-validation among outputs and flexible selection of the optimal ratio for available instrumentation. Collectively, by exploiting material-interface properties, this work provided a versatile platform for accurate biomarker detection adaptable to diverse analytical scenarios and laboratory settings.},
}

@article {pmid42987558,
year = {2026},
author = {Huang, H and Li, Z and Young, CB and Smith, V and Ang, TFA and Kolachalama, VB and Au, R and Chen, J},
title = {Linguistic features from constrained spontaneous speech as potential markers of preclinical Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100689},
doi = {10.1016/j.tjpad.2026.100689},
pmid = {42987558},
issn = {2426-0266},
abstract = {BACKGROUND: Language impairment is an early sign of Alzheimer's disease (AD) that may emerge before more obvious cognitive decline. Linguistic features derived from verbal responses to cognitive tests have shown promise for identifying mild cognitive impairment and predicting AD risk; however, their relationships with established AD biomarkers remain insufficiently characterized.

OBJECTIVES: To examine relationships between a comprehensive set of linguistic features derived from logical memory delayed recall (LMDR) responses and amyloid status as well as regional tau burden among cognitively normal participants.

DESIGN: In this cross-sectional study, we evaluated associations between two types of AD biomarkers (amyloid status and regional tau burden) and linguistic features using covariate-adjusted regression models tailored to each feature's distribution (e.g., linear, negative binomial, zero-inflated beta, and gamma regression). We then used LASSO regression and the Boruta feature-selection algorithm to identify features most informative of biomarker status.

SETTING: A community-based subcohort from the Framingham Heart Study.

PARTICIPANTS: A total of 238 cognitively unimpaired participants who completed the LMDR test within 1 year before or after tau positron emission tomography (PET) were included. Of these, 228 also underwent amyloid PET and 227 had LMDR voice recordings available.

MEASUREMENTS: Verbal responses to the LMDR test were digitally recorded and manually transcribed. We extracted 54 linguistic and paralinguistic features from transcribed responses using natural language processing, capturing lexical diversity and density, syntactic complexity, semantic/information density, and speech fluency and rate. Tau SUVR values were quantified from PET imaging in 5 brain regions (amygdala, entorhinal cortex, inferior temporal [IT], inferior parietal [IP], and precuneus). Amyloid status was classified as Aβ- or Aβ+ using Gaussian mixture modeling of PiB PET DVR values. LMDR total score and participant demographics (age, sex, education) were included as covariates.

RESULTS: After adjusting for age, sex, education, amyloid status, and LMDR score, 23 linguistic features were associated with tau burden in at least one brain region. For example, reduced semantic richness, captured by lower uniqueIdeaDensity, was associated with higher tau burden across multiple regions, including the amygdala (average marginal effect (AME)=-0.007, 95% CI: (-0.013, -0.001)), entorhinal (AME=-0.007, 95% CI: (-0.013, -0.002)), IT (AME=-0.008, 95% CI: (-0.014, -0.002)), and precuneus (AME=-0.006, 95% CI: (-0.012, -1.51e^-5)). More between-utterance pauses were associated with higher tau burden in the entorhinal (AME=0.259, 95% CI: (0.026, 0.493)), IT (AME=0.272, 95% CI: (0.025, 0.518)), and IP (AME=0.404, 95% CI: (0.160, 0.648)) regions. No linguistic features were associated with amyloid status, and LMDR total score was not associated with either tau burden or amyloid status. LASSO regression selected 3-7 features per brain region, capturing multiple aspects of language use (e.g., speech disfluency and semantic density) associated with tau burden. The nonlinear Boruta algorithm selected a larger set of biomarker-informative features, including predictors of amyloid positivity, and identified additional syntactic measures (e.g., Yngve score, mean dependency distance) as important predictors of regional tau burden.

CONCLUSIONS: Linguistic features derived from neuropsychological (NP) tests capture subtle language changes associated with regional tau pathology in cognitively normal individuals, beyond conventional NP test scores. These findings highlight the potential of language-based measures as non-invasive digital biomarkers for early AD risk stratification and for supporting clinical decision-making about biomarker testing for possible preclinical AD.},
}

@article {pmid42987582,
year = {2026},
author = {Wu, AH and Wu, J and Tseng, C and Silva, SJ and Park, SL and Shariff-Marco, S and He, Q and Sangaramoorthy, M and Binder, AM and Atherwood, S and Inamdar, P and Stram, DO and Marchand, LL and Wilkens, LR and Haiman, C and Crimmins, E and Cheng, I},
title = {Long-term ambient heat and overall mortality among California participants in the Multiethnic Cohort study.},
journal = {Environment international},
volume = {217},
number = {},
pages = {110580},
doi = {10.1016/j.envint.2026.110580},
pmid = {42987582},
issn = {1873-6750},
abstract = {BACKGROUND AND OBJECTIVES: Most heat-mortality studies have investigated short-term exposures, and few studies have examined the impacts of long-term heat exposure on mortality, on an individual level. We investigated prospectively the associations of long-term average daily maximum temperature (TMMX) at residential locations, and heat waves, averaged annually for up to 25 years, with overall and cause-specific mortality.

METHODS: 88,283 California participants of the Multiethnic Cohort Study (∼70% African American and Latinos) were followed for mortality from 1993 to 1996 (baseline) through 2019. Using Cox proportional hazards models we estimated hazard ratios (HR) and 95% confidence intervals (CI) per 5°F (interquartile range) increase in time-varying TMMX adjusting for individual- and neighborhood-level, and other heat-related and adaptation factors. We investigated the modifying effects of PM2.5 and O3 and conducted various subgroup analyses.

RESULTS: Overall mortality (n = 48,272 deaths) increased 5% (HR 1.05, CI 1.03-1.08) per 5°F increase in TMMX. This statistically significant association remained when further adjusted for other climate factors. Cumulative heatwave exposures at the 75th and 90th percentile TMMX thresholds were also associated with mortality. Although formal tests for heterogeneity were not statistically significant for age, sex, race/ethnicity, neighborhood socioeconomic status (nSES), or climate zone, statistically significant associations were observed among those aged ≥ 85 (HR 1.06, CI 1.02-1.10), African American participants (HR 1.06, CI 1.01-1.11), and those living in inland climate zones (HR > 1.05). Participants in the highest tertiles of PM2.5 and O3 showed an HR of 1.52 (CI 1.30-1.78) per 5°F TMMX compared to 1.06 (CI 0.97-1.15) for those in the lowest tertiles of PM2.5 and O3. TMMX was associated with increased mortality due to Alzheimer's disease and related dementia and heart diseases.

CONCLUSION: Our findings of increased risk of all-cause and cause-specific mortality with increasing long-term average TMMX in a racially, ethnically, and socioeconomically diverse cohort provides timely evidence that sustained ambient heat as a chronic driver of mortality as well as an acute hazard. This evidence helps to inform future climate health research and intervention development.},
}

@article {pmid42987827,
year = {2026},
author = {Isacson, O and Tsai, LH and Akay, L and Platt, F and Hallett, P},
title = {Lipid homeostasis and cellular metabolism in neurodegenerative diseases: A maturing framework to guide therapeutic development.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {103130},
doi = {10.1016/j.xcrm.2026.103130},
pmid = {42987827},
issn = {2666-3791},
abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies have long been viewed through the lens of protein aggregation. Emerging evidence, however, highlights lipid transfer, load, metabolism, and cellular homeostasis as upstream drivers of pathology. This perspective integrates established neurobiological, genetic, and mechanistic evidence of lipid dysfunction and outlines how these pathways can guide patient stratification, biomarker discovery, and therapeutic development. Of critical importance, lipid transport and lysosomal and trafficking networks are at the center of cholesterol regulation, glycosphingolipid clearance, endolysosomal function, and neuron-glia lipid exchange across genetic and sporadic neurodegenerative diseases. We present an integrated framework where correcting lipid imbalances and metabolic dysregulation may complement or obviate protein-targeted approaches, creating more precise clinical trials and combination strategies. By re-centering the therapeutic focus on lipid and cellular metabolism, we aim to catalyze translational advances in neurodegenerative disease treatment.},
}

@article {pmid42988015,
year = {2026},
author = {Chai, F and Shan, Q and Hu, Y and Liu, L and Zou, J and Xia, G and Wang, Y},
title = {Sirt1 Modulates p53‑Acetylation‑Dependent Yy2‑Elf‑1‑Associated NLRP3‑Relevant Signaling in CUMS‑Evoked Aggravated Alzheimer's Disease‑Related Phenotypes.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112202},
doi = {10.1016/j.brainresbull.2026.112202},
pmid = {42988015},
issn = {1873-2747},
abstract = {Depressive disorder (DD) is recognized as an important comorbidity of Alzheimer's disease (AD) and is associated with aggravated cognitive impairment and neuroinflammatory responses; however, the underlying molecular mechanisms remain largely unknown. This study investigated the role of the Sirtuin 1 (Sirt1)/p53 acetylation/Yin-Yang 2 (Yy2)/E74-like ETS transcription factor 1 (Elf-1)/NLR family pyrin domain-containing 3 (NLRP3) axis in DD-associated AD phenotypes and evaluated the effects of resveratrol intervention. Bioinformatics analysis, CoIP-MS, ChIP-seq, and dual-luciferase assays were applied to identify and validate the regulatory relationships among these molecules. APP/PS1 double-transgenic mice subjected to chronic unpredictable mild stress (CUMS) and LPS-stimulated BV2 microglia were used as in vivo and in vitro models. Behavioral tests demonstrated that CUMS-induced depressive-like stress aggravated cognitive deficits and depression- and anxiety-related behavioral abnormalities in AD mice. Sirt1 expression was decreased, whereas acetylated p53 (ac-p53), Yy2, Elf-1, and NLRP3 levels were elevated in the hippocampus of DD+AD mice and activated BV2 microglia, accompanied by enhanced inflammatory and oxidative stress responses. Resveratrol treatment reduced p53 acetylation, suppressed the Yy2/Elf-1/NLRP3 pathway, alleviated inflammatory and oxidative stress responses, and improved behavioral deficits. Yy2 overexpression partially reversed the effects of resveratrol treatment. Collectively, our findings suggest that reduced Sirt1 expression promotes p53 acetylation and activates the Yy2/Elf‑1‑associated NLRP3‑relevant axis (the regulatory link between Elf‑1 and NLRP3 requires further experimental validation), contributing to neuroinflammatory responses and behavioural deficits in CUMS‑aggravated AD‑related phenotypes. Resveratrol treatment partially restored Sirt1‑related signalling and ameliorated these pathological manifestations, although further studies are required to determine its therapeutic potential and exclude Sirt1‑independent effects.},
}

@article {pmid42988023,
year = {2026},
author = {Wang, Y and Wang, WS and Liu, JF and Jiang, MM and Li, BH and Zhan, XK and Zhang, XT and Zhang, ZJ and Zhang, ZY and Lv, C},
title = {Gastrodin Attenuates Neuroinflammation and Depressive-Like Phenotypes via Modulation of the PHD2-HIF-1α/Glycolysis Axis.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122603},
doi = {10.1016/j.jep.2026.122603},
pmid = {42988023},
issn = {1872-7573},
abstract = {Gastrodia elata is commonly used in traditional Chinese medicine to calm the spirit, soothe the liver, and relieve depression, primarily treating central emotional disorders such as low mood and irritability caused by emotional imbalances. Our previous research has confirmed that its main active component, gastrodin, can prevent and treat Alzheimer's disease by alleviating neuroinflammation.

AIM OF THE STUDY: To explore the therapeutic effect and molecular mechanism of GAS on inflammatory depression.

MATERIALS AND METHODS: A classic LPS-induced mouse model of inflammatory depression was established, and model mice were subjected to continuous intervention with gradient doses of GAS to explore dose-dependent therapeutic effects. Multiple behavioral paradigms were applied to comprehensively evaluate depressive-like behaviors, while cortical histopathological staining was performed to assess neuronal injury and brain tissue lesions. High-throughput multi-omic screening and single-cell transcriptomic profiling were further utilized to screen key functional genes, metabolic pathways, and microglial phenotypic alterations. Combined with HIF-1α pharmacological rescue experiments, the core molecular pathway mediated by GAS was systematically verified.

RESULTS: Behavioral and pathological detection results confirmed that GAS treatment significantly and dose-dependently relieved LPS-induced depressive-like behaviors and alleviated neuronal damage and structural lesions in the prefrontal cortex. Network pharmacology and untargeted metabolomics indicated that gastrodin modulates HIF-1α-related pathways. Single-cell analyses further highlighted the critical role of microglia, with elevated Egln1 (PHD2) transcript abundance specifically detected in surveillance microglia. Mechanistic assays further validated that GAS markedly upregulated PHD2 activity, which facilitated the ubiquitination and proteasomal degradation of HIF-1α, thereby effectively reversing neuroinflammation-triggered aberrant cerebral glycolysis and potentially contributing to the restoration of brain metabolic homeostasis.

CONCLUSIONS: GAS alleviates inflammatory depression by modulating the PHD2-HIF-1α-glycolysis axis in a microglial subtype-dependent manner, providing a novel targeted strategy for inflammatory depression.},
}

@article {pmid42988058,
year = {2026},
author = {Huang, Q and Chen, Y and Liu, Y and Lv, Y and Xie, X and Liyang, C and Tong, F and Gao, H and Sun, J},
title = {Masitinib-loaded poly(lactic-co-glycolic acid) nanoparticles reinstate lysosomal acidification and drive immunomodulation in Alzheimer's disease.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {115518},
doi = {10.1016/j.jconrel.2026.115518},
pmid = {42988058},
issn = {1873-4995},
abstract = {Alzheimer's disease (AD) poses a formidable therapeutic challenge due to its intricate pathological mechanisms and the blood-brain barrier (BBB). Via transcriptomic analyses and experimental validation, we identify that a malignant neuro-immune pathological cycle, driven by neuronal lysosomal acidification dysfunction and microglial immune activation, potently accelerates AD pathogenesis. Then, we engineer a simple bifunctional intranasal delivery system (PLGA@M) by loading masitinib into poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Following intranasal administration, PLGA@M bypasses the BBB to enter the brain directly via olfactory and trigeminal nerves. PLGA degrades to release acidic moieties, lowering lysosomal pH and restoring autophagic flux, while masitinib inhibits microglial colony stimulating factor 1 receptor signaling, attenuating microglial proliferation, excessive activation and neuroinflammation. Behavioral assays confirm that PLGA@M markedly reverses cognitive deficits in AD mice. This system upgrades PLGA from a mere carrier to a therapeutic component, featuring simplicity, high efficiency and great clinical translation potential.},
}

@article {pmid42988190,
year = {2026},
author = {Huang, E and He, Y and Ran, X and Lin, B and Zhang, Y and Liao, H},
title = {RDP-modified extracellular vesicles from brain organoid-derived mesenchymal stem cells improve the behavior and pathology of 5×FAD mice.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109739},
doi = {10.1016/j.phrs.2026.109739},
pmid = {42988190},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which treatment options remain limited. Extracellular vesicles (EVs) offer a potential cell-free therapeutic approach, but limited brain exposure after systemic administration remains a major obstacle. Mesenchymal stem-like cells derived from human brain organoids (hBO-MSCs) may provide an alternative EV source with a molecular profile shaped by the neural culture environment. This study aimed to generate RDP-modified hBO-MSC-EVs and evaluate their physicochemical characteristics, acute safety, brain-associated biodistribution, and treatment-associated effects in the 5×FAD mouse model of AD. hBO-MSCs were isolated from dorsal forebrain-like human brain organoids and engineered to express an RDP-Lamp2b-HA fusion protein. EV preparations were characterized by morphology, particle measurements, EV-associated protein markers, and relative RDP-Lamp2b-HA abundance. Brain-associated biodistribution and acute safety were assessed in C57BL/6J mice, whereas treatment-associated outcomes were evaluated in 5×FAD mice receiving PBS, unmodified hBO-MSC-EVs, or hBO-MSC-RDP-EVs. Behavioral testing, hippocampal Aβ histopathology, and exploratory transcriptomic profiling were used to assess the response. Following intravenous administration, RDP modification was associated with greater brain-associated fluorescence than unmodified EVs, without evidence of overt acute organ histopathology or a consistent systemic pro-inflammatory response at the tested endpoints. In 5×FAD mice, hBO-MSC-RDP-EV treatment was associated with improvements in selected behavioral measures, most consistently in the Morris water maze, together with reduced histologically detectable hippocampal Aβ plaque burden and changes in inflammation- and neuronal-associated transcripts. These findings warrant further preclinical evaluation of surface-engineered hBO-MSC-EVs as a candidate cell-free approach for AD. Intact-EV blood-brain barrier transport, cargo-dependent mechanisms, source-specific advantages, and long-term safety remain unestablished.},
}

@article {pmid42411937,
year = {2026},
author = {Brown, SC and Dewald, JR and Rundle, AG and Tom, S and Rundek, T and Ma, R and Zarnegarnia, Y and Szpiro, AA and Lombard, J and Elkind, MSV and Szapocznik, J},
title = {Design and procedures for the greenness, cognitive performance and vascular outcomes in the Northern Manhattan Study.},
journal = {American journal of epidemiology},
volume = {195},
number = {11},
pages = {2959-2971},
doi = {10.1093/aje/kwag155},
pmid = {42411937},
issn = {1476-6256},
support = {K12TR004555//the National Center for Advancing Translational Sciences through the Clinical and Translational Science Institute/ ; UL1TR002736//the National Center for Advancing Translational Sciences through the Clinical and Translational Science Institute/ ; 1R01AG074306//US National Institutes of Health/National Institute on Aging/ ; },
mesh = {Humans ; *Cognition ; New York City/epidemiology ; Aged ; Female ; Male ; Middle Aged ; Prospective Studies ; Aged, 80 and over ; *Neighborhood Characteristics/statistics & numerical data ; Research Design ; Longitudinal Studies ; *Residence Characteristics/statistics & numerical data ; },
abstract = {The Greenness, Cognitive Performance, and Vascular Outcomes in the Northern Manhattan Study investigates the protective effects of cumulative residential greenness exposure on cognitive performance and vascular outcomes, from 1993-2023. Greenness is quantified using satellite-derived Normalized Difference Vegetation Index (NDVI) within 250-meter residential buffers. For each participant, up to 35 years of greenness exposure data are used, with a median of 15.7 years of vascular follow-up, (i.e. adjudicated stroke, myocardial infarction, and vascular death) and among those with repeated testing, using comprehensive neurocognitive measures a median of 5.1 between the first and second assessments and 12.3 years between the first and third measures. The main sample's median age was 69.2 years at baseline (range=40-107). The study will prospectively examine: (1) associations of cumulative greenness with cognitive and vascular outcomes; (2) mediation through behavioral, cardiometabolic, inflammatory, and vascular brain imaging biomarkers; and (3) effect modification by individual and neighborhood factors. Additional aims include: (4) longitudinal associations of greenness with brain reserve; (5) moderation by brain reserve in greenness-cognition relationships; and (6) associations with adjudicated Mild Cognitive Impairment, Alzheimer's disease, and related dementias.},
}

Humans
*Cognition
New York City/epidemiology
Aged
Female
Male
Middle Aged
Prospective Studies
Aged, 80 and over
*Neighborhood Characteristics/statistics & numerical data
Research Design
Longitudinal Studies
*Residence Characteristics/statistics & numerical data

@article {pmid42838742,
year = {2026},
author = {Dixit, SB and Czernecki, C and Riezman, I and Innocenti, S and Bornmann, C and Guérard, L and Pfrieger, FW and Riezman, H and Scheiffele, P},
title = {Cell Type-Specific Assessment of Cholesterol Distribution in Models of Neurodevelopmental Disorders.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {46},
number = {44},
pages = {},
doi = {10.1523/JNEUROSCI.1339-26.2026},
pmid = {42838742},
issn = {1529-2401},
mesh = {Animals ; *Cholesterol/metabolism ; *Neurodevelopmental Disorders/metabolism/pathology/genetics ; Mice ; Female ; Male ; Mice, Knockout ; Disease Models, Animal ; *Brain/metabolism/pathology ; Niemann-Pick C1 Protein ; *Neurons/metabolism ; Mice, Inbred C57BL ; Intracellular Signaling Peptides and Proteins ; },
abstract = {Most nervous system disorders manifest through alterations in neuronal signaling based on abnormalities in neuronal excitability, synaptic transmission, and cell survival. However, such neuronal phenotypes are frequently accompanied or even caused by metabolic dysfunctions in neuronal or non-neuronal cells. The tight packing and highly heterogeneous properties of neural, glial, and vascular cell types pose significant challenges to dissecting metabolic aspects of brain disorders. Perturbed cholesterol homeostasis has recently emerged as a key parameter associated with subsets of neurodevelopmental disorders and neurodegeneration. However, approaches for tracking and visualizing endogenous cholesterol distribution in the brain have limited capability of resolving cell type-specific differences. We here develop tools for genetically encoded sensors that report on accessible cholesterol distribution in the mouse brain with cellular resolution. We apply these probes to examine subcellular cholesterol accumulation in two genetic mouse models of brain disorders, male Ptchd1 knock-out and male and female Npc1 knock-out mice. While both genes encode proteins with sterol-sensing domains that have been implicated in cholesterol transport, we uncover highly selective and cell type-specific phenotypes in cholesterol homeostasis. The tools established in this work should facilitate probing subcellular cholesterol distribution in complex tissues like the mammalian brain and enable capturing cell type-specific alterations in cholesterol flow between cells in models of brain disorders.},
}

Animals
*Cholesterol/metabolism
*Neurodevelopmental Disorders/metabolism/pathology/genetics
Mice
Female
Male
Mice, Knockout
Disease Models, Animal
*Brain/metabolism/pathology
Niemann-Pick C1 Protein
*Neurons/metabolism
Mice, Inbred C57BL
Intracellular Signaling Peptides and Proteins

@article {pmid42976852,
year = {2026},
author = {Horvath, TL and Romanov, R and Matarese, G and Cota, D},
title = {Hypothalamus-driven brain health through metabolic flexibility.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.028},
pmid = {42976852},
issn = {1097-4199},
abstract = {Organismal physiology depends on continuous, non-hierarchical communication among cells, tissues, and organs. We argue that this communication rests on metabolic flexibility-the capacity of cells and tissues to adapt substrate use to changing energetic demands-and that the hypothalamus serves as the central hub coordinating this flexibility across the body. Using hypothalamic agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons as a model, we show these melanocortin neurons do more than regulate hunger and satiety: by integrating metabolic, hormonal, and immune signals, they shape reward, learning, executive function, and social behavior, while imposing coordinated metabolic states on peripheral tissues. When this flexibility is lost, as with aging or overnutrition, body-brain communication becomes rigid, driving cognitive decline, chronic inflammation, and neurodegenerative disease. We propose that signals from the body are not peripheral modifiers of brain function but fundamental determinants of it, with direct implications for hypothalamus-centered strategies to preserve brain health across the lifespan.},
}

@article {pmid42977184,
year = {2026},
author = {Afkhami, H and Yousefi, MH and Zarei Taher, T and Mahmoudvand, G and Rezaei, P and Salehi, S and Fath-Bayati, L and Hosseinzadeh, F},
title = {CD4[+] T Cell Subsets in CNS Disorders: Pathogenic Roles, Immune Dysregulation, and Therapeutic Perspectives.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {115219},
doi = {10.1016/j.yexcr.2026.115219},
pmid = {42977184},
issn = {1090-2422},
abstract = {The central nervous system (CNS), previously considered immune-isolated due to the blood-brain barrier (BBB) and absence of lymphatic drainage, is now understood as a dynamic interface with the peripheral immune system. CNS neurons and glia actively modulate immune responses, and circulating T cells survey and sometimes infiltrate this privileged site. While essential for host defense and tissue homeostasis, dysregulated immune surveillance may contribute to chronic neuroinflammation and, in specific disease contexts, autoimmune pathology. A key question is how T cell responses are initiated in the CNS, given its limited antigen presentation. This review synthesizes current evidence on the pathogenic and protective roles of Th1, Th2, Th17, and Treg cells across autoimmune demyelinating and neurodegenerative CNS disorders, with a focus on multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD). We also evaluate emerging T cell-targeted immunotherapies and their potential to rebalance CNS immunity and impede disease progression.},
}

@article {pmid42977507,
year = {2026},
author = {Li, M and Xu, D and Li, Y and Zhao, Q},
title = {Mitochondria-Associated Membranes as a Convergent Hub of Brain Aging: From Neurodegeneration to Cerebral Ischemia.},
journal = {The European journal of neuroscience},
volume = {64},
number = {9},
pages = {},
doi = {10.1111/ejn.70746},
pmid = {42977507},
issn = {1460-9568},
support = {CY2024-MS-A05//Lanzhou University Second Hospital/ ; CY2023-MS-A01//Lanzhou University Second Hospital/ ; 82660095//National Natural Science Foundation of China/ ; GSWSQNPY2024-13//Major Scientific and Technological Innovation Project of the Gansu Provincial Health Sector/ ; 2022RCCX0023//Science and Technology Planning Project of Chengguan District/ ; 2025B-017//Gansu Provincial Department of Education/ ; },
mesh = {Humans ; *Aging/metabolism/pathology ; *Mitochondria Associated Membranes/metabolism ; *Brain Ischemia/metabolism/pathology ; Animals ; *Brain/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; },
abstract = {Brain aging is the principal risk factor for both neurodegenerative diseases (NDDs) and cerebral ischemic disorders, yet the subcellular mechanisms linking these conditions remain incompletely defined. Mitochondria-associated membranes (MAMs)-specialized contact sites between the endoplasmic reticulum (ER) and mitochondria-sit at the intersection of two well-established hallmarks of aging, mitochondrial dysfunction, and loss of proteostasis, making them an attractive mechanistic node for understanding age-related brain decline. In this review, we propose a MAM-centered framework that unifies neurodegenerative and ischemic brain pathology under the broader paradigm of brain aging. We first summarize the molecular architecture of MAMs and their core functions in neuronal Ca[2+] transfer, mitochondrial dynamics, lipid metabolism, inflammasome assembly, and autophagic quality control, together with emerging evidence from non-neuronal brain cells. We then examine how MAM dysfunction intersects with five hallmarks of aging-mitochondrial dysfunction, loss of proteostasis, disabled macroautophagy, chronic inflammation (inflammaging), and altered intercellular communication-drawing on evidence from physiological aging and cellular senescence models. Next, we discuss disease-specific roles of MAMs in cerebral ischemia and in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. A central theme emerges: Rather than a unidirectional decline of MAMs, brain aging is associated with a loss of MAM homeostasis, in which both insufficient and excessive ER-mitochondria coupling can be pathological and the shared deficit is the failure to maintain contact-site function within an optimal range. Finally, we consider age-relevant therapeutic and biomarker strategies targeting MAMs and their potential translation into geriatric neurology. To our knowledge, this is the first review to integrate MAM biology across physiological brain aging, cerebral ischemia, and the four major NDDs within a single homeostatic framework, offering a unified perspective on the mechanisms of age-related brain decline.},
}

Humans
*Aging/metabolism/pathology
*Mitochondria Associated Membranes/metabolism
*Brain Ischemia/metabolism/pathology
Animals
*Brain/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Mitochondria/metabolism/pathology

@article {pmid42977753,
year = {2026},
author = {Tuunanen, J and Hautamäki, K and Väyrynen, T and Järvelä, M and Korhonen, V and Huotari, N and Kaakinen, M and Kananen, J and Helakari, H and Raitamaa, L and Jukkola, J and Herukka, SK and Laurén, K and Salmi, U and Eklund, L and Nikkinen, J and Nedergaard, M and Kiviniemi, V},
title = {Vasomechanic treatment is associated with increased efflux of human brain proteins.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42977753},
issn = {2041-1723},
support = {360508//Academy of Finland (Suomen Akatemia)/ ; TERVA grants 1-2//Academy of Finland (Suomen Akatemia)/ ; 275342//Academy of Finland (Suomen Akatemia)/ ; 338599//Academy of Finland (Suomen Akatemia)/ ; 314497//Academy of Finland (Suomen Akatemia)/ ; 335720//Academy of Finland (Suomen Akatemia)/ ; R01AT012312//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AT011439//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U19NS128613//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 00018024//Simons Foundation/ ; NNF20OC0066419//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; R386-2021-165//Lundbeckfonden (Lundbeck Foundation)/ ; R523-2025-1486//Lundbeckfonden (Lundbeck Foundation)/ ; R523-2025-1486//Lundbeckfonden (Lundbeck Foundation)/ ; 2022-120//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; 1//Jane ja Aatos Erkon Säätiö (Jane and Aatos Erkko Foundation)/ ; 210043//Jane ja Aatos Erkon Säätiö (Jane and Aatos Erkko Foundation)/ ; },
mesh = {Humans ; Female ; *Brain/metabolism/diagnostic imaging/blood supply ; Male ; Adult ; *Nitric Oxide/administration & dosage/metabolism ; Amyloid beta-Peptides/metabolism/blood ; Middle Aged ; Glial Fibrillary Acidic Protein/blood/metabolism ; Aged ; Biomarkers/blood ; Young Adult ; Alzheimer Disease/metabolism/therapy ; Vasoconstriction/physiology ; Vasodilation ; Ion Channels/metabolism ; Peptide Fragments ; },
abstract = {An age-related neurovascular impairment in nitric oxide (NO)-mediated vasodilation and reciprocal Piezo1-dependent vascular vasoconstriction may precede the accumulation of soluble brain proteins such as amyloid-β (Aβ) and disruption of brain fluid homeostasis in Alzheimer's disease (AD). Preclinical studies suggest that restoring these pathways can enhance neurofluid transport and improve cognitive outcomes. In this study (EudraCT 2021-000625-27), we investigated the effects of sublingual NO and Piezo1-targeted whole-body vibrations (WBVp) in healthy adults (n = 29) using multimodal neuroimaging and blood biomarker analysis. The combined intervention (NO+WBVp) was associated with correlating changes in brain fluid dynamics and increased blood levels of soluble brain-derived proteins (Aβ40&42, GFAP). These effects increased with age and the magnitude of NO-induced hypotension. The interventions were well tolerated under controlled experimental conditions. Overall, the findings are consistent with transient redistribution of brain-derived proteins toward circulation, suggesting a potential non-invasive approach to increase neurofluidic solute efflux in humans. Pre-specified primary endpoints, changes in circulating brain-derived protein concentrations, brain fluid imaging and brain pulsation measures, were met. Secondary outcomes included physiological analyses.},
}

Humans
Female
*Brain/metabolism/diagnostic imaging/blood supply
Male
Adult
*Nitric Oxide/administration & dosage/metabolism
Amyloid beta-Peptides/metabolism/blood
Middle Aged
Glial Fibrillary Acidic Protein/blood/metabolism
Aged
Biomarkers/blood
Young Adult
Alzheimer Disease/metabolism/therapy
Vasoconstriction/physiology
Vasodilation
Ion Channels/metabolism
Peptide Fragments

@article {pmid42978183,
year = {2026},
author = {Shirani, A and Stopschinski, BE and Herz, J and Calvier, L and Stuve, O},
title = {Lower recorded prevalence of Alzheimer's disease in natalizumab-exposed older adults with multiple sclerosis: A hypothesis-generating observation.},
journal = {Multiple sclerosis (Houndmills, Basingstoke, England)},
volume = {},
number = {},
pages = {13524585261499995},
doi = {10.1177/13524585261499995},
pmid = {42978183},
issn = {1477-0970},
abstract = {Adaptive immune mechanisms, including CD8 T cell-mediated neuroinflammation, are increasingly implicated in Alzheimer's disease. We examined whether exposure to natalizumab, an α4-integrin antagonist that restricts leukocyte trafficking into the central nervous system, was associated with Alzheimer's disease prevalence among older adults with multiple sclerosis. Using Epic Cosmos electronic health record data, we identified 875,226 individuals with MS, of whom 9095 had an Alzheimer's disease diagnosis after age 65 years. Alzheimer's disease prevalence differed significantly across disease-modifying therapies, with natalizumab-treated patients demonstrating the lowest prevalence (0.13%; 95% confidence interval: 0.10-0.17%). These findings demonstrate a lower recorded prevalence of late-life Alzheimer's disease among natalizumab-exposed patients; however, given the aggregated nature of the data, this observation should be considered descriptive and hypothesis-generating.},
}

@article {pmid42978226,
year = {2026},
author = {Pitz, ME and Mickol, RL and Pyles, CG and Brown, SM and Fidler, AP and Fears, KP and Beasley, MA},
title = {Methods for Identification and Structural Characterization of Tau Polymorphs in Neurodegenerative Disease.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.10.034},
pmid = {42978226},
issn = {1542-0086},
abstract = {Tauopathies are neurodegenerative diseases associated with the misfolding and aggregation of the tau protein in the brain, including Alzheimer's Disease (AD) and Chronic Traumatic Encephalopathy (CTE). Current medical technology is only able to definitively diagnose tauopathies post-mortem, which limits patient treatment options and reduces quality of life. Structural differences related to specific tauopathies ultimately result in unique disease progression and require unique treatments. In particular, CTE-related tauopathies are relatively understudied compared to AD. To improve diagnosis and treatment options for patients with CTE, it is essential to understand the role of tau in disease onset and progression. Experimental methods such as atomic force microscopy (AFM) and computational methods such as molecular dynamics simulations have been used to gain an understanding of pathological tau structure and mechanics. Spectroscopy and molecular probes have also been effective in revealing mechanisms of tau aggregation. State-of-the-art methods such as cryogenic electron microscopy and two-dimensional infrared spectroscopy (2DIR) are now being used to further explore tau at atomic resolution. In this review, we discuss the current state of both experimental and computational strategies in the assessment of tauopathies, specifically related to structural characterization. We highlight technological advances in relevant methods, such as AFM and 2DIR, that are pivotal to our understanding of structural amyloid formation and progression ante-mortem.},
}

@article {pmid42978234,
year = {2026},
author = {Björk, L and Vidal, R and Ghetti, B and Lindgren, M and Klingstedt, T and Nilsson, KPR},
title = {Amino Acid Functionalization Influences the Binding of Thiophene-Vinylene-Benzothiazolium-Based Fluorescent Ligands to Protein Deposits in Tissue Sections With Alzheimer's Disease Pathology.},
journal = {ChemMedChem},
volume = {21},
number = {21},
pages = {},
pmid = {42978234},
issn = {1860-7187},
support = {2RF1NS110437-06/NH/NIH HHS/United States ; P30-AG010133/NH/NIH HHS/United States ; P30-AG072976/NH/NIH HHS/United States ; 2023-03275//Vetenskapsrådet/ ; FO2022-0072//Hjärnfonden/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism/diagnostic imaging ; Ligands ; Humans ; *Thiophenes/chemistry ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *Benzothiazoles/chemistry ; *Amino Acids/chemistry ; *Fluorescent Dyes/chemistry/chemical synthesis ; Brain/pathology/metabolism ; Protein Binding ; Molecular Structure ; Protein Aggregates ; Fluorescent Chemosensor Compounds ; },
abstract = {Detecting and distinguishing between structurally diverse protein aggregates involved in various neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), remain key challenges in the development of molecular imaging tools. Recently, bi-thiophene-vinyl-benzothiazoliums (bTVBTs), a class of thiophene-based optical ligands, were synthesized and shown to enable selective labeling of tau pathology in AD brain tissue. Building on this framework, we report here the design and evaluation of a novel series of bTVBT ligands functionalized with L-amino acids (glycine, alanine, valine, tyrosine, or glutamate) to explore their influence on ligand-filament interactions. When applied to sporadic AD brain tissue sections, the ligands displayed preferential binding to tau deposits when using 100 nM ligand, whereas all ligands bound to both amyloid-β (Aβ) and tau aggregates at higher concentrations. The glycine-functionalized bTVBT scaffold demonstrated the strongest fluorescence upon binding and was labeling all types of tau inclusions present in sAD brain tissue, whereas the glutamate-functionalized ligand was the least potent. Thus, the chemical nature of the amino acid influenced the binding mode of the ligand to protein deposits. The observed trend in the ligands' binding mode to the protein aggregates could also be correlated with distinct solvatochromic effects, indicating that certain amino acid side chains interfere with favorable interligand π-π stacking, thereby reducing binding specificity. Collectively, these results pinpoint that minor chemical alterations of the bTVBT scaffold influence the binding mode of the ligands to protein deposits, and we foresee that our findings will aid in designing ligands targeting proteinaceous aggregated species in AD and related neurodegenerative diseases.},
}

*Alzheimer Disease/pathology/metabolism/diagnostic imaging
Ligands
Humans
*Thiophenes/chemistry
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
*Benzothiazoles/chemistry
*Amino Acids/chemistry
*Fluorescent Dyes/chemistry/chemical synthesis
Brain/pathology/metabolism
Protein Binding
Molecular Structure
Protein Aggregates
Fluorescent Chemosensor Compounds

@article {pmid42978421,
year = {2026},
author = {Chiaravalloti, A and Schillaci, O},
title = {Cerebral amyloid PET in obstructive sleep apnoea: a systematic review and exploratory meta-analysis.},
journal = {Nuclear medicine communications},
volume = {},
number = {},
pages = {},
doi = {10.1097/MNM.0000000000002256},
pmid = {42978421},
issn = {1473-5628},
abstract = {This study aimed to evaluate cerebral amyloid-PET findings in adults with obstructive sleep apnoea (OSA), account for overlapping cohorts, and quantify global cortical amyloid burden where outcomes were commensurable. PubMed, Scopus, and Web of Science were searched from inception to 17 July 2026 for adult human studies relating OSA or sleep-disordered breathing to cerebral amyloid PET. One estimate per independent data source was retained. The second author independently verified eligibility, cohort independence, extracted quantitative data, and risk-of-bias judgements for all reports entering any quantitative model. Global outcomes were pooled as Hedges' g using restricted maximum-likelihood random-effects models with modified Hartung-Knapp confidence intervals. Fifteen reports representing 12 independent data sources were included. Tracers, reference regions, partial-volume correction, OSA ascertainment, and cognitive status varied substantially. Three global-outcome cohorts of cognitively unimpaired participants (n = 291) yielded g = 0.42 (95% confidence interval, -0.14 to 0.99; I2 = 0%). In a secondary analysis, adding one cohort with established Alzheimer's disease yielded g = 0.54 (95% confidence interval, 0.22-0.86; n = 471; I2 = 0%). A sensitivity model adding one selected regional 11C-PiB estimate yielded g = 0.47 (95% confidence interval, 0.17-0.78). In a secondary analysis combining cognitively unimpaired adults and patients with established Alzheimer's disease, OSA was associated with higher global cerebral amyloid-PET burden. However, the primary evidence in cognitively unimpaired adults remains imprecise, and longitudinal studies do not consistently demonstrate an association between conventional OSA severity and amyloid accumulation.},
}

@article {pmid42978515,
year = {2026},
author = {Sy, J and Tsiknia, A and Sussman, BL and Ali, N and Villarreal, I and Juarez, M and Estrada, JG and Nikkhah Bahrami, S and Ganesan, S and Nimmo, S and Jann, K and Wang, DJJ and Borzage, MT and Braskie, MN and Yassine, HN},
title = {Brain Mechanisms Linking Type 2 Diabetes to Alzheimer Disease: A Multimodal Imaging Framework.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000756},
pmid = {42978515},
issn = {1546-4156},
abstract = {Type 2 diabetes mellitus is associated with an increased risk of Alzheimer disease and cognitive impairment; however, the mechanisms underlying these associations remain incompletely understood. Here, we propose and justify a mechanistic, multimodal imaging framework to examine how type 2 diabetes-associated hyperglycemia and neurovascular dysfunction may contribute to cognitive vulnerability and accelerated brain aging. Dynamic metabolic stress testing using multimodal glucose-challenge imaging methods is proposed as the central component of this framework to investigate cerebral blood flow, blood-brain barrier integrity, metabolic demand, functional connectivity, and structural brain alterations under conditions of acute hyperglycemia. By examining these complementary neurovascular and metabolic responses together, rather than as individual imaging measures, this proposed approach is intended as a mechanistic discovery platform to identify neurovascular pathways linking type 2 diabetes mellitus-related dysglycemia with cognitive vulnerability in a population with a high burden of metabolic risk. By integrating current mechanistic evidence with a proposed multimodal imaging approach, this work aims to generate testable mechanistic hypotheses and inform future biomarker-driven and longitudinal studies of diabetes-related dementia risk.},
}

@article {pmid42978683,
year = {2026},
author = {Lee, H and Kumar, V and Shin, SJ and Nam, Y and Jang, S and Kim, HS and Lee, M and Song, GY and Lim, EK and Chae, HJ and Moon, M},
title = {Integrated computational screening and biochemical validation identify natural small molecules targeting Aβ aggregation and dissociation.},
journal = {Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques},
volume = {29},
number = {},
pages = {17216},
pmid = {42978683},
issn = {1482-1826},
mesh = {*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry ; Molecular Docking Simulation ; Humans ; Blood-Brain Barrier/metabolism ; Alzheimer Disease/drug therapy/metabolism ; *Small Molecule Libraries/pharmacology/chemistry ; Protein Aggregates/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ), a pathological hallmark implicated in disease onset and progression. Aβ undergoes self-assembly from monomers into soluble oligomers, protofibrils, insoluble fibrils, and extracellular plaques. Our previous studies have shown that Jowiseungchungtang, which consists of 14 medicinal herbs, inhibits Aβ aggregation and ameliorates Aβ-mediated pathology in AD models. However, the active small molecules underlying these effects remain unidentified. To identify small molecules from these 14 medicinal herbs, we constructed a library of 1,751 compounds and applied an integrated in silico and in vitro workflow. First, these 1,751 compounds were filtered based on drug-likeness and predicted blood-brain barrier permeability, yielding 566 candidates. Second, molecular docking of 566 selected compounds against Aβ conformers identified five candidates predicted to interact with aggregation-prone residues critical for Aβ aggregation and fibril stabilization. Third, Thioflavin T assays demonstrated that four compounds-1-monopalmitin, isobutyl octyl oxalate, pentadecanoic acid, and dimethyl azelate-significantly inhibited Aβ42 aggregation. Additionally, isobutyl octyl oxalate and pentadecanoic acid disaggregated preformed Aβ42 aggregates. Fourth, molecular dynamics simulations were performed to examine the short-timescale behavior of the candidate compounds with the Aβ17-42 dimer, showing transient ligand-Aβ interactions associated with structural rearrangements at the dimer interface. Pharmacokinetic predictions supported drug-likeness, showing blood-brain barrier permeability and systemic clearance. Collectively, these findings identify four Jowiseungchungtang (JWS)-derived candidate compounds with Aβ aggregation-inhibitory activity and provide a mechanistic and pharmacokinetic basis for further development of these compounds as potential therapeutic agents in AD.},
}

*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry
Molecular Docking Simulation
Humans
Blood-Brain Barrier/metabolism
Alzheimer Disease/drug therapy/metabolism
*Small Molecule Libraries/pharmacology/chemistry
Protein Aggregates/drug effects

@article {pmid42978767,
year = {2026},
author = {Melonashi, E and Vilaça, M and Pereira, MG},
title = {Editorial: Caregiver burden in Alzheimer's and other chronic conditions.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {2007129},
doi = {10.3389/fpsyg.2026.2007129},
pmid = {42978767},
issn = {1664-1078},
}

@article {pmid42978812,
year = {2026},
author = {Sankhe, K and Vellone, D and Guan, DX and Creese, B and Ismail, Z and Kumar, S and Lanctôt, KL and Mortby, ME and de Oliveira, FF and Sinclair, L and Gatchel, J and Munro, CE},
title = {Neuropsychiatric symptoms across the revised Alzheimer's disease clinical staging framework: A review of current evidence and implications.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70510},
pmid = {42978812},
issn = {2352-8729},
abstract = {The field of Alzheimer's disease (AD) research has seen major advances in understanding manifestations of AD-related neuropsychiatric symptoms (NPS), including recent addition of NPS to the 2024 National Institute of Aging-Alzheimer's Association (NIA-AA) clinical staging framework. This focused review highlights key publications (49 in 2024; 28 in 2025) indexed in MEDLINE examining AD-related NPS, in alignment with the Scale for the Assessment of Narrative Review Articles guidelines. Data were thematically organized across NIA-AA clinical stages, with emphasis on measurement, diagnosis, and biomarker-cognition correlates of AD-related NPS. Together, these findings can inform future research and clinical practice through enhanced understanding of AD-related NPS and their relationships with pathology and clinical outcomes. Finally, three key priorities were identified for future research: (1) incorporating sex/gender and ethnocultural diversity; (2) integrating NPS assessment with cognitive, fluid, and neuroimaging biomarkers; and (3) including perspectives of individuals with lived experience to support personalized NPS management.},
}

@article {pmid42978977,
year = {2026},
author = {Biondo, N and Suntay, JM and Mandelli, ML and Sandhu, M and Estaban, JS and Pillai, J and Mamuyac, E and Reyes, RJ and Guevarra, A and Henry, ML and Dronkers, NF and Gorno-Tempini, ML and Grasso, SM and de Leon, J},
title = {Cognitive and brain reserve in bilingual speakers with clinical AD variants.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70506},
pmid = {42978977},
issn = {2352-8729},
abstract = {INTRODUCTION: Bilingualism may confer resilience through enhanced neural integrity. However, evidence for its neuroprotective effect is mixed, and studies across Alzheimer's disease (AD) variants are limited. This study examined gray matter volume (GMV) differences between bilinguals and monolinguals with amnestic AD and logopenic variant primary progressive aphasia (lvPPA).

METHODS: In 125 amnestic AD and 78 lvPPA participants with neuropsychological assessments and structural magnetic resonance imaging, we analyzed GMV differences between monolinguals and bilinguals within each variant, adjusting for demographic covariates.

RESULTS: In amnestic AD, bilinguals showed lower GMV than monolinguals in several regions, including bilateral fusiform and right occipital regions, after correction for multiple comparisons. In lvPPA, regional differences did not survive correction for multiple comparisons, although at the nominal threshold, bilinguals showed lower GMV in temporal and occipital regions and greater GMV in inferior parietal regions. Cognitive performance was comparable between monolinguals and bilinguals within each group.

DISCUSSION: Comparable cognitive performance despite lower GMV is consistent with a potential role of bilingualism in cognitive reserve. The observed regional patterns in lvPPA are exploratory and require replication in a larger sample.},
}

@article {pmid42979005,
year = {2026},
author = {Shukla, R and Bhattacharya, S and Singh, TR},
title = {Identification of potential inhibitors against monoamine oxidase (MAO-B) using an integrative chemoinformatics approach: a lead against neurodegenerative disorder.},
journal = {In silico pharmacology},
volume = {14},
number = {3},
pages = {278},
pmid = {42979005},
issn = {2193-9616},
abstract = {UNLABELLED: The Monoamine Oxidase-B (MAO-B) is a flavin adenine dinucleotides enzyme found in the brain, intestine liver, and placenta. Recently MAO-B has drawn important attention for neurodegenerative disease treatment. Firstly, the Smina-A fork of AutoDock Vina and idock tools were used for the screening of 98,072 compounds. Based on a binding cut-off of >= - 11.5 Kcal/mol, the potential inhibitors were selected and evaluated through the ADMET filters. The ADMET analysis revealed that 18 compounds were best in the pharmacokinetics descriptors evaluation hence we have used the cross-docking approach to confirm the virtual screening result for these 18 compounds. Cross-docking results revealed that four compounds showed a higher binding affinity and interaction with the key catalytic residues. Hence, we have taken these four hits and employed them for the MDS analysis. The MAO-B-RGZ, MAO-B-ZINC2147610, MAO-B-ZINC4237106, MAO-B-ZINC4701203 and MAO-B-ZINC5818772 showed - 67.45, - 103.75, - 88.39, - 96.27 and - 104.11 kJ/mol binding free energy. The overall result of docking, MDS, and binding free energy showed that all the predicted leads are favorable towards the MAO-B binding site. Therefore, we have proposed that ZINC2147610, ZINC4237106, ZINC4701203, and ZINC5818772 as potential hit compounds against MAO-B to open a new gate for the neurodegenerative disease treatment. However, experimental validation is necessary to confirm their biological activity, binding affinity, and therapeutic potential before they can be advanced as putative hits.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00783-5.},
}

@article {pmid42979019,
year = {2026},
author = {Sandoval-Boczkowska, O and Best, JR and Smith, RJY and Burns, L and Helbling, C and Hsiung, GR and Pettersen, JA and Lee, PE and Henri-Bhargava, A and Nygaard, HB and DeMarco, ML},
title = {Multi-platform comparison of plasma phosphorylated tau assays: analytical and workflow factors drive clinical implementation decisions.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70465},
pmid = {42979019},
issn = {2352-8729},
abstract = {INTRODUCTION: Multiple plasma phosphorylated tau assays are now commercially available for Alzheimer's disease (AD), yet clinical laboratories lack comprehensive comparative data to guide implementation.

METHODS: We assessed diagnostic accuracy and analytical performance in 273 participants with paired plasma and cerebrospinal fluid (CSF). CSF AD core biomarkers served as the reference standard. Index tests included three plasma tau phosphorylated at residue 217 (pTau217) assays (Roche, Fujirebio, Meso Scale Discovery [MSD]) and a pTau181 assay (Roche).

RESULTS: Participants: median age 70 [IQR: 64 to 76] years, 42% female, and 60% AD-positive. pTau217 assays showed comparable accuracy (area under the curve [AUC] 0.88 to 0.89) exceeding pTau181 (AUC 0.85). All assays were resistant to hemolysis, icterus, and lipemia. Automated assays (Roche, Fujirebio) showed superior analytical precision and freeze/thaw stability (≥6 cycles) compared to the manual MSD assay (two cycles).

DISCUSSION: With comparable diagnostic accuracy across pTau217 platforms, analytical performance, and operational suitability became decisive implementation differentiators.},
}

@article {pmid42979024,
year = {2026},
author = {Shiao, YJ},
title = {A comprehensive review of the two most commonly studied traditional Chinese medicines for treating Alzheimer's disease.},
journal = {Journal of traditional and complementary medicine},
volume = {16},
number = {6},
pages = {573-583},
pmid = {42979024},
issn = {2225-4110},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder primarily characterized by progressive cognitive decline. Its pathological hallmarks include senile plaques, neurofibrillary tangles, chronic neuroinflammation, and widespread neuronal loss. Beyond aging, several major hypotheses have been proposed to explain AD pathology, including amyloid cascade hypothesis, tau hyperphosphorylation hypothesis, mitochondrial dysfunction hypothesis, neuroinflammation hypothesis, and microbiota-gut-brain axis hypothesis. These mechanisms often interact with one another, further complicating the disease process. While genetic factors contribute significantly to AD susceptibility, other modifiable risk factors-such as traumatic brain injury, hyperlipidemia, diabetes, hypertension, and obesity-also play critical roles. Despite decades of intensive research, current drug development for AD remains largely inadequate. Traditional Chinese medicine, with its multi-component and multi-target approach, holds promise as a potential therapeutic strategy for this multifactorial disease. Comparing the biomedical hypothesis with traditional Chinese medicine theory, both frameworks recognize the multifactorial, systemic, and progressive nature of dementia. However, their theories are complementary, with concepts such as "Phlegm and dampness" in traditional Chinese medicine aligning well with amyloid plaques and lipid/protein aggregates. "Qi and essence deficiency" correspond to mitochondrial and metabolic dysfunction. This article reviews recent progress in the therapeutic mechanisms of Huanglian Jiedu Decoction and Liuwei Dihuang Decoction in AD, aiming to provide a reference for future research on AD and the development of traditional Chinese medicine treatment. Future traditional Chinese medicine studies should integrate syndrome-based therapeutic principles with modern systems biology approaches to establish mechanism-based, personalized, and clinically translatable strategies for AD management.},
}

@article {pmid42979031,
year = {2026},
author = {Leng, Y and He, Y and Mechanic-Hamilton, D and Clark, LR and Sachs, BC and Lamar, M and Beattie, ZT and Saykin, AJ and Barnes, LL and Duff, K and Capuano, AW and Das, S},
title = {Remote versus in-person cognitive testing: the impact of visit modality on longitudinal cognitive outcomes in older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70530},
pmid = {42979031},
issn = {2352-8729},
abstract = {INTRODUCTION: The COVID-19 pandemic accelerated adoption of remote cognitive assessments in Alzheimer's disease (AD) research, yet comparability across visit modalities remains unclear. This study evaluated whether visit modality influenced cognitive performance.

METHODS: We analyzed 27,144 visits from 13,219 participants across 37 Alzheimer's Disease Research Centers (March 2020 to December 2024), including in-person, telephone, and video visits, among adults aged ≥65 years. Linear mixed-effects models examined associations between visit modality and cognitive performance.

RESULTS: Remote assessments comprised 20.8% of visits and were associated with slightly higher Montreal Cognitive Assessment scores than in-person visits for both telephone and video modalities (p < 2.0E-16; Cohen's d = 0.21 to 0.26). Domain analyses showed modestly higher memory and attention performance during remote visits, with minimal differences in executive function or language.

DISCUSSION: Remote cognitive assessments showed largely comparable performance to in-person testing, supporting their validity and potential to improve accessibility and inclusiveness in AD research.},
}

@article {pmid42979035,
year = {2026},
author = {Sugarman, MA and Stabile, M and Clark, DG and Nietert, PJ and Rodriguez-Porcel, F and Bushnell, J and Benitez, A},
title = {Item-level verbal fluency psycholinguistic metrics predict preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70533},
pmid = {42979035},
issn = {2352-8729},
abstract = {INTRODUCTION: Preclinical Alzheimer's disease (pAD) is characterized by subtle disruptions in semantic network functioning. Psycholinguistic metrics from item-level responses during verbal fluency tasks could reflect these changes in the asymptomatic stage.

METHODS: We analyzed psycholinguistic metrics for Animal and F Fluency (age of acquisition [AoA], semantic neighborhood density [SND], and lexical frequency [LF]), testing whether these metrics differentiated 50 participants with positron emission tomography (PET)-confirmed pAD (Aβ+) from 99 controls (Aβ-) and predicted cognitive decline.

RESULTS: Aβ+ participants generated Animal Fluency responses with younger AoA, higher LF, and marginally higher SND than Aβ- (ds = 0.33-0.44), despite comparable total scores. All three metrics predicted amyloid positivity in models controlling for age and total score. No significant findings were observed for F Fluency, and no metrics predicted cognitive decline.

DISCUSSION: Psycholinguistic metrics for Animal, but not F Fluency responses may reflect changes in semantic network functioning in pAD not captured by the total score.},
}

@article {pmid42979037,
year = {2026},
author = {Rinne, JO and Cummings, JL and Breznoscakova, D and Hakulinen, P and Hänninen, J and Goetghebeur, P and Miller, DS and Rouru, J},
title = {Efficacy of ORM-12741 on agitation/aggression symptoms in participants with Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70332},
pmid = {42979037},
issn = {2352-8737},
abstract = {INTRODUCTION: ORM-12741 is a potent and selective alpha-2C adrenoceptor antagonist. The primary objective of this study was to evaluate the efficacy of ORM-12741 in treating agitation/aggression symptoms in patients with Alzheimer's disease (AD).

METHODS: This was a phase II, double-blind, placebo-controlled study of 308 community-dwelling participants with mild to moderate AD (Mini-Mental State Examination [MMSE] scores 10 to 24) and Neuropsychiatric Inventory agitation/aggression scores of ≥4. Participants were randomized to 60 or 120 mg of ORM-12741 or placebo twice daily for 12 weeks. Efficacy was assessed primarily with the sum of Neuropsychiatric Inventory Clinician Rating (NPI-C) Agitation and Aggression domain scores. In addition, effects on cognition, psychotic, depressive, and overall neuropsychiatric symptoms were assessed.

RESULTS: No relevant treatment effects as compared to placebo group were detected on either the primary or secondary efficacy measures. ORM-12741 was generally well tolerated.

DISCUSSION: The study does not support the efficacy of ORM-12741 on agitation/aggression symptoms in patients with AD.},
}

@article {pmid42979167,
year = {2026},
author = {Decourt, B and Azarfar, K and Reyna, EM and Kennedy, JM and Sabbagh, MN},
title = {Emerging and Repurposed Immune System Modulators for Alzheimer's Disease.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {559284},
pmid = {42979167},
issn = {1177-8881},
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; Animals ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors/immunology ; *Immunologic Factors/therapeutic use/pharmacology ; Adaptive Immunity/drug effects ; Immunity, Innate/drug effects ; },
abstract = {Alzheimer's disease (AD) remains an incurable neurodegenerative condition to date. Pathologically, the hallmarks of AD are (i) extracellular senile plaques mainly composed of amyloid beta peptides (Aβ), (ii) intracellular neurofibrillary tangles comprised of abnormally folded and hyperphosphorylated tau proteins, and (iii) neuroinflammation. In the past two decades, the investigation of these brain pathologies has led to the identification of novel diagnostic biomarkers and putative therapeutic targets, ultimately resulting in the first two commercial disease-modifying anti-Aβ immunotherapies. More recently, modulation of the overactivated central immune system has emerged as a unique putative approach to slow down the progression of AD. In the present narrative review, we summarize the main findings on modulators of inflammation tested in Phase 2 and 3 trials in AD patients. After a deep literature review, we ended up selecting 19 agents spanning immune primers, monoclonal antibodies, recombinant proteins, synthetic peptides, immunomodulatory drugs, ion channel blockers, tyrosine kinase inhibitors, senolytics, antivirals, and herbal formulations. For each agent, we briefly explain the preclinical findings that led to translation into clinical trials and provide details about each trial design, and, when available, the main findings from the trials. Overall, it appears that Aβ and abnormal tau activate both the innate and adaptive immune systems, which in turn galvanize the production of Aβ and abnormal tau, thereby forming a viscous cycle that inflates AD neuropathology and is difficult to interrupt. Based on the successes and failures of the 19 agents reported here, we postulate that immune system modulators with the strongest potential for AD treatment are those displaying pleiotropic actions on both innate and adaptive immune responses rather than those exhibiting very targeted mechanisms. We conclude that modulators of inflammation need to be studied further, both as stand-alone AD therapies and in combination with anti-amyloid and anti-tau approaches.},
}

Humans
*Alzheimer Disease/drug therapy/immunology
Animals
Amyloid beta-Peptides/metabolism/antagonists & inhibitors/immunology
*Immunologic Factors/therapeutic use/pharmacology
Adaptive Immunity/drug effects
Immunity, Innate/drug effects

@article {pmid42979591,
year = {2026},
author = {Davtyan, A and Khachatryan, A and Petrosyan, R},
title = {AmyloDeep: protein language model-based ensemble model for predicting amyloid propensity from the amino acid sequence.},
journal = {Bioinformatics advances},
volume = {6},
number = {1},
pages = {vbag296},
pmid = {42979591},
issn = {2635-0041},
abstract = {MOTIVATION: Amyloids are predominantly β-sheet-rich, stable protein structures that can maintain their presence in the human body for multiple years. Amyloid protein aggregates contribute to the development of multiple neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and are involved in different vital functions, such as memory formation and immune system function.

RESULTS: Here, we used advanced machine learning and deep learning techniques to predict amyloid propensity from the amino acid sequence. First, we aggregated labeled amino acid sequence data from multiple sources, obtaining a roughly balanced dataset of 2365 sequences for binary classification. We leveraged that data to both fine-tune the ESM2 model and to train new models based on protein embeddings from ESM2 and UniRep. The predictions from these models were then unified into a single soft voting ensemble model, yielding highly robust and accurate results. We further made a tool where users can provide the amino acid sequence and get the amyloid formation probabilities of different segments of the input sequence.

Users can access the light version of AmyloDeep through the web server at https://amylodeep.com/, and the full model is available as a Python package at https://pypi.org/project/amylodeep/.},
}

@article {pmid42979808,
year = {2026},
author = {Ayembilla, JA and Osagie, RO and Akinade, AT and Sako, O and Ogunmiluyi, OE and Awe, OI},
title = {Causal inference analysis of the effect of amyloid-β and tau proteins on dementia risk: A Mendelian randomization analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251415494},
doi = {10.1177/13872877251415494},
pmid = {42979808},
issn = {1875-8908},
abstract = {BackgroundThe global burden of dementia is escalating due to the aging population. While amyloid and tau biomarkers are central to Alzheimer's disease (AD) pathology, their causal roles across dementia subtypes are not fully understood.ObjectiveThis study investigated the causal effects of cerebrospinal fluid (CSF) and plasma amyloid, tau, and hyperphosphorylated tau (p-tau) proteins on dementia [AD, frontotemporal dementia (FTD), and vascular dementia (VaD)] risk.MethodsIn this study, we conducted a two-sample Mendelian randomization analysis using genome-wide association study (GWAS) summary statistics. The AD, CSF, and plasma amyloid, tau, and p-tau data were obtained from the GWAS catalog, while those for FTD and VaD were obtained from the FINNGEN database. The inverse variance weighting method, combined with sensitivity analysis, was used to obtain the estimates.ResultsCSF p-tau in individuals with abnormal amyloid and APOE ε4 non-carriers was positively associated with AD risk [IVW: OR = 1.07, 95% CI = 1.01-1.13, p = 0.016; OR = 1.08, 95% CI = 1.02-1.14, p = 0.014, respectively]. CSF p-tau was also associated with VaD (IVW: OR = 1.11, 95% CI = 1.03-1.20, p = 0.008). Plasma Aβ1-42 reduced the odds of FTD (IVW: OR = 0.83, 95% CI = 0.70-0.98, p = 0.03), whereas CSF Aβ42 increased FTD risk (weighted median: OR = 1.58, 95% CI = 1.02-2.44, p = 0.041).ConclusionsThe findings support the causal roles of tau and amyloid across dementia subtypes, reinforcing the value of biomarker-driven prevention and therapeutic strategies.},
}

@article {pmid42979863,
year = {2026},
author = {Choudhury, AK and Rani, P and Gupta, R and Gulati, M and Kapoor, B},
title = {Liposomal Delivery of a Riluzole-Butyric Acid Mutual Prodrug Enhances Neuroprotection and Cognitive Recovery in Experimental Alzheimer's Disease.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/1061186X.2026.2759730},
pmid = {42979863},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, impaired synaptic signaling, and persistent neuroinflammation. Current therapies primarily provide symptomatic relief and have limited effects on disease progression. Riluzole, approved for amyotrophic lateral sclerosis, exhibits neuroprotective effects through modulation of glutamatergic signaling, but its poor oral bioavailability limits its therapeutic potential. Butyric acid, a short-chain fatty acid postbiotic produced by gut microbial fermentation, possesses well-established anti-inflammatory and neuroprotective properties. In this study, a mutual prodrug of riluzole and butyric acid was synthesized and encapsulated into liposomes to investigate its effects on drug distribution and preclinical efficacy. The prodrug-loaded liposomes exhibited an average particle size of 322 nm, zeta potential of -7.95 mV, and entrapment efficiency of 43.49%. Oral administration significantly improved cognitive performance and attenuated neuroinflammation and oxidative stress in an AlCl3-induced AD-like rat model. Administration of prodrug-loaded liposomes led to the highest concentrations of riluzole in brain homogenates among the relevant treatment groups. Overall, the prodrug-loaded liposomes demonstrated better therapeutic efficacy than the prodrug suspension, individual drug-loaded liposomes, and their respective conventional formulations. The enhanced therapeutic performance is attributed to the complementary pharmacological actions of riluzole and butyric acid, combined with the ability of the liposomal system to improve drug bioavailability and facilitate cerebral delivery.},
}

@article {pmid42979926,
year = {2026},
author = {Zhong, H and Sheng, J and Zhang, Q and Gong, Z and Zhang, R and Sun, Z and Zhu, X and Cheng, Y},
title = {A Support Vector Machine Method With Correlation-Based Recursive Feature Elimination for the Early Diagnosis of Alzheimer's Disease.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {10},
pages = {51378},
doi = {10.31083/JIN51378},
pmid = {42979926},
issn = {0219-6352},
support = {62271177//National Natural Science Foundation of China (CN)/ ; LZ24F010007//Key Program of the Natural Science Foundation of Zhejiang Province (CN)/ ; 2026XMHD004//Zhejiang Province Applied Basic Research Program (New Seedling Project)/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/pathology ; Humans ; *Support Vector Machine ; Early Diagnosis ; Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Aged ; Female ; *Neuroimaging/methods ; Male ; *Image Interpretation, Computer-Assisted/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder where early diagnosis is critical. While magnetic resonance imaging (MRI) provides valuable structural information, most methods rely solely on imaging features, limiting clinical interpretability.

METHODS: A novel feature selection method using support vector machine with correlation factor-based recursive feature elimination and cross-validation (SVM_CF_RFECV) integrated correlation factors from mini-mental state examination (MMSE) scores into the feature weighting process is proposed for the early identification of Alzheimer's disease. This approach balances statistical discriminative power with clinical relevance and mitigates the local-optimum issue of traditional recursive feature elimination (RFE).

RESULTS: Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the proposed method achieved a peak accuracy of 87.5% in a single-split experiment and an average accuracy of 0.8489 ± 0.0330 across multiple random partitions, outperforming conventional SVM_RFECV. The selected 74 discriminative brain regions, including the hippocampus and cingulate cortex, align with established AD pathology.

CONCLUSIONS: These findings demonstrate that SVM_CF_RFECV provides both accuracy and interpretability, supporting its potential as a clinically meaningful tool for early AD diagnosis.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis/pathology
Humans
*Support Vector Machine
Early Diagnosis
Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/pathology
Aged
Female
*Neuroimaging/methods
Male
*Image Interpretation, Computer-Assisted/methods

@article {pmid42979929,
year = {2026},
author = {Jiang, Z and Yue, W and Zhang, Y and Yu, S and Wang, H and Luo, T},
title = {The Glymphatic System: From Basic Research Advances to Non-Invasive Brain Stimulation Applications-A Narrative Review.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {10},
pages = {50308},
doi = {10.31083/JIN50308},
pmid = {42979929},
issn = {0219-6352},
support = {82460707//National Natural Science Foundation of China/ ; 82430042//National Natural Science Foundation of China/ ; 20211022//Famous Clinical Doctor Program of the Zunyi Medical University/ ; MS(2026)977//Basic Research Program of Guizhou Province, general project, Qian Science and Technology Foundation/ ; HZ(2025)379//Key Project of Zunyi City Science and Technology Plan (Technology Cooperation), Zun City Science and Technology Foundation/ ; },
mesh = {*Glymphatic System/physiology/metabolism ; Humans ; Animals ; *Transcranial Magnetic Stimulation ; },
abstract = {The glymphatic system (GS) is a pathway for waste clearance in the brain and a promising therapeutic target for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). GS function is governed by multiple interacting factors, such as aquaporin-4 (AQP4) polarization, cerebral arterial pulsatility, and the integrity of meningeal lymphatic vessels (MLVs). Despite growing recognition of the importance of the GS, effective strategies to actively and non-invasively enhance glymphatic function have long been lacking. In recent years, non-invasive neuromodulatory approaches-most notably focused ultrasound (FUS), repetitive transcranial magnetic stimulation (rTMS), and transcranial photobiomodulation (tPBM)-have emerged as novel strategies to modulate GS activity. Growing evidence suggests that these interventions can enhance glymphatic transport by influencing key regulatory mechanisms, including cerebrovascular dynamics, AQP4 expression and localization, and meningeal lymphatic drainage. In this review, we summarize current experimental advances in non-invasive, external alterations of the GS, discuss underlying mechanisms and translational challenges, and highlight the therapeutic potential of GS modulation in neurological diseases characterized by impaired waste clearance. However, further research about the function and dysfunction of the GS in humans is needed to evaluate the findings from animal studies and thereby fill the translational gap in the human pathophysiology of the GS.},
}

*Glymphatic System/physiology/metabolism
Humans
Animals
*Transcranial Magnetic Stimulation

@article {pmid42979938,
year = {2026},
author = {Alqahtani, A and Al-Ahmadi, S and Soudani, A},
title = {A Lightweight EEG-Based Alzheimer's Disease Detection Framework on an Edge-Computing Platform Toward Future Intelligent Digital Twin Systems.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {10},
pages = {53849},
doi = {10.31083/JIN53849},
pmid = {42979938},
issn = {0219-6352},
support = {STU-54//King Abdelaziz City for Science and Technology(KACST), represented by the Science Technology and Innovation Unit at King Saud University(STU-KSU), Riyadh, Saudi Arabia/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology ; *Electroencephalography/methods/standards ; *Deep Learning ; *Signal Processing, Computer-Assisted ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) progresses slowly through several stages until the patient reaches full cognitive decline. The electroencephalography (EEG) alterations associated with AD often emerge before symptom onset, suggesting that accessible and repeated EEG-based assessment could facilitate earlier detection and longitudinal monitoring. However, this type of assessment requires an AD detection model operating on edge-computing platforms within the Internet of Medical Things (IoMT). At present, many existing AD detection models rely on complex deep learning architectures with numerous parameters, which significantly limit their practicality for on-edge deployment.

METHODS: We propose an on-edge AD detection framework comprising a lightweight dilated hybrid deep learning (DHDL) model with a channel selection approach to reduce the computational and power demands on the evaluated edge-computing platform. A key architectural component is the inclusion of dual-granularity dilated temporal convolutions. This method expands the receptive field at two scales to capture both short- and long-term temporal features from EEG signals without increasing the number of parameters. Subsequently, several hybrid lightweight layers extract distinct temporal and spatial features and are integrated with attention mechanisms. Additionally, our channel selection approach first forms an initial subset of EEG channels guided by individual channel classification accuracy, and then iteratively refines the selected channels using hill-climbing optimization. Here, we evaluated our framework on two publicly available EEG datasets recorded for the same group of subjects (n = 48 subjects): a conventional closed-eye (CE) dataset and a more challenging open-eye (OE) dataset. Validation followed a subject-independent Leave-2-Subjects-Out (L2SO) cross-validation protocol. Real-time deployment was tested on an edge-computing platform.

RESULTS: The proposed framework achieved 92.56% accuracy for the CE dataset and 75.15% accuracy for the OE dataset. Inference required 10.45 ms and 8.23 ms per segment for the CE and OE datasets, respectively, and consumed 9.69 mJ and 6.95 mJ of energy per segment, respectively.

CONCLUSIONS: These results demonstrate the feasibility of the proposed framework as a real-time, on-edge inference module for AD detection. Although a complete intelligent digital twin system is not implemented in this work, the proposed framework can serve as an inference component for future digital twin systems, supporting early AD detection and progression monitoring.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology
*Electroencephalography/methods/standards
*Deep Learning
*Signal Processing, Computer-Assisted

@article {pmid42980051,
year = {2026},
author = {Bayragi, SR and Hossain, R and Islam, MZ and Sumi, SA and Ahmed, FF},
title = {Integrative Transcriptomic and Network Analyses Reveal Common Molecular Signatures and Turmeric-Derived Common Therapeutic Candidates for Neurological Diseases.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {},
pmid = {42980051},
issn = {2314-6141},
support = {25-FoS-06//Jashore University of Science and Technology/ ; },
mesh = {*Curcuma/chemistry ; Humans ; *Gene Regulatory Networks/drug effects ; Protein Interaction Maps/drug effects/genetics ; *Nervous System Diseases/genetics/drug therapy ; Gene Expression Profiling ; *Transcriptome/genetics/drug effects ; Molecular Docking Simulation ; Computational Biology/methods ; MicroRNAs/genetics/metabolism ; },
abstract = {BACKGROUND: Neurological diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and brain tumors, impose a substantial global health burden. Although these disorders have distinct clinical manifestations and etiologies, accumulating evidence suggests that they share certain molecular mechanisms. However, their common molecular signatures and the therapeutic potential of turmeric-derived bioactive compounds have not been systematically investigated.

OBJECTIVES: This study is aimed at identifying shared molecular mechanisms and key hub genes across AD, PD, stroke, and glioblastoma (GBM) using an integrative bioinformatics framework and at investigating turmeric-derived compounds as potential multitarget common therapeutic candidates.

MATERIALS AND METHODS: Gene expression datasets (GSE22491, GSE5281, GSE122709, and GSE4290) were retrieved from the Gene Expression Omnibus (GEO) database. Common host differentially expressed genes (cHDEGs) were identified through integrated bioinformatics analysis. Protein-protein interaction (PPI) networks were subsequently constructed to identify common hub genes (cHubGs), followed by functional enrichment and transcription factor (TF) and miRNA-mediated regulatory network analyses. The interactions between the identified cHubGs and turmeric-derived compounds were further investigated using molecular docking and 500-ns molecular dynamics simulations (MDS).

RESULTS: A total of 81 cHDEGs and four cHubGs (CCNB1, CDK1, CYCS, and STAT3) were identified. Functional enrichment and regulatory network analysis revealed shared biological processes and signaling pathways, as well as key TFs and miRNAs potentially associated with ND pathogenesis. Among the 77 turmeric-derived compounds that passed the toxicity screening, demethoxycurcumin, cyclocurcumin, and (1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-5-(4-hydroxyphenyl)-1,4-pentadien-3-one exhibited the strongest predicted binding affinities. The selected compound-target complexes also showed stable behavior during the MDS.

CONCLUSION: This study provides insights into the shared molecular features across AD, PD, stroke, and GBM and prioritizes turmeric-derived compounds as potential multitarget therapeutic candidates. These computational findings require further validation through independent datasets and experimental studies.},
}

*Curcuma/chemistry
Humans
*Gene Regulatory Networks/drug effects
Protein Interaction Maps/drug effects/genetics
*Nervous System Diseases/genetics/drug therapy
Gene Expression Profiling
*Transcriptome/genetics/drug effects
Molecular Docking Simulation
Computational Biology/methods
MicroRNAs/genetics/metabolism

@article {pmid42980082,
year = {2026},
author = {Eassa, NE and Perez, SM and Yang, OJ and Boley, AM and Lodge, DJ},
title = {Hippocampal 5-HT4/6 Receptor Antagonists Normalize Dopaminergic Dysfunction in a Rodent Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {21},
pages = {3517-3525},
doi = {10.1021/acschemneuro.6c00432},
pmid = {42980082},
issn = {1948-7193},
support = {R01AG076030/AG/NIA NIH HHS/United States ; T32AG082661/AG/NIA NIH HHS/United States ; T32GM145432/GM/NIGMS NIH HHS/United States ; T32NS082145/NS/NINDS NIH HHS/United States ; BX004646//U.S. Department of Veterans Affairs/ ; BX004693//U.S. Department of Veterans Affairs/ ; T32TR004545/TR/NCATS NIH HHS/United States ; Pilot Award//San Antonio Nathan Shock Center of Excellence Pilot Grant/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Hippocampus/drug effects/metabolism ; *Receptors, Serotonin/metabolism/drug effects ; Male ; Disease Models, Animal ; Rats ; *Dopamine/metabolism ; *Serotonin Antagonists/pharmacology ; Receptors, Serotonin, 5-HT4/metabolism ; *Serotonin 5-HT4 Receptor Antagonists/pharmacology ; *Dopaminergic Neurons/drug effects/metabolism ; Piperazines/pharmacology ; Mesolimbic System ; Rats, Sprague-Dawley ; },
abstract = {Psychosis affects approximately 4 million Americans with Alzheimer's disease (AD), yet safe and effective pharmacological treatments remain limited. The clinical utility of traditional antipsychotics is constrained by an FDA black box warning regarding increased mortality in the elderly. A potential mechanistic driver for these symptoms is hyperactivity in the ventral hippocampus (vHipp), a feature common to both AD and psychosis that has been shown in preclinical models to induce dopamine system dysregulation. This study explores the hypothesis that such hippocampal dysfunction is facilitated by aberrant serotonergic signaling. Clinical and preclinical studies suggest that activation of two serotonin-responsive G-protein-coupled receptors (GPCRs), 5-HT4R and 5-HT6R, in the hippocampus contributes to symptoms of psychosis in AD. Although targeting these receptors could provide therapeutic benefits, their widespread expression throughout the brain raises concerns about whether systemic administration would yield selective effects specifically in the hippocampus. To investigate this, we microinfused the selective 5-HT4 receptor antagonist (SB-204070) or the 5-HT6 receptor antagonist (PRX-07034) directly into the vHipp of TgWKY-AD and WKY-WT rats. Intra-vHipp blockade of either receptor reversed the pathological elevation of ventral tegmental area (VTA) dopamine neuron population activity; notably, these effects were fully recapitulated following systemic administration. We further demonstrated that 5-HT4R and 5-HT6R mRNA expressions in the vHipp and nucleus accumbens (NAc) are preserved in 12-month-old TgWKY-AD rats, suggesting that these targets remain viable as the disease progresses. Together, these findings identify systemic 5-HT4R or 5-HT6R antagonism as a viable therapeutic strategy to attenuate hippocampal hyperactivity and restore dopaminergic homeostasis, offering a mechanistically grounded and potentially safer alternative for managing psychosis in AD.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy
*Hippocampus/drug effects/metabolism
*Receptors, Serotonin/metabolism/drug effects
Male
Disease Models, Animal
Rats
*Dopamine/metabolism
*Serotonin Antagonists/pharmacology
Receptors, Serotonin, 5-HT4/metabolism
*Serotonin 5-HT4 Receptor Antagonists/pharmacology
*Dopaminergic Neurons/drug effects/metabolism
Piperazines/pharmacology
Mesolimbic System
Rats, Sprague-Dawley

@article {pmid42980191,
year = {2026},
author = {Adhikary, K and Prameela, G and Das, J and Ramzan, M and Ganguly, K and Datta, N and Banerjee, P and Barman, S and Sridhar, SB and Taj, T and Mondal, M and Ashique, S and Chopra, S and Chopra, H},
title = {Phytomicronutrients in neurodegeneration: modulating microglial dynamics for neuroprotection.},
journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences},
volume = {81},
number = {11-12},
pages = {703-737},
pmid = {42980191},
issn = {1865-7125},
mesh = {*Microglia/drug effects/pathology/metabolism ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Animals ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; *Plant Extracts/pharmacology/therapeutic use/chemistry ; *Phytochemicals/pharmacology/therapeutic use/chemistry ; Oxidative Stress/drug effects ; *Neuroprotection/drug effects ; Plants, Medicinal/chemistry ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; },
abstract = {Microglial dysfunction plays a critical role in the pathophysiology of several neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Emerging evidence suggests that targeting microglial activation could be a promising therapeutic strategy. This review critically examines recent studies investigating the effects of medicinal plant extracts and their bioactive compounds on microglial function. Relevant data from experimental and preclinical studies were analyzed to assess their neuroprotective and anti-inflammatory potential. Phytochemicals that are found in plants, especially flavonoids, alkaloids, and terpenoids, demonstrate important modulatory effects on microglials. These compounds control microglial polarization, inhibit the release of proinflammatory cytokines, and alleviate oxidative stress, thus, alleviating neuroinflammation and enhancing neuro-restoration. The results suggest that medicine plant extracts have effects on major molecular pathways associated with neuroinflammation, which provide new adjunctive treatment to neurodegenerative diseases. Nevertheless, there are still problems in the translation of these preclinical successes into clinical practice. The limited bioavailability, variability in phytochemical composition, and the absence of standardized formulations are some of the challenges that discourage clinical use. Also, thorough safety assessments should be conducted to achieve therapeutic effectiveness with no adverse effects. The medicinal plants and their bioactive compounds hold potential promise in regulating the dysfunction of microglia and in decreasing neuroinflammation. Future studies are needed to enhance the pharmacokinetic characteristics, to provide consistency in formulations, and to perform stringent clinical studies that would substantiate these findings and allow their use in therapeutic regimens of neuroinflammatory disorders.},
}

*Microglia/drug effects/pathology/metabolism
Humans
*Neuroprotective Agents/pharmacology/therapeutic use/chemistry
Animals
*Neurodegenerative Diseases/drug therapy/pathology/metabolism
*Plant Extracts/pharmacology/therapeutic use/chemistry
*Phytochemicals/pharmacology/therapeutic use/chemistry
Oxidative Stress/drug effects
*Neuroprotection/drug effects
Plants, Medicinal/chemistry
Anti-Inflammatory Agents/pharmacology/therapeutic use

@article {pmid42980247,
year = {2026},
author = {Fujishiro, H and Takeda, K and Iwata-Endo, K and Arafuka, S and Miyata, S and Iwamoto, K and Torii, Y and Iritani, S},
title = {Clinical Trajectory of Late-Onset Delusional Disorder Toward Evolving Dementia With Lewy Bodies.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {},
pmid = {42980247},
issn = {1479-8301},
support = {JP26K10487//Japan Society for the Promotion of Science/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP25wm0625126//Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; *Lewy Body Disease/diagnosis/psychology/pathology/complications ; *Schizophrenia, Paranoid/diagnosis/complications/psychology ; Aged ; Male ; Age of Onset ; Female ; Delusions ; Disease Progression ; Middle Aged ; Aged, 80 and over ; },
abstract = {Recent clinical observations indicate that late-onset psychosis can precede the onset of dementia with Lewy bodies (DLB). However, its longitudinal clinical trajectory remains poorly understood. Delusional disorder (DD) in older adults is relatively uncommon and poor insight frequently leads to refusal of psychiatric care, limiting available data despite its long-standing diagnostic recognition. This article focuses on late-onset DD in relation to subsequent development of DLB. We revisited our previously reported cases in which delusions were the initial manifestation of Lewy body disease (LBD) and aimed to identify the shared clinical features to help delineate more homogeneous subgroups within the heterogeneous spectrum of late-onset psychosis. These cases with late-onset DD revealed a recurring phenotype characterised by onset in the 50s and 60s, reluctance to seek psychiatric care, eventual hospitalisation, poor antipsychotic tolerance and delayed emergence of dementia accompanied by core features of DLB. Clinicopathological examination of four cases raises the hypothesis that persistent delusions may emerge in the presence of relatively restricted Lewy pathology, preceding the development of widespread cortical involvement and overt dementia. Relative preservation of neuronal populations in the substantia nigra may account for the absence of parkinsonism during the early phases dominated by isolated delusions. Despite long-standing delusions beginning in the 50s and 60s, a common age range for DLB onset (mid-70s and older) was observed, indicating an exceptionally prolonged prodromal period. These findings suggest that late-onset DD associated with LBD may follow a clinical trajectory distinct from that of mild cognitive impairment with Lewy bodies (MCI-LB), the most common clinical phenotype of prodromal DLB. Differentiating DD from broader late-onset psychosis categories may facilitate future research by reducing heterogeneity and stratifying cases with potentially prolonged periods without dementia or parkinsonism. Clinical and pathological reports of late-onset DD remain scarce and further case documentation is warranted.},
}

Humans
*Lewy Body Disease/diagnosis/psychology/pathology/complications
*Schizophrenia, Paranoid/diagnosis/complications/psychology
Aged
Male
Age of Onset
Female
Delusions
Disease Progression
Middle Aged
Aged, 80 and over

@article {pmid42980257,
year = {2026},
author = {Arpacı, MF and Akçiçek, M and Uzun, GB and İnceoğlu, F and Altıparmak, A and Deniz, MA and Bolayır, A and Aygül, G and Pekmez, H and Acer, N},
title = {The Effect of Alzheimer's Disease and Diabetes on the Volume of Brain Structures.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {237},
pages = {},
doi = {10.3791/73630},
pmid = {42980257},
issn = {1940-087X},
mesh = {Humans ; *Alzheimer Disease/pathology ; Female ; *Brain/pathology ; Magnetic Resonance Imaging/methods ; Male ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; Adolescent ; Young Adult ; *Diabetes Mellitus, Type 1/pathology ; Retrospective Studies ; },
abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) are increasingly prevalent chronic disorders with overlapping effects on brain structure. However, direct volumetric comparisons among patients with AD alone, DM alone, both conditions, and healthy controls remain limited. This retrospective study compared regional brain volumes in 160 adults (18-90 years) assigned equally to four groups (n = 40 each): AD+type 1 DM, AD-only, type 1 DM-only, and healthy controls. Brain magnetic resonance imaging (MRI) scans were analyzed using VolBrain, an automated, multiatlas, patch-based segmentation platform, on 3D T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) images acquired at 1.5 T. Regions evaluated included white and gray matter, subcortical structures, selected cortical gyri, and the ventricular system. Analyses were stratified by sex. No significant volumetric differences were observed between the AD+DM and AD-only groups. Compared with DM-only, differences were limited to the right amygdala (p = 0.004) and left thalamus (p = 0.001) in females. Relative to controls, both AD groups showed reductions in the bilateral amygdala, bilateral caudate, right thalamus, and middle temporal gyrus, together with third-ventricle enlargement (all p ≤ 0.005). The DM-only group showed fewer abnormalities. Reduced left caudate volume was the only finding consistently observed across all patient groups and both sexes (p ≤ 0.007). Overall, AD and DM showed partially overlapping regional differences in brain volume. The consistent left caudate reduction may represent a shared structural marker and warrants further prospective and longitudinal investigation in AD-DM comorbidity.},
}

Humans
*Alzheimer Disease/pathology
Female
*Brain/pathology
Magnetic Resonance Imaging/methods
Male
Middle Aged
Aged
Adult
Aged, 80 and over
Adolescent
Young Adult
*Diabetes Mellitus, Type 1/pathology
Retrospective Studies

@article {pmid42980311,
year = {2026},
author = {Harsh R, P and Urvesh D, P and Maunik D, P and Dhaval T, F},
title = {Comparative and combined neurotoxic effects of lithium carbonate and lead acetate in rats: From clinical alterations to molecular insights.},
journal = {Toxicology and industrial health},
volume = {},
number = {},
pages = {7482337261500537},
doi = {10.1177/07482337261500537},
pmid = {42980311},
issn = {1477-0393},
abstract = {Heavy metal contamination in soil and water is a global concern with significant ecological and health implications. Lithium (Li), increasingly used in electric vehicles, and lead (Pb), a well-established pollutant, poses neurotoxic risks to animals and humans. This study evaluated the individual and combined effects of lithium carbonate (Li; 20 mg/kg) and lead acetate (Pb; 20 mg/kg) administered orally for 28 days in adult rats. Forty-eight rats were divided into four groups: control, Li, Pb, and Li + Pb. Clinical signs included hair loss, diarrhoea, dehydration, dullness, and foul-smelling faeces, with Li + Pb rats showing greater feed reduction and weight loss than single-exposure groups. Behavioural assessments revealed impaired motor coordination, anxiety-like behaviour, and significantly increased grip strength in Li + Pb as compared to the control group. Oxidative stress markers demonstrated significantly reduced Superoxide Dismutase (SOD), catalase, glutathione, and total antioxidant capacity, along with significantly elevated Malondialdehyde (MDA) and Nitric Oxide (NO) levels in the Li + Pb group compared with the control group. Brain AChE activity was significantly reduced in the Pb and Li + Pb groups compared with the control group. Gene expression analysis revealed significant downregulation of apoe (3.93-fold), app (6.15-fold), and ache (4.75-fold) genes, alongside bax (4.98-fold) upregulation in the Li + Pb group compared with the control group, indicating enhanced apoptosis, impaired antioxidant defense, and Alzheimer's-like neurodegeneration. Gross pathology revealed mild cerebral congestion in the Li and Pb alone groups, and marked congestion in the Li + Pb rats. Histopathology confirmed neuronal degeneration, Purkinje cell loss, perineuronal space widening, and astrocytic proliferation, with the Li + Pb group exhibiting the most severe lesions. Collectively, these findings suggest that co-exposure to lithium and lead exerts more pronounced neurotoxic effects, mediated by oxidative stress, apoptosis, and gene alterations linked to neurodegeneration.},
}

@article {pmid42980691,
year = {2026},
author = {Sasner, M and Rangel-Barajas, C and Oblak, AL},
title = {Progress towards improving mouse models for preclinical testing of treatments for Alzheimer's disease.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {37},
number = {1},
pages = {},
pmid = {42980691},
issn = {1432-1777},
support = {AG054345/AG/NIA NIH HHS/United States ; AG054345/AG/NIA NIH HHS/United States ; AG054345/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/genetics/therapy/pathology/drug therapy ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Drug Evaluation, Preclinical ; tau Proteins/genetics ; },
abstract = {Alzheimer's disease (AD) research has accomplished significant strides in recent years, particularly with the first regulatory approvals of disease-modifying therapies and a comprehensive revision of disease diagnostic criteria. Both developments place new demands on preclinical mouse models used to test potential treatments. This review summarizes recent progress in optimizing mouse models for Alzheimer's research, using the NIA-funded Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD) program as a case study, with specific focus on their relevance for preclinical therapeutic testing, their genetic and molecular fidelity to the human disease, and the contribution of the MODEL-AD program. Key advancements discussed include the shift from transgenic overexpression models to knock-in and genome-replacement strategies; the development of late-onset Alzheimer's models (LOAD), LOAD1, LOAD2, LOAD3 and related LOAD-platform mice expressing humanized APOE, APP, and MAPT; the integration of environmental risk factors such as high-fat diet and toxic metal exposure into gene x environment interaction models; detection of prodromal stages of disease using multi-omics signatures; and the use of clinically relevant biomarkers, including plasma NfL, GFAP, and p-tau217, as cross-species translational endpoints. We discuss the importance of diverse genetic backgrounds, the contribution of the AD Knowledge Portal as an open-science data-sharing resource, and the principles of rigorous preclinical study design required to maximize translational success. We also discuss the limitations of these models and the evidence still needed to establish their predictive validity for therapeutics. These advances do not yet amount to validated models of late-onset AD, but they give the field better tools and frameworks for selecting and validating mouse models for specific human mechanisms and therapeutic questions.},
}

Animals
*Alzheimer Disease/genetics/therapy/pathology/drug therapy
*Disease Models, Animal
Humans
Mice
Mice, Transgenic
Drug Evaluation, Preclinical
tau Proteins/genetics

@article {pmid42980692,
year = {2026},
author = {Babu, HWS and Muthukumar, S and Lakhanpal, V and Wander, A and Narayanaswamy, A and Reddy, DH and Vellingiri, B},
title = {MCU Dysregulation in Alzheimer's Disease: Linking Calcium Overload to Mitochondrial Failure, Neurodegeneration, and Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42980692},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/therapy ; Animals ; *Mitochondria/metabolism/pathology ; *Calcium Channels/metabolism ; *Calcium/metabolism ; *Nerve Degeneration/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder defined by accumulation of amyloid-β (Aβ), tau pathology, synaptic failure and neuronal loss. Increasing evidence suggests that perturbation of mitochondrial Ca[2][+] homeostasis is something important in AD pathogenesis. The Mitochondrial Calcium Uniporter (MCU) complex brings the major route for Ca[2][+] uptake into mitochondria, linking cellular Ca[2][+] signalling to Adenosine triphosphate (ATP) production and neuronal function. Factors related to AD, including Aβ oligomers, presenilin mutations, pathological tau and apolipoprotein E ε4 (APOE4) promote enhanced transfer of Ca[2][+] from the endoplasmic reticulum (ER) to mitochondria, resulting in mitochondrial Ca[2][+] overload. This initiates toxic pathways including neuroinflammation, production of reactive oxygen species (ROS), mitochondrial permeability transition pore opening (mPTP), ATP depletion and neuronal cell death. Recent studies have identified miR-25 as a regulator of MCU expression in experimental systems, while other AD-associated miRNAs, including miR-132, miR-124, and miR-155, are implicated in synaptic dysfunction, mitochondrial stress, and neuroinflammatory signalling. Their direct involvement in MCU regulation in Alzheimer's disease remains to be established. Here we review the composition and function of the MCU complex and its contribution to AD pathology, including the outstanding question of whether increased or decreased MCU activity occurs at different stages of disease development. Treatment strategies that target mitochondrial Ca[2][+] homeostasis, including the use of MCU blockers, mitochondrial Na[+]/Ca[2][+] exchanger (NCLX) activators, therapies that target ER-mitochondria contacts, and microRNA-based therapies will also be discussed. So, the MCU complex shows considerable promise as a potential therapeutic target and disease biomarker.},
}

Humans
*Alzheimer Disease/metabolism/pathology/therapy
Animals
*Mitochondria/metabolism/pathology
*Calcium Channels/metabolism
*Calcium/metabolism
*Nerve Degeneration/metabolism/pathology

@article {pmid42980722,
year = {2026},
author = {Yang, T and Yang, Y and Cheng, J and Fan, K and Ma, Y and Zou, D and Shu, H and Yu, S},
title = {Noncanonical Signaling Network of Nogo-A: A New Perspective on Multi-target Regulation, Neuroplasticity, and Disease Intervention Beyond NgR.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {42980722},
issn = {1573-6830},
support = {2025-wjzd-11//Key Project of the Qinghai Provincial Health System/ ; 25MSZX474//Special Project for Scientific and Technological Research of the Sichuan Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Nogo Proteins/metabolism ; *Neuronal Plasticity/physiology ; Animals ; *Signal Transduction/physiology ; *Nogo Receptors/metabolism ; },
abstract = {The membrane protein Nogo-A, initially identified for its inhibitory role in axonal regeneration through the Nogo receptor (NgR), is now recognized as a central hub in a complex noncanonical signaling network. Recent evidence indicates that Nogo-A engages diverse receptors and intracellular pathways beyond NgR to modulate neuroplasticity, synaptic stability, and glial function. This multi-target regulatory capacity characterizes Nogo-A as a critical determinant of neural repair and degeneration, with implications for conditions such as spinal cord injury, multiple sclerosis, and Alzheimer's disease. Noncanonical Nogo-A signaling intersects with growth factor cascades, inflammatory responses, and cytoskeletal dynamics, offering novel therapeutic targets for neural repair. This review synthesizes current knowledge on alternative Nogo-A signaling mechanisms and highlights their potential to redefine strategies for neuroregeneration and disease intervention.},
}

Humans
*Nogo Proteins/metabolism
*Neuronal Plasticity/physiology
Animals
*Signal Transduction/physiology
*Nogo Receptors/metabolism

@article {pmid42980730,
year = {2026},
author = {Manna, P and Maity, A and Roy, S and Sahu, S and Pradhan, S and Ganguly, SC and Chakraborty, M and Kundu, M},
title = {From molecular pathways to nanocarrier design: a translational framework for lipid-based nanoparticles in Alzheimer's disease.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {42980730},
issn = {2731-9229},
abstract = {Alzheimer's disease, being a complicated neurodegenerative disoder affects cognitive as well as memory functions. Characterised by amyloid-β aggregation, along with tau hyperphosphorylation, and cholinergic dysfunction, this disease is also associated with oxidative stress and neuroinflammation. Conventional clinical interventions, like acetylcholinesterase inhibitors and novel monoclonal antibodies predominantly rely on symptomatic alleviation of symptoms. Nevertheless, these conventional treatments come across considerable constraints, like temporary effectiveness, lesser therapeutic reach due to the blood brain barrier, apart from additional adverse effects. To overcome these delivery obstacles and achieve intracellular targeting, lipid nanoparticles, such as liposomes, solid lipid nanoparticles, and drugs, that can effectively traverse biological barriers, and facilitate precise intracellular release. This review introduces a translational, pathway-integrated framework that connects key molecular mechanisms of the disease with rational design strategies of lipid nanocarriers. The review also illustrates how essential internal factors, such as lipid composition, ionizable lipid pKa, selection of helper lipids, PEG density, along with methods of endosomal escape, and the protein corona, affect brain targeting efficacy and toxicity. It further focuses on pathway-enforced nano lipidic therapeutic approaches, where nanocarrier design is tailored to cater to specific biological targets. Nano lipidic delivery of siRNA, miRNA, mRNA, monoclonal antibodies, and along with other neuroprotective agents has been emphasised. Additionally, advancements in surface functionalization, intranasal administration, as well as receptor-mediated transcytosis, and focused ultrasound-driven blood-brain barrier penetration have also been highlighted in this review. Therefore, it aims to bridge the gap between molecular pathology and formulation design through alignment of design principles that emphasize on nanocarrier properties and its relevance to disease-specific requirements, an approach that has never been comprehensively addressed in previous literature.Registration number of clinical trial: Not applicable.},
}

@article {pmid42980747,
year = {2026},
author = {He, BH and Yang, W and Yang, M and Lv, X and Zhao, JJ},
title = {Advances in plant polysaccharide research for neurodegenerative diseases therapy.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42980747},
issn = {1573-4978},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Polysaccharides/therapeutic use/pharmacology/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Oxidative Stress/drug effects ; *Plants/chemistry ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), represent a growing global public health burden with limited therapeutic options. Plant polysaccharides are natural, biocompatible, and multi-target bioactive macromolecules that have emerged as promising candidates for ND intervention. This review systematically summarizes recent progress in elucidating the structural characteristics, structure-activity relationships, and neuroprotective mechanisms of plant polysaccharides. Key structural features such as molecular weight, monosaccharide composition, glycosidic bond configuration, and spatial conformation critically modulate the biological activity of these molecules. Furthermore, we summarize the numerous protective effects of plant polysaccharides against NDs, including inhibiting abnormal protein aggregation, alleviating oxidative stress via the Nrf2/HO-1 pathway, suppressing neuroinflammation through the NF-κB and MAPK signaling pathways, regulating neuronal apoptosis, and modulating the gut-brain axis. Clinical translation challenges, primarily blood-brain barrier penetration, structural heterogeneity, and insufficient clinical validation, are discussed. Future directions include developing advanced delivery systems, conducting large-scale randomized controlled trials, and exploring synergistic combination therapies. Collectively, plant polysaccharides show considerable promise as potential multi-target candidates for the intervention of NDs, although further studies are needed to clarify their therapeutic potential and facilitate clinical translation.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Polysaccharides/therapeutic use/pharmacology/chemistry
Animals
*Neuroprotective Agents/pharmacology/therapeutic use/chemistry
Oxidative Stress/drug effects
*Plants/chemistry

@article {pmid42980769,
year = {2026},
author = {Kamikubo, Y},
title = {TREM2-LRP1 axis in Alzheimer's disease: pharmacological trade-offs of receptor shedding and functional restoration.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {83},
number = {1},
pages = {},
pmid = {42980769},
issn = {1420-9071},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Animals ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; Microglia/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; },
abstract = {The interplay between triggering receptor expressed on myeloid cells 2 (TREM2) and low-density lipoprotein receptor-related protein 1 (LRP1) is critical for amyloid-beta (Aβ) clearance in Alzheimer's disease (AD). Current therapeutic strategies targeting this axis can be broadly divided into two pharmacological approaches: indirect induction via metabolic modulation (e.g., ACAT1 inhibition) and direct functional restoration of LRP1. While ACAT1 inhibition effectively upregulates LRP1, recent findings suggest that this effect is mechanistically coupled to ADAM10/17-mediated shedding of TREM2. This raises a critical pharmacological dilemma: balancing the benefit of LRP1 upregulation against the reduction of cell-surface TREM2. While TREM2 shedding may represent a functional shift from membrane-bound sensing to soluble Aβ clearance rather than a simple loss of function, cell-surface TREM2 signaling remains essential for Aβ sensing and microglial fitness in the long term. Conversely, strategies focusing on the direct restoration of LRP1 transport achieve robust Aβ clearance but face challenges regarding delivery specificity. Integrating emerging evidence on lipid droplet-driven microglial dysfunction and membrane fluidity, this article discusses the trade-offs of these strategies and proposes that preserving surface TREM2 signaling while enhancing LRP1 activity is key to long-term therapeutic efficacy. Clinical evidence from the INVOKE-2 trial further supports the need for combination strategies targeting both TREM2 signaling and LRP1-mediated clearance.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Low Density Lipoprotein Receptor-Related Protein-1/metabolism
Animals
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism
Microglia/metabolism
Amyloid Precursor Protein Secretases/metabolism

@article {pmid42980859,
year = {2026},
author = {Ning, X and Lan, J and Miao, J},
title = {Oligodendrocyte Lineage Dysfunction in Alzheimer's Disease: A Bidirectional, Stage-Dependent Account.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {42980859},
issn = {1573-6830},
support = {SZZYSM202406002//Sanming Project of Medicine in Shenzhen/ ; 82505709//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Animals ; *Oligodendroglia/pathology/metabolism ; Myelin Sheath/metabolism/pathology ; *Cell Lineage ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) has traditionally been framed as a neuronal disorder, yet white matter and myelin abnormalities are consistently detected in the preclinical period, before overt amyloid pathology or cognitive decline. This temporal relationship suggests that oligodendrocyte (OL) dysfunction acts upstream of, rather than downstream from, amyloid accumulation. In this review we argue that OL dysfunction and loss are a fundamental, mechanistically integrated component of AD pathogenesis, and we develop this argument as a single causal sequence. Central to it is the dual role of OLs in amyloid homeostasis: they express the complete amyloidogenic machinery and produce a quantitatively significant, comparatively aggregation-prone fraction of Aβ, while intact myelin is required for both axonal metabolic support and efficient Aβ clearance. A single lesion in the OL-myelin unit therefore simultaneously increases Aβ production and impairs its removal. We then examine why this lineage fails early: the exceptional metabolic and iron burden of myelin maintenance, combined with low glutathione reserves, renders OLs selectively vulnerable to oxidative injury and ferroptosis. This injury becomes self-sustaining through a metabolic-epigenetic feedback loop, diversion of finite microglial clearance toward myelin debris, and exhaustion of precursor-mediated repair, converting reversible injury into progressive myelin loss that further amplifies amyloid pathology. Together, these mechanisms define OL dysfunction as a self-reinforcing driver of AD and identify myelin preservation as a point of preventive leverage.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Animals
*Oligodendroglia/pathology/metabolism
Myelin Sheath/metabolism/pathology
*Cell Lineage
Amyloid beta-Peptides/metabolism