@article {pmid42885915,
year = {2026},
author = {Gries, M and Schäfer, KH and Endres, K},
title = {Targeting the microbiota-gut-brain axis in Alzheimer's and Parkinson´s disease: recent therapeutic approaches.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2748747},
pmid = {42885915},
issn = {1744-7631},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders with limited disease-modifying treatment options. Evidence suggests that the microbiota-gut-brain axis (MGBA) plays a role in these diseases by facilitating communication between the gut and the central nervous system. Associations have been found between altered gut microbiota composition and function, impaired barrier integrity, dysregulated metabolite production, and immune activation to neuroinflammation and progressive neurodegeneration.

AREAS COVERED: This review summarizes and critically assesses recent studies from the past year to provide an updated overview of therapeutic strategies targeting the MGBA in both diseases. We discuss dietary interventions, probiotics, postbiotics, microbial metabolites, and approaches targeting gut barrier function. We also highlight strategies such as fecal transplantation, photobiomodulation, and PD-targeted metabolism therapies using butyrate and resistant starch.

EXPERT OPINION: While these interventions have shown promising results in preclinical and early clinical trials, their clinical application is limited by methodological heterogeneity, interindividual variability and a lack of standardized protocols. Successful implementation requires carefully designed clinical trials, particularly longitudinal studies of presymptomatic cohorts, standardized microbiome analyses, and integrated multi-omics approaches to elucidate causal relations and facilitate personalized treatment strategies.},
}

@article {pmid42885968,
year = {2026},
author = {Ho, S and Shen, Z and Lewis, A and Patel, M and Zheng, A and Proscino, G and Ho, T and Wang, J and Albert, M and Moghekar, A},
title = {Alzheimer's Disease Biomarkers Measured by Capillary Blood Collection Versus Venous Plasma and Cerebrospinal Fluid.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
pmid = {42885968},
issn = {2328-9503},
support = {P30AG066507/AG/NIA NIH HHS/United States ; U19AG033655/AG/NIA NIH HHS/United States ; //Lantry Family Foundation/ ; },
abstract = {OBJECTIVE: Blood biomarkers are increasingly critical for non-invasive Alzheimer's Disease (AD) diagnostics and research but typically require on-site processing. Remote point-of-care collection methods could enhance biomarker testing in clinical and research settings. We evaluated the safety and accuracy of blood collection via venous blood and two capillary blood collection devices (Tasso+ and TAPII) for measurements of amyloid-beta 42/40 ratio (Aβ42/40), phosphorylated-tau-217 (pTau217), neurofilament-light (NfL), and glial fibrillary acidic protein (GFAP) from capillary plasma to simultaneously collected venous plasma and cerebrospinal fluid (CSF).

METHODS: Patients seen at the Johns Hopkins Center for CSF Disorders (N = 192) underwent diagnostic lumbar punctures and venipuncture. Warming packs were held to the skin for 5 min before collecting capillary blood (via TAPII or Tasso+ device) and numeric pain scores. CSF, venous, and capillary plasma were analyzed using Quanterix SIMOA immunoassays. Statistical analysis included Pearson/Spearman correlations, Lasso regression, and quantitative comparisons using Bland-Altman plots.

RESULTS: 86 TAPII and 126 Tasso+ plasma samples were collected (77 M, 115 F; mean age 61 ± 18.3 years, range 16-91). Tasso+ devices were 90.3% successful in collecting > 50 μL whole blood, and TAPII devices were 86% successful. Mean pain scores were significantly higher in venous than capillary collections (Venous 2.24/10, TAPII 0.73/10, Tasso+ 0.2/10, p < 0.001). Capillary Aβ42/40, NfL, and GFAP strongly correlated with venous plasma analytes (Tasso+: Aβ42/40 r = 0.75, NfL r = 0.91, GFAP r = 0.80, all p < 0.001; TAPII: Aβ42/40 r = 0.74, NfL r = 0.86, GFAP r = 0.84, all p < 0.001). Tasso+ capillary pTau217 weakly correlated with venous (r = 0.23, p = 0.04). Capillary NfL and GFAP correlated modestly with CSF NfL and GFAP (TAPII NfL r = 0.74, GFAP r = 0.6, all p < 0.0001; Tasso+ NfL r = 0.69, GFAP r = 0.59, all p < 0.0001). Capillary Aβ42/40 and pTau217 did not significantly correlate with CSF measures. Lasso regression identified age and GFAP as significant predictors of AD across capillary and venous samples (Tasso+ AUC = 0.87, TAPII AUC = 0.75, Venous AUC = 0.83).

INTERPRETATION: Neurodegeneration biomarkers Aβ42/40, NfL, and GFAP in capillary plasma (Tasso+, TAPII) strongly correlated with venous plasma measures. Capillary and venous pTau217 correlated weakly, indicating further assay refinement is needed. Tasso+ collection was less painful and caused less hemolysis compared to TAPII.},
}

@article {pmid42885984,
year = {2026},
author = {Luan, X and Shen, J and Wang, Y and Qiu, H and Cheng, H and Zheng, C and Hu, S and Wen, C and Cao, G and Kwpaong, WR and Wang, Z},
title = {Multimodal Retinal Imaging Correlates With Brain Atrophy and Plasma Biomarkers in Alzheimer's Disease.},
journal = {Translational vision science & technology},
volume = {15},
number = {10},
pages = {24},
doi = {10.1167/tvst.15.10.24},
pmid = {42885984},
issn = {2164-2591},
mesh = {Humans ; Female ; Cross-Sectional Studies ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; *Biomarkers/blood ; Male ; Atrophy ; Tomography, Optical Coherence/methods ; *Multimodal Imaging/methods ; *Brain/pathology/diagnostic imaging ; Aged ; Amyloid beta-Peptides/blood ; *Retina/diagnostic imaging/pathology ; tau Proteins/blood ; Magnetic Resonance Imaging ; Aged, 80 and over ; Peptide Fragments ; },
abstract = {PURPOSE: To investigate retinal structural and microvascular changes in Alzheimer's disease (AD) and evaluate their associations with neuroimaging markers, plasma biomarkers, and cognitive impairment.

METHODS: This cross-sectional study included 181 participants (95 with AD and 86 cognitively unimpaired controls). AD diagnosis was established according to National Institute on Aging-Alzheimer's Association criteria with positive amyloid-β positron emission tomography imaging. Retinal structure and microvasculature were assessed using swept-source optical coherence tomography (OCT) and OCT angiography (OCTA). Cortical thickness and gray matter volume were quantified using structural magnetic resonance imaging. Plasma Aβ42 and phosphorylated tau-217 (p-tau217) were measured, and cognitive function was evaluated using the Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA).

RESULTS: Compared with controls, patients with AD demonstrated reduced retinal nerve fiber layer, ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer, and outer retinal layer thicknesses, together with lower superficial vascular complex (SVC) and deep vascular complex densities (all P < 0.001). GCIPL thickness and SVC density were associated with cortical atrophy in AD-vulnerable regions, including temporal, parietal, and occipital cortices. Lower plasma Aβ42 levels were associated with reduced retinal layer thickness and vascular density, whereas higher p-tau217 levels were associated with reduced outer retinal layer thickness and SVC density. GCIPL thickness showed the strongest association with cognitive performance, while lower SVC density was associated with poorer MoCA scores. APOE ε4 carriers exhibited greater GCIPL thinning, reduced retinal vascular density, and more extensive cortical abnormalities despite similar plasma Aβ42 and p-tau217 levels.

CONCLUSIONS: Retinal neuronal and microvascular alterations are associated with AD-related molecular pathology, cerebral neurodegeneration, APOE ε4-related vulnerability, and cognitive impairment. OCT/OCTA may provide a noninvasive adjunct approach for characterizing neurodegenerative and neurovascular changes in AD.

TRANSLATIONAL RELEVANCE: Retinal imaging may provide a scalable and noninvasive approach for detecting and monitoring AD pathology.},
}

Humans
Female
Cross-Sectional Studies
*Alzheimer Disease/blood/diagnostic imaging/pathology
*Biomarkers/blood
Male
Atrophy
Tomography, Optical Coherence/methods
*Multimodal Imaging/methods
*Brain/pathology/diagnostic imaging
Aged
Amyloid beta-Peptides/blood
*Retina/diagnostic imaging/pathology
tau Proteins/blood
Magnetic Resonance Imaging
Aged, 80 and over
Peptide Fragments

@article {pmid42886279,
year = {2026},
author = {Zhou, Y and Fu, H and Chen, K and Jiang, Y and Wang, Z and Wu, W and Cao, X},
title = {Capillary-integrated chiral gold nanocrystals for label-free SERS detection of serum amyloid-β 1-42 in Alzheimer's disease rats.},
journal = {Mikrochimica acta},
volume = {193},
number = {11},
pages = {},
pmid = {42886279},
issn = {1436-5073},
support = {81403232//the National Natural Science Foundation of China/ ; 19KJA480003//the Major Programs of Natural Science Foundation of higher education in Jiangsu Province/ ; No. BK20171290//the Natural Science Foundation of Jiangsu Province/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/blood ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; *Alzheimer Disease/blood/diagnosis ; *Peptide Fragments/blood ; *Spectrum Analysis, Raman/methods ; Rats ; Limit of Detection ; Stereoisomerism ; },
abstract = {Chiral plasmonics was integrated with surface-enhanced Raman scattering (SERS) technology to develop a high-performance chiral SERS sensor with promising applications for the early identification and ultrasensitive detection of Alzheimer's disease. The sensor utilizes the self-assembly of chiral gold nanocrystals (CG NCs) on the inner wall of a capillary, introducing a surface-enhanced Raman scattering chiral anisotropy (SERS-ChA) effect. Consequently, a label-free chiral SERS sensor ‌is‌ constructed. In the presence of the target analyte Amyloid-β 1-42 (Aβ1-42, Aβ42), CG NCs generate an electric-dipole-magnetic-dipole coupling effect within the chiral plasmonic field, resulting from selective resonance coupling between enantiomer-induced electric and magnetic dipole (MD) moments. This process significantly enhances the chiral asymmetric response and amplifies the SERS signal, allowing highly sensitive recognition and detection of Aβ42. The sensor exhibits excellent analytical performance, achieving a limit of detection (LOD) as low as 0.0899 pg/mL. Furthermore, it demonstrates strong selectivity for Aβ42 and robust resistance to interference from other substances commonly present in serum. By analyzing serum samples from rat models of Alzheimer's disease and comparing the results with those from an Aβ1-42 ELISA kit, a high correlation (R[2] = 0.976) was demonstrated, validating the sensor's practicality and accuracy and indicating its stable and reliable quantitative performance in complex biological matrices. This study provides new insights and theoretical foundations for the early screening and diagnosis of Alzheimer's disease.},
}

Animals
*Amyloid beta-Peptides/blood
*Gold/chemistry
*Metal Nanoparticles/chemistry
*Alzheimer Disease/blood/diagnosis
*Peptide Fragments/blood
*Spectrum Analysis, Raman/methods
Rats
Limit of Detection
Stereoisomerism

@article {pmid42886392,
year = {2026},
author = {Erbil, G and Aykora, D and Uzun, M},
title = {Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42886392},
issn = {1573-4978},
mesh = {*RNA, Small Interfering/administration & dosage/genetics/therapeutic use ; Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; Blood-Brain Barrier/metabolism ; Nanoparticles/chemistry ; Gene Silencing ; Gene Transfer Techniques ; Exosomes/metabolism ; Drug Delivery Systems/methods ; },
abstract = {Neurodegenerative diseases remain largely untreatable at the disease-modifying level, with currently approved therapies providing primarily symptomatic benefits. Small interfering RNA (siRNA) has emerged as a promising therapeutic modality because of its ability to selectively silence disease-associated genes. However, a major obstacle to clinical translation is not the gene-silencing mechanism itself, but the efficient delivery of therapeutic siRNAs to target cells within the central nervous system.This review examines the barriers that limit siRNA-based therapies for neurodegenerative diseases. We adopt a barrier-oriented framework that follows the sequential challenges encountered during siRNA delivery, including extracellular instability, unfavorable pharmacokinetics, immune recognition, limited transport across the blood-brain barrier, inefficient cellular internalization, and endosomal entrapment. Rather than cataloguing available delivery systems, we evaluate how nanocarrier engineering strategies have been developed to address these barriers and assess their impact on delivery. Evidence from Alzheimer's disease, Parkinson's disease, and Huntington's disease is synthesized to distinguish shared limitations from disease-specific challenges and to evaluate the translational performance of lipid-based nanoparticles, polymeric nanocarriers, engineered exosomes, and hybrid platforms.Available evidence indicates that delivery platforms can improve specific aspects of siRNA transport but have not consistently overcome the sequential biological barriers required for therapy. Although nanocarrier engineering has enhanced siRNA stability, brain targeting, intracellular trafficking, and gene-silencing efficiency in preclinical models, manufacturing scalability, biological heterogeneity, long-term safety, reproducibility, and regulatory feasibility remain important barriers to clinical translation. Future progress will likely depend on delivery systems that integrate effective brain transport, endosomal escape, controlled intracellular release, and scalable manufacturing within clinical platforms.},
}

*RNA, Small Interfering/administration & dosage/genetics/therapeutic use
Humans
*Neurodegenerative Diseases/genetics/therapy
Animals
Blood-Brain Barrier/metabolism
Nanoparticles/chemistry
Gene Silencing
Gene Transfer Techniques
Exosomes/metabolism
Drug Delivery Systems/methods

@article {pmid42886802,
year = {2026},
author = {Liu, J and Xu, C and Ruan, H and Zhang, K and Wang, F and Qin, Q and Li, X and Chen, Y and Tan, Y and Qiu, Y and Chen, H and Wang, Y and Yang, Z and Zhang, Y and Zhu, Y and Chang, C and Jiang, X and Peng, N},
title = {Noninvasive ultrashort wave neuromodulation enhances glymphatic clearance to alleviate traumatic brain edema and Alzheimer's pathology.},
journal = {Science advances},
volume = {12},
number = {42},
pages = {eaeh8870},
doi = {10.1126/sciadv.aeh8870},
pmid = {42886802},
issn = {2375-2548},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/therapy/physiopathology ; *Glymphatic System/metabolism ; *Brain Injuries, Traumatic/complications/metabolism/therapy/physiopathology/pathology ; Mice ; *Brain Edema/metabolism/therapy/etiology/pathology/physiopathology ; Aquaporin 4/metabolism ; Disease Models, Animal ; Male ; Astrocytes/metabolism ; Neurons/metabolism ; },
abstract = {The glymphatic system clears cerebral waste, yet strategies to enhance its function remain elusive. Here, we show that 40.68 MHz ultrashort wave (USW) rapidly enhances glymphatic bulk flow in healthy mice within 10 minutes. USW potentiates both glymphatic influx and efflux, concomitant with increased Delta wave neuronal synchronization, as confirmed by local field potentials and electroencephalograms. Chemogenetic silencing confirms that USW-driven glymphatic enhancement depends on neuronal activity, while pharmacological blockade of aquaporin-4 (AQP4) abolishes the effects, revealing dual reliance on neural dynamics and astrocytic water channels. Mechanistically, USW-induced Delta oscillations promote AQP4 polarization, coupling synchronized firing to perivascular AQP4 redistribution. Moreover, USW ameliorates traumatic brain injury-induced cerebral edema and improves cognitive deficits in Alzheimer's mice by restoring glymphatic function. Our findings establish USW as a non-invasive neuromodulatory strategy for enhancing glymphatic clearance, offering therapeutic potential for neurological disorders characterized by glymphatic dysfunction.},
}

Animals
*Alzheimer Disease/metabolism/pathology/therapy/physiopathology
*Glymphatic System/metabolism
*Brain Injuries, Traumatic/complications/metabolism/therapy/physiopathology/pathology
Mice
*Brain Edema/metabolism/therapy/etiology/pathology/physiopathology
Aquaporin 4/metabolism
Disease Models, Animal
Male
Astrocytes/metabolism
Neurons/metabolism

@article {pmid42886871,
year = {2026},
author = {Colbeth, HL and Posis, AIB and Rizvi, BM and Decarli, CS and Glymour, MM and George, KM and Corrada, MM and Gilsanz, P and Whitmer, RA},
title = {Role of APOE ɛ4 and ɛ2 With Longitudinal Cognitive Decline Among Those With Exceptional Longevity: The LifeAfter90 Study.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218596},
doi = {10.1212/WNL.0000000000218596},
pmid = {42886871},
issn = {1526-632X},
mesh = {Humans ; *Apolipoprotein E4/genetics ; Female ; Male ; Longitudinal Studies ; *Apolipoprotein E2/genetics ; *Longevity/genetics ; Aged, 80 and over ; Neuropsychological Tests ; Executive Function/physiology ; Genotype ; Memory, Episodic ; *Cognitive Dysfunction/genetics ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: APOE ɛ4 is the strongest genetic risk factor for late-onset Alzheimer disease, while ɛ2 is associated with decreased risk. However, it is unclear how these genotypes relate to cognitive decline among those aged older than 90+. We examined associations of ɛ4 and ɛ2 with longitudinal change in 3 cognitive domains among individuals aged 90+.

METHODS: LifeAfter90 is an ongoing longitudinal multiethnic cohort study of those aged 90+. APOE genotyping was conducted using DNA extracted from saliva. Two dichotomous exposures were defined as ɛ4 carriers (ɛ2/ɛ4, ɛ3/ɛ4, or ɛ4/ɛ4 genotypes) vs non-ɛ4-carriers with no ɛ4 allele and ɛ2 carriers (ɛ2/2, ɛ2/3 genotypes) vs non-ɛ2-carriers (ɛ3/ɛ3, ɛ2/ɛ4, ɛ3/ɛ4, or ɛ4/ɛ4). Executive function (EF), semantic memory (SM), and verbal episodic memory (VEM) were measured every 6 months on up to 11 occasions using the Spanish and English Neuropsychological Scales. Time to all-cause mortality was calculated from baseline to death. We fit linear mixed-effects (LME) models and joint models (LME and Cox proportional hazard submodels) to account for the competing risk of death. Models adjusted for age and sex.

RESULTS: We evaluated 445 participants (mean age at baseline 93 years, SD 2.31, range 90-104; 59% female). In total, 20% were ɛ4 carriers, 15% were ɛ2 carriers, and 54% died during follow-up. The ethnoracial composition was 21% African American/Black, 22% as Asian, 16% as Hispanic/Latinx, 9% as multiracial/other, and 32% as White. The mean follow-up time was 3.9 years (SD 1.63, range 0.68-6.67). Neither ɛ4 nor ɛ2 carriers averaged substantially greater or lesser mortality hazard than noncarriers. In joint models, ɛ4 carriers had faster decline in EF (β = -0.07, 95% CI -0.12 to -0.02), but similar decline in VEM (β = -0.01, 95% CI -0.08 to 0.05) and SM (β = -0.03; 95% CI -0.08 to 0.02). APOE ɛ2 carriers had similar decline in EF (β = 0.01, 95% CI -0.05 to 0.08) and SM (β = 0.01, 95% CI -0.05 to 0.08) but slower decline in VEM (β = 0.07, 95% CI 0.00-0.15) compared with noncarriers. Longitudinal results were similar for LME and joint models.

DISCUSSION: After accounting for the competing risk of death, the negative consequences of ɛ4 on EF decline extend to those with exceptional longevity.},
}

Humans
*Apolipoprotein E4/genetics
Female
Male
Longitudinal Studies
*Apolipoprotein E2/genetics
*Longevity/genetics
Aged, 80 and over
Neuropsychological Tests
Executive Function/physiology
Genotype
Memory, Episodic
*Cognitive Dysfunction/genetics
Cohort Studies

@article {pmid42886876,
year = {2026},
author = {Smith, JR and Pike, JR and Lu, Y and Walker, KA and Sullivan, KJ and Windham, BG and Thyagarajan, B and Mielke, MM and Lutsey, PL and Hughes, TM and Knopman, DS and Gottesman, RF and Mosley, TH and Coresh, J and Deal, JA and Sharrett, AR and Palta, P},
title = {Midlife and Late-Life Alzheimer Disease Blood Biomarkers and 11-Year Cognitive Decline.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218692},
doi = {10.1212/WNL.0000000000218692},
pmid = {42886876},
issn = {1526-632X},
mesh = {Humans ; Female ; Biomarkers/blood ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/psychology ; Male ; *Glial Fibrillary Acidic Protein/blood ; *tau Proteins/blood ; Middle Aged ; *Cognitive Dysfunction/blood/psychology ; Peptide Fragments/blood ; Aged ; Prospective Studies ; Neurofilament Proteins/blood ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma biomarkers of Alzheimer disease (AD) neuropathology (amyloid-β42 to amyloid β40 [Aβ42/40] ratio, phosphorylated tau at threonine [p-tau181]), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]) in late-life are associated with cognitive decline. Whether these biomarkers in midlife are predictive of subsequent cognitive decline, and whether they are associated with different cognitive domains, is uncertain. In this study, we investigated associations of midlife and late-life plasma Aβ42/40, p-tau181, NfL, and GFAP with late-life change in domain-specific (memory, language, and executive function) and global cognitive function.

METHODS: We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Outcome follow-up was from ARIC visit 5 (2011-2013) to visit 9 (2021-2022). We included all individuals from ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; and Minneapolis suburbs, Minnesota) with biomarkers measured from stored specimens in midlife (visit 3, 1993-1995, mean age 59.0 years) and late-life (visit 5, 2011-2013, mean age 76.8 years). Aβ42/40, p-tau181, NfL, and GFAP were measured with the Quanterix Simoa platform and standardized to visit 3 to facilitate cross-biomarker comparisons of their rate of change from midlife to late-life. We estimated change in memory, language, executive function, and global cognition factor scores from visit 5 to visit 9 with linear mixed-effect models.

RESULTS: In 1,515 included participants, 60.7% (n = 920) were female and 25.5% (n = 387) were Black. Each SD increase in p-tau181 in midlife was significantly associated with faster late-life memory decline (β = -0.030 [95% CI -0.059 to -0.001] SD. Midlife Aβ42/40, NfL, and GFAP were not associated with subsequent decline in any cognitive domain. In late-life, p-tau181, NfL, and GFAP were significantly associated with faster decline in different cognitive domains, with the strongest associations seen with memory (β = -0.091 [95% CI -0.123 to -0.058] SD; β = -0.064 [95% CI -0.106 to -0.023] SD; and β = -0.048 [95% CI -0.082 to -0.013] SD, respectively).

DISCUSSION: Midlife p-tau181 was associated with faster 11-year memory decline beginning 20 years later in the ARIC cohort, which underscores a potentially long prodromal phase of cognitive decline that could precede dementia onset. In late-life, biomarkers for AD, neurodegeneration, and neuroinflammation were associated with faster decline across different cognitive domains, but associations remained strongest for p-tau181 and memory.},
}

Humans
Female
Biomarkers/blood
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/psychology
Male
*Glial Fibrillary Acidic Protein/blood
*tau Proteins/blood
Middle Aged
*Cognitive Dysfunction/blood/psychology
Peptide Fragments/blood
Aged
Prospective Studies
Neurofilament Proteins/blood

@article {pmid42886878,
year = {2026},
author = {Felici, C and Green, RE and Warren-Gash, C and Butt, J and Waterboer, T and Hughes, A and Chaturvedi, N and Keshavan, A and Coath, W and Schott, JM and Richards, M and Williams, DM},
title = {Associations of Antibodies Against Several Infections With Alzheimer Disease Neuropathology: A Prospective Cohort Study Analysis.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218584},
doi = {10.1212/WNL.0000000000218584},
pmid = {42886878},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/blood/immunology/pathology/diagnostic imaging/epidemiology ; Female ; Male ; Prospective Studies ; Middle Aged ; Aged ; Amyloid beta-Peptides/metabolism ; tau Proteins/blood ; Cohort Studies ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND AND OBJECTIVES: Associations of common infections with Alzheimer disease (AD) risk have been reported. A hypothesized mechanism for these is cerebral β-amyloid (Aβ) aggregation as a defense to infection. We studied whether serologic measures of several infections in the UK population are associated with measures of AD neuropathology.

METHODS: This prospective association study used data from the 1946 British birth cohort. Circulating antibodies against 14 pathogens, measured at age 60-64 years, were modelled as pathogen serostatus (indicating lifetime exposure to an agent), pathogen burden indices (measuring cumulative exposure to 2+ pathogens), and seroreactivity tertiles (indicating recent immunologic activity against pathogens). Associations of these were tested with plasma phosphorylated tau at threonine 217 (p-tau217) (primary outcome) and Aβ status (secondary outcome), measured with PET scans, at ages 69-71 years. Modelling used multivariable quantile and logistic regression. Model 1 adjusted for sex and ages at serology and outcome assessment, and models 2 and 3 additionally adjusted for APOE ε4 carriage and education, respectively. We also tested for interactions in associations by APOE ε4 carriage, education, and sex, and for interactions between herpes simplex virus 1 exposure with cytomegalovirus (CMV) and varicella zoster virus (VZV) exposure.

RESULTS: A total of 1,356 and 424 individuals had complete data for p-tau217 and Aβ-PET analyses, respectively. Mean age at p-tau217 was 69.9 years (SD 0.7), and 51.3% of participants were female. Median p-tau217 was 0.30 pg/mL (interquartile range 0.21-0.44). 28.3% had Aβ-positive scans. No notable associations were observed for serology measures with either outcome in main models, except for an unexpected association of herpes simplex virus 2 seropositivity with lower p-tau217 at the 75th quantile (-0.07 pg/mL in seropositive individuals; 95% CI -0.10 to -0.03). Odds of Aβ-PET positivity may have been higher for individuals seropositive for Epstein-Barr virus (odds ratio [OR] 2.84; 95% CI 0.95-8.52) and Toxoplasma gondii (OR 1.69; 95% CI 0.94-3.05). There were also potential interactions in p-tau217 associations by APOE ε4 carriage (for Helicobacter pylori and CMV) and educational attainment (for H pylori).

DISCUSSION: These findings do not imply associations between exposures to many common infections and AD neuropathologies. The possibility of pathogen interactions with APOE ε4 carriage and education in relation to AD neuropathology warrants further study.},
}

Humans
*Alzheimer Disease/blood/immunology/pathology/diagnostic imaging/epidemiology
Female
Male
Prospective Studies
Middle Aged
Aged
Amyloid beta-Peptides/metabolism
tau Proteins/blood
Cohort Studies
Apolipoprotein E4/genetics

@article {pmid42886879,
year = {2026},
author = {Jang, SH and Jung, J},
title = {APOE Beyond Alzheimer Disease: Cognitive Aging in the Oldest Old.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218660},
doi = {10.1212/WNL.0000000000218660},
pmid = {42886879},
issn = {1526-632X},
}

@article {pmid42887030,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Iwatsubo, T},
title = {Amyloid-β Immunotherapy in Alzheimer's Disease: Challenges and Opportunities.},
journal = {Annual review of pathology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-pathmechdis-032025-030232},
pmid = {42887030},
issn = {1553-4014},
abstract = {Passive anti-amyloid-β immunotherapy has shifted from repeated phase 3 failure to reproducible, although modest, clinical slowing in biomarker-defined early Alzheimer's disease. We review lessons from first-generation antibodies, including inadequate target engagement, late-stage enrollment, and limited outcome sensitivity. We then compare second-generation agents (i.e., aducanumab, lecanemab, and donanemab) highlighting amyloid-β species selectivity, plaque clearance kinetics, and durability, and we discuss emerging delivery innovations. Safety is dominated by amyloid-related imaging abnormalities, likely reflecting cerebrovascular amyloid vulnerability, and requires timely baseline magnetic resonance imaging (MRI) screening; APOE-informed counseling; and standardized, front-loaded MRI surveillance with symptom-triggered evaluation. We summarize prevention trials in autosomal dominant and sporadic preclinical populations and consider prospects for combination or sequential regimens with tau-targeting therapies. Finally, we focus on biomarker-guided implementation: blood-based prescreening, confirmation pathways, monitoring of biological response, and treat-to-clear or stopping concepts, alongside unresolved issues of health-system readiness, equity, and budget impact. Registry-enabled learning is emphasized to generate real-world safety and effectiveness evidence.},
}

@article {pmid42887066,
year = {2026},
author = {Nkpabo, TO},
title = {Sulphonamide derivatives: A comprehensive review of their diverse therapeutic applications.},
journal = {European journal of medicinal chemistry},
volume = {321},
number = {Pt 2},
pages = {119421},
doi = {10.1016/j.ejmech.2026.119421},
pmid = {42887066},
issn = {1768-3254},
abstract = {The sulphonamide functionality (-SO2NR2) remains a highly adaptable privileged functional group that has expanded far beyond its traditional antibacterial role. This review thoroughly explores its ongoing importance in modern drug discovery, focusing on structure-activity relationships (SARs) across various therapeutic fields. This article evaluates recent developments (2008-present) in areas such as antimicrobial, anti-inflammatory, antidiabetic, anti-Alzheimer's, antiviral, and anticonvulsant applications. Critical structural modifications such as substitution at the sulphonamide nitrogen, changes to the aromatic ring, and hybridization with other pharmacophores-are examined for their impact on potency, selectivity, pharmacokinetics, and safety. Overall, these insights highlight the continued relevance of the sulphonamide moiety as a powerful foundation for designing agents aimed at complex disease mechanisms.},
}

@article {pmid42887235,
year = {2026},
author = {Zhu, X and Liang, H and Fan, L and Bo, J and Diao, F and Qian, Y and Zhang, G and Li, W},
title = {A tunable brain-targeted PEGylated ginsenoside Rg1 derivative disrupts the ROS-mediated inflammasome-pyroptosis cascade to ameliorate Alzheimer's cognitive deficits.},
journal = {Biomaterials},
volume = {338},
number = {Pt B},
pages = {124707},
doi = {10.1016/j.biomaterials.2026.124707},
pmid = {42887235},
issn = {1878-5905},
abstract = {The pathogenic cascade of oxidative stress, neuroinflammation, and pyroptosis serves as a core driving factor in the pathogenesis and progression of Alzheimer's disease (AD). Although ginsenoside Rg1 exhibits pleiotropic neuroprotective activities, its poor blood-brain barrier (BBB) permeability severely hinders its clinical translation. To overcome this limitation, a brain-targeted delivery system was constructed using a covalent conjugation strategy, linking purified Rg1 with rhodamine B-modified polyethylene glycol (PEG) of varying chain lengths (Rg1s-PEG). After screening, the derivative Rg1s-PEG-600 was identified as achieving an optimal balance between hydrophilic stealth properties and steric hindrance, demonstrating enhanced brain accumulation and favorable biosafety profiles. In both in vitro and in vivo models of lipopolysaccharide-induced acute neuroinflammation, Rg1s-PEG-600 attenuated reactive oxygen species (ROS) accumulation, inhibited canonical neuronal pyroptosis mediated by the NLRP1/3 inflammasomes, and significantly ameliorated behavioral deficits and synaptic loss. Furthermore, in chronic 5xFAD transgenic mice, systemic administration of Rg1s-PEG-600 for 12 weeks markedly reversed spatial memory decline, anxiety-like behavior, and synaptic protein depletion. Mechanistic studies further revealed that this targeted nanotherapeutic not only suppressed the ROS-NLRP1 signaling axis and subsequent neuronal pyroptosis in the AD brain but also comprehensively inhibited amyloidogenesis and Tau hyperphosphorylation. This work provides a promising, multitarget nanotherapeutic strategy to overcome BBB limitations and disrupt the complex pathological networks underlying neurodegenerative diseases.},
}

@article {pmid42887239,
year = {2026},
author = {Fatima, K and Cho, HS and Olawuyi, IF and Lee, WY},
title = {Exploring the neuroprotective potential of saponins through the gut microbiota-brain axis: a narrative review of emerging mechanisms and research directions.},
journal = {Nutrition research (New York, N.Y.)},
volume = {155},
number = {},
pages = {106-119},
doi = {10.1016/j.nutres.2026.09.007},
pmid = {42887239},
issn = {1879-0739},
abstract = {Neurodegenerative diseases are defined as progressive and irreversible disorders involving the degeneration of neurons in the brain, giving rise to both cognitive deterioration and motor dysfunction. Diseases such as Alzheimer's, Parkinson's, and Huntington's pose major public health challenges, particularly in aging populations, and are driven by complex mechanisms including oxidative stress, neuroinflammation, and abnormal protein aggregation. Recent evidence suggests that alterations in gut microbiota composition are closely linked to the onset and progression of these disorders. Saponins have been reported to modulate gut microbiota composition and preclinical studies indicate that certain saponins may exert neuroprotective actions in specific models of neurodegeneration. This review summarizes and interprets the emerging, preliminary role of saponins in modulating pathways implicated in neurodegeneration, with a particular focus on their capacity to influence the gut microbiota-brain axis. Specifically, we summarize scientific evidence on how the structural features of saponins shape gut microbial composition and activity, thereby influencing their potential to modulate the development and progression of neurodegenerative disorders. Microbial metabolites, neuroinflammatory cascades, and redox balance represent key pathways potentially influenced by saponins in preclinical contexts, 2 central drivers of neurodegenerative progression. This review also highlights the preliminary nature of current evidence on these potential mechanisms and discusses major knowledge gaps, including saponin toxicity and the need for clinical studies before meaningful translation.},
}

@article {pmid42887430,
year = {2026},
author = {Jiao, H and Huang, H and Chen, S and Wang, P and Xiang, J and Xiang, G and Zhao, L},
title = {Low-dose radiotherapy ameliorates Alzheimer's-like pathology in 5xFAD mice and is associated with HIF-1α-related inflammatory signaling downregulation.},
journal = {Pathology, research and practice},
volume = {288},
number = {},
pages = {156715},
doi = {10.1016/j.prp.2026.156715},
pmid = {42887430},
issn = {1618-0631},
abstract = {BACKGROUND: Whether fractionated low-dose radiotherapy (LDRT) alleviates Alzheimer's disease-like pathology and whether these effects are associated with microglial HIF-1α-related signaling remain unclear.

METHODS: Male 5xFAD mice received whole-brain irradiation at 2 Gy per fraction for 5 fractions (total dose, 10 Gy). One month later, cognition was assessed by the Morris water maze and novel object recognition tests, and brain pathology was evaluated by immunofluorescence and Western blot. LPS-stimulated BV2 cells were used as an in vitro model to examine the effects of LDRT on nitric oxide, cytokines, and reactive oxygen species. Transcriptomic analysis was performed with 3 biological replicates per group, followed by pharmacological validation using the HIF-1α inhibitor YC-1.

RESULTS: LDRT improved spatial and recognition memory, reduced Aβ plaque burden in the hippocampus and cortex, and attenuated microglial activation in 5xFAD mice. In particular, LDRT decreased the hippocampal Aβ plaque area fraction (P = 0.0065) and reduced HIF-1α expression in Iba1-positive microglia in the hippocampus (P = 0.0077). In addition, LDRT reduced Iba1 expression and CD68-positive area while preserving Aβ phagocytosis by primary microglia. In BV2 cells, LDRT inhibited LPS-induced inflammatory responses and altered 123 differentially expressed genes enriched in the HIF-1, IL-17, TNF, MAPK, and p53 signaling pathways. Pharmacological inhibition of HIF-1α by YC-1 recapitulated, but did not further enhance, the anti-inflammatory effects of LDRT.

CONCLUSIONS: Fractionated whole-brain LDRT ameliorates cognitive deficits and Aβ pathology in 5xFAD mice, with effects associated with downregulation of microglial HIF-1α-related signaling.},
}

@article {pmid42887433,
year = {2026},
author = {Suri, P and Daartey, AB and Olive Khan, DMI and Rayana, NP and Chilamakuri, R and Godugu, D and Azad, MG and Reeb, KL and Richardson, DR},
title = {Harnessing autophagy and its transcriptional regulation in tumorigenesis and neurodegeneration: Potential and existing therapeutic strategies.},
journal = {Pharmacological reviews},
volume = {78},
number = {6},
pages = {100158},
doi = {10.1016/j.pharmr.2026.100158},
pmid = {42887433},
issn = {1521-0081},
abstract = {Autophagy is a fundamental cellular process that maintains homeostasis by degrading and recycling cellular components. As autophagy is essential for metabolizing damaged organelles and toxic substances, it plays a crucial role in both normal physiology and pathological conditions. However, autophagy has dual roles in both tumorigenesis and neurodegeneration. In cancer, autophagy can act as a tumor suppressor by clearing damaged components in early stages, but promotes tumor survival and growth in later stages, particularly under stress. In neurodegeneration, impaired autophagy is implicated in the disease progression of conditions such as Alzheimer, Parkinson, and Huntington diseases, in which the failure to clear misfolded proteins and damaged organelles exacerbates disease pathology. This review is organized to cover the molecular machinery and transcriptional regulation of autophagy, its disease-specific subtypes, its dual roles in tumorigenesis and neurodegeneration, and the current pharmacological landscape for therapeutic targeting. Attention is given to pharmacological modulation of autophagy, including senolytic drugs that selectively eliminate senescent cells by exploiting their dependence on antiapoptotic survival pathways, and small-molecule regulators targeting key pathways such as phosphoinositide 3-kinase/Akt serine/threonine kinase/mechanistic target of rapamycin and AMP-activated protein kinase. Depending on the pathological context, these drugs are under development to either inhibit or induce autophagy. Additionally, we address the challenges and limitations in developing effective autophagy-targeting drugs, underscoring the need for further research to identify new compounds that can modulate cellular autophagic flux. SIGNIFICANCE STATEMENT: Autophagy is an important homeostatic mechanism, and its dysregulation contributes to a wide range of diseases, including cancer and neurodegenerative disorders. Therefore, a deeper mechanistic understanding of the regulation of autophagy is crucial for advancing targeted therapies with significant clinical impact.},
}

@article {pmid42887664,
year = {2026},
author = {},
title = {Expression of Concern to: "Gamma Secretase-Activating Protein Is a Substrate for Caspase-3: Implications for Alzheimer's Disease," by Chu et al. (Biol Psychiatry 2015; 77:720-728); https://doi.org/10.1016/j.biopsych.2014.06.003.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.10.007},
pmid = {42887664},
issn = {1873-2402},
}

@article {pmid42887669,
year = {2026},
author = {Otto, B and Zantvoord, JB and Siskind, D and Vermeulen, JM},
title = {Modulating neuroinflammation with glucagon-like peptide-1 receptor agonists: a scoping review exploring their therapeutic potential in schizophrenia.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111978},
doi = {10.1016/j.pnpbp.2026.111978},
pmid = {42887669},
issn = {1878-4216},
abstract = {Neuroinflammation is a key contributor to the pathophysiology and symptomatology of schizophrenia spectrum disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), clinically approved anti-diabetic and -obesity medication, have been associated with anti-inflammatory properties. It remains unclear whether GLP-1RA treatment can improve neuroinflammation within psychiatric disorders, including schizophrenia. This scoping review synthesizes evidence from clinical and preclinical studies on the anti-inflammatory effects of GLP-1RAs in psychiatric, neurodegenerative and neurological disease models, identifying crucial research gaps and providing future recommendations to guide potential clinical translation. The literature search was conducted in PubMed, Embase and PsycINFO and included outcomes of cytokine levels within blood and brain samples. Within the 40 included studies, two were clinical (schizophrenia and alcohol-use disorder) and 38 were preclinical models of psychiatric diseases, Alzheimer's -, Parkinson's Disease, Multiple Sclerosis, Epilepsy and lipopolysaccharide (LPS)-induced neuroinflammation. Preclinical studies showed anti-(neuro)inflammatory effects of GLP-1RAs, whereas the two available clinical studies found no significant changes in peripheral inflammatory markers. As these trials were not primarily designed or powered to test neuroinflammatory effects, the clinical findings remain inconclusive. Differences in study design, inflammatory measurements, pharmacokinetics and dosing may have contributed to the discrepancy between preclinical and clinical findings. Future research should prioritize early-phase dose-finding trials in non-diabetic, or -overweight patients diagnosed with schizophrenia spectrum disorders, evaluating the effects of alternative GLP-1RA regimens on neuroinflammatory markers, safety and clinical symptomatology. This is an essential step to determine their potential mental health-enhancing effects through the modulation of neuroinflammation within schizophrenia spectrum disorders.},
}

@article {pmid42887705,
year = {2026},
author = {Roy, J and Tsui, KC and Poon, CH and Zhang, J and Lai, Y and Wong, KY and Mihardja, M and Tse, V and Li, PC and Au, C and Ng, J and Kocabicak, E and Aquili, L and Wong, KH and Lu, Z and Temel, Y and Fung, ML and Lim, LW},
title = {Melatonin ameliorates behavioral deficits in 5xFAD mice through modulation of neurogenesis, neuroimmune responses, neurotransmission, and metabolic pathways.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {107077},
doi = {10.1016/j.bbi.2026.107077},
pmid = {42887705},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited disease-modifying treatment options. Melatonin, an endogenous hormone, has been shown to have therapeutic effects on amyloid deposition, oxidative stress, and neuroinflammation in AD. However, the mechanisms of its neuroprotective effects in the hippocampus remain largely unknown. This study aimed to investigate the multi-mechanistic neuroprotective effects of melatonin in AD. Eight-month-old female 5xFAD transgenic mice were treated with melatonin (10 mg/kg) for 4 weeks. Temozolomide and bromodeoxyuridine were used to block neurogenesis and to label proliferating neurons, respectively. Our results showed that 5xFAD mice treated with melatonin exhibited improved exploratory behavior, enhanced memory performance, reduced depressive-like symptoms, and decreased levels of stress hormones. At the molecular level, melatonin reduced amyloid-beta (Aβ) plaque accumulation, elevated hippocampal neurogenesis markers (DCX and BrdU), increased Trem2 expression and anti-inflammatory microglial activation, restored serotonergic, dopaminergic, catecholaminergic, and GABAergic neurotransmission, and partially normalized broader hippocampal metabolic pathways. Notably, temozolomide treatment abrogated the beneficial effects of melatonin on memory performance and depressive-like behavior in 5xFAD mice, indicating a neurogenesis-dependent mechanism. Collectively, these findings suggest that melatonin ameliorates behavioral deficits in 5xFAD mice through both neurogenesis-independent (reduced Aβ plaque accumulation, Trem2-microglial activation, neurotransmission restoration, and metabolic remodeling) and hippocampal neurogenesis-dependent mechanisms. Overall, melatonin holds therapeutic potential for attenuating the neuropathology and behavioral deficits in AD.},
}

@article {pmid42887710,
year = {2026},
author = {Samantaray, P and Verma, P},
title = {Neuroinflammation in Alzheimer's disease: From glial cell states and molecular networks to biomarkers and precision therapeutics.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104130},
doi = {10.1016/j.mcn.2026.104130},
pmid = {42887710},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is now recognized as a biologically heterogeneous syndrome in which amyloid-β pathology, Tau-related alterations, and neuroinflammation are key interconnected processes. Microglia, astrocytes, oligodendrocytes, complement, inflammasomes, neurovascular cells, and peripheral immunity are implicated as both adaptive and disease-promoting contributors to the pathophysiology of AD. Here, we highlight mechanisms by which innate immunity and peripheral immune cells influence amyloid β-peptide metabolism, Tau pathophysiology, excitatory synaptic function, oxidative stress response, blood-brain barrier integrity, and systemic inflammation in the context of Alzheimer's disease. A particular focus is made on the role of TREM2-related microglial function and the NLRP3 inflammasome, complement-mediated synaptic pruning, astrocyte crosstalk, and the limitations of the M1/M2 and A1/A2 concepts. A distinction is made between biomarkers of core AD pathophysiology and those specific to neuroinflammation and neurodegeneration. An emphasis is placed on the clinical utility of plasma p-tau217 in combination with Aβ42/Aβ40, GFAP, NfL, sTREM2, YKL-40, and neuroinflammation imaging. With respect to therapeutics, an effort is made to focus on the need to harness desirable inflammatory pathways while specifically targeting deleterious processes rather than adopting an overarching anti-inflammatory approach. Single-cell, spatial, multi-omics, and biomarker-driven approaches may enable patient stratification based on underlying pathophysiology, allowing for stage-specific combination therapeutic strategies. Overall, studies presented in this review highlight a precision-neuroimmunology concept in which neuroinflammatory processes are both triggers and effectors of disease pathology and can be selectively modulated for clinical benefit.},
}

@article {pmid42887875,
year = {2026},
author = {Luo, H and Jiang, D and Hao, Z and Bu, J and Wang, J and Xu, N and Nie, X and Zhang, Y and Yin, Q and Zhuang, P},
title = {zDHHC11 is a Common Palmitoyltransferase Regulating Microglia-Mediated Neuroinflammation across Neurodegenerative Diseases.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111226},
doi = {10.1016/j.neuropharm.2026.111226},
pmid = {42887875},
issn = {1873-7064},
abstract = {PURPOSE: Microglia-mediated neuroinflammation is a shared feature across Alzheimer's disease (AD), Parkinson's disease (PD), and diabetic cognitive impairment (DCI), but the convergent molecular mechanisms remain unclear. This study investigated whether protein S-palmitoylation serves as a common regulator of microglial neuroinflammation across distinct neurodegenerative diseases etiologies and aimed to identify the key palmitoyltransferase involved.

METHODS: In vivo ND models (APP/PS1 for AD, MPTP for PD, STZ/high-fat diet for DCI) and in vitro BV2 microglial models stimulated with amyloid-β (Aβ), lipopolysaccharide (LPS), or high glucose (HG) were established. Microglial morphology, inflammatory responses, and the TLR4/MyD88 pathway were assessed by immunofluorescence, RNA-seq, RT-qPCR, and ELISA. Protein palmitoylation levels were evaluated using 2-BP and ABE assays. Palmitoyltransferase expression profiling was performed, and protein-level validation was conducted both in vitro and in vivo. Subsequently, the identified common enzyme, zDHHC11, was knocked down by siRNA to determine its functional role.

RESULTS: All three ND models showed robust microglial activation with a pro-inflammatory amoeboid morphology. Aβ, LPS, and HG each upregulated pro-inflammatory cytokines and activated the TLR4/MyD88 pathway in BV2 cells. Palmitoylation inhibition with 2-BP attenuated cytokine production, and all three stimuli increased total protein palmitoylation. Among all palmitoyltransferases screened, zDHHC11 was uniquely and consistently upregulated by all three stimuli. This upregulation was further corroborated at the protein level, with elevated zDHHC11 expression observed both in cultured cells and in brain tissue sections. Knockdown of Zdhhc11 suppressed cytokine expression/secretion and reduced TLR4/MyD88 levels, indicating that zDHHC11 acts upstream of this common pathway.

CONCLUSION: Protein S-palmitoylation mediated by zDHHC11 is a convergent mechanism driving microglial pro-inflammatory activation across distinct ND etiologies. zDHHC11 represents a common regulator of TLR4/MyD88-dependent neuroinflammation and a potential therapeutic target for multiple NDs.},
}

@article {pmid42887984,
year = {2026},
author = {Lu, Y and He, W and Li, Y and Liu, Y and Li, Z and Zhang, R and Kong, F and Li, F and Zhou, Y},
title = {A blood-brain barrier-penetrating NIR fluorescent probe enables cross-model optical imaging of H2O2 in three neuroinflammation-related experimental mice models of brain injury.},
journal = {Analytica chimica acta},
volume = {1424},
number = {},
pages = {346241},
doi = {10.1016/j.aca.2026.346241},
pmid = {42887984},
issn = {1873-4324},
mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Hydrogen Peroxide/analysis/metabolism ; *Optical Imaging ; Mice ; Disease Models, Animal ; *Brain Injuries/diagnostic imaging/metabolism ; Fluorescent Chemosensor Compounds ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Male ; Infrared Rays ; },
abstract = {BACKGROUND: Hydrogen peroxide (H2O2) is a key mediator of oxidative stress in neuroinflammation-related brain injury, yet brain H2O2 imaging remains challenging because of the blood-brain barrier (BBB) and tissue autofluorescence. In addition, most reported probes have been evaluated in only one or a few disease models, limiting cross-model comparison. Here, we developed MH-1, an H2O2-responsive near-infrared (NIR) fluorescent probe for brain-section optical mapping after systemic administration.

RESULTS: MH-1 exhibited an approximately 60-fold fluorescence turn-on at 667 nm, enabled H2O2 detection over 0.107-1000 μmol/L, and reached a stable response within approximately 30 min, with high selectivity, interference resistance, pH stability, and low cytotoxicity. Its fluorescence quantum yield increased from 0.72% to 2.45% upon activation. CD31 co-staining confirmed MH-1-associated fluorescence in extravascular brain parenchyma after systemic administration. Ex vivo brain-section imaging further revealed model-dependent H2O2-associated fluorescence in LPS-induced neonatal neuroinflammation, hypoxic-ischemic encephalopathy (HIE), and Alzheimer's disease (AD), with an effective imaging window of approximately 12 h.

SIGNIFICANCE: Rather than relying on a single best-in-class analytical parameter, MH-1 integrates NIR emission, a large fluorescence turn-on, BBB access, and applicability across three mechanistically distinct brain-injury models. This combined performance enables region-resolved, cross-model comparison of H2O2-associated oxidative stress in preclinical brain tissue.},
}

Animals
*Blood-Brain Barrier/metabolism
*Fluorescent Dyes/chemistry/chemical synthesis
*Hydrogen Peroxide/analysis/metabolism
*Optical Imaging
Mice
Disease Models, Animal
*Brain Injuries/diagnostic imaging/metabolism
Fluorescent Chemosensor Compounds
*Neuroinflammatory Diseases/diagnostic imaging/metabolism
Male
Infrared Rays

@article {pmid42888083,
year = {2026},
author = {Roberts, A and Andreescu, C and Cohen, A and Nadkarni, NK and Minhas, D and Laymon, C and Lopresti, B and Snitz, B and Karim, HT},
title = {Altered Resting State Hippocampal Connectivity Associated With Amyloid and Tau in Older Adults Without Dementia From a Population-Based Cohort Study.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.09.003},
pmid = {42888083},
issn = {1545-7214},
abstract = {OBJECTIVE: Default mode network (DMN) structures, including hippocampus, accumulate amyloid-beta and tau pathology in Alzheimer's disease (AD) and display connectivity changes prior to the onset of cognitive dysfunction.

METHODS: We recruited cognitively healthy older adults who underwent PiB and AV1451 imaging and resting state functional imaging. We evaluated nonlinear associations between hippocampal DMN connectivity and amyloid-beta and tau in cross-sectional analyses.

RESULTS: Left and right anterior hippocampal to DMN intranetwork connectivity was greater with greater amyloid and was lower with even greater levels of amyloid (inverted U-shape association). We found that inter-network hippocampal connectivity was greater with greater amyloid and tau. Greater intra and inter-DMN connectivity was associated with greater cognitive function especially memory and attention, consistent with protective association processes.

CONCLUSION: Intranetwork DMN connectivity was greater with low to moderate amyloid and was lower with greater amyloid and tau in preclinical AD-connectivity may help maintain cognitive function, especially memory. Functional connectivity may potentially offset the impact of early amyloid and tau accumulation and transitionally spare cognitive function.},
}

@article {pmid42888163,
year = {2026},
author = {Wang, J and Zhao, G and Lu, Q and Zhang, X and Piao, Z and Lin, A and Wang, S and Feng, Q and Wen, X and Qin, W and Zhang, N},
title = {Regional atrophy and hypoperfusion mediate the association between affective symptoms and cognitive impairment in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100304},
doi = {10.1016/j.inpsyc.2026.100304},
pmid = {42888163},
issn = {1741-203X},
abstract = {OBJECTIVE: Affective symptoms are common and associated with poor cognitive outcomes in patients with Alzheimer's disease (AD); however, their underlying neural correlations remain poorly understood.

METHODS: This study included 105 patients with AD. Patients were classified into an AD with affective symptoms (AD-A) group and an AD without affective symptoms (AD-NA) group according to scores obtained on the depression and anxiety items of the Neuropsychiatric Inventory. All of the participants underwent neuropsychological assessments and multimodal magnetic resonance imaging (MRI) scans.

RESULTS: Compared with the AD-NA group, the AD-A group was younger and exhibited more severe, widespread cognitive impairments. Neuroimaging revealed that the AD-A group exhibited reduced grey matter volume (GMV) in the bilateral posterior cerebellum and right fusiform gyrus, along with reduced global cerebral blood flow (CBF) and lower CBF in the left parieto-temporo-occipital region. Mediation analyses revealed significant indirect associations between affective symptoms and cognitive function via cerebellar GMV and left parieto-temporo-occipital CBF.

CONCLUSION: Cerebellar structural atrophy and left parieto-temporo-occipital hypoperfusion are associated with both affective symptoms and cognitive impairment and may represent neural correlates of the affective-cognitive association in AD patients.},
}

@article {pmid42888346,
year = {2026},
author = {Wang, MH and Zhang, Y and Sun, R and Li, F and Zhang, T and Gu, X and Lou, J and Cao, L and Su, S and Zheng, H and Liu, C and Chong, MKC and Wu, WKK and Yu, J and Zee, BC and Lin, J},
title = {A genome-wide association study of cognitive impairment in a Chinese cohort of 1,040 individuals.},
journal = {Human genetics},
volume = {145},
number = {1},
pages = {},
pmid = {42888346},
issn = {1432-1203},
support = {32322088//National Natural Science Foundation of China/ ; RFS2526-4S03//Hong Kong RGC Research Fellowship Scheme/ ; 2025.084//CUHK Direct Grant/ ; 14105925//Hong Kong RGC General Research Fund (GRF)/ ; LGKCSDPT2025001//Warshel Institute for Computational Biology funding from Shenzhen City and Longgang District/ ; LTGY24H260004//Zhejiang Provincial Natural Science Foundation of China/ ; },
mesh = {Humans ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Asian People/genetics ; China ; Female ; Genetic Predisposition to Disease ; *Alzheimer Disease/genetics ; Male ; Case-Control Studies ; Aged ; *Cognitive Dysfunction/genetics ; Cohort Studies ; *Cognition Disorders/genetics ; Cadherins/genetics ; East Asian People ; },
abstract = {While genetic heritability plays a major role in the development of cognitive impairment, most genetic risk factors are identified from studies of European populations. We conducted a genome-wide association study (GWAS) on cognitive impairment in the Chinese population by sequencing 1,040 matched case-control individuals from a longitudinal cohort of Zhejiang Province, China. We detected 19 SNPs clustered in 15 genomic loci reaching suggestive significance (P < 1 × 10[- 5]). Eleven of these genomic loci are newly associated with Alzheimer's disease (AD) or cognitive impairment, among which five (GRP39, FAT1, EDIL3, ZNF596, and PDGFD) show nominal evidence of replication in both external GWAS of AD in East-Asian populations and summary statistics of AD in diverse populations. The detected loci are implicated in micronutrient homeostasis including zinc (GPR39), iron (STEAP1), potassium (KCNJ6), and vitamin K (VKORC1L1), cell connections (EVPLL) through cadherin regulations (PCDH18, FAT1), regulating amyloid-beta precursor protein (APP) (EDIL3), formation of amyloid-β (EDEM1) and neurofibrillary tangles (PDGFD, ZNF596), neuronal growth (NEGR1), and phosphatase regulations (SETBP1, TPTE). This study presents a robust GWAS for cognitive impairment in the Chinese population and highlights a promising set of therapeutic targets for neurodegenerative disorder.},
}

Humans
*Genome-Wide Association Study
Polymorphism, Single Nucleotide
Asian People/genetics
China
Female
Genetic Predisposition to Disease
*Alzheimer Disease/genetics
Male
Case-Control Studies
Aged
*Cognitive Dysfunction/genetics
Cohort Studies
*Cognition Disorders/genetics
Cadherins/genetics
East Asian People

@article {pmid42888370,
year = {2026},
author = {Porsteinsson, AP and Chumki, SR and Palma, AM and Zhang, Z and Wang, D and Such, P and Montano, CB},
title = {Brexpiprazole for Individual Agitation Symptoms in Alzheimer's Dementia: A Caregiver-Centered Post Hoc Analysis.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42888370},
issn = {2193-8253},
abstract = {INTRODUCTION: People with Alzheimer's dementia commonly experience agitation symptoms, which are distressing to caregivers and can influence long-term care decisions. The aim of this exploratory post hoc analysis was to test the hypothesis that brexpiprazole can improve individual agitation symptoms over 12 and 24 weeks, including symptoms that caregivers find the most distressing.

METHODS: Data were included from two phase 3, 12-week, randomized (brexpiprazole or placebo), double-blind trials and a phase 3, 12-week, brexpiprazole-treatment extension trial. Participants had Alzheimer's dementia with agitation, and lived at home or in long-term care. The frequency of 29 agitation symptoms over 12 and 24 weeks was assessed using Cohen-Mansfield Agitation Inventory (CMAI) item scores. The focus of this post hoc analysis was the 11 CMAI agitation symptoms that caregivers found the most distressing in a prior survey.

RESULTS: Among 610 participants (median age 74 years, 55.5% female, 44.5% male), each of the 11 most-distressing agitation symptoms reduced in frequency from baseline to Week 12, with further improvements to Week 24 (n = 159). Improvements over 12 weeks were numerically greater with brexpiprazole 2 or 3 mg/day (n = 363) compared with placebo (n = 247) on 9 of 11 symptoms: cursing or verbal aggression, spitting, repetitive sentences or questions, hitting, constant unwarranted requests for attention/help, trying to get to a different place, pacing or aimless wandering, grabbing onto people or things, and kicking. Each of the 18 other agitation symptoms (beyond the most distressing) also reduced in frequency. After 24 weeks, 15 of 29 agitation symptoms occurred less than once a week.

CONCLUSION: Brexpiprazole was associated with improvement in a range of agitation symptoms in people with Alzheimer's dementia, including those that are the most distressing to caregivers. These exploratory results suggest that brexpiprazole may improve the specific agitation symptoms that can have the biggest impact on the caregiver experience.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, NCT03594123.},
}

@article {pmid42888935,
year = {2026},
author = {Liu, B},
title = {Sublexical compensatory reorganization of Chinese character recognition in Alzheimer's disease.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/13803395.2026.2751126},
pmid = {42888935},
issn = {1744-411X},
abstract = {OBJECTIVE: This study investigated the cognitive-functional shift in visual character recognition across the cognitive decline trajectory, ranging from healthy aging through Mild Cognitive Impairment (MCI) to Mild Alzheimer's Disease (AD). Specifically, it was hypothesized that as global semantic networks degrade, the reliance on rapid holistic processing decreases, prompting a compensatory shift toward sublexical features.

METHOD: Using a controlled unmasked priming lexical decision paradigm, this study evaluated behavioral performance across three distinct participant groups (N = 30 per group): healthy controls (HC), individuals with MCI, and patients with Mild AD. The experimental stimuli consisted of 80 Chinese phonograms matched across key psycholinguistic properties. This study utilized mixed-design Analyses of Variance (ANOVAs) alongside item-level hierarchical multiple regression (HMR) models to isolate the specific drivers of reaction times, assessing the predictive power of visual complexity, whole-character frequency, semantic transparency, and phonetic regularity.

RESULTS: The analytical models revealed distinctly divergent psycholinguistic trajectories. The HC group demonstrated highly efficient holistic processing, with performance primarily driven by whole-character frequency. Conversely, the MCI group exhibited a unique transitional cognitive profile, characterized by a simultaneous reliance on both holistic whole-word access and analytic sublexical features. Crucially, in the Mild AD tgroup, the holistic processing advantage was entirely abolished. This functional disintegration triggered a compensatory reorganization toward bottom-up sublexical properties, with patients relying heavily on semantic transparency and phonetic regularity to achieve semantic access.

CONCLUSIONS: These findings demonstrate a linguistic Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH) effect within the degenerating brain. As top-down lexical-semantic hubs deteriorate, reflected behaviorally in this paradigm by the loss of holistic processing advantages, the cognitive system actively compensates by upregulating bottom-up, sublexical pathways. Furthermore, the transitional sublexical dependency observed during the MCI stage highlights the translational potential of psycholinguistic variables as sensitive, noninvasive behavioral biomarkers for the early screening and monitoring of dementia.},
}

@article {pmid42888952,
year = {2026},
author = {Gonzales, MM and Ho, NH and Wang, DH and Rashid, T and Brandigampala, SR and Dong, M and Martinez, D and Charisis, S and Hohman, TJ and Seshadri, S and Davatzikos, C and Maestre, G and Kautz, TF and LaRoche, A and Young, VM and Sullivan, AC and Yaffe, K and Toledo, JB and , and Habes, M},
title = {Integration of neuroimaging signatures of aging and Alzheimer's with fluid biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71889},
doi = {10.1002/alz.71889},
pmid = {42888952},
issn = {1552-5279},
support = {R01AG085571 R01AG077472 P30AG094848 P30AG066546 R01AG083865 R01AG080821 R01AG059421/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Texas Alzheimer's Research and Care Consortium Investigator Grant Program/ ; //Texas Council on Alzheimer's Disease and Related Disorders/ ; T32AG021890//DKR Texas Alzheimer's Initiative/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/pathology ; *Biomarkers/blood ; *Aging/pathology ; *Neuroimaging/methods ; Female ; Male ; Disease Progression ; Machine Learning ; Magnetic Resonance Imaging ; tau Proteins/blood ; *Brain/pathology/diagnostic imaging ; Aged ; Neurofilament Proteins/blood ; Aged, 80 and over ; Atrophy ; },
abstract = {INTRODUCTION: Machine learning algorithms applied to neuroimaging may aid diagnosis and disease monitoring. This study aimed to derive neuroimaging signatures of brain aging (Spatial Pattern of Atrophy for Recognition-Brain Age [SPARE-BA]) and Alzheimer's disease (SPARE-AD) in a diverse sample and to examine their associations with plasma biomarkers, diagnosis, and disease progression.

METHODS: SPARE-BA and SPARE-AD were calculated using T1-images from 1297 participants without dementia. Associations between neuroimaging signatures and plasma biomarkers were assessed with partial correlations. Logistic regression and cox proportional hazard models evaluated diagnostic accuracy and clinical progression.

RESULTS: SPARE-AD displayed the strongest association with plasma phosphorylated tau 217, whereas SPARE-BA correlated most strongly with plasma neurofilament light. The combination of neuroimaging signatures with plasma biomarkers achieved the highest diagnostic discriminability and strongest associations with clinical progression.

DISCUSSION: Neuroimaging signatures of aging and Alzheimer's disease display distinct associations with plasma biomarkers. Neuroimaging signatures combined with plasma biomarkers may improve the detection and prediction of cognitive impairment.},
}

Humans
*Alzheimer Disease/diagnostic imaging/blood/pathology
*Biomarkers/blood
*Aging/pathology
*Neuroimaging/methods
Female
Male
Disease Progression
Machine Learning
Magnetic Resonance Imaging
tau Proteins/blood
*Brain/pathology/diagnostic imaging
Aged
Neurofilament Proteins/blood
Aged, 80 and over
Atrophy

@article {pmid42889096,
year = {2026},
author = {Gidwani, SH and Chattopadhyay, T and Thomopoulos, SI and Thompson, PM},
title = {MEMOIR-VLM-a multimodal vision-language model for Alzheimer's disease classification and question answering.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1902258},
doi = {10.3389/fncom.2026.1902258},
pmid = {42889096},
issn = {1662-5188},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects an estimated 55 million people worldwide and is projected to nearly double by 2050, creating a need for scalable, non-invasive AI systems that can classify disease stage, support multimodal clinical reasoning, and interact in natural language. Most deep learning work on AD focuses on single-modality classification without natural-language interaction and typically assumes complete input data.

METHODS: We present MEMOIR-VLM (Multimodal Encoder with Missing-modality and Open-ended Inference for Retrieval), a modular two-stage vision-language framework trained and evaluated on 2,363 ADNI subjects. The first stage is a missing-modality-aware encoder that fuses T1-weighted MRI and DTI fractional anisotropy maps with structured clinical scores via cross-attention fusion with stochastic modality dropout, allowing a single set of weights to operate on any of the seven non-empty modality subsets without imputation. After CLIP/InfoNCE contrastive pretraining, the encoder is fine-tuned for multi-task prediction of 3-way diagnosis, binary diagnosis, CDR-SB, age, and sex. The second stage extends the frozen encoder into a retrieval-augmented generation pipeline for case-based reasoning and open-ended visual question answering.

RESULTS: On held-out ADNI test data, with CDR-SB excluded from the inputs to remove a cognitive-score leak, the encoder achieved 91.3% balanced accuracy for CN vs. dementia and 68.2% balanced accuracy for 3-class diagnosis (macro-F1 = 0.681); age was predicted with a 5.96-year MAE. When the diagnosis field was withheld from retrieved captions, no evaluated LLM exceeded a retrieval-only k-NN majority vote (0.673), which itself closely matched the encoder's 3-class accuracy (0.682). The RAG-VQA layer showed strong text fidelity (BERTScore = 0.894; SBERT cosine similarity = 0.811). Zero-shot external validation on OASIS-3 (1,048 subjects, no diffusion data) retained 78.7% balanced accuracy for CN vs. impaired (AUC = 0.889) using identical ADNI-trained weights with the DTI branch masked.

DISCUSSION: MEMOIR-VLM combines missing-modality-aware multimodal encoding, multi-task clinical prediction, and retrieval-grounded natural-language reasoning within a single modular framework. The results support using the encoder, optionally with k-NN voting, as the diagnostic component and the RAG-VQA layer as an interpretable natural-language interface that surfaces comparable cases and readable clinical summaries. The external validation results further demonstrate the practical value of the missing-modality mechanism when an imaging modality is unavailable.},
}

@article {pmid42889099,
year = {2026},
author = {Manabe, Y},
title = {Influence of Curcuma longa extract on cognitive function in mild cognitive impairment due to Alzheimer's disease: a single-arm, open-label, observational study.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1951923},
doi = {10.3389/fnut.2026.1951923},
pmid = {42889099},
issn = {2296-861X},
abstract = {OBJECTIVES: Curcuma longa, commonly known as turmeric, is a dietary spice with potential biological effects. This study evaluated the association between intake of C. longa extracts (CLE) and cognitive function in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD).

METHODS: This was a 4-month, single-arm, open-label, observational study of participants with MCI due to AD who were awaiting anti-amyloid therapy. Participants (n = 13) consumed the test food containing CLE, which includes the compounds bisacurone and turmeronols. Cognitive function was assessed at baseline and after 4 months using various cognitive assessments.

RESULTS: After excluding participants with insufficient intake of CLE capsules or invalid data, 10 participants were included in the analysis set, consisting of 2 men and 8 women, with a mean ± standard deviation age of 74.8 ± 6.1 years. CLE intake was associated with significantly higher memory scores (Composite B) and significantly lower estimated brain age at 4 months compared with baseline, as measured by a digital cognitive assessment tool (Nou-Know). In the Japanese version of the Montreal Cognitive Assessment, total scores did not differ significantly after CLE intake, but subscale scores for the attention domain and digit span test increased significantly from baseline.

DISCUSSION: This observational study provides preliminary evidence of a potential association between CLE intake and changes in frontal lobe-mediated functions, particularly working memory, in individuals with MCI due to AD, and further investigation is warranted.

CLINICAL TRIAL REGISTRATION: https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000058932, identifier UMIN-CTR, UMIN000052043.},
}

@article {pmid42889177,
year = {2026},
author = {Frisch, C and Baker, L and Srinivasan, G and Mintah, AE and Leyasi, S and Pedroza, M and Galyon, B and Brafman, DA},
title = {Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1856154},
doi = {10.3389/fnagi.2026.1856154},
pmid = {42889177},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder influenced by both causal mutations and genetic modifiers. The rare APOE3 Christchurch (APOE3ch) variant has been associated with delayed disease onset in a familial Alzheimer's disease case, suggesting a potential protective role. However, the mechanisms underlying this protection, particularly across different genetic backgrounds, remain unclear.

METHODS: We generated isogenic human induced pluripotent stem cell (hiPSC)-derived neural cultures harboring either PSEN1 E280A or amyloid precursor protein duplication (APPdp) mutations, with and without the APOE3ch variant, using prime editing. Neural differentiation, amyloid-beta production, amyloid precursor protein processing, tau phosphorylation and transcriptomic profiles were assessed.

RESULTS: APOE3ch did not affect neural differentiation or apolipoprotein E secretion. However, it exhibited mutation-dependent effects on Alzheimer's disease phenotypes. In amyloid precursor protein duplication cultures, APOE3ch significantly reduced amyloid-beta production and shifted processing toward non-amyloidogenic pathways, accompanied by decreased phosphorylated tau. In contrast, in PSEN1 E280A cultures, APOE3ch had minimal impact on amyloid-beta levels but increased non-amyloidogenic processing and altered total tau without affecting phosphorylation. Transcriptomic analysis revealed both shared and mutation-specific effects, with consistent modulation of pathways related to synaptic function, including Wnt and cadherin signaling.

DISCUSSION: These findings demonstrate that APOE3ch acts as a context-dependent modifier of Alzheimer's disease pathology, with protective effects varying by genetic background. The variant consistently influences pathways associated with synaptic resilience while differentially modulating amyloid and tau pathology. This work provides mechanistic insight into APOE3ch-mediated protection and highlights the importance of genetic context in developing targeted therapeutic strategies for Alzheimer's disease.},
}

@article {pmid42889214,
year = {2026},
author = {Librizzi, F and Seppälä, S and Linne, ML and Migliore, M and Saudargiene, A},
title = {Network-level restoration of impaired memory function in early Alzheimer's disease via GluN2B modulation: insights from a hippocampal CA1-CA3 model.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1953352},
doi = {10.3389/fncom.2026.1953352},
pmid = {42889214},
issn = {1662-5188},
abstract = {Memory storage and recall are essential tasks for the healthy function of the hippocampus, adversely affected by neurodegenerative diseases, such as Alzheimer's Disease (AD). Pathological levels of amyloid-β peptide (Aβ), found already in early-stage AD, can disrupt the NMDAR-dependent plasticity at hippocampal networks. Here we investigate these effects in a biophysically detailed computational model of a hippocampal CA1-CA3 network and examine potential mechanisms of functional recovery. We show that, at a network level, long-term potentiation (LTP) impairments caused by Aβ accumulation can be substantially restored by partially blocking the GluN2B-NMDA receptors-a mechanism previously observed and modeled only at a single cell level. Experimental access to network-level processes of memory storage and recall in pathological conditions remains highly challenging. Therefore, computational modeling may help to bridge the gap between cellular impairments and system-level cognitive dysfunction. Our work transfers the established GluN2B-dependent rescue mechanisms from single cells to a network-level system of hippocampal pyramidal neurons and interneurons. The results demonstrate that also at a higher cognition level, the partial inhibition of the activity of GluN2B-NMDA receptors can be an effective strategy to counteract early AD impairments on memory storage and recall.},
}

@article {pmid42889296,
year = {2026},
author = {Kueck, PJ and Green, ZD and Camones, R and John, CS and Honea, RA and Burns, JM and Vidoni, ED and Morris, JK},
title = {Cardiorespiratory fitness is associated with cerebral oxygen extraction in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1943472},
doi = {10.3389/fnagi.2026.1943472},
pmid = {42889296},
issn = {1663-4365},
abstract = {Cardiorespiratory fitness (CRF) is a modifiable determinant of brain health and has been associated with greater brain volume, improved cognition, and reduced dementia risk. However, whether CRF influences cerebral oxygen extraction fraction (OEF), a marker reflecting the balance between cerebral oxygen delivery and metabolic demand, remains poorly understood in aging and Alzheimer's disease (AD). We performed a secondary analysis of the Acute Exercise Response on Brain Imaging and Cognition (AEROBIC) study to investigate relationships among CRF, cerebral blood flow (CBF), and OEF in cognitively healthy older adults (CH) and individuals with AD. Multivariable linear regression demonstrated that higher CRF was independently associated with lower OEF. A significant CRF × diagnosis interaction indicated that this relationship was present in AD but not CH. Across the full cohort, higher CBF was strongly associated with lower OEF, and this relationship was preserved across diagnostic groups. Regional analyses demonstrated similar inverse associations between CBF and OEF in multiple cortical regions involved in cognitive and autonomic regulation. These findings suggest that greater CRF may reduce reliance on oxygen extraction by improving the adequacy of cerebral oxygen delivery in AD. Together, CRF, CBF, and OEF provide complementary physiological information regarding cerebral oxygen metabolism and may improve understanding of cerebrovascular physiology in aging and AD.},
}

@article {pmid42889352,
year = {2026},
author = {Fu, H and Yang, J and Zhang, M},
title = {CD8[+] t cell-mediated regulation of synaptic integrity in Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1903001},
doi = {10.3389/fimmu.2026.1903001},
pmid = {42889352},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/pathology ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; Animals ; *Synapses/immunology/metabolism/pathology ; Microglia/immunology/metabolism ; Brain/immunology/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) has traditionally been interpreted through amyloid, tau, and innate immune frameworks, with the complement cascade long regarded as the principal driver of aberrant synaptic pruning. Synaptic loss is increasingly recognized as one of the strongest correlates of cognitive decline. This review examines an emerging CD8[+] T cell-synapse axis that extends beyond complement-centric models. We discuss how brain-infiltrating CD8[+] T cells intersect with synaptic integrity through MHC-I-dependent and MHC-I-independent mechanisms, including IFN-γ-mediated microglial reprogramming and granzyme K-driven non-canonical complement activation. Early effector-like subsets may promote neuroinflammation and synaptic injury, whereas later tissue-resident or regulatory populations can exert protective functions by gating microglial states. The net outcome depends on disease stage, antigenic milieu, anatomical niche, and microglial context. We emphasize that direct antigen-specific, MHC-I-restricted synaptic attack remains unproven in human AD, and that observed T-cell infiltration may reflect reverse causality. Translational limitations across species are evaluated, and we outline subset-specific immunomodulation, ApoE4-stratified strategies, and biomarker-guided trial designs as future directions. Overall, CD8[+] T cells are positioned not as uniform cytotoxic executors, but as dynamic, context-dependent regulators of synaptic outcomes in AD.},
}

Humans
*Alzheimer Disease/immunology/metabolism/pathology
*CD8-Positive T-Lymphocytes/immunology/metabolism
Animals
*Synapses/immunology/metabolism/pathology
Microglia/immunology/metabolism
Brain/immunology/metabolism/pathology

@article {pmid42889485,
year = {2026},
author = {Warrick, T and Misra, M and Kataria, S and Patel, J and Ajmera, B},
title = {No evidence that serum metabolite slopes improve held-out prediction of clinical progression in the Alzheimer's disease neuroimaging initiative.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1942662},
doi = {10.3389/fnagi.2026.1942662},
pmid = {42889485},
issn = {1663-4365},
abstract = {BACKGROUND: Repeated serum metabolite measurements may contribute to predicting clinical progression, but their incremental value requires evaluation beyond established clinical predictors.

METHODS: We linked Alzheimer's Disease Neuroimaging Initiative (ADNI) clinical data to Biocrates Quant 500 serum measurements. Annualized metabolite slopes were estimated from baseline through month 12, usually from two observations. At the month-12 landmark, participants without dementia were characterized by diagnosis, memory performance, and APOE ε4 status; progression was assessed at approximately month 36. Models were developed in ADNI1 (225 participants; 26 events) and applied without refitting to ADNI-GO/2 (269 participants; 50 events). We compared a clinical logistic model with a model that added a data-derived phosphatidylcholine (PC) aa C42:1 candidate slope. Models using 88 phosphatidylcholine-family metabolite slopes or 598 full-panel slopes were exploratory.

RESULTS: The clinical model achieved an area under the receiver operating characteristic curve (AUROC) of 0.758 (95% CI, 0.675-0.838). Adding PC aa C42:1 changed the AUROC by +0.0004 (-0.013 to 0.017). Both partially penalized lasso models retained no metabolite slopes at the selected penalty. A post-hoc evaluation restricted to 233 participants with mild cognitive impairment, including 38 events, also found no evidence of incremental discrimination. Other sensitivity analyses yielded similar results.

CONCLUSION: We found no evidence that annualized serum metabolite slopes improved held-out prediction in this sample. The 26 development events limited estimation and feature selection, so these results cannot distinguish between a lack of incremental prognostic information and insufficient data to identify such information. Larger development samples and independent validation are needed to assess the value of serial metabolomics.},
}

@article {pmid42889489,
year = {2026},
author = {Trudel, L and Therriault, J and Ghisays, V and Macedo, AC and Gauthier, S and Vitali, P and Benedet, AL and Zetterberg, H and Su, Y and Singh, A and Marques, T and Denkinger, MN and Seyfried, NT and Levey, AI and Weiner, MW and Van Keuren-Jensen, K and Reiman, EM and Ashton, NJ and Rosa-Neto, P},
title = {Comparison of brain-derived versus conventional pTau biomarkers in CSF and plasma for detecting Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag376},
doi = {10.1093/braincomms/fcag376},
pmid = {42889489},
issn = {2632-1297},
abstract = {Brain-derived phosphorylated tau species are postulated to improve the detection of Alzheimer's disease pathology by mitigating non-specific increases. However, their true diagnostic performance, relative to conventional CSF and plasma phosphorylated tau assays, remains uncharacterized. The objective was to compare the diagnostic performance of brain-derived and conventional phosphorylated tau assays across multiple analytes (phosphorylated tau 181, phosphorylated tau 217, phosphorylated tau 231) in CSF and plasma, and to examine biomarker differences across amyloid-β status and cognitive groups. This study included 1098 participants with amyloid-PET imaging and CSF samples from the Alzheimer's Disease Neuroimaging Initiative, and a subset of 925 individuals with plasma samples. Diagnostic performance of brain-derived and conventional phosphorylated tau assays was assessed by receiver operating characteristic curves, with calculation of area under the curve, sensitivity, specificity and optimal cutpoints. Associations with amyloid-β burden were evaluated using Spearman correlations, and fold-changes between amyloid-PET-positive and amyloid-PET-negative participants were computed in cognitively unimpaired and cognitively impaired subgroups with 95% confidence intervals from 2000 bootstrap resamples. Brain-derived phosphorylated tau assays showed significantly higher diagnostic performance than conventional phosphorylated tau assays at the same phosphorylation site in both CSF and plasma in the overall sample and in cognitively impaired individuals, except for CSF phosphorylated tau 217. While CSF brain-derived phosphorylated tau correlations with amyloid-PET were similar to conventional CSF assays, pairwise comparisons using DeLong's test revealed significantly higher diagnostic accuracy for brain-derived assays. Receiver operating characteristic performance was generally better in cognitively impaired participants than in cognitively unimpaired participants. Additionally, using a three-range method with cutpoints corresponding to 90% sensitivity and 90% specificity, plasma brain-derived phosphorylated tau 181, phosphorylated tau 217 and brain-derived phosphorylated tau 217 had <20% of participants in the intermediate range overall and in cognitively impaired individuals. In summary, brain-derived phosphorylated tau assays improve detection of amyloid-β positivity relative to conventional assays, especially in plasma, and provide robust differentiation of amyloid-PET-positive and amyloid-PET-negative participants. If these findings are confirmed using fully automated diagnostic platforms that are intended for use in clinical settings, brain-derived phosphorylated tau assays may support future blood-based biomarker triage workflows for identifying Alzheimer's disease.},
}

@article {pmid42878720,
year = {2026},
author = {Hariharan, A and Vigderman, A and Isaacs, DP and Weir, N and Park, G and Edwards, S and Longden, TA},
title = {Early disruptions in brain capillary blood flow control in a mouse model of Alzheimer's disease.},
journal = {The Journal of general physiology},
volume = {158},
number = {6},
pages = {},
doi = {10.1085/jgp.202614014},
pmid = {42878720},
issn = {1540-7748},
support = {R01AG066645//NIH National Institute on Aging/ ; DP2NS121347/NS/NINDS NIH HHS/United States ; 5F31NS139505/NS/NINDS NIH HHS/United States ; R01NS138179/NS/NINDS NIH HHS/United States ; R21NS142439/NS/NINDS NIH HHS/United States ; CP2-1-0000000385//Chan Zuckerberg Initiative/ ; 830093//American Heart Association/ ; https://doi.org/10.58275/AHA.26CDA1592450.pc.gr.243187//D.C. Women's Board/ ; 26CDA1592450//D.C. Women's Board/ ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology/metabolism ; *Cerebrovascular Circulation/physiology ; Disease Models, Animal ; *Capillaries/physiopathology/metabolism ; *Brain/blood supply/physiopathology/metabolism ; Mice ; Mice, Transgenic ; KATP Channels/metabolism ; Humans ; },
abstract = {In Alzheimer's disease (AD), vascular dysfunction and impaired control of brain blood flow can disrupt cellular bioenergetics decades before cognitive decline. Identifying the earliest vascular changes is therefore critical for developing therapies that intervene before the cascading events leading to neuronal decline. Brain energy supply is dynamically controlled by the cerebral vasculature, where capillary thin-strand pericytes are emerging as key players. We recently identified a central role for ATP-sensitive potassium (K+, KATP) channels in enabling thin-strand pericytes to sense local neuronal activity and generate hyperpolarizing signals that are transmitted via capillary endothelial cells to upstream arterioles, eliciting increases in blood flow. Importantly, thin-strand pericyte KATP channels are the centerpiece of an electro-metabolic "energy switch" mechanism that couples decreases in local glucose to hyperemia, providing a failsafe to ensure continual energy substrate supply to support neuronal function. Disruption of this mechanism could therefore precipitate an imbalance between demand and supply, creating an energy gap for neurons that leads to deleterious consequences. We demonstrate that capillary control of blood flow is disrupted in the early stages of disease progression in mice expressing familial AD mutations (5xFAD). Transgenic 5xFAD mice exhibit early disruption of capillary signaling, beginning with dysfunctional endothelial inward rectifier K+ (Kir)2.1 channels at 2-4 mo, disabling transmission of KATP-mediated signals to upstream blood flow control machinery, followed by direct impairment of pericyte KATP channel function by 6-8 mo. Together, these deficits cause early and sustained failure of electrical signaling from deep capillary pericytes to upstream arterioles and arteriole-capillary transition (ACT) zone vessels, limiting KATP-dependent energy-switch-mediated blood flow control. Our findings define a temporal and mechanistic framework linking familial AD mutations to early capillary signaling dysfunction and highlight preservation of capillary blood flow control as a potential therapeutic target to protect against downstream effects of amyloid β accumulation.},
}

Animals
*Alzheimer Disease/physiopathology/metabolism
*Cerebrovascular Circulation/physiology
Disease Models, Animal
*Capillaries/physiopathology/metabolism
*Brain/blood supply/physiopathology/metabolism
Mice
Mice, Transgenic
KATP Channels/metabolism
Humans

@article {pmid42878916,
year = {2026},
author = {Abbas, T and Rashid, S and Imran, M},
title = {Fractional-order dynamical modelling of neurophysiological reaction-diffusion model of adiposity-induced cognitive decline using physics-informed neural networks.},
journal = {Journal of biological physics},
volume = {52},
number = {1},
pages = {},
pmid = {42878916},
issn = {1573-0689},
mesh = {Diffusion ; *Neural Networks, Computer ; Humans ; *Cognitive Dysfunction/etiology/physiopathology ; *Adiposity ; *Models, Neurological ; },
abstract = {Obesity, hyperglycemia, and aging are major risk factors for dementia-related disorders, particularly Alzheimer's disease. We develop a time-fractional reaction-diffusion mathematical framework integrating nine interacting biological compartments governed by Michaelis-Menten kinetics and Hill functions to characterize the nonlinear interplay between metabolic dysfunction and neurodegeneration. Rigorous analysis establishes boundedness, stability, and the existence of a global attractor describing long-term system behavior. To enhance biological realism and predictive capability, we implement fractional physics-informed neural networks that embed fractional partial differential equations within deep learning architectures. This approach captures memory-dependent and spatiotemporal diffusion dynamics characteristic of neurological disorders while enabling estimation of time-varying parameters, fractional orders, and latent states. Global sensitivity analysis using partial-rank correlation coefficients identifies key drivers of tau pathology, insulin dysregulation, and dementia progression. Simulations reveal heterogeneous diffusion patterns linking obesity to accelerated neurodegenerative processes. An optimal control framework incorporating behavioral interventions and personalized anti-amyloid therapies is proposed to delay obesity-induced cognitive decline. The model highlights the critical roles of neuroinflammation and blood-brain barrier permeability in disease acceleration. The proposed FPI-NN framework achieves high predictive accuracy, with R 2 values of 0.95, 0.93, 0.92, and 0.92 for Y 1 , W β , W τ , and V d , respectively. The corresponding RMSE values are 0.078, 0.094, 0.098, and 0.099, while the MAE values are 0.065, 0.079, 0.082, and 0.084, respectively. The MAPE values are 6.50 % , 7.90 % , 8.20 % , and 8.40 % , respectively. Cross-validation further confirms the stability and robustness of the proposed framework. This work provides a reproducible and interpretable computational platform for modeling fractional-order neurodegenerative dynamics and optimizing therapeutic strategies in obesity-associated dementia.},
}

Diffusion
*Neural Networks, Computer
Humans
*Cognitive Dysfunction/etiology/physiopathology
*Adiposity
*Models, Neurological

@article {pmid42878972,
year = {2026},
author = {Kumar, S and Paswan, SK and Verma, P and Chaturvedi, S and Vishwakarma, VK and Yadav, HN},
title = {Molecular Pathogenesis of Cerebral Amyloid Angiopathy in Alzheimer's Disease: The Role of the Central Fibrinolytic Cascade at the Neurovascular Unit.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42878972},
issn = {1559-1182},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Animals ; *Fibrinolysis/physiology ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multifactorial neurodegenerative disorder involving complex neurovascular pathology. Departing from classic neurocentric paradigms, this review provides a conceptually novel perspective on how vascular inflammation and dysfunction actively drive AD progression through the lens of cerebral amyloid angiopathy (CAA) pathology. We evaluate the bidirectional cascade between amyloid-β pathology and the neurovascular unit, highlighted by cerebrovascular alterations and blood-brain barrier disruption. Crucial for cerebral homeostasis, the central nervous system's fibrinolytic pathway plays a dual role in this cascade, where the dysregulation of tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and plasminogen accelerates CAA. We posit that suppressed fibrinolytic activity impedes amyloid-β clearance, while aberrant plasminogen-amyloid-β interactions paradoxically trigger localized inflammatory and thrombotic cascades that exacerbate vascular injury. By looking beyond traditional, neuron-centered models of Alzheimer's, fibrinolytic regulation and vascular repair offer a powerful new way to intervene. Bringing these discoveries to the clinic means finding a way to clear amyloid-β without tipping the scale toward bleeding risks. If we can map these complex vascular-fibrinolytic links, we can open the door to early intervention to design targeted therapies that prevent vascular damage and fundamentally change the trajectory of CAA and Alzheimer's disease.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
Animals
*Fibrinolysis/physiology
Amyloid beta-Peptides/metabolism
Blood-Brain Barrier/pathology/metabolism

@article {pmid42879058,
year = {2026},
author = {Liu, Y and Xu, J and Wang, X and Liu, L and Ren, X and Gong, Y and Miao, C and Sun, M and Zhou, S and Guo, X and Yuan, L},
title = {Docosahexaenoic acid remodels lipid composition of lipid rafts and mitochondrial function in ApoE4/4 mouse brain: a multi-omic investigation.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42879058},
issn = {2662-8651},
support = {82173508//National Natural Science Foundation of China/ ; CNS-NCL2024-04//Nutrilite Plant Functional Components and Health Research Fund of Chinese Nutrition Society/ ; QY25427//Beijing Natural Science Foundation/ ; },
mesh = {Animals ; *Membrane Microdomains/metabolism/drug effects ; *Docosahexaenoic Acids/pharmacology ; *Brain/metabolism/drug effects/pathology ; *Mitochondria/metabolism/drug effects ; Female ; *Apolipoprotein E4/genetics/metabolism ; Mice ; Lipidomics ; Lipid Metabolism/drug effects ; Alzheimer Disease/metabolism ; Mice, Transgenic ; Humans ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder lacking curative therapies, with ApoE4 as the strongest genetic risk factor driving lipid dyshomeostasis and neuronal damage in the central nervous system. Lipid rafts, cholesterol- and sphingolipid-rich membrane microdomains, govern key neuronal signalling, and dysfunction of these microdomains mediates the progression of preclinical pathological lesions in ApoE4 carriers. Dietary docosahexaenoic acid (DHA) is widely reported to mitigate brain lipid disorders, yet how DHA remodels subfractions of lipid raft and non-raft membrane domains to rescue ApoE4-related energy metabolism disorder remains unclear. Most existing studies have only quantified total brain lipids without distinguishing membrane subdomains, and few characterized the liver-brain metabolic axis underlying ApoE4-associated neurodegeneration. We constructed female ApoE3/3 and ApoE4/4 knock-in mice with 6- and 12-month DHA dietary interventions, combining behavioral, histological, lipidomic and proteomic assays to characterize genotype-specific lipid remodelling and downstream mitochondrial changes. Here we show that ApoE4 mice develop severe hepatic steatosis, neuroinflammation and lipid raft rigidification characterized by elevated sulfatides and ceramides levels, DHA upregulates Lpin1, Atgl and nSMase2 while suppressing Acer3 and Sgms2, thereby rebalancing lipids raft and restoring mitochondrial bioenergetics. Our work resolves raft and non-raft lipid profiles in ApoE humanized mice, and links peripheral hepatic metabolic disturbances to cerebral membrane microdomain dysfunction. These multi-omics mechanistic findings advance genotype-specific preventive nutritional strategies for ApoE4 carriers and reveal potential subcellular lipid targets for early AD intervention.},
}

Animals
*Membrane Microdomains/metabolism/drug effects
*Docosahexaenoic Acids/pharmacology
*Brain/metabolism/drug effects/pathology
*Mitochondria/metabolism/drug effects
Female
*Apolipoprotein E4/genetics/metabolism
Mice
Lipidomics
Lipid Metabolism/drug effects
Alzheimer Disease/metabolism
Mice, Transgenic
Humans

@article {pmid42879070,
year = {2026},
author = {Ferrari, RR and Garofalo, M and Di Gerlando, R and Pellegrini, E and Dragoni, F and Rizzo, B and Rossi, M and Calatozzolo, C and Guaita, A and Davin, A and Gagliardi, S and Poloni, TE},
title = {A pattern to rule them all: tracing a human brain map of molecular aspects shared by Alzheimer's disease and dementia with Lewy bodies.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42879070},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) and dementia with Lewy bodies (LBD) are the most widespread forms of degenerative dementia. However, little is known about the molecular aspects that link these conditions with each other and with aging itself. Whole transcriptome analysis and Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) of subjects with a neuropathological diagnosis of AD or LBD. According to the Abbiategrasso Brain Bank (ABB) protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring. Transcriptomic results show major differences in the number of differentially expressed genes (DEGs) between the two pathologies. In AD, gene expression is more affected compared to LBD. DEGs have peculiar spatial distribution: HI and TC show transcriptomic changes related to synapses, while in CG, SN, and PC, changes are related to proteostasis; in LBD, DEGs are predominant in SN and PC affecting proteostasis, oxidative stress, and inflammation. In AD, GSEA shows that different regions cluster by shared biological processes. AD appears much more complex, and different forms of AD do exist. Nonetheless, the molecular signature of same regions across the two pathologies can be interestingly overlapped. Exploring the molecular processes that occur before the deposition of pathological lesions may reveal individual neurodegeneration trajectory to achieve personalized therapies, which could be much more effective than the mere immunological removal of protein deposits.},
}

@article {pmid42879228,
year = {2026},
author = {Di Domenico, C and Bonarota, S and Caruso, G and Sperati, S and Di Lorenzo, F and Rodini, M and Caltagirone, C and Koch, G and Giove, F and Bozzali, M and Serra, L},
title = {Retrieval-induced forgetting and facilitation across the Alzheimer's disease continuum: Behavioral and neuroanatomical evidence from a recognition-based paradigm.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001126},
pmid = {42879228},
issn = {1931-1559},
support = {//Ministero della Salute/ ; },
abstract = {OBJECTIVE: The aim of the present study was to investigate facilitation (FAC) and retrieval-induced forgetting (RIF) during episodic memory retrieval across the Alzheimer's disease (AD) continuum and to examine their gray matter correlates in verbal and visual recognition tasks.

METHOD: One hundred participants (28 AD, 29 amnestic mild cognitive impairment, 23 subjective cognitive decline [SCD], 20 healthy subjects) completed a modified retrieval-practice paradigm (mRPP) involving verbal and visual recognition tasks, a comprehensive neuropsychological battery, and 3T magnetic resonance imaging. FAC and RIF were computed at the group level and via individual proxy scores, and voxel-based morphometry was used to assess the association between mRPP indices and regional gray matter volumes.

RESULTS: The verbal mRPP showed reduced overall recognition in AD compared with healthy subjects (p = .003 - ηp² = 0.23). A robust FAC effect in AD, amnestic mild cognitive impairment, and SCD was observed, whereas RIF emerged only in SCD, suggesting intact inhibitory control at the earliest stage and its disruption with disease progression (p < .001 - ηp² = 0.48). The visual mRPP showed a strong FAC effect across all groups, with no RIF, indicating modality-specific reliance on recognition-based retrieval (p < .001 - ηp² = 0.63). Voxel-based morphometry analyses revealed distinct gray matter correlates across groups and tasks: Verbal RIF was negatively associated with frontotemporal regions in AD patients and parieto-occipital regions in healthy subjects, while visual indices showed widespread associations with temporal, subcortical, cerebellar, and sensorimotor regions, particularly in amnestic mild cognitive impairment and SCD groups.

CONCLUSIONS: This study shows shared and modality-specific brain mechanisms of retrieval practice across AD stages. Preserved compensatory processes in SCD individuals give way to progressive regional disruption, supporting early, modality-tailored, and multimodal cognitive interventions to enhance cognition and delay cognitive decline. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42879726,
year = {2026},
author = {Reynolds, EL and Elafros, MA and Muthukumar, L and Shippey, E and Budhu, JA and Terman, SW and Burke, JF and Callaghan, BC},
title = {Predictors of Antiamyloid Medication Utilization and Adherence Among People With Alzheimer Disease and Mild Cognitive Impairment.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218594},
doi = {10.1212/WNL.0000000000218594},
pmid = {42879726},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/drug therapy ; Male ; Aged ; *Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Drug Monitoring ; *Medication Adherence ; },
abstract = {BACKGROUND AND OBJECTIVES: From 2021 to 2024, 3 amyloid monoclonal antibody medications (aducanumab, lecanemab, and donanemab) were approved by the US Food and Drug Administration for treatment of mild cognitive impairment (MCI) and mild dementia due to Alzheimer disease (AD). We determined the demographics and social drivers of health associated with utilization and initial adherence of these medications.

METHODS: We used the Vizient database to identify patients with MCI or dementia using an ICD-10 coding definition. Propensity score matching was used to match patients who received an antiamyloid medication to those who did not, based on date of MCI/dementia diagnosis and follow-up. Social drivers of health were assessed using the Vizient Vulnerability Index (VVI), a neighborhood-level measure of socioeconomic vulnerability. Logistic regression determined associations between demographics, Elixhauser comorbidity, and VVI, with utilization of antiamyloid medications. Poisson regression determined associations between demographic, Elixhauser comorbidity, and VVI and initial adherence (measured as days supplied) of antiamyloid medications.

RESULTS: We identified 1,198,362 participants with MCI/dementia, of whom 2,427 (0.2%) were prescribed an antiamyloid medication. Of those prescribed an antiamyloid medication, 1,696 (69.9%) were matched to participants with MCI/dementia that were not prescribed antiamyloid medications (mean age 75.5 [SD 9.5], 56.1% female, 80.1% non-Hispanic White). We found that higher age (odds ratio [OR] 0.93, 95% CI 0.92-0.94), higher Elixhauser comorbidity index (OR 0.56, 95% CI 0.52-0.59), being non-Hispanic Black (OR 0.14, 95% CI 0.09-0.23), and being Hispanic (OR 0.21, 95% CI 0.13-0.36) associated with lower odds of receiving an antiamyloid medication. Furthermore, having greater VVI was associated with lower odds of receiving an antiamyloid medication. By contrast, only higher Elixhauser comorbidity score was associated with lower initial medication adherence (rate ratio 0.94, 95% CI 0.93-0.96), but not age, sex, race/ethnicity, and overall vulnerability.

DISCUSSION: We found that younger, non-Hispanic White patients, with fewer comorbidities, and lower vulnerability, were more likely to receive antiamyloid medications. By contrast, among patients receiving an antiamyloid medication, only higher comorbidity score associated with lower initial medication adherence. These findings indicate a potential disparity in medication access for US patients with MCI/dementia that could become problematic barriers to care as medications for dementia continue to evolve.},
}

Humans
Female
*Alzheimer Disease/drug therapy
Male
Aged
*Cognitive Dysfunction/drug therapy
Aged, 80 and over
Antibodies, Monoclonal, Humanized/therapeutic use
*Drug Monitoring
*Medication Adherence

@article {pmid42879727,
year = {2026},
author = {Planche, V and Bouteloup, V and Pellegrin, I and Mangin, JF and Dubois, B and Ousset, PJ and Pasquier, F and Blanc, F and Paquet, C and Hanon, O and Bennys, K and Ceccaldi, M and Annweiler, C and Krolak-Salmon, P and Godefroy, O and Wallon, D and Sauvee, M and Boutoleau-Bretonnière, C and Bourdel-Marchasson, I and Jalenques, I and Chene, G and Dufouil, C},
title = {Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218790},
doi = {10.1212/WNL.0000000000218790},
pmid = {42879727},
issn = {1526-632X},
}

@article {pmid42879974,
year = {2026},
author = {Elbatawy, A and Elbanoby, T},
title = {Deep cervical lymphaticovenous anastomosis for Alzheimer disease: A critical narrative assessment and translational framework.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {155},
number = {},
pages = {112349},
doi = {10.1016/j.jocn.2026.112349},
pmid = {42879974},
issn = {1532-2653},
abstract = {Deep cervical lymphaticovenous anastomosis (dcLVA) has been proposed to augment cerebral waste clearance in Alzheimer disease. This critical narrative assessment examines the mechanistic premise, available human reports, registered studies, and governance implications. Experimental loss-of-function and gain-of-function studies support a role for meningeal lymphatics in brain-fluid homeostasis, but they do not establish a rate-limiting cervical outflow abnormality in human Alzheimer disease. The clinical reports identified through this narrative search were uncontrolled single-arm investigations, including patients with severe impairment, substantial attrition, and outcomes vulnerable to floor effects and perioperative influences. Randomised studies are now recruiting. Their value will depend on whether they measure intervention-specific flow, target engagement, clinically meaningful outcomes, and harms. The procedure should remain investigational until studies demonstrate intervention-specific biological target engagement, controlled clinical benefit, and acceptable long-term safety.},
}

@article {pmid42879978,
year = {2026},
author = {Rebord, F and Picciuto, O and Laner, J and Champendal, M and Sá Dos Reis, C},
title = {Behavioural and environmental strategies implemented by radiographers to care for patients with neurocognitive disorders during medical imaging and therapeutic procedures.},
journal = {Radiography (London, England : 1995)},
volume = {32},
number = {8},
pages = {103596},
doi = {10.1016/j.radi.2026.103596},
pmid = {42879978},
issn = {1532-2831},
abstract = {INTRODUCTION: As the population ages, radiographers are increasingly likely to care for patients with dementia, Alzheimer's disease and other neurocognitive disorders in medical imaging or radiation therapy departments. Since the cognitive and behavioural presentation of these patients can vary, radiographers must be prepared to adapt their approach. To investigate behavioural and environmental strategies used by radiographers when caring for patients with neurocognitive disorders (NCDs) during medical imaging and radiation therapy procedures.

METHODS: A cross-sectional survey comprising 18 questions was conducted among radiographers working across medical imaging and radiotherapy modalities. The questionnaire explored attitudes towards patients with NCDs, behavioural communication strategies, environmental adaptations, and institutional support measures. Descriptive statistics and thematic analysis of open-ended responses were performed.

RESULTS: A total of 160 radiographers participated. Most respondents reported positive attitudes toward patients with NCDs, with 94% indicating no fear when interacting with this population. Behavioural communication strategies were frequently used, particularly maintaining eye contact (85%), using simple language (80%), and speaking slowly and clearly (76%). Caregivers were commonly involved to facilitate communication (81%). Despite this, 45% of radiographers reported frustration at not always knowing how to help effectively. Institutional environmental adaptations were limited, with most participants reporting no dementia-specific training (85%) or departmental protocols (78%).

CONCLUSION: Radiographers frequently implement behavioural strategies to support patients with NCDs, but this relies on individual initiative rather than structured organisational support, which remains limited.

IMPLICATIONS FOR PRACTICE: Radiographers should use clear, simple communication strategies with NCD patients, involve caregivers during imaging procedures, and develop dementia-specific training and departmental protocols.},
}

@article {pmid42880003,
year = {2026},
author = {Dharia, SY and Valderrama, CE and Smith, SD},
title = {Cross-cohort transfer of clinical Alzheimer's EEG signatures to cognitively healthy APOE-ε4 and PICALM rs3851179 risk carriers using differentiable logic gate networks.},
journal = {Computers in biology and medicine},
volume = {217},
number = {},
pages = {111981},
doi = {10.1016/j.compbiomed.2026.111981},
pmid = {42880003},
issn = {1879-0534},
abstract = {Neural alterations associated with Alzheimer's disease (AD) may emerge years before clinical diagnosis, and genetic risk factors such as APOE-ε4 and PICALM rs3851179 may identify individuals vulnerable to these shifts. We tested whether electroencephalography (EEG) signatures learned from clinically diagnosed AD patients transfer to cognitively healthy middle-aged adults carrying these variants. Differentiable logic gate networks (Diff-Logic) and neural baselines were trained on log-relative power spectral density features from a clinical cohort of AD patients and cognitively normal (CN) controls. These models were then applied without retraining to an independent genetic-risk cohort of neutral-risk non-carriers (N), APOE-ε4-only carriers (A+P-), and dual APOE-ε4/PICALM G-allele carriers (A+P+), yielding a continuous AD-like EEG signature score per participant. Diff-Logic matched neural baselines in clinical classification (balanced accuracy 0.809±0.028; AUROC 0.845±0.023) while enabling edge inference with a 7.4× model-size reduction and 0.22 ms model-only latency on a 7 W single-core CPU. In the genetic-risk cohort, scores were highest in A+P+ participants (0.393±0.167) relative to N (0.296±0.154) and A+P- (0.285±0.143; subject-level mean ± SD). This elevation was nominally significant before correction (A+P+ vs. A+P-, punc=0.036) but did not survive Holm correction (pHolm=0.109), and the cohort carried no AD pathology or conversion ground truth; the association was therefore exploratory. Integrated gradients attribution of the trained model showed genetic-risk relevance in delta, theta, and alpha, partially overlapping clinical AD topography. These findings support the feasibility of zero-shot EEG transfer in genetically at-risk individuals and highlight the need for replication in larger cohorts. Code is publicly available at https://github.com/Shyamal-Dharia/ad-difflogic-transfer.},
}

@article {pmid42880054,
year = {2026},
author = {Benussi, A and Agosta, F and Agnello, L and Alfano, AR and Altini, M and Antico, A and Basilico, S and Bellelli, G and Bonanni, L and Bottini, G and Bozzali, M and Brignoli, O and Bruno, G and Cagnin, A and Calloni, SF and Cappa, SF and Caraci, F and Cecchin, D and Ciaccio, M and Cocozza, S and Cosottini, M and De Leo, D and Falini, A and Gaetani, L and Gandolfo, N and Gotta, F and Lodi, R and Logroscino, G and Marcello, E and Marra, C and Marrocco, W and Morbelli, S and Mecocci, P and Mossello, E and Palleschi, L and Palumbo, P and Pantoni, L and Parnetti, L and Roccatagliata, L and Sorbi, S and Spadin, P and Splendiani, A and Tessitore, A and Ungar, A and Zappalà, G and Padovani, A},
title = {Updated Italian intersocietal recommendations for the appropriate use of anti-amyloid monoclonal antibodies in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100685},
doi = {10.1016/j.tjpad.2026.100685},
pmid = {42880054},
issn = {2426-0266},
abstract = {With the European authorisation of lecanemab and donanemab, Italy is entering the era of disease-modifying therapy for early symptomatic Alzheimer's disease. The Italian Expert Panel on Alzheimer (EPA), which convened 21 scientific societies and patient associations and published a first set of intersocietal recommendations in 2025, was reconvened in Rome on 24 January 2026 (EPA2) to address the operational gaps that had emerged during the implementation of that document. A modified Delphi process was adopted to formalise consensus on the most controversial points raised during the meeting. Thirty-six declarative statements covering five domains, namely the tiered organisation of the Centres for Cognitive Disorders and Dementia (CDCD), clinical staging and treatment monitoring, eligibility considerations in mild cognitive impairment and atypical phenotypes, composition of the multidisciplinary team, and magnetic resonance imaging thresholds, ARIA monitoring and biomarker pathway, were submitted to a multidisciplinary panel of experts. Strong agreement was reached on the large majority of statements, providing quantitative endorsement for a competence-based reorganisation of the CDCD network, the harmonised use of the Clinical Dementia Rating, an explicit composition of the multidisciplinary team, trial-aligned magnetic resonance imaging eligibility criteria with a move towards risk-adapted ARIA monitoring, and a stepwise biomarker pathway integrating plasma assays, cerebrospinal fluid analysis on automated platforms and amyloid positron emission tomography. The document provides Italian regional and national health systems, prescribing centres and reimbursing authorities with a quantitative blueprint for the appropriate, equitable and sustainable use of anti-amyloid monoclonal antibodies in clinical practice.},
}

@article {pmid42880056,
year = {2026},
author = {Wang, M and Li, J and Wang, X and Chai, X and Luo, J and Zhang, Y and Chang, X and Sun, Y and Wang, H},
title = {Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.},
journal = {Cytokine & growth factor reviews},
volume = {92},
number = {},
pages = {101537},
doi = {10.1016/j.cytogfr.2026.101537},
pmid = {42880056},
issn = {1879-0305},
abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of innate immunity, has emerged as a critical driver of sterile neuroinflammation in the aging brain. Age-related decline in mitochondrial quality control, coupled with nuclear and lysosomal erosion, fosters the aberrant accumulation of cytosolic self-DNA, establishing a permissive environment for chronic cGAS-STING activation. This review synthesizes recent breakthroughs elucidating how major neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-converge on this pathway through distinct, disease-specific triggers, ranging from PINK1/Parkin deficiency-driven mitochondrial DNA leakage to TDP-43 proteinopathy-associated retrotransposon de-repression. Critically, we evaluate the translational landscape, highlighting the profound challenge posed by species-specific pharmacology, as exemplified by the failure of the covalent inhibitor H-151 to engage human STING. We argue that the future of therapeutic intervention lies not in wholesale pathway ablation, but in nuanced, context-dependent fine-tuning that disentangles its detrimental chronic effects from its indispensable homeostatic functions. This review positions the cGAS-STING axis as a promising yet delicate frontier for combating age-related neurodegeneration.},
}

@article {pmid42880287,
year = {2026},
author = {Akay, LA and Bright, A and Dong, D and Smith, ED and Hurt, RC and Boix, CA and Louderback, K and Medrano, J and Sun, D and Lin, H and King, O and Welch, GM and Nawaid, H and Agbas, E and Jiang, A and Bubnys, A and Cheng, JX and Blanchard, JW and Tsai, LH},
title = {Genome-wide CRISPR screen reveals that Wnt signaling regulates lipid accumulation in APOE4 oligodendrocytes.},
journal = {Cell stem cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.stem.2026.09.012},
pmid = {42880287},
issn = {1875-9777},
abstract = {APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease, yet the cellular mechanisms linking APOE variants to disease risk remain unclear. We previously found that APOE4 expression causes lipid droplet accumulation in oligodendrocytes, reducing myelination, but the underlying mechanisms were unknown. Using a genome-wide CRISPR screen and assay for transposase-accessible chromatin (ATAC) sequencing in human-induced pluripotent stem cell (iPSC)-derived oligodendrocytes, we identified decreased Wnt signaling and overactive glycogen synthase kinase-3 beta (GSK3B) as key regulators of lipid-droplet accumulation. Genetic and pharmacological inhibition of GSK3B reduced lipid droplets in APOE4 oligodendrocytes and increased myelination in three-dimensional iPSC-derived brain organoids. Pharmacological GSK3B inhibition also reduced lipid droplets and improved myelination in APOE4;PS19 tau transgenic mice. Together, these findings establish a mechanistic framework linking Wnt/GSK3B signaling to APOE4-driven disruptions in oligodendrocyte lipid metabolism and myelination, pointing to GSK3B as a potential therapeutic target for APOE4-associated Alzheimer's disease.},
}

@article {pmid42880289,
year = {2026},
author = {Ma, K and Park, K and Honma, PS and Zhang, Y and Brady, E and Qiu, Y and Opitz-Araya, X and Ting, JT and Levi, BP and Akassoglou, K and Palop, JJ},
title = {Parvalbumin cell state dynamics regulate gamma oscillations and are disrupted in Alzheimer's disease.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.025},
pmid = {42880289},
issn = {1097-4199},
abstract = {Gamma oscillations are fundamental for cognitive processing, but the cellular and circuit dynamics that generate them remain poorly defined. Establishing a method for simultaneous calcium imaging and electrocorticography recordings in awake mice, we found that spontaneous gamma oscillations are accompanied by dynamic transitions between parvalbumin (PV) interneuron states. Rather than acting as a uniformly synchronized population, PV interneurons showed sequential recruitment, transient inactivation, and frequent transitions between activity states, indicating the formation of dynamic functional networks. In J20 Alzheimer's disease mice, these state transitions became dysregulated, leading to abnormal PV recruitment, impaired coupling between PV activity and gamma oscillations, and network hyperexcitability. Increasing interneuron excitability through expression of the voltage-gated sodium channel Nav1.1 restored PV cell dynamics, gamma oscillations, and network stability. These findings reveal dynamic PV cell states as an organizing feature of gamma oscillations and identify their disruption as a circuit mechanism of network dysfunction in Alzheimer's disease.},
}

@article {pmid42880555,
year = {2026},
author = {Ivantsova, E and Lu, A and Martyniuk, CJ},
title = {A comprehensive review of the neurobehavioral and neurotoxic effects of 6PPD-Q in fish, rodents, and humans.},
journal = {Neurotoxicology and teratology},
volume = {},
number = {},
pages = {107725},
doi = {10.1016/j.ntt.2026.107725},
pmid = {42880555},
issn = {1872-9738},
abstract = {N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a widely used tire additive that undergoes environmental transformation to 6PPD-quinone (6PPD-Q), which is ubiquitously detected in environmental matrices. Increasing evidence demonstrates that exposure to 6PPD-Q adversely affects organisms through neurobehavioral disruption and neurotoxicity. While studies document behavioral abnormalities and molecular alterations, a comprehensive synthesis linking these outcomes remains limited. The objective of this review was to synthesize current literature reporting neurobehavioral and neurotoxic effects of 6PPD-Q in fish, rodents, and humans using experimental and computational approaches. Using PRISMA guidelines, a search was conducted in PubMed and Google Scholar using several key phrases related to 6PPD-Q and neurotoxicity, capturing 1874 records. Relevant articles were assessed by full-text review for criteria eligibility, and the final review included 27 articles. In fish, exposure to 6PPD-Q can alter neurobehaviors like locomotor activity, anxiety-like responses, social and aggressive behaviors, and disturbances in circadian-regulated activities. Such behavioral outcomes correspond closely with neurotransmitter imbalance, neuroendocrine disruption, blood-brain barrier dysfunction, and transcriptome changes affecting neural signaling pathways. In rodents, repeated or chronic exposure to 6PPD-Q leads to neuronal damage, cognitive impairment, anxiety-like behavior, and memory deficits. Human biomonitoring and mechanistic studies further associate 6PPD-Q exposure with oxidative stress, mitochondrial dysfunction, and molecular responses relevant to neurological diseases. Leveraging the Comparative Toxicogenomics Database, computational analysis revealed entities associated with 6PPD-Q in the database were related to Alzheimer's disease, dopaminergic synapses, neurotrophin signaling pathways, and Parkinson's disease. Taken together, data suggests that 6PPD-Q may interfere with neuronal signaling, connectivity, and plasticity, leading to behavioral deficits. Based on predictive docking scores using fish, rodent, and human orthologs, 6PPD-Q may interact with tyrosine hydroxylase and L-dopa decarboxylase which can potentially lead to disrupted dopamine biosynthesis pathways. Given the widespread environmental presence of 6PPD-Q and its continuous introduction into aquatic ecosystems, characterizing such mechanisms is critical for improving ecological and human health risk assessments.},
}

@article {pmid42880558,
year = {2026},
author = {Liu, J and Wyatt-Johnson, SK and Chen, J and Chen, J and Liu, Z and Wu, H and Feng, L and Brutkiewicz, RR and Wang, N},
title = {Characterizing age-dependent diamagnetic and paramagnetic susceptibility properties in 5xFAD Alzheimer's mouse brain using high-resolution MRI.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122276},
doi = {10.1016/j.neuroimage.2026.122276},
pmid = {42880558},
issn = {1095-9572},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disorder and the most common cause of dementia. This study aimed to characterize magnetic susceptibility changes associated with beta-amyloid (Aβ) plaques during AD progression using diamagnetic and paramagnetic susceptibility measurements in the 5xFAD mouse model.

METHODS: Ex vivo multi-echo gradient-echo imaging (MGRE) with a spatial resolution of 40 × 40 × 40 μm[3] was performed in three age groups of 5xFAD mice (4, 12, and 18 months) using a 9.4T Bruker MRI scanner. Quantitative susceptibility mapping (QSM) was reconstructed, and DECOMPOSE-QSM was applied to derive diamagnetic component susceptibility (DCS) and paramagnetic component susceptibility (PCS). Aβ plaques were automatically detected based on DCS and quantified to assess age-dependent plaque accumulation, changes in plaque burden, and associated susceptibility alterations. Cortical regions were further segmented into plaque-detected and plaque-undetected regions to assess regional susceptibility variations among the three age groups. In addition, Aβ/ferritin immunostaining was performed on the imaged murine brains.

RESULTS: The results demonstrated progressive, spatially heterogeneous, age-dependent accumulation of amyloid plaques, as evidenced by significant increases in plaque burden. In plaque-detected and whole-region cortical areas, DCS consistently shifted toward more negative values (greater diamagnetic susceptibility) with disease progression, while PCS became more positive (greater paramagnetic susceptibility). The concurrent increase in plaque burden, together with progressively more negative DCS and more positive PCS within plaques, is consistent with increasing diamagnetic and paramagnetic tissue contributions associated with amyloid and iron-related pathology, respectively. Histological analysis showed colocalized Aβ aggregation and ferritin deposition within plaques, both of which increased with age.

CONCLUSIONS: The decomposed susceptibility components, DCS and PCS, provide complementary biophysical information beyond conventional QSM, enabling improved characterization of plaque-associated susceptibility changes during AD progression. High-resolution MRI facilitates the visualization and detection of individual plaques, allowing detailed analysis of their susceptibility properties. These findings highlight the importance of high-resolution MRI and the potential of diamagnetic and paramagnetic susceptibility measures as sensitive imaging biomarkers for monitoring neurodegenerative pathology.},
}

@article {pmid42880559,
year = {2026},
author = {Li, Y and Khandelwal, P and Jena, R and Xie, L and Duong, MT and Denning, AE and Brown, CA and Wisse, LEM and Das, SR and Wolk, DA and Yushkevich, PA},
title = {Achieving detailed medial temporal lobe segmentation with upsampled isotropic training from implicit neural representation.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122294},
doi = {10.1016/j.neuroimage.2026.122294},
pmid = {42880559},
issn = {1095-9572},
abstract = {Imaging biomarkers in magnetic resonance imaging (MRI) are important tools for diagnosing, tracking and treating Alzheimer's disease (AD). Neurofibrillary tau pathology in AD is closely linked to neurodegeneration and generally follows a pattern of spread in the brain, with early stages involving subregions of the medial temporal lobe (MTL). Accurate segmentation of MTL subregions is needed to extract granular biomarkers of AD progression. MTL subregions are often imaged using T2-weighted (T2w) MRI scans that are highly anisotropic due to constraints of MRI physics and image acquisition, making it difficult to reliably model MTL subregions geometrically and extract morphological measures, such as thickness. In this study, we propose a segmentation framework for MTL subregions in isotropic space, in which an implicit neural representation is used to construct the isotropic training atlas from the anisotropic low-resolution T2w data, with T1w MRI as an auxiliary modality to support the INR and segmentation. In an independent test set, the morphological measures extracted using this isotropic model showed stronger effect sizes than those from models trained on anisotropic data in distinguishing participants with mild cognitive impairment (MCI) from cognitively unimpaired individuals. In the test-retest analysis, the morphological measures extracted using the isotropic model showed greater stability than those from the anisotropic segmentation. This study demonstrates improved reliability of MRI-derived MTL subregion biomarkers without additional atlas annotation effort, which may more accurately quantify and track the relationship between AD pathology and brain atrophy for monitoring disease progression.},
}

@article {pmid42880601,
year = {2026},
author = {Barberà-Parada, S and Biosca-Brull, J and Gabaldón-Díaz, R and Rodulfo-Cárdenas, R and Guardia-Escoté, L and Blanco, J and Cabré, M and Colomina, MT},
title = {Sex-divergent vulnerability to chronic peripheral LPS challenge in aged ApoE4 mice: Male systemic fragility versus female central neuroinflammation.},
journal = {Behavioural brain research},
volume = {517},
number = {},
pages = {116524},
doi = {10.1016/j.bbr.2026.116524},
pmid = {42880601},
issn = {1872-7549},
abstract = {Inflammageing links chronic inflammation to biological aging, contributing to senescence and multimorbidity common in the elderly. In neurodegenerative diseases, such as Alzheimer's disease, inflammatory processes play a causal role in accelerating neurodegeneration. Interestingly, apolipoprotein E (APOE), particularly the APOEε4 allele, is a major genetic risk factor for neurodegeneration, acting as a key immunomodulator with sex differences. This is especially relevant given the lack of clear prevention strategies for APOEε4 carriers. Therefore, this study characterized the sex-specific neuroinflammatory and cognitive vulnerability of APOE4 genotype under a chronic lipopolysaccharide (LPS) challenge in senescence-transition stage. Male and female homozygous apoE4 mice (15-16 months old) were administered intraperitoneal doses of 0 or 0.25 mg/kg LPS three times per week for a total of 17 doses. Body weight was monitored, and behavioural assessments were conducted from the 12th injection until the 17th. Serum and tissues were collected to assess hippocampal, cortical and systemic markers of inflammation, antioxidant-related genes, genes implied in myelin dynamics, and neurotrophin-related transcripts. Findings revealed basal sex-dependent divergent phenotypes with specific responses under LPS challenge. Under LPS treatment, males exhibited higher systemic fragility, with significantly increased mortality, which may have conditioned cognitive outcomes. Females showed greater central alterations related to neuroinflammation along with altered expression of myelin-related transcripts. However, the results suggest a stablished tolerance to LPS. These results highlight how chronic systemic inflammation during ageing in an APOE4 genotype background shapes sex-divergent pathological trajectories, underscoring the need to address sex-specific therapeutic strategies.},
}

@article {pmid42880847,
year = {2026},
author = {Ma, Y and Chen, KW and DE Jager, P},
title = {Epigenetic mechanisms in brain development and in neurodegeneration.},
journal = {Handbook of clinical neurology},
volume = {219},
number = {},
pages = {361-380},
doi = {10.1016/B978-0-443-19043-8.00030-X},
pmid = {42880847},
issn = {0072-9752},
mesh = {Humans ; *Epigenesis, Genetic/physiology/genetics ; *Brain/growth & development/metabolism ; *Neurodegenerative Diseases/genetics/pathology ; Animals ; DNA Methylation/genetics ; MicroRNAs/genetics ; },
abstract = {Epigenetic mechanisms are important heritable modifications beyond genetic mechanisms. Interindividual epigenetic variants can lead to phenotypic variations even in identical genotypes. Studies on the epigenetic contributions to Alzheimer disease and other neurodegenerative diseases could provide more comprehensive and precise insights into the heritable and nonheritable mechanisms. This knowledge will enable the development of individually tailored preventive and therapeutic pharmacologic interventions. This chapter is divided into three sections. First, we provide a detailed introduction to four epigenetic mechanisms: DNA methylation, histone modifications, chromatin remodeling, and microRNAs. Next, we review published studies that explore the contributions of these epigenetic modifications to Alzheimer disease. Finally, we summarize the current understanding of each epigenetic modification and its influence on the development of the central nervous system.},
}

Humans
*Epigenesis, Genetic/physiology/genetics
*Brain/growth & development/metabolism
*Neurodegenerative Diseases/genetics/pathology
Animals
DNA Methylation/genetics
MicroRNAs/genetics

@article {pmid42880851,
year = {2026},
author = {Pappas, JJ and Khoueiry, R and Godderis, L and Herceg, Z},
title = {The epigenetic mechanisms mediating the long-term impacts of toxicants on brain functions and health.},
journal = {Handbook of clinical neurology},
volume = {219},
number = {},
pages = {449-481},
doi = {10.1016/B978-0-443-19043-8.00021-9},
pmid = {42880851},
issn = {0072-9752},
mesh = {Humans ; Animals ; *Epigenesis, Genetic/drug effects ; *Brain/drug effects ; DNA Methylation/drug effects ; },
abstract = {Recent advances in toxicoepigenetics have significantly enhanced our understanding of epigenetic modifications induced by toxicant exposures. This review synthesizes current knowledge regarding epigenetic alterations - primarily DNA methylation, histone acetylation, and miRNA perturbations - associated with common toxicants, including arsenic, lead, methylmercury, formaldehyde, α-hexabromocyclododecane, bisphenol A, and fluoxetine. While substantial evidence derives from rodent models, human studies have made crucial contributions by characterizing toxicant-specific epigenetic signatures, identifying affected genes and pathways, and establishing epigenetic regulation as a critical mediator of biologic responses. This review highlights parallels between toxicant-induced epigenetic changes and those observed in neurologic disorders, particularly focusing on the potential of epigenetic marks as early diagnostic tools for synaptic dysfunction in Alzheimer disease, but also focusing on Huntington disease and Parkinson disease. It relies on evidence ranging from exposures in vitro and in vivo (mainly in rodents) to human exposures. It also highlights parallels between toxicant-induced epigenetic changes and those observed in brain cancers. The findings underscore the therapeutic potential of targeting epigenetic mechanisms to mitigate toxicant-induced neurologic effects. We conclude by proposing a strategic framework for further advancing toxicoepigenetic research, emphasizing the creation of a centralized databank for toxicant-induced brain epigenetic alterations, the development of validated epigenetic bioassays, and the integration of functional neuroimaging. Our proposed comprehensive approach, combining genetics, toxicology, epidemiology, and environmental science, aims to inform and enhance risk assessment protocols and therapeutic interventions.},
}

Humans
Animals
*Epigenesis, Genetic/drug effects
*Brain/drug effects
DNA Methylation/drug effects

@article {pmid42880986,
year = {2026},
author = {Zhang, X and Li, Z and Zhang, Q and Yin, Z and Lu, Z and Li, Y},
title = {Retraction notice to "A new weakly supervised deep neural network for recognizing Alzheimer's disease" [Computers in Biology and Medicine 163 (2023) 107079].},
journal = {Computers in biology and medicine},
volume = {},
number = {},
pages = {111991},
doi = {10.1016/j.compbiomed.2026.111991},
pmid = {42880986},
issn = {1879-0534},
}

@article {pmid42881131,
year = {2026},
author = {Shimoda, K},
title = {Recognising Mild Cognitive Impairment and Early Alzheimer's Disease in General and Psychiatric Practice: Clinical Clues and Appropriate Referral.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70228},
doi = {10.1111/psyg.70228},
pmid = {42881131},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Referral and Consultation ; *Cognitive Dysfunction/diagnosis/psychology ; Activities of Daily Living ; Aged ; General Practice ; Neuropsychological Tests ; },
abstract = {Early cognitive decline may become evident through changes in daily activities or behaviour before it is apparent in a brief consultation. This selective narrative review supports case-finding and appropriate referral in general and psychiatric practice. Four actions organise the review: identify decline in previously mastered instrumental activities of daily living; recognise new apathy or sustained behavioural change; use a cognitive screen sensitive to mild impairment, such as the Montreal Cognitive Assessment; and refer when clinically meaningful concern remains. Functional and behavioural findings require interpretation alongside medical, psychiatric and social factors. Mild behavioural impairment has reported associations with both amyloid and tau, varying across populations. Depression, medication exposure or a reassuring screening score should not end the assessment of otherwise unexplained decline. Collateral information strengthens the assessment but living alone and lacking a reliable informant are distinct circumstances. Municipal and care services may contribute observations without resolving every gap. Dementia disease medical centres should coordinate assessment and support with referring clinicians and community services.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
*Referral and Consultation
*Cognitive Dysfunction/diagnosis/psychology
Activities of Daily Living
Aged
General Practice
Neuropsychological Tests

@article {pmid42881137,
year = {2026},
author = {Ren, H and Wen, T and Falvey, J and Huang, Y and Chen, C},
title = {A Doubly Robust Approach to Evaluating the Impact of Hospital Length of Stay on Post-Fracture Recovery in Older Adults With Cognitive Impairment.},
journal = {Statistics in medicine},
volume = {45},
number = {23-24},
pages = {e70768},
doi = {10.1002/sim.70768},
pmid = {42881137},
issn = {1097-0258},
support = {R01AG089377/NH/NIH HHS/United States ; P30AG028747/NH/NIH HHS/United States ; },
mesh = {Humans ; *Length of Stay/statistics & numerical data ; *Hip Fractures/rehabilitation/complications ; Computer Simulation ; Aged ; Models, Statistical ; Female ; Aged, 80 and over ; Recovery of Function ; },
abstract = {For older adults diagnosed with Alzheimer's Disease and Related Dementias, recovery outcomes after a hip fracture are often poor, with extended hospital stays and prolonged rehabilitation being common. This paper examines the impact of hospitalization on post-discharge outcomes, focusing on the differential effects of hospital length of stay on recovery, measured by the number of healthy days spent at home (DAH). Our analysis faces important analytical challenges, including baseline confounding, missing outcome, and the complexity of assessing a continuous exposure. To address these issues, we develop a doubly robust estimator that accommodates a continuous exposure and accounts for outcome missingness and provides practical guidance for end-users, including diagnostics for conditional density and missing data models and sensitivity analyses for assumption violation. Extensive simulations demonstrate that our method consistently outperforms existing doubly robust method for continuous exposures when outcome data are missing at random. Application to real-world data suggests that hospital stays longer than 20 days are associated with substantially reduced DAH.},
}

Humans
*Length of Stay/statistics & numerical data
*Hip Fractures/rehabilitation/complications
Computer Simulation
Aged
Models, Statistical
Female
Aged, 80 and over
Recovery of Function

@article {pmid42881165,
year = {2026},
author = {Harvey, J and Imm, J and Kouhsar, M and Smith, AR and Creese, B and Smith, RG and Wheildon, G and Laroche, V and Leung, SK and Chouliaras, L and Shireby, G and Jaunmuktane, Z and De Pablo-Fernández, E and Warner, T and Lett, DJ and Gveric, D and Brooks, H and Attems, J and Thomas, A and Van de Berg, WD and Dempster, E and Ballard, C and T O'Brien, J and Aarsland, D and Mill, J and Pihlstrøm, L and Pishva, E and Lunnon, K},
title = {Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42881165},
issn = {2041-1723},
support = {MR/S011625/1//RCUK | Medical Research Council (MRC)/ ; G0400074//RCUK | Medical Research Council (MRC)/ ; MR/M008924/1//RCUK | Medical Research Council (MRC)/ ; R01AG067015//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AS-PG-16b-012/ALZS_/Alzheimer's Society/United Kingdom ; AS-PDF-23-017/ALZS_/Alzheimer's Society/United Kingdom ; ARUK-PG2023A-037//Alzheimer's Research UK (ARUK)/ ; MJFF-023152//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; 733050516//ZonMw (Netherlands Organisation for Health Research and Development)/ ; },
mesh = {*DNA Methylation ; Humans ; Genome-Wide Association Study ; *Lewy Body Disease/genetics/pathology ; Quantitative Trait Loci ; alpha-Synuclein/genetics/metabolism ; *Brain/metabolism/pathology ; *Lewy Bodies/pathology/metabolism ; Parkinson Disease/genetics/pathology ; Epigenesis, Genetic ; Cohort Studies ; Genetic Predisposition to Disease ; },
abstract = {Here, we conduct a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of Lewy body pathology. Utilizing a dataset of 1205 samples (832 unique donors), we identify 24 false discovery rate significant differentially methylated loci associated with Lewy body pathology, with loci located in UBASH3B and PTAFR, and an intergenic locus passing the genome-wide significance threshold. Ontological enrichment analysis highlights several neurologically relevant traits, including synaptic alterations. We compare methylation signatures between neurodegenerative pathologies and highlight a shared epigenetic profile across Lewy body, Alzheimer's and Huntington's diseases, although the top-ranked loci show disease specificity. Utilizing summary statistics from large-scale genome-wide association studies, we identify significant enrichment of DNA methylation differences with respect to increasing Lewy body pathology in the SNCA genomic region. We also identify specific relationships between genetic risk variants for Lewy body dementia and Parkinson's disease to methylation quantitative trait loci in the SNCA 5' region and expression of alternative transcript isoforms.},
}

*DNA Methylation
Humans
Genome-Wide Association Study
*Lewy Body Disease/genetics/pathology
Quantitative Trait Loci
alpha-Synuclein/genetics/metabolism
*Brain/metabolism/pathology
*Lewy Bodies/pathology/metabolism
Parkinson Disease/genetics/pathology
Epigenesis, Genetic
Cohort Studies
Genetic Predisposition to Disease

@article {pmid42881225,
year = {2026},
author = {Vicidomini, C and Goode, TD and Yu, R and Mehta, I and McAvoy, KM and Beveridge, CH and Randolph, CE and Iyer, SN and Victor, MB and Leary, N and Evans, L and Steinbaugh, MJ and Lai, ZW and Lyon, MC and San Silvestre, MRF and Tosoni, G and Ayyildiz, D and Ho Sui, S and Yamamoto, K and Murakami, M and Salta, E and Tsai, LH and Chopra, G and Sahay, A},
title = {An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42881225},
issn = {1546-1726},
abstract = {Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.},
}

@article {pmid42881935,
year = {2026},
author = {Stafstrom, CE and Shao, LR},
title = {Epilepsy Mechanisms in Down Syndrome: Genetic and Pathophysiological Perspectives Across the Lifespan.},
journal = {Journal of clinical medicine},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/jcm15197471},
pmid = {42881935},
issn = {2077-0383},
support = {FJL 2421_GRT-2025B//Fondation Jérôme-Lejeune/ ; },
abstract = {Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability. Seizures are a frequent comorbidity in individuals with Down syndrome and can exert significant negative consequences on cognitive capacity and quality of life. In Down syndrome, seizures cluster at two extremes of the lifespan. In the first year of life, infantile epileptic spasms syndrome affects 5-10% of children with Down syndrome. The second peak occurs after age 30 years, when myoclonic seizures appear at the time of onset of Down syndrome-related dementia of the Alzheimer type (late-onset myoclonic epilepsy in Down syndrome or LOMEDS). While epilepsy at these two disparate time points has been long recognized in the Down syndrome population, the mechanisms underlying seizure pathogenesis have not been studied in detail. For example, it is not known whether the brain developmental abnormalities that characterize Down syndrome are primarily responsible for the epilepsies or whether distinct mechanisms underlie seizures at the two ages. This narrative review addresses possible mechanisms of seizure propensity across the lifespan, with special reference to potential age-specific treatments.},
}

@article {pmid42882298,
year = {2026},
author = {Prieur-Coloma, Y and Prado, P and El-Deredy, W and Weinstein, A},
title = {An Interpretable Framework for Identifying EEG Spectral Biomarkers of Pathological Brain Aging.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {19},
pages = {},
doi = {10.3390/diagnostics16193143},
pmid = {42882298},
issn = {2075-4418},
support = {FONDECYT 3260279//Agencia Nacional de Investigación y Desarrollo/ ; BASAL CIA250006//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT 1231132//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT 1241695//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT 1260530//Agencia Nacional de Investigación y Desarrollo/ ; 13240064//Agencia Nacional de Investigación y Desarrollo/ ; },
abstract = {Background: Normal aging involves gradual declines in brain function, whereas neurodegenerative disorders show accelerated deterioration. Electroencephalography (EEG) captures alterations in brain oscillatory activity, making it promising for detecting neurodegenerative disorders. However, existing approaches often emphasize classification performance over spectral biomarker identification, limiting clinical translation. Methods: We propose an EEG-based framework integrating explainable machine learning, analyses of inter-subject heterogeneity and temporal stability, and probabilistic modeling to identify reproducible spectral biomarkers of pathological brain aging. Two independent public EEG datasets comprising cognitively normal (CN) individuals and patients with Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD) were analyzed. Spectral features from canonical frequency bands were analyzed using SHAP to identify reproducible biomarkers in two datasets. The identified biomarker was subsequently characterized through inter-subject heterogeneity, temporal stability, and empirical distributions to assess disease-related alterations in oscillatory activity. Results: Several spectral features showed consistent disease-related associations across classification tasks. The θ/α ratio emerged as a representative biomarker, showing reduced temporal stability and broader empirical distributions in most neurodegenerative groups than in CN. Conclusions: Reduced temporal stability of reproducible EEG spectral biomarkers may represent an observable signature of disrupted oscillatory brain organization during pathological aging. The proposed framework characterizes a dimension of EEG spectral biomarkers that static summaries discard, offering an interpretable basis on which future longitudinal studies may build diagnostic and monitoring tools.},
}

@article {pmid42882419,
year = {2026},
author = {Mao, J and Zhang, Y and Wang, P and Qin, D},
title = {Clockophagy in Alzheimer's Disease: An Emerging Hypothesis Linking Circadian Dysfunction to Ferroptotic Vulnerability.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191721},
pmid = {42882419},
issn = {2073-4409},
support = {82374425//National Natural Science Foundation of China/ ; 82474377//National Natural Science Foundation of China/ ; 202501AZ070001-033//Yunnan Provincial Department of Finance/ ; D20230035//Enshi Science and Technology Program - Qihang Special Project/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/pathology ; *Autophagy ; *Circadian Rhythm/physiology ; *Ferroptosis ; Animals ; ARNTL Transcription Factors/metabolism ; Oxidative Stress ; Lipid Peroxidation ; },
abstract = {Alzheimer's disease (AD) is frequently associated with sleep disturbances and circadian dysfunction, which may precede or accompany clinical manifestations and have been associated with amyloid-β (Aβ) pathology, tau abnormalities, oxidative stress, lipid peroxidation, and neuronal vulnerability. Increasing evidence suggests that circadian regulation intersects with multiple cellular processes implicated in AD pathogenesis, including autophagy and ferroptosis. Among these mechanisms, clockophagy, an SQSTM1/p62-mediated selective autophagic process involved in BMAL1 degradation, has recently emerged as a potential molecular link between circadian regulation and cellular stress responses. In this review, we summarize current evidence connecting sleep disruption, circadian dysfunction, lipid peroxidation, and ferroptotic susceptibility in AD, while highlighting the current limitations of mechanistic evidence. We further discuss the molecular basis of clockophagy and its potential relationship with BMAL1 regulation, oxidative lipid damage, and ferroptosis. Collectively, clockophagy is currently viewed as an emerging hypothesis that may contribute to AD-related pathological processes. Finally, we discuss potential therapeutic implications, including approaches targeting sleep and circadian organization, BMAL1-associated regulatory pathways, and lipid oxidative stress. Further studies are required to determine whether modulation of clockophagy can influence AD-related neurodegenerative processes.},
}

Humans
*Alzheimer Disease/metabolism/physiopathology/pathology
*Autophagy
*Circadian Rhythm/physiology
*Ferroptosis
Animals
ARNTL Transcription Factors/metabolism
Oxidative Stress
Lipid Peroxidation

@article {pmid42882436,
year = {2026},
author = {Chmiel, J and Leszek, J},
title = {Skull Bone Marrow as a Cranial Neuroimmune Reservoir in Alzheimer's Disease: Amyloid, Osteoimmune Remodeling, and Translational Imaging Evidence.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191738},
pmid = {42882436},
issn = {2073-4409},
mesh = {*Alzheimer Disease/immunology/pathology/diagnostic imaging ; Humans ; *Skull/immunology/pathology/diagnostic imaging ; *Bone Marrow/immunology/pathology/diagnostic imaging ; Animals ; *Translational Research, Biomedical ; Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; },
abstract = {Alzheimer's disease (AD) has traditionally been conceptualized as a disorder driven primarily by cerebral amyloid-β accumulation, tau pathology, synaptic failure, vascular dysfunction, and chronic neuroinflammation. However, emerging evidence suggests that AD pathobiology may also involve extracerebral cranial compartments positioned at the interface between the brain, meninges, cerebrospinal fluid, and skull bone marrow. Recent anatomical and experimental studies have identified direct vascular and osseous channels connecting skull bone marrow with the dura mater, allowing bidirectional exchange of immune cells, soluble mediators, and cerebrospinal fluid-derived signals. These findings support the concept that skull bone marrow functions as a specialized cranial immune reservoir capable of sensing central nervous system-derived molecular cues and supplying myeloid and lymphoid cells to meningeal and brain-border compartments. In AD models and human imaging studies, amyloid-β-related signals have been detected in skull marrow, where they may promote IL-6-dependent B lymphopoiesis, expansion of age-associated B cells, microglial activation, and amplification of cerebral amyloid pathology. In parallel, AD-related amyloid precursor protein and amyloid-β signaling may remodel the skull marrow niche through osteoblast dysfunction, altered osteoclast activity, vascular channel expansion, marrow adiposity, and inflammatory reprogramming. Human PET and MRI studies indicate that skull marrow-associated inflammatory, amyloid-related, and cerebrospinal-fluid drainage signals can be detected in vivo; however, these observations remain indirect, method-dependent, and insufficiently validated for diagnostic or prognostic use. Importantly, much of the anatomical foundation for skull marrow-meninges-brain communication derives from non-AD studies of CNS-border physiology, stroke, meningitis, spinal cord injury, and infection, whereas the strongest AD-specific mechanistic evidence is currently derived from transgenic mouse models. Accordingly, we frame the skull marrow-meninges-brain axis as a testable conceptual model rather than an established causal pathway in human AD. This review integrates anatomical, immunological, osteoimmune, and imaging evidence while explicitly distinguishing AD-specific findings from evidence extrapolated from other neurological or inflammatory contexts. Determining whether skull marrow alterations represent a cause, consequence, compensatory response, or amplifier of AD pathology will require longitudinal, biomarker-defined human studies and further mechanistic validation. The review also compares the principal in vivo strategies used to distinguish skull-marrow-derived immune cells from circulating leukocytes and examines ischemic stroke and brain tumors as comparator CNS conditions. These disease models demonstrate that cranial marrow responses can be rapid, spatially organized, and either protective or pathogenic depending on cellular phenotype and disease context, reinforcing the interpretation of skull marrow as a general CNS-border immune organ rather than an AD-specific compartment.},
}

*Alzheimer Disease/immunology/pathology/diagnostic imaging
Humans
*Skull/immunology/pathology/diagnostic imaging
*Bone Marrow/immunology/pathology/diagnostic imaging
Animals
*Translational Research, Biomedical
Amyloid beta-Peptides/metabolism
*Amyloid/metabolism

@article {pmid42882446,
year = {2026},
author = {Janković, T and Pilipović, K and Gržeta Krpan, N and Rajič Bumber, J and Mežnarić, S and Pelčić, A and Dolenec, P and Ćelić, T and Mršić-Pelčić, J},
title = {1,8-Cineole (Eucalyptol) in Neurodegeneration: From Pharmacological Mechanisms to Therapeutic Applications.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191748},
pmid = {42882446},
issn = {2073-4409},
support = {100.24.0009 to T.J.//Researcher support fund of the Faculty of Medicine, Rijeka/ ; },
mesh = {Humans ; *Eucalyptol/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases represent an enormous global burden, and due to the lack of effective therapies, the number of affected individuals continues to rise, placing a significant pressure on patients and their families. Phytochemicals such as terpenes are a group of compounds that have the potential to provide long-term neuroprotective effects by targeting multiple pathobiological pathways and supporting the brain's natural defense mechanisms. 1,8-cineole (eucalyptol) is a monoterpene known for its anti-inflammatory and antioxidant properties, mainly utilized in the respiratory system. However, due to its ability to cross the blood-brain barrier, beneficial effects have been observed in the central nervous system. Here we examine the pharmacological mechanisms and neuroprotective potential of 1,8-cineole in the nervous tissue. Studies have shown that 1,8-cineole has the potential to suppress neuroinflammation and reduce glial activation, activate antioxidant defense mechanisms and scavenge reactive oxygen species. Additionally, 1,8-cineole has been shown to modulate central neurotransmission and synaptic plasticity, inhibit apoptotic neuronal death and regulate ion channels involved in pain modulation. This review aims to examine the therapeutic potential of 1,8-cineole in the most prevalent neurodegenerative diseases in the population, such as Alzheimer's and Parkinson's diseases, as well as brain injuries, including ischemic stroke and traumatic brain injury, which may lead to neurodegeneration. We also explore the potential benefits of 1,8-cineole for anxiety and depression, which occur as early symptoms or common complications of neurodegenerative diseases. Given the need for novel therapeutic approaches, combination therapies that utilize the therapeutic potential of phytochemicals, such as 1,8-cineole, may enable more effective targeting of the multiple, interconnected pathobiological processes underlying neurodegenerative diseases.},
}

Humans
*Eucalyptol/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy
Animals
*Neuroprotective Agents/therapeutic use/pharmacology

@article {pmid42882466,
year = {2026},
author = {Burdman, G and Hanna, M and Arias, AY and Vashist, A and Lakshmana, MK},
title = {Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191768},
pmid = {42882466},
issn = {2073-4409},
support = {1R21DA060111, 1R61AG086971, R03AG08475//National Institute of Health (NIH)/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Brain/pathology/cytology ; *Organoids/pathology/cytology ; *Nervous System Diseases/pathology ; Animals ; Microphysiological Systems ; Neurons/pathology ; Models, Biological ; },
abstract = {Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.},
}

Humans
*Induced Pluripotent Stem Cells/cytology/metabolism
*Brain/pathology/cytology
*Organoids/pathology/cytology
*Nervous System Diseases/pathology
Animals
Microphysiological Systems
Neurons/pathology
Models, Biological

@article {pmid42882491,
year = {2026},
author = {Colasuonno, F and Valenza, A and Rossin, F and Moreno, S},
title = {From Amyloid Exposure to Genetic Causality: Converging hiPSC-Based Models of Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191793},
pmid = {42882491},
issn = {2073-4409},
support = {AGYR2020//Italian Alzheimer Research Association Onlus/ ; PRIN 2022, CUP E53D23007150006//Ministry of Universities and Research/ ; PNRR-MAC2-II.3 project PE6 "Heal Italia" CUP E83C22004670001//Ministry of Universities and Research/ ; PNRR (DM 629) CUP: F81J24000490006//Ministry of Universities and Research/ ; 27116//Italian Association for Cancer Research/ ; Grant of Excellence Department 2023-2027//Ministero dell'università e della ricerca/ ; PNRR-MAD-2022-12375639//Ministero della Salute/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Models, Biological ; Neuroglia/metabolism/pathology ; *Amyloid/metabolism ; Organoids/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder in which genetic susceptibility, aging, protein aggregation, and neuroglial dysfunction converge to drive progressive neuronal loss. Although animal models and conventional cell systems have provided fundamental insights into pathomechanisms, they only partially reproduce the human-specific and multifactorial nature of AD. Human induced pluripotent stem cell (hiPSC)-based models have emerged as a powerful platform to investigate disease-relevant processes within a patient-specific genetic background while enabling the generation of multiple neural cell types and multicellular systems. In this review, we present the evolution of hiPSC-based AD modeling, from reductionist paradigms based on exogenous amyloid-β exposure to CRISPR-engineered isogenic models addressing causal mutations and genetic risk variants associated with either familial or sporadic forms. We examine the contribution of three-dimensional brain organoids and neuroglial co-culture systems in recapitulating cell-cell interactions, neuroinflammatory responses, and tissue-level pathological processes. We focus on current challenges, including the limited representation of neuronal aging, variability among organoids, and the need for standardized protocols. Finally, we discuss the translational potential of hiPSC-derived systems for target identification, drug discovery, and regenerative medicine. Collectively, these advances position hiPSC-based platforms as essential complementary models for elucidating AD pathogenesis and accelerating the development of precision therapeutic strategies.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Induced Pluripotent Stem Cells/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Models, Biological
Neuroglia/metabolism/pathology
*Amyloid/metabolism
Organoids/metabolism/pathology

@article {pmid42882500,
year = {2026},
author = {Alam, JJ and Germann, UA and Maruff, P},
title = {Targeting Pro-Inflammatory Interleukin-1 Beta Signaling to Modulate Neuroinflammatory Processes Associated with Cognitive Decline in Dementia with Lewy Bodies.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191803},
pmid = {42882500},
issn = {2073-4409},
support = {//CervoMed Inc/ ; #R01AG080536/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Interleukin-1beta/metabolism ; *Lewy Body Disease/drug therapy/complications/metabolism ; *Signal Transduction/drug effects ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Cognitive Dysfunction/drug therapy/complications/metabolism ; Amyloid beta-Peptides ; Female ; Alzheimer Disease/drug therapy ; Male ; Interleukin-6/metabolism ; },
abstract = {Interleukin-1 beta (IL-1β) is implicated as a molecular driver of cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), potentially through activation of pro-inflammatory pathways within the neuron that impair synaptic function. Because pro-inflammatory IL-1β signaling depends on p38α kinase, the oral brain-penetrant p38α inhibitor neflamapimod has the potential to reverse synaptic dysfunction and treat cognitive decline in these contexts. Neflamapimod has also shown positive effects in animal models and in clinical studies in AD and DLB. Herein we evaluated neflamapimod effects on pro-inflammatory IL-1β signaling in vitro and in patients with AD or DLB. In human PBMCs, neflamapimod inhibited IL-1β-induced IL-6 and IL-8 production with EC50 values of 6.3 ± 1.3 nM and 7.1 ± 3.2 nM, respectively. In AD, six weeks of neflamapimod 40 mg BID treatment reduced CSF levels of IL-6 and IL-8, with maximal effects at trough drug concentration ≥4 ng/mL (9 nM). In DLB, neflamapimod 40 mg TID increased the plasma Aβ42/40 ratio and reduced plasma GFAP levels, treatment effects consistent with reduced pro-inflammatory IL-1β signaling. Collectively, these results support the hypothesis that inhibition of p38α-dependent IL-1β signaling may beneficially modulate neuroinflammatory processes that otherwise are associated with cognitive decline in DLB, and potentially in AD.},
}

Humans
*Interleukin-1beta/metabolism
*Lewy Body Disease/drug therapy/complications/metabolism
*Signal Transduction/drug effects
*Neuroinflammatory Diseases/metabolism/drug therapy
*Cognitive Dysfunction/drug therapy/complications/metabolism
Amyloid beta-Peptides
Female
Alzheimer Disease/drug therapy
Male
Interleukin-6/metabolism

@article {pmid42882520,
year = {2026},
author = {Yang, T and Tran, KC and Leng, A and Langness, VF and Massa, SM and Longo, FM},
title = {A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191822},
pmid = {42882520},
issn = {2073-4409},
support = {//Scully Initiative/ ; //Taube Family Foundation/ ; //Jean Perkins Foundation/ ; //Horngren Family/ ; },
mesh = {Animals ; *Proto-Oncogene Proteins c-fyn/metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Receptor, trkB/agonists/metabolism ; Signal Transduction/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *Synapses/metabolism/drug effects ; Mice ; Hippocampus/metabolism ; Dendritic Spines/metabolism/drug effects ; Neurons/metabolism/drug effects ; Phosphorylation/drug effects ; Alzheimer Disease/metabolism/drug therapy/pathology ; *Membrane Glycoproteins/metabolism/agonists ; Male ; },
abstract = {BACKGROUND: Pathogenic amyloid-beta and tau oligomers (oAβ, oTau) drive synaptic degeneration and cognitive decline in Alzheimer's disease (AD). Tropomyosin receptor kinase B (TrkB), expressed in neurons and glia, supports synaptic integrity in AD-affected regions. We tested whether PTX-BD4-3, a small-molecule TrkB partial agonist, promotes neuroprotective signaling, reduces degenerative signaling, and prevents synaptic loss in an AD mouse model and hippocampal neurons exposed to oAβ or oTau.

METHODS: Cultured hippocampal neurons were treated with oAβ or oTau ± PTX-BD4-3. Effects on synaptic proteins (±TrkB-blocking antibody), spine density, and Fyn, NR2B, and tau phosphorylation as well as tau oligomerization were assessed. Two cohorts of APP[L/S] mice, 5 and 12 months of age, received intraperitoneal PTX-BD4-3 or vehicle for 3 months, followed by assessment of synaptic proteins, dendritic spines, TrkB signaling, and Y-maze analysis.

RESULTS: In vitro, PTX-BD4-3 prevented oAβ-induced synaptic marker loss in a TrkB-dependent manner, reduced phosphorylation of Fyn, NR2B, and tau, suppressed oligomeric tau formation, and attenuated oTau-induced spine loss. In APP[L/S] mice, PTX-BD4-3 mitigated deficient TrkB/Akt signaling, reduced phosphorylation of Fyn and tau, preserved synaptic markers and dendritic spines, and improved Y-maze performance.

CONCLUSIONS: Small-molecule TrkB partial agonists may normalize TrkB signaling and promote synaptic resilience, supporting their potential as AD therapeutics.},
}

Animals
*Proto-Oncogene Proteins c-fyn/metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
*Receptor, trkB/agonists/metabolism
Signal Transduction/drug effects
*Proto-Oncogene Proteins c-akt/metabolism
*Synapses/metabolism/drug effects
Mice
Hippocampus/metabolism
Dendritic Spines/metabolism/drug effects
Neurons/metabolism/drug effects
Phosphorylation/drug effects
Alzheimer Disease/metabolism/drug therapy/pathology
*Membrane Glycoproteins/metabolism/agonists
Male

@article {pmid42883264,
year = {2026},
author = {Sun, L and Apweiler, M and Schulzki, R and Grathwol, CW and Normann, C and Bräse, S and Fiebich, BL},
title = {Anti-Neuroinflammatory Effects of Cardenolides in IL-1β-Activated SK-N-SH Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193501},
pmid = {42883264},
issn = {1420-3049},
support = {284178167//Deutsche Forschungsgemeinschaft/ ; 266379491//Deutsche Forschungsgemeinschaft/ ; //Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg/ ; },
mesh = {Humans ; *Interleukin-1beta/metabolism/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; NF-kappa B/metabolism ; *Cardenolides/pharmacology/chemistry ; Cyclooxygenase 2/metabolism ; Cell Line, Tumor ; Dinoprostone/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Cell Survival/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Interleukin-6/metabolism ; Prostaglandin-E Synthases/metabolism ; },
abstract = {Neuroinflammation is a key feature of neurological disorders such as Alzheimer's or Parkinson's disease, depression or amyotrophic lateral sclerosis. This study investigates the anti-neuroinflammatory effects of three cardenolide derivatives, digitoxigenin, digitoxigenone, and coroglaucigenin (all at concentrations of 1, 5, 10, and 25 µM), in IL-1β-stimulated human neuroblastoma SK-N-SH cells. All compounds significantly reduced PGE2 production without affecting cell viability by downregulation of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthases (mPGES)-1 expression and synthesis. Among them, digitoxigenin notably inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) and suppressed interleukin (IL)-6 and IL-8 expression and release. These findings demonstrate that cardenolide derivatives exert potent anti-neuroinflammatory effects by at least partially targeting key enzymes of the arachidonic acid pathway and modulating MAPK/NF-κB signaling, highlighting their potential as novel therapeutic candidates for neuroinflammatory diseases. Future research should focus on effects of the cardenolides in mixed-cell cultures, organoids and in vivo experiments, to evaluate possible side effects and the potential in disease models.},
}

Humans
*Interleukin-1beta/metabolism/pharmacology
*Anti-Inflammatory Agents/pharmacology/chemistry
NF-kappa B/metabolism
*Cardenolides/pharmacology/chemistry
Cyclooxygenase 2/metabolism
Cell Line, Tumor
Dinoprostone/metabolism
p38 Mitogen-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
Cell Survival/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism
Interleukin-6/metabolism
Prostaglandin-E Synthases/metabolism

@article {pmid42883292,
year = {2026},
author = {McDermott, C and Cole, MH and Pearson, M and Winberg, P and Fernandez, F},
title = {Targeting Specific Sirtuin Modulation: Emerging Therapeutic Strategies for Healthy Cognitive Ageing and Potential Implications for Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193528},
pmid = {42883292},
issn = {1420-3049},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Sirtuins/metabolism ; Animals ; *Cognitive Aging ; Aging ; *Healthy Aging ; },
abstract = {Nicotinamide adenine dinucleotide (+)-dependent class III histone deacetylases, widely known as sirtuins (SIRTs), have been found to play key functions in a wide range of biological processes implicated in ageing processes. The downregulation of some specific SIRTs was reported in ageing and in some neurological diseases such as Alzheimer's disease. SIRT modulator factors, such as diet, exercise and various natural compounds, have recently emerged as a potential new avenue of therapy to modify the progression of Alzheimer's disease and delay some ageing effects. This review synthesises recent advances in the understanding of the modulatory effects of SIRTs in the context of healthy ageing with a particular focus on cognitive function and implications for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Sirtuins/metabolism
Animals
*Cognitive Aging
Aging
*Healthy Aging

@article {pmid42883328,
year = {2026},
author = {Garbarek, J and Hys, O and Woźniak, A and Szewczyk-Golec, K and Nuszkiewicz, J},
title = {Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193564},
pmid = {42883328},
issn = {1420-3049},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidation-Reduction/drug effects ; Antioxidants/pharmacology/chemistry/therapeutic use ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Bees/chemistry ; Propolis/chemistry/therapeutic use ; Oxidative Stress/drug effects ; Royal Jelly ; *Bee Venoms/chemistry/therapeutic use/pharmacology ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Signal Transduction/drug effects ; Honey/analysis ; },
abstract = {Oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation are closely interconnected processes involved in the pathogenesis and progression of neurodegenerative diseases. Bee-derived products, including honey, propolis, royal jelly, bee pollen, bee bread, and bee venom, contain diverse bioactive constituents with antioxidant, anti-inflammatory, immunomodulatory, and redox-modulating properties. This narrative review summarizes the major bioactive compounds present in bee-derived products and evaluates their potential relevance to neuroprotection. Particular attention is given to mechanisms involving activation of the Nrf2/ARE antioxidant response, inhibition of NF-κB-dependent inflammatory signaling, modulation of the NLRP3 inflammasome, mitochondrial protection, regulation of apoptosis, and maintenance of proteostasis. Available evidence from cellular and animal models, together with the limited clinical data, is discussed primarily in the context of Alzheimer's and Parkinson's diseases, with additional consideration of amyotrophic lateral sclerosis and other neurodegenerative or neuroinflammatory conditions. Although several bee-derived products and isolated constituents show promising biological effects, their therapeutic translation remains limited by variable chemical composition, insufficient standardization, low or uncertain bioavailability, limited evidence of central nervous system exposure, and safety concerns. Further mechanistic, pharmacokinetic, and well-controlled clinical studies are therefore required before their potential neuroprotective applications can be reliably established.},
}

Humans
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
Oxidation-Reduction/drug effects
Antioxidants/pharmacology/chemistry/therapeutic use
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use
Bees/chemistry
Propolis/chemistry/therapeutic use
Oxidative Stress/drug effects
Royal Jelly
*Bee Venoms/chemistry/therapeutic use/pharmacology
Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use
Signal Transduction/drug effects
Honey/analysis

@article {pmid42883332,
year = {2026},
author = {Işık, M and Syla, GH and Karakaya, A and Çevik, UA and Daoud, NE and Fırat, M and Öğünç Keçeci, Y and Özkay, Y and Kaplancıklı, ZA and Beydemir, Ş},
title = {Design and Synthesis of New Thiazole Derivatives for Alzheimer's Disease Therapy as a Potential Cholinesterase Inhibitor; Toxicity Prediction and Molecular Docking Studies and Biological Evaluation.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193568},
pmid = {42883332},
issn = {1420-3049},
support = {//Anadolu University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Thiazoles/chemistry/chemical synthesis/pharmacology ; *Alzheimer Disease/drug therapy/enzymology ; Humans ; Butyrylcholinesterase/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; *Drug Design ; Structure-Activity Relationship ; Molecular Structure ; Animals ; },
abstract = {In this study, thiazole derivatives 13-23 were synthesized as novel cholinesterase inhibitors. Their structures were elucidated using [1]H-NMR, [13]C-NMR, and elemental analysis techniques. The binding positions and efficiencies of the designed compounds on the enzyme were investigated through molecular docking studies, and the properties of ADMET were examined using computational methods. Cytotoxicity analyses of the synthesized compounds were performed to screen their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. It has been determined that these compounds do not exhibit a significant cytotoxic effect on healthy endothelial cells. Although the compounds showed lower efficacy in AChE inhibition compared to the reference compound tacrine (IC50: 0.136 μM; KI: 0.46 ± 0.01 nM), they exhibited moderate inhibitory effects. Among these, compounds 16 and 23 were found to be the most potent AChE inhibitors, with IC50 values of 36.47 µM and 34.65 µM, and KI values of 22.20 ± 1.23 and 21.10 ± 1.58 µM, respectively, while compounds 15 and 20 were found to be the most potent BChE inhibitors, with IC50 values of 17.76 µM and 16.90 µM, and KI values of 14.10 ± 0.58 and 13.40 ± 0.48 µM, respectively, on other cholinesterases. These tested compounds can be considered potential candidates for further research in the treatment of Alzheimer's disease (AD).},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Molecular Docking Simulation
*Thiazoles/chemistry/chemical synthesis/pharmacology
*Alzheimer Disease/drug therapy/enzymology
Humans
Butyrylcholinesterase/chemistry/metabolism
Acetylcholinesterase/chemistry/metabolism
*Drug Design
Structure-Activity Relationship
Molecular Structure
Animals

@article {pmid42883433,
year = {2026},
author = {Li, P and Qi, ZM and Wu, JZ and Liu, J and Yu, P},
title = {Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.},
journal = {Biology},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/biology15191760},
pmid = {42883433},
issn = {2079-7737},
support = {NO.20250204060YY//Jilin Province Science and Technology Department/ ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by progressive and irreversible neuronal loss, whereas current treatments remain largely symptomatic. Ferroptosis is an iron-dependent form of regulated cell death whose execution is defined by iron-enabled phospholipid peroxidation and failure of cellular ferroptosis-defense systems. Mitochondrial metabolism can modify ferroptosis susceptibility, but its contribution varies with cell type and initiating stimulus. Converging evidence implicates ferroptosis in multiple NDs, in which affected regions commonly show iron accumulation, glutathione depletion, and increased lipid peroxidation. With their multi-component and multi-target properties, traditional Chinese medicine (TCM) interventions may modulate several nodes in this network. This review summarizes the core execution and defense mechanisms of ferroptosis, evaluates their roles in major NDs, and critically appraises bioactive herbal compounds, compound formulas, acupuncture, electroacupuncture, and moxibustion. The reported interventions mainly engage the Nrf2/GPX4 antioxidant axis, TFR1/FPN1/FTH1/NCOA4-mediated iron handling, ACSL4-dependent lipid peroxidation, and GPX4-independent defense systems. Because most studies are preclinical and many infer ferroptosis from non-specific markers, the evidence is graded here as direct, supportive, indirect, mixed, or complementary. Translation will require standardized formulations, causal ferroptosis validation, pharmacokinetic and brain-exposure data, validated human biomarkers, and rigorously designed clinical trials.},
}

@article {pmid42883782,
year = {2026},
author = {Hashioka, S},
title = {Minocycline-Mediated Inhibition of Microglial Activation in Neuroinflammation-Related Neuropsychiatric Disorders: Preclinical Promise and Clinical Limitations.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198533},
pmid = {42883782},
issn = {1422-0067},
support = {JP22H02999//Japan Society for the Promotion of Science/ ; },
mesh = {*Minocycline/therapeutic use/pharmacology ; Humans ; *Microglia/drug effects/metabolism/pathology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; *Mental Disorders/drug therapy ; Alzheimer Disease/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Schizophrenia/drug therapy ; Major Depressive Disorder/drug therapy ; },
abstract = {Minocycline, a second-generation tetracycline antibiotic, has attracted interest as a CNS-active anti-inflammatory agent because it crosses the blood-brain barrier and inhibits microglial activation. This review summarizes preclinical and clinical evidence for minocycline in neuroinflammation-related neuropsychiatric disorders, focusing on Alzheimer's disease (AD), Lewy body disease (LBD), schizophrenia, and major depressive disorder (MDD). Across these disorders, preclinical studies have generally shown that minocycline attenuates microglial activation or maladaptive microglial responses and improves disease-relevant behavioral, synaptic, or neuropathological outcomes. However, clinical translation has been inconsistent. Clinical trials in AD, related parkinsonian disorders, schizophrenia, and MDD have failed to demonstrate robust and reproducible efficacy, despite encouraging preclinical findings. Moreover, direct clinical evidence that minocycline suppresses microglial activation in the human brain remains very limited. These discrepancies between preclinical findings and clinical evidence may reflect heterogeneity in disease stage and microglial states, suboptimal timing of intervention, lack of direct evidence that minocycline suppresses microglial activation in the human brain, and its non-selective anti-inflammatory actions. Future studies should incorporate biomarker-based patient stratification and direct measures of central microglial target engagement.},
}

*Minocycline/therapeutic use/pharmacology
Humans
*Microglia/drug effects/metabolism/pathology
Animals
*Neuroinflammatory Diseases/drug therapy
*Mental Disorders/drug therapy
Alzheimer Disease/drug therapy
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Schizophrenia/drug therapy
Major Depressive Disorder/drug therapy

@article {pmid42883821,
year = {2026},
author = {Kim, KY and Shin, KY and Chang, KA},
title = {Plasma Neurofilament Light Chain as a Complementary Biomarker for Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198574},
pmid = {42883821},
issn = {1422-0067},
support = {RS-2026-25481253//National Research Foundation of Korea/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; RS-2026-25474868//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Neurofilament Proteins/blood ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnosis ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss, ultimately leading to a loss of independence and reduced quality of life. As current treatments are most effective in the early stages, reliable blood-based biomarkers are required for early diagnosis, therapeutic monitoring, and disease staging. Plasma neurofilament light chain (NfL), a marker of neuroaxonal injury, is a candidate biomarker; its value relative to established amyloid- and tau-based biomarkers is unclear. A systematic review and meta-analysis comparing plasma NfL with Aβ42, Aβ40, the Aβ42/Aβ40 ratio, and p-tau217 across cognitively normal (control, Con), mild cognitive impairment (MCI), and AD groups was conducted. Fourteen studies that met specific criteria were included. Plasma NfL and p-tau217 increased across disease stages. Aβ42 and Aβ42/Aβ40 were lower in AD/MCI than in Con; Aβ40 was similar across groups. Heterogeneity (I[2] < 99%) was observed across biomarkers. Plasma NfL reliably reflected neuroaxonal injury and disease severity from the earliest clinically detectable stage of AD. Plasma NfL may be most valuable when combined with p-tau217/Aβ-based assays to provide a more comprehensive, blood-based assessment of both AD-specific pathology and neurodegeneration. Further studies are needed to validate its prognostic utility and establish clinically applicable cut-off values.},
}

Humans
*Neurofilament Proteins/blood
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
*Cognitive Dysfunction/blood/diagnosis
Amyloid beta-Peptides/blood
tau Proteins/blood

@article {pmid42883839,
year = {2026},
author = {Acosta-Martínez, M and Carter, V and Nessim, A and Murphy, S and Dhawan, J and Beach, TG and Serrano, GE and Sundermann, EE and Biegon, A},
title = {Sex-Divergent Patterns in Hippocampal and Cortical NMDA Receptor Density Across the Alzheimer's Disease Continuum.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198590},
pmid = {42883839},
issn = {1422-0067},
support = {R01 AG074221-01//E.E. Sundermann/ ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610 and P30 AG072980/AG/NIA NIH HHS/United States ; contract 211002//Arizona Department of Health Services/ ; contracts 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; MJFF-020402//Michael J. Fox Foundation for Parkinson's Research./ ; },
mesh = {Humans ; *Receptors, N-Methyl-D-Aspartate/metabolism ; *Alzheimer Disease/metabolism/pathology ; Female ; Male ; *Hippocampus/metabolism ; Aged ; tau Proteins/metabolism ; Cognitive Dysfunction/metabolism ; Aged, 80 and over ; Entorhinal Cortex/metabolism ; Sex Characteristics ; },
abstract = {While the loss of NMDA receptors (NMDARs) is associated with Alzheimer's disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined. We performed quantitative in vitro autoradiography of the hippocampus, entorhinal cortex (EC), and parietal cortex using NMDAR and tau radioligands. Relationships between regional NMDAR density and cognitive status assessed by the Mini Mental State Examination (MMSE), and between NMDAR and tau density, were examined by bivariate correlations. In both sexes, the largest AD-related decreases in NMDAR density were observed in the cornu ammonis 1 (CA1) field. However, there was a significant diagnosis by sex interaction driven by sex-specific differences in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls. Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men. Our data show that differences in hippocampal NMDAR density across the AD continuum are modulated by sex and may contribute to the known sex differences in the clinical trajectory of the disease.},
}

Humans
*Receptors, N-Methyl-D-Aspartate/metabolism
*Alzheimer Disease/metabolism/pathology
Female
Male
*Hippocampus/metabolism
Aged
tau Proteins/metabolism
Cognitive Dysfunction/metabolism
Aged, 80 and over
Entorhinal Cortex/metabolism
Sex Characteristics

@article {pmid42883891,
year = {2026},
author = {Ali, MY and Park, SE and Jung, HA and Choi, JS},
title = {In Vitro Screening of Sargassum spp. Ethanolic Extracts for Antioxidant Activity and Inhibition of Disease-Associated Enzymatic Targets Related to Diabetes, Alzheimer's Disease, and Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198643},
pmid = {42883891},
issn = {1422-0067},
mesh = {*Sargassum/chemistry ; *Antioxidants/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/enzymology ; Humans ; *Parkinson Disease/drug therapy/enzymology ; *Diabetes Mellitus/drug therapy/enzymology ; Ethanol/chemistry ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Enzyme Inhibitors/pharmacology/chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors/metabolism ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *Plant Extracts/pharmacology/chemistry ; },
abstract = {Sargassum is a large and diversified genus of marine brown algae that is distributed widely in tropical and subtropical areas. They have been used for centuries in Asian countries, and have demonstrated a variety of health advantages, including anti-cardiovascular disease, anti-osteoarthritis, anti-cancer, anti-inflammatory, antioxidant, and hypopigmentation effects. However, the putative anti-diabetic, anti-Alzheimer's, and anti-Parkinson's diseases activities of various Sargassum spp. have not been investigated and compared thoroughly. Thus, the purpose of this study was to examine the anti-diabetic, anti-Alzheimer's, and anti-Parkinson's diseases' activities of ten Sargassum and one myagroides species collected off the Korean coast. In this study, we examined the inhibitory activity of 70% ethanolic extract of the Sargassum and myagroides species against protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, peroxynitrite (ONOO[-]), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), BACE1, MAO-A, and MAO-B. Among the Sargassum and myagroides species tested, S. hemiphyllum, S. filicinum, and S. miyabei showed potent PTP1B inhibitory activity (IC50 values of 2.11, 1.87, and 6.49 μg/mL, respectively), α-glucosidase inhibitory activity (IC50 values of 3.67, 2.30, and 11.12 μg/mL, respectively), and ONOO[-] scavenging activity, with IC50 values of 2.07, 4.49, and 2.46 μg/mL, respectively. Moreover, S. miyabei exhibited the highest BACE1 and BChE inhibitory activity, with IC50 values of 3.38 and 39.76 μg/mL, respectively. The highest MAO-A inhibitory activity was seen in S. miyabei, S. serratifolium, and S. macrocarpum, with IC50 values of 16.91, 12.46, and 14.02 μg/mL, respectively. Therefore, our findings showed that Sargassum species have health benefits and may be useful in treating diabetes and neurological disorders.},
}

*Sargassum/chemistry
*Antioxidants/pharmacology/chemistry
*Alzheimer Disease/drug therapy/enzymology
Humans
*Parkinson Disease/drug therapy/enzymology
*Diabetes Mellitus/drug therapy/enzymology
Ethanol/chemistry
Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
*Enzyme Inhibitors/pharmacology/chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors/metabolism
Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism
*Plant Extracts/pharmacology/chemistry

@article {pmid42883894,
year = {2026},
author = {Melrose, J},
title = {The Glyco-Code Molecular Template Instructively Guides Skeletal and Neural Development, Tissue Regeneration and Dynamic Repair Responses Following Trauma and Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198646},
pmid = {42883894},
issn = {1422-0067},
support = {//The University of Sydney/ ; },
mesh = {Humans ; Animals ; *Glycosaminoglycans/metabolism/chemistry ; *Nerve Regeneration ; Tissue Engineering/methods ; },
abstract = {Glycosaminoglycans encode instructional information that cells can decipher to regulate tissue development, repair responses, regeneration and recovery of tissue function following trauma or disease. This information has been termed the glyco-code and is a road map for tissue development and repair. This review shows that a clearer understanding of the glyco-code will support improved strategies in repair biology, particularly in skeletal and neural repair, regeneration, and therapeutic biomaterial design. Emerging therapeutic approaches for peripheral nerve repair increasingly combine multimodal delivery, microenvironmental control, and biomimetic structural support; however, the electroconductive properties of glycosaminoglycans have not yet been fully incorporated into these strategies. This gap is clinically important because neurological disorders affect more than 40% of the global population, representing approximately three billion people across conditions such as stroke, migraine, Alzheimer's disease, and diabetic neuropathy. Nanoparticle-engineered platforms and glyco-code-driven biomaterials may, therefore, provide future regenerative therapies that integrate glycosaminoglycan structure, charge, ligand-binding capacity, informational functions, and electroconductive control of resident cell populations to drive neural recovery. Multifunctional glycosaminoglycan interactions with a diverse range of binding proteins orchestrate tissue form and function in a diverse range of tissues in health and disease and have been widely used in tissue engineering protocols in repair biology. Tissue atlases, advanced glycomics, and molecular dynamics binding studies are now identifying roles for glycosaminoglycan binding proteins in therapeutic repair processes at the single-cell level, aiding in the identification of molecular targets for more effective recovery of tissue function. DynamicBind and SurfDock are deep learning methods that accurately demonstrate state-of-the-art performance in understanding the docking of potential therapeutic drugs with prospective targets, identifying cryptic pockets in unseen protein targets, and accelerating the development of small molecules for previously undruggable targets, potentially expanding the horizons of computational drug discovery with glycan structures.},
}

Humans
Animals
*Glycosaminoglycans/metabolism/chemistry
*Nerve Regeneration
Tissue Engineering/methods

@article {pmid42883911,
year = {2026},
author = {Rojas-Sánchez, I and Cortes-Flores, E and Camacho-Concha, N and Almazán, JL and Ramírez-Lugo, L and Crivelli-Galindo, E and Ramirez-Serrano, CE and Pedraza-Alva, G and Pérez-Martínez, L},
title = {Therapeutic Administration of Malva parviflora Hydroalcoholic Extract Restores Cognitive Function Consistent with a Resilient Phenotype in Female 5XFAD.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198665},
pmid = {42883911},
issn = {1422-0067},
support = {PAPIIT IN217822//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN222925//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN216922//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; CBF2023-2024-878//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IFC 2016-2282//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; },
mesh = {Animals ; Female ; *Plant Extracts/pharmacology/chemistry/administration & dosage ; *Cognition/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; *Malva/chemistry ; Mice, Transgenic ; Long-Term Potentiation/drug effects ; Phenotype ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Neuronal Plasticity/drug effects ; },
abstract = {The remarkable increase in human life expectancy has been accompanied by a rising global incidence of neurodegenerative disorders, particularly Alzheimer's disease. This condition is characterized by progressive accumulation of soluble and insoluble amyloid-beta peptides, neuroinflammation, and synaptic dysfunction in the hippocampus, leading to impaired higher-order cognition. Epidemiological evidence indicates that women are disproportionately affected; however, female-specific pathology remains understudied. Here, we evaluated the therapeutic potential of a hydroalcoholic extract of Malva parviflora in female 5XFAD mice following prolonged intragastric administration initiated after disease establishment. Long-term treatment shifted cognitive performance toward a phenotype comparable to wild-type littermates, an improvement associated with reduced soluble amyloid-beta levels in the hippocampus and peripheral circulation, and significant attenuation of reactive astrogliosis as evidenced by reduced hippocampal glial fibrillary acidic protein levels. Because reactive astrocytes impair synaptic activity and metabolic homeostasis during disease progression, we examined the direct effects of Malva parviflora on synaptic plasticity ex vivo. Incubation of hippocampal synaptosomes from adult female 5XFAD mice with the extract restored chemically induced long-term potentiation. These findings demonstrate that Malva parviflora attenuates key pathological hallmarks of Alzheimer's disease and promotes cognitive recovery, supporting its potential as a plant-derived therapeutic candidate, particularly in females most affected by Alzheimer's disease. Future studies including both sexes under a therapeutic paradigm are needed to determine the generalizability of these findings.},
}

Animals
Female
*Plant Extracts/pharmacology/chemistry/administration & dosage
*Cognition/drug effects
*Alzheimer Disease/drug therapy/metabolism
Mice
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
*Malva/chemistry
Mice, Transgenic
Long-Term Potentiation/drug effects
Phenotype
Disease Models, Animal
Glial Fibrillary Acidic Protein/metabolism
Neuronal Plasticity/drug effects

@article {pmid42883925,
year = {2026},
author = {Seol, SI and Kim, JE and Davaanyam, D and Park, SY and Lee, EH and Han, PL and Kim, TK and Lee, JK},
title = {HMGB1 in Amyloid-Beta Pathology: Mechanistic Insights and Therapeutic Implications for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198681},
pmid = {42883925},
issn = {1422-0067},
support = {2021R1A2C2010920//Mid-carrier Research Grant (2021R1A2C2010920) for J.-K.L. from the National Research Foun-dation (NRF), Republic of Korea/ ; },
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; Microglia/metabolism/pathology ; Neurons/metabolism/pathology ; Phagocytosis ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. Beyond these hallmark pathological features, the complex pathogenesis of AD involves cellular dysfunctions associated with chronic oxidative stress and neuroinflammation. Central to these inflammatory pathways is the extracellular release of the nuclear protein high-mobility group box 1 (HMGB1) from neurons and microglia. Extracellular HMGB1 disrupts homeostatic and reparative microglial functions, impairing the phagocytic clearance of amyloid-beta and driving neuroinflammation to accelerate AD pathogenesis. Consequently, targeting HMGB1 offers a promising therapeutic strategy for AD. This review examines recent progress and key insights regarding HMGB1-associated neuroinflammatory pathology in AD. We evaluate its regulation across transcriptional upregulation, cellular redistribution, age-related alterations, and Aβ-associated pathology. We further detail the pleiotropic effects of extracellular HMGB1, including neuroinflammation, defective Aβ phagocytic clearance, and genomic instability. Finally, we discuss the potential clinical utility of targeting HMGB1 to mitigate AD progression and provide HMGB1-related perspectives for future studies.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
Microglia/metabolism/pathology
Neurons/metabolism/pathology
Phagocytosis

@article {pmid42883945,
year = {2026},
author = {Bellver-Sanchis, A and Griñán-Ferré, C and Sutour, S and Marchev, AS},
title = {Effect of Rhodiola rosea L. Extract on Alzheimer's Disease-like Symptoms in Caenorhabditis elegans.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198701},
pmid = {42883945},
issn = {1422-0067},
support = {KП-06-КОСТ/14//Bulgarian National Science Fund/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Rhodiola/chemistry ; *Plant Extracts/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Glucosides/pharmacology ; Phenols/pharmacology ; Amyloid beta-Peptides/metabolism ; Antioxidants/pharmacology ; *Neuroprotective Agents/pharmacology/chemistry ; Disease Models, Animal ; Caenorhabditis elegans Proteins/metabolism/genetics ; Locomotion/drug effects ; Disaccharides ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and amyloid-beta accumulation. Natural products with antioxidant and stress-response-modulating properties are increasingly being investigated as candidate neuroprotective agents. In this study, we evaluated the effects of Rhodiola rosea L. extract, salidroside, and rosavin in Caenorhabditis elegans models of AD. Phenotypic, behavioral, biochemical, and molecular assays were used to assess locomotion, egg laying, chemotaxis, reactive oxygen species (ROS), gene expression, and amyloid-like aggregation. The extract and its related compounds improved locomotor performance, partially rescued reproductive and sensory defects, reduced ROS accumulation, modulated stress-response genes including skn-1/nrf2, daf-2, and sod-1, and decreased thioflavin-S-positive aggregates. Together, these findings support the potential neuroprotective effect of R. rosea extract and its key marker compounds, suggesting the involvement of conserved antioxidant pathways.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Rhodiola/chemistry
*Plant Extracts/pharmacology/chemistry
*Alzheimer Disease/drug therapy/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress/drug effects
Glucosides/pharmacology
Phenols/pharmacology
Amyloid beta-Peptides/metabolism
Antioxidants/pharmacology
*Neuroprotective Agents/pharmacology/chemistry
Disease Models, Animal
Caenorhabditis elegans Proteins/metabolism/genetics
Locomotion/drug effects
Disaccharides

@article {pmid42883949,
year = {2026},
author = {Delgado-Minjares, KM and Flores-Maldonado, C and Campos-Blázquez, JP and Díaz-Miranda, SY and Andrade-Guerrero, J and Colín-García, W and León-Arcia, K and Martinez-Fong, D and Contreras, RG and Soto-Rojas, LO},
title = {Age-Stratified Analysis of Blood-Brain Barrier Proteins Identifies Lower Occludin Abundance in the 3xTg-AD Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198705},
pmid = {42883949},
issn = {1422-0067},
support = {20932//Universidad Nacional Autónoma de México through the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica/ ; IN227026//the Universidad Nacional Autónoma de México through the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica/ ; CBF-2025-G35//Ciencia básica y de Frontera/ ; 2019/7357//Ciencia básica y de Frontera/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Occludin/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Male ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Cadherins/metabolism ; Pericytes/metabolism ; Humans ; Endothelial Cells/metabolism ; Aging/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which blood-brain barrier (BBB) dysfunction may arise early. We performed an age-stratified, cross-sectional analysis of pericyte- and endothelial-associated markers and junctional proteins (claudin-1, -3, -5, occludin, and VE-cadherin) in cerebral capillary-enriched fractions from male Non-Tg and 3xTg-AD mice at asymptomatic, early, and advanced stages (3, 6, 12, and 16 months of age). Protein abundance was assessed by Western blot, and BBB permeability to 3-5 kDa FITC-dextran was evaluated at 3 months in an independent cohort. At 3 months, the pSRC/SRC ratio and an MMP-9-immunoreactive band were also evaluated in a separate cohort as candidate signaling markers related to occludin dysregulation. We detected no significant age or genotype effects for the pericyte- and endothelial-associated markers or for most junctional protein outcomes. Occludin was the only protein outcome with a significant overall genotype effect, with the largest mean reductions observed at 3 (~80%) and 6 months (~68%). A small exploratory cohort showed a higher hemisphere-derived permeability index in 3xTg-AD mice at 3 months. Neither pSRC/SRC nor the abundance of the MMP-9-immunoreactive band differed significantly between genotypes. These findings identify lower occludin abundance as the principal BBB-associated protein alteration in the 3xTg-AD model and provide exploratory evidence of increased BBB permeability at 3 months. These independent observations warrant longitudinal and translational evaluation to determine whether occludin abundance and BBB permeability could serve as indicators of early neurovascular dysfunction in AD.},
}

Animals
*Blood-Brain Barrier/metabolism
*Occludin/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
Male
Mice
Mice, Transgenic
Disease Models, Animal
Cadherins/metabolism
Pericytes/metabolism
Humans
Endothelial Cells/metabolism
Aging/metabolism

@article {pmid42883986,
year = {2026},
author = {Popa, E and Popa, AE and Poroch, V and Schreiner, TG and Slanina, AM and Poroch, M and Hatneanu, AM and Ungureanu, MI and Petroaie, AD and Bacusca, AI and Coman, EA},
title = {GLP-1, GIP, and Glucagon Receptor Agonism at the Obesity-Neurodegeneration Interface: A Narrative Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198738},
pmid = {42883986},
issn = {1422-0067},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Receptors, Gastrointestinal Hormone/agonists/metabolism ; Animals ; *Receptors, Glucagon/agonists/metabolism ; *Obesity/metabolism/drug therapy ; *Neurodegenerative Diseases/drug therapy/metabolism ; Semaglutide ; *Glucagon-Like Peptide 1/metabolism ; Tirzepatide ; *Gastric Inhibitory Polypeptide/metabolism ; },
abstract = {Glucagon-like peptide-1 receptor agonism has attracted interest in neurodegeneration because of its effects on metabolic and inflammatory pathways implicated in neuronal dysfunction. This narrative review examines the molecular rationale and neurological evidence for selective glucagon-like peptide-1 receptor agonists, dual agonists additionally targeting the glucose-dependent insulinotropic polypeptide receptor, and triple agonists also engaging the glucagon receptor. English-language literature retrieved from PubMed, Scopus, and Web of Science was synthesized according to study design and neurological relevance. Preclinical findings indicate modulation of insulin signaling, synaptic function, mitochondrial homeostasis, and neuroinflammation, but responses vary across compounds and experimental models. In Alzheimer's disease, liraglutide did not meet its primary trial endpoint, and semaglutide did not slow clinical progression. Parkinson's disease trials have yielded mixed results without establishing disease modification. Observational associations with reduced dementia risk remain susceptible to confounding. Neurological evidence for tirzepatide and retatrutide remains predominantly observational or preclinical. Greater metabolic efficacy does not establish neuroprotection, while nutritional vulnerability may constrain therapeutic applicability. Dedicated randomized trials integrating clinical outcomes with pharmacological exposure, target engagement, and metabolic mediation are required to distinguish systemic effects from direct neural actions and determine whether these therapies can prevent cognitive decline or modify established neurodegenerative disease.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
*Receptors, Gastrointestinal Hormone/agonists/metabolism
Animals
*Receptors, Glucagon/agonists/metabolism
*Obesity/metabolism/drug therapy
*Neurodegenerative Diseases/drug therapy/metabolism
Semaglutide
*Glucagon-Like Peptide 1/metabolism
Tirzepatide
*Gastric Inhibitory Polypeptide/metabolism

@article {pmid42884007,
year = {2026},
author = {Gu, T and Wei, X and Hua, S},
title = {Cuproptosis: New Mechanisms Linking Endothelial Dysfunction to Neurodegenerative Diseases and Therapeutic Prospects.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198765},
pmid = {42884007},
issn = {1422-0067},
mesh = {Humans ; *Cuproptosis ; *Neurodegenerative Diseases/metabolism/pathology/etiology/therapy ; Animals ; *Copper/metabolism ; Mitochondria/metabolism ; Oxidative Stress ; *Endothelium, Vascular/metabolism/pathology/physiopathology ; Homeostasis ; },
abstract = {Cuproptosis is a copper-dependent form of regulated cell death driven by disrupted copper homeostasis and mitochondrial metabolic reprogramming. It is distinct from other cell death pathways and has been increasingly linked to vascular endothelial dysfunction and neurodegenerative diseases such as Alzheimer's and Parkinson's disease. This article comprehensively reviews the core molecular mechanisms of cuproptosis and its emerging roles in endothelial dysfunction and neurodegeneration, synthesizing recent findings from cellular, animal, and human studies. Cuproptosis exacerbates vascular pathology by impairing endothelial barrier function, inducing oxidative stress, and promoting inflammation and senescence. In the brain, it drives neurodegeneration both directly-via mitochondrial damage and neuronal loss-and indirectly by interacting with pathological proteins such as amyloid-beta and α-synuclein, creating a vicious cycle of copper dysregulation and protein aggregation. This review provides new insights into the pathophysiology of vascular endothelial dysfunction and neurodegenerative diseases by highlighting the pivotal role of cuproptosis. Understanding how cuproptosis links copper metabolism to cell death pathways opens avenues for identifying novel therapeutic targets. Interventions that restore copper homeostasis or block cuproptosis-specific molecular events may offer promising strategies for treating these devastating diseases.},
}

Humans
*Cuproptosis
*Neurodegenerative Diseases/metabolism/pathology/etiology/therapy
Animals
*Copper/metabolism
Mitochondria/metabolism
Oxidative Stress
*Endothelium, Vascular/metabolism/pathology/physiopathology
Homeostasis

@article {pmid42884019,
year = {2026},
author = {Abbate, C},
title = {The Adult Neurogenesis Theory of Alzheimer's Disease Predicts Where Tauopathy Develops in the Brain.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198776},
pmid = {42884019},
issn = {1422-0067},
support = {Ricerca Corrente 2026; RRC-2026-23687902//Fondazione Don Carlo Gnocchi ETS/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/physiopathology ; *Neurogenesis ; *Tauopathies/pathology/metabolism/physiopathology ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Animals ; Neurons/metabolism/pathology ; },
abstract = {Adult neurogenesis is impaired in Alzheimer's disease (AD) and contributes to neuronal and cognitive dysfunction. Furthermore, efficient neurogenesis promotes cognitive resilience. I recently proposed a theory suggesting that neurogenesis plays a more central role in the pathogenesis of AD. The main hypothesis posits that new neurons harboring tau seeds propagate tauopathy as they mature and integrate into the brain. The aim of this study is to demonstrate that the theory successfully predicts the distribution of the earliest foci of tauopathy in AD. To this end, I synthesized data from the literature regarding the earliest localizations of tauopathy in AD. I then indicated where one would expect to find the earliest seeds of tauopathy if the theory were true. Finally, I compared the localization data with the theory's predictions. Overall, the theory's predictions were entirely consistent with the initial localization of tauopathy. Specifically, the theory is consistent with the exclusively neuronal and somatodendritic involvement of tauopathy; the preference for layer II and the transentorhinal/entorhinal complex; the early involvement of subcortical nuclei; phenotypic heterogeneity; differences between early- and late-onset AD; hemispheric asymmetries; and clinical-anatomical convergence. The theory demonstrates predictive power, economicity, compatibility with other theories, and generalizability to other diseases.},
}

Humans
*Alzheimer Disease/pathology/metabolism/physiopathology
*Neurogenesis
*Tauopathies/pathology/metabolism/physiopathology
*Brain/pathology/metabolism
tau Proteins/metabolism
Animals
Neurons/metabolism/pathology

@article {pmid42884062,
year = {2026},
author = {Kuikel, K and McEwen, A and Mathiske, TJ and Wojtaszak, L and John, JAS and Delbaz, A},
title = {Combined Effects of Chlamydia pneumoniae Infection and Hypoxia on Glial Metabolism and Alzheimer's Disease-Related Pathways.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198820},
pmid = {42884062},
issn = {1422-0067},
support = {//Clem Jones Foundation/ ; //Goda Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/pathology ; *Chlamydophila pneumoniae ; Amyloid beta-Peptides/metabolism ; *Neuroglia/metabolism ; Astrocytes/metabolism/microbiology ; Cell Hypoxia ; *Hypoxia/metabolism ; Microglia/metabolism/microbiology ; Cell Line ; Proteomics/methods ; *Chlamydophila Infections/metabolism ; *Chlamydia Infections/metabolism ; },
abstract = {Alzheimer's disease involves complex interactions among neuroinflammation and metabolic dysfunction. Emerging evidence implicates microbial pathogens and hypoxia as converging stressors, yet their combined impact on glial function remains poorly understood. Human astrocyte and microglial cell lines were exposed to four experimental conditions: (i) normoxic control, (ii) Chlamydia pneumoniae infection under normoxia, (iii) hypoxia control and (iv) Chlamydia pneumoniae infection under hypoxic conditions. Hypoxia was induced at 3% oxygen for 72 h. Cellular responses were assessed using NanoString nCounter transcriptomics using the Alzheimer's Disease and Metabolic Pathways panels, Tandem Mass Tag proteomics, MTT reduction, glucose uptake, intracellular ATP quantification and amyloid beta quantification by ELISA. Combined exposure to infection and hypoxia was associated with cell-type-specific alterations in glial metabolic and transcriptional responses. Factorial transcriptomic analysis identified significant infection × oxygen interactions across both NanoString panels and glial cell types. Proteomic responses differed according to cell type and oxygen availability. Aβ40 and Aβ42 measurements demonstrated treatment-associated alterations in the extracellular Aβ peptide profile, including increased Aβ42/Aβ40 ratios following infection. Together, these findings demonstrate distinct and interacting effects of infection and hypoxia on glial metabolic and molecular responses and identify Alzheimer's disease-related cellular changes warranting further investigation in physiologically relevant models.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/pathology
*Chlamydophila pneumoniae
Amyloid beta-Peptides/metabolism
*Neuroglia/metabolism
Astrocytes/metabolism/microbiology
Cell Hypoxia
*Hypoxia/metabolism
Microglia/metabolism/microbiology
Cell Line
Proteomics/methods
*Chlamydophila Infections/metabolism
*Chlamydia Infections/metabolism

@article {pmid42884579,
year = {2026},
author = {Intharuksa, A and Prasansuklab, A and Techarang, T and Chaikhong, K and Arunotayanun, W and Jenraumjit, R},
title = {The Role of Herbal Medicines in Cognitive Impairment: A Narrative Review of Neuroprotective Mechanisms and Therapeutic Perspectives.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193126},
pmid = {42884579},
issn = {2072-6643},
mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Cognitive Dysfunction/drug therapy ; *Phytotherapy/methods ; *Plant Preparations/therapeutic use/pharmacology ; Plant Extracts/pharmacology/therapeutic use ; Plants, Medicinal ; Cognition/drug effects ; },
abstract = {Cognitive impairment encompasses a clinical spectrum ranging from mild cognitive impairment to dementia, particularly Alzheimer's disease (AD), and involves interconnected pathological processes including cholinergic dysfunction, oxidative stress, neuroinflammation, mitochondrial impairment, amyloid-β accumulation, tau hyperphosphorylation, and synaptic loss. Herbal medicines have attracted increasing attention because their complex phytochemical composition may provide multi-target neuroprotective effects. This narrative review aimed to summarize current preclinical and clinical evidence on herbal medicines and traditional herbal formulations for cognitive impairment, with emphasis on their mechanisms, therapeutic potential, safety, and translational limitations. Relevant evidence from in vitro studies, animal models, randomized clinical trials, systematic reviews, and meta-analyses was narratively synthesized. The review considered single herbal medicines, standardized extracts, isolated phytochemicals, and traditional multi-herbal formulations, together with their reported cognitive outcomes and molecular targets. Preclinical studies suggest that selected herbal preparations may modulate pathways implicated in cognitive impairment through acetylcholinesterase and butyrylcholinesterase inhibition, antioxidant and mitochondrial protection, suppression of neuroinflammatory signaling, modulation of amyloidogenic and tau-related pathways, and enhancement of BDNF/TrkB- and CREB-associated neuroplasticit; however, clinical evidence remains limited and heterogeneous. Clinical studies of Bacopa monnieri, Panax ginseng, Crocus sativus, and several traditional Chinese, Korean, and Persian formulations have reported improvements in memory and global cognitive measures, including MMSE, MoCA, and ADAS-cog scores. However, evidence remains constrained by heterogeneity of products, small sample sizes, short treatment periods, inconsistent outcome measures, limited biomarker integration, and incomplete long-term safety assessment. Herbal medicines show potential as preventive, complementary, or adjunctive approaches for cognitive impairment, but they cannot yet be considered established replacements for conventional therapy. Standardized products, rigorous pharmacokinetic and toxicological evaluation, disease-relevant models, and adequately powered multicenter trials are required to support evidence-based clinical application.},
}

Humans
*Neuroprotective Agents/therapeutic use/pharmacology
Animals
*Cognitive Dysfunction/drug therapy
*Phytotherapy/methods
*Plant Preparations/therapeutic use/pharmacology
Plant Extracts/pharmacology/therapeutic use
Plants, Medicinal
Cognition/drug effects

@article {pmid42884593,
year = {2026},
author = {Chen, R},
title = {Association of Nut Consumption with Dementia and Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193143},
pmid = {42884593},
issn = {2072-6643},
mesh = {Humans ; *Nuts ; Aged ; Male ; Female ; *Alzheimer Disease/epidemiology/prevention & control ; Case-Control Studies ; Middle Aged ; *Dementia/epidemiology/prevention & control ; Aged, 80 and over ; China/epidemiology ; Risk Factors ; *Diet ; Odds Ratio ; Logistic Models ; },
abstract = {Background: Nut consumption reduces risks of cardiovascular disease, respiratory disease and depression. However, its association with dementia and Alzheimer's disease (AD) remains unclear. Methods: A population-based case-control study was conducted in China, including 466 participants aged 52-100 years (233 with dementia). Data on socio-demographic characteristics, lifestyle factors, comorbidities, and dietary intake over the past two years were collected through structured face-to-face interviews. Nut consumption was categorised as non-consumption or }

Humans
*Nuts
Aged
Male
Female
*Alzheimer Disease/epidemiology/prevention & control
Case-Control Studies
Middle Aged
*Dementia/epidemiology/prevention & control
Aged, 80 and over
China/epidemiology
Risk Factors
*Diet
Odds Ratio
Logistic Models

@article {pmid42884594,
year = {2026},
author = {Ben Mohamed, A and Vauzour, D},
title = {Do Grape- and Wine-Derived (Poly)Phenols Contribute to the Hallmarks of Healthy Brain Ageing?.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193144},
pmid = {42884594},
issn = {2072-6643},
mesh = {Humans ; *Wine/analysis ; *Vitis/chemistry ; *Brain/drug effects/physiology ; *Polyphenols/pharmacology/pharmacokinetics ; *Aging/drug effects ; Gastrointestinal Microbiome/drug effects ; Animals ; Biological Availability ; Antioxidants/pharmacology ; Cognitive Aging ; Neuroprotective Agents/pharmacology ; *Phenols/pharmacology ; },
abstract = {Population ageing is associated with a rising burden of cognitive decline, dementia and late-life affective disorders. Grape- and wine-derived (poly)phenols represent a chemically diverse group of bioactives whose biological relevance is shaped by structural complexity, the intervention matrix, host conjugation and gut microbial metabolism. Rather than acting as simple antioxidants, these compounds and their derived metabolites may influence interrelated pathways implicated in brain ageing, including neuroinflammation, endothelial function, synaptic plasticity, oxidative stress and gut-brain axis signalling. The gut microbiota is central to this framework as it converts poorly absorbed parent compounds into smaller phenolic metabolites and is modulated by (poly)phenol exposure. This review summarises the chemical and bioavailability features that determine intestinal and colonic availability, evaluates preclinical evidence concerning the neuroprotective potential of grape- and wine-derived (poly)phenols, and integrates clinical evidence from studies of cognitive ageing, mild cognitive impairment and Alzheimer's disease. Current evidence supports biological plausibility and justifies further investigation, but clinical findings remain heterogeneous. Future studies should prioritise chemically standardised preparations, metabolomic profiling, functional microbiome readouts, and integrated cognitive, vascular and inflammatory endpoints.},
}

Humans
*Wine/analysis
*Vitis/chemistry
*Brain/drug effects/physiology
*Polyphenols/pharmacology/pharmacokinetics
*Aging/drug effects
Gastrointestinal Microbiome/drug effects
Animals
Biological Availability
Antioxidants/pharmacology
Cognitive Aging
Neuroprotective Agents/pharmacology
*Phenols/pharmacology

@article {pmid42884597,
year = {2026},
author = {Kamalakar, K and Akerele, C and Lafont, E and Koralnik, LR and Gilman, C and Litran, JC and Lee, J and Robinson-Papp, J and Malaspina, D},
title = {Gut Microbiome-Mediated Neuroprotective Effect of the Mediterranean Diet: A Narrative Review of Cognitive Aging, Alzheimer's Disease, and Parkinson's Disease.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193146},
pmid = {42884597},
issn = {2072-6643},
mesh = {Humans ; *Diet, Mediterranean ; *Gastrointestinal Microbiome/physiology ; *Parkinson Disease/microbiology/prevention & control ; *Alzheimer Disease/prevention & control/microbiology ; *Cognitive Aging/physiology ; *Neuroprotection ; Animals ; },
abstract = {Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are major neurodegenerative disorders for which disease-modifying therapies are limited. Increasingly, evidence suggests that diet influences neurodegenerative risk through interactions among the gut microbiome, immune system, and brain. The Mediterranean diet (MD) is associated with improved cognitive health, but the mechanisms underlying its potential neuroprotective effects remain incompletely understood. Objective: In this narrative review, evidence on microbiome-mediated mechanisms linking MD adherence to neuroprotection was synthesized, and how Mediterranean dietary components influence microbial ecology, metabolites, immune regulation, and neuroinflammation relevant to cognitive aging, AD, and PD was evaluated. Methods: Evidence from experimental, observational, and clinical studies was reviewed, focusing on microbial metabolites, intestinal barrier integrity, immune regulation, and inflammatory pathways. Discussion: Mediterranean dietary components, including fiber, polyphenols, whole grains, legumes, nuts, extra-virgin olive oil, and omega-3 fatty acids, may promote beneficial microbial communities and metabolite production. Short-chain fatty acids, secondary bile acids, indole derivatives, and phenolic metabolites may strengthen the intestinal and blood-brain barriers, regulate immune responses, and suppress neuroinflammation. Conversely, dysbiosis may increase intestinal permeability, lipopolysaccharide translocation, systemic inflammation, and microglial activation. However, evidence remains heterogeneous and largely observational or experimental. Conclusions: The MD may promote neuroprotection through interconnected diet-microbiome-immune pathways. Longitudinal and intervention studies integrating microbiome, metabolomic, inflammatory, neuroimaging, and cognitive measures are needed to establish causality and advance precision nutrition strategies to prevent neurodegenerative disease.},
}

Humans
*Diet, Mediterranean
*Gastrointestinal Microbiome/physiology
*Parkinson Disease/microbiology/prevention & control
*Alzheimer Disease/prevention & control/microbiology
*Cognitive Aging/physiology
*Neuroprotection
Animals

@article {pmid42884661,
year = {2026},
author = {Yue, M and Zhou, L and He, W and Li, B and Yang, Z and Liu, Y and Chen, L and Chen, C and Zhang, Y},
title = {Neuroprotective Potential of the Edible Seaweed Pterocladiella capillacea: Bioactivity Coupled LC-MS/MS, Metabolomics Annotation, Validation, and Network Pharmacology.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193210},
pmid = {42884661},
issn = {2072-6643},
support = {2025A1515010941//Guangdong Provincial Natural Science Foundation/ ; KCXFZ20240903093925033//the Sustainable Development Program of Shenzhen Science and Technology Major Program/ ; 2025KCJS_057//Guangdong Provincial Graduate Student Course Construction Project/ ; 2024ZDZX2086//Special Project in Key Fields of Guangdong Provincial Higher Education Institutions/ ; 2024B01265//Zhanjiang Science and Technology Plan Projects/ ; 2024A1515110066//Guangdong Provincial Natural Science Foundation/ ; GDOU2025092//Guangdong Provincial College Student Innovation & Entrepreneurship Training Project/ ; },
mesh = {*Neuroprotective Agents/pharmacology/chemistry ; Tandem Mass Spectrometry ; Metabolomics/methods ; *Edible Seaweeds/chemistry ; Antioxidants/pharmacology ; Network Pharmacology ; Liquid Chromatography-Mass Spectrometry ; Humans ; Animals ; Chromatography, Liquid ; *Rhodophyta/chemistry ; Molecular Docking Simulation ; Neurons/drug effects ; *Plant Extracts/pharmacology ; Cell Survival/drug effects ; },
abstract = {Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder with a global impact, highlighting an urgent need for effective dietary therapeutic agents for the development of brain-healthy functional foods and medicines. This study focuses on the edible red alga Pterocladiella capillacea from Zhanjiang, China, investigating its anti-neuronal injury activity, active principles, and underlying mechanisms. Methods: Based on antioxidant and neuroprotection evaluations and column fractioning, bioactivity-coupled liquid chromatography-tandem mass spectrometry (Bio-LC-MS/MS) was employed to recognize the neuroprotective compounds, which were further annotated by comprehensive metabolomics analysis. The annotated compounds were validated by LC-MS/MS and bioassay. Computational prediction techniques were further used to reveal their mechanism of action. Results: The study demonstrated that P. capillacea extract and fractions exhibited significant antioxidant and anti-neuronal injury activities. Among the annotated and MS-validated potential compounds, erucamide standard exhibited the strongest neuroprotective effect, maintaining cell viability above 85% at low concentrations. Network pharmacology and molecular docking revealed that erucamide may exert neuroprotective effects by modulating the AKT1 and BCL2 targets. ADMET prediction suggested a low risk of central side effects. Conclusions: The neuroprotective potential of P. capillacea provides a primary foundation for new brain-healthy functional foods and drug development in future.},
}

*Neuroprotective Agents/pharmacology/chemistry
Tandem Mass Spectrometry
Metabolomics/methods
*Edible Seaweeds/chemistry
Antioxidants/pharmacology
Network Pharmacology
Liquid Chromatography-Mass Spectrometry
Humans
Animals
Chromatography, Liquid
*Rhodophyta/chemistry
Molecular Docking Simulation
Neurons/drug effects
*Plant Extracts/pharmacology
Cell Survival/drug effects

@article {pmid42884668,
year = {2026},
author = {Choe, YM and Kim, JH and Choi, HJ and Lee, BC and Suh, GH and Kim, SG and Kim, HS and Hwang, J and Yi, D and Kim, JW},
title = {Nutritional Status and Cognition in Older Adults: Modification by Apolipoprotein E ε4.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193217},
pmid = {42884668},
issn = {2072-6643},
support = {HURF-2023-36//Hallym University/ ; RS-2023-00210820//National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (MSIT)/ ; },
mesh = {Humans ; *Apolipoprotein E4/genetics ; *Nutritional Status/genetics ; *Cognition ; Aged ; Cross-Sectional Studies ; Female ; Male ; Nutrition Assessment ; Aged, 80 and over ; *Malnutrition/genetics ; Republic of Korea ; Risk Factors ; },
abstract = {Background: Malnutrition is a modifiable risk factor for late-life cognitive decline, but whether its cognitive correlates vary by genetic risk is unclear. We examined whether the apolipoprotein E ε4 allele (APOE4) modifies associations of the Mini-Nutritional Assessment (MNA) and its subscales with global cognition. Methods: In this cross-sectional analysis of 196 non-demented older Korean adults from the General Lifestyle and Alzheimer's Disease (GLAD) cohort, multiple linear regression tested associations of MNA total (MNA-T), screening (MNA-S), and assessment (MNA-A) scores with the CERAD total score (TS), including MNA × APOE4 interactions. Exploratory analyses examined one representative item per a priori nutritional domain. Results: After adjustment, MNA-T (p = 0.006) and MNA-A (p = 0.003), but not MNA-S (p = 0.065), were associated with TS. APOE4 carrier status modified these associations (interaction p = 0.005 and 0.007, respectively); associations were evident in non-carriers but not in carriers, an underpowered subgroup (n = 40). Among the domain-representative items, only self-rated health survived Bonferroni correction (p = 0.006); protein intake (p = 0.025) and calf circumference (p = 0.043) showed nominal associations only. Conclusions: Better nutritional status was associated with better global cognition, predominantly in APOE4 non-carriers. These hypothesis-generating findings require confirmation in larger longitudinal and interventional studies.},
}

Humans
*Apolipoprotein E4/genetics
*Nutritional Status/genetics
*Cognition
Aged
Cross-Sectional Studies
Female
Male
Nutrition Assessment
Aged, 80 and over
*Malnutrition/genetics
Republic of Korea
Risk Factors

@article {pmid42884681,
year = {2026},
author = {Cornelis, MC and van Dam, RM and Bennett, DA and Schneider, JA},
title = {Interaction Between COMT Genotype and MIND Diet, Cognitive Decline, and Incident Dementia: A Prospective Cohort Study.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193232},
pmid = {42884681},
issn = {2072-6643},
support = {R01AG065398/AG/NIA NIH HHS/United States ; R01AG17917/AG/NIA NIH HHS/United States ; R01AG054476/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Catechol O-Methyltransferase/genetics ; *Dementia/genetics/epidemiology ; Female ; Prospective Studies ; Male ; Genotype ; Aged, 80 and over ; Aged ; *Diet, Mediterranean ; *Cognitive Dysfunction/genetics/epidemiology ; Cognition ; Incidence ; Proportional Hazards Models ; },
abstract = {Background: Catechol-O-methyltransferase (COMT) metabolizes catecholamines and polyphenols unique to the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND). The COMT Val158Met variant modified the effect of MIND on change in perceptual speed after 3 years in a randomized controlled trial. We aimed to evaluate and extend these findings to dementia incidence in a community-based prospective cohort. Methods: We included 745 older adults (mean age 80.0 years) from the Rush Memory and Aging Project. MIND adherence was estimated using a validated food-frequency questionnaire (0-15 points). Repeated cognitive assessments and dementia diagnoses were based on standardized clinical neurological examinations and criteria. Linear regression, linear mixed-effects, and Cox proportional hazards models examined associations of COMT Val158Met and its interactions with MIND with baseline cognition, cognitive decline, and incident dementia. Associations with neuropathology and COMT protein were also explored. Results: Significant COMT × MIND interactions were observed for Alzheimer's (p = 0.003) and all-cause (p = 0.004) dementia and for COMT × MIND × time interactions with declines in global cognition (p = 0.008), episodic memory (p = 0.009), and visuospatial ability (p = 0.01). Cognitive benefits associated with MIND adherence were greater among Met/Met carriers (lower COMT activity). The hazard ratio (95% CI) per MIND point for Alzheimer's dementia was 0.82 (0.69-0.98) for Met/Met, 1.00 (0.87-1.15) for Met/Val, and 1.05 (0.84-1.33) for Val/Val. Greater MIND adherence was associated with lower plasma COMT (p = 0.01), while each additional Val allele was associated with higher brain COMT (p < 0.0001). Conclusions: Individuals with genetically reduced COMT activity may be especially responsive to cognitive benefits of the MIND diet. Further study is needed to determine whether these effects differ across cognitive domains.},
}

Humans
*Catechol O-Methyltransferase/genetics
*Dementia/genetics/epidemiology
Female
Prospective Studies
Male
Genotype
Aged, 80 and over
Aged
*Diet, Mediterranean
*Cognitive Dysfunction/genetics/epidemiology
Cognition
Incidence
Proportional Hazards Models

@article {pmid42884722,
year = {2026},
author = {Dube, K and Stoinescu, A and Sadler, J and Truong, M and Malakoti-Negad, N and Chaudhry, M and Talukdar, R and Cohen, J and Pandey, S},
title = {Multidimensional Neuroprotective Effects of Combined Ubisol-Q10 and Ashwagandha (Withania somnifera) in Male and Female 5XFAD Mice.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193270},
pmid = {42884722},
issn = {2072-6643},
support = {809194//This work was supported through donations from the Szecsei and Dhar families (grant # 809194)./ ; },
mesh = {Animals ; Male ; Female ; *Neuroprotective Agents/pharmacology ; *Withania/chemistry ; *Alzheimer Disease/drug therapy/pathology ; *Plant Extracts/pharmacology ; Mice ; Disease Models, Animal ; Autophagy/drug effects ; Mice, Transgenic ; Brain/drug effects/pathology ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by interconnected pathological processes including mitochondrial dysfunction, oxidative stress, impaired autophagic processes, neuroinflammation, neuronal degeneration, and progressive functional decline. Natural health products (NHPs), coenzyme-Q10 (CoQ10) and Ashwagandha (Withania somnifera) (ASH), have been previously reported to possess antioxidant, anti-inflammatory, mitochondrial-supportive, neuroprotective, and neurotrophic properties. This work investigates the neuroprotective effects of a bioavailability-enhanced formulation, Ubisol-Q10 (UQ), and ethanolic ASH extract, combined as a "Tonic," across multiple domains of AD pathology.

METHODS: The effects of long-term administration were evaluated in male and female 5XFAD mice from 2.5 to 11 months of age. Longitudinal magnetic resonance imaging assessed hippocampal and white matter volumes, a frailty index assessed physiological resilience, Novel Object and Novel Location Recognition testing assessed spatial and non-spatial memory, while post-mortem Nissl, Golgi-Cox, and immunofluorescence evaluated cellular density, dendritic morphology, amyloid pathology, neuroinflammation, autophagy-associated signaling, and astrocytic activity.

RESULTS: Across these measures, Tonic treatment preserved brain volumes, reduced amyloid pathology and inflammation, and modulated autophagy-associated pathways. Treatment also preserved dendritic architecture, frailty progression, and novelty-recognition behavior. Females demonstrated particularly pronounced preservation of white matter structure and increased dendritic density, whereas males showed strong modulation of inflammatory and autophagy-associated markers. Astrocytic immunoreactivity also demonstrated sex- and region-specific patterns, suggesting that glial responses may contribute differently to structural preservation in males and females.

CONCLUSIONS: Together, these findings support that UQ + ASH may provide diverse protection against AD neurodegeneration. The observed sex-specific responses emphasize the importance of incorporating sex into preclinical evaluation of novel interventions for neurodegenerative diseases.},
}

Animals
Male
Female
*Neuroprotective Agents/pharmacology
*Withania/chemistry
*Alzheimer Disease/drug therapy/pathology
*Plant Extracts/pharmacology
Mice
Disease Models, Animal
Autophagy/drug effects
Mice, Transgenic
Brain/drug effects/pathology

@article {pmid42884726,
year = {2026},
author = {Cai, H and Chen, C and Cai, H and Zhang, D and Huang, Q},
title = {Planetary Health Diet and the Gut-Liver-Brain Axis: Implications for MASLD and Cognitive Aging.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193275},
pmid = {42884726},
issn = {2072-6643},
mesh = {Humans ; Gastrointestinal Microbiome/physiology ; *Brain/metabolism ; *Cognitive Aging/physiology ; *Liver/metabolism ; *Diet, Healthy ; Animals ; *Fatty Liver ; *Brain-Gut Axis/physiology ; },
abstract = {Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cognitive aging are prevalent, interrelated conditions that share gut-derived pathomechanisms. The Planetary Health Diet (PHD), a sustainable plant-forward framework proposed by the EAT-Lancet Commission, may offer dual-target benefits for hepatic and neurological health through the gut-liver-brain axis. Methods: A structured narrative literature search of PubMed, Web of Science, and Scopus (2015-2026) was conducted to identify observational, mechanistic, and interventional studies addressing PHD adherence in relation to MASLD, cognitive aging, and gut-liver-brain axis pathways. Results: Epidemiological evidence from large cohorts links higher PHD adherence to lower MASLD prevalence and severity, slower cognitive decline, reduced dementia incidence, and more favorable Alzheimer's disease neuropathology. Mechanistically, PHD components may modulate gut microbiota composition and diversity, enhance short-chain fatty acid production, regulate bile acid signaling through farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), reinforce intestinal barrier integrity, and attenuate metabolic endotoxemia and neuroinflammation. Conclusions: Although current evidence remains predominantly observational, the PHD is a promising dietary framework for simultaneously supporting liver and brain health. Future research should prioritize randomized controlled trials integrating liver imaging, cognitive assessment, microbiome profiling, and culturally adapted dietary interventions.},
}

Humans
Gastrointestinal Microbiome/physiology
*Brain/metabolism
*Cognitive Aging/physiology
*Liver/metabolism
*Diet, Healthy
Animals
*Fatty Liver
*Brain-Gut Axis/physiology

@article {pmid42885145,
year = {2026},
author = {Blessing, E},
title = {The right temperature at the right time: A framework for understanding thermoregulatory pathophysiology in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71847},
doi = {10.1002/alz.71847},
pmid = {42885145},
issn = {1552-5279},
support = {5R01AG070866/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/physiopathology ; Humans ; *Body Temperature Regulation/physiology ; Animals ; Neurons/physiology ; *Brain/physiopathology ; tau Proteins/metabolism ; Circadian Rhythm/physiology ; },
abstract = {The neuromodulatory subcortical system (NSS) includes thermoregulatory neurons that maintain core body temperature (Tb) and brain temperature within a narrow, diurnally varying range. Cellular pathways in NSS neurons implicated in Alzheimer's disease (AD) may be vulnerable to Tb rhythm disturbance because of their sensitivity to temperature and their thermoregulatory function. This review evaluates a framework for pathophysiological interactions between thermoregulation and AD anchored in the functional anatomy of thermoregulatory neurons. Findings in humans show that thermoregulatory neurons exhibit tau pathology in early AD, and abnormal Tb rhythm is seen in advanced AD. In rodents, cellular risk pathways for tau aggregation are both modulated by diurnal range temperature change and involved in thermoregulation. Further research is needed to bridge human and rodent findings, to understand how sex differences in Tb impact AD risk, and to identify modifiable causal links between Tb disturbance and pathophysiology toward improving clinical outcomes in early AD.},
}

*Alzheimer Disease/physiopathology
Humans
*Body Temperature Regulation/physiology
Animals
Neurons/physiology
*Brain/physiopathology
tau Proteins/metabolism
Circadian Rhythm/physiology

@article {pmid42885186,
year = {2026},
author = {Joseph, JM and Rachel, J and Han, G and Smith, ML},
title = {Comparing Health Care Utilization Between Medicare Advantage and Traditional Medicare by Dementia Status: A Propensity-Weighted Analysis.},
journal = {Health services research},
volume = {61},
number = {5},
pages = {e70174},
doi = {10.1111/1475-6773.70174},
pmid = {42885186},
issn = {1475-6773},
mesh = {Humans ; United States ; Female ; Aged ; *Medicare Part C/statistics & numerical data ; Male ; Cross-Sectional Studies ; *Patient Acceptance of Health Care/statistics & numerical data ; *Dementia/epidemiology/therapy ; *Medicare/statistics & numerical data ; Aged, 80 and over ; Propensity Score ; Alzheimer Disease ; },
abstract = {OBJECTIVE: To compare health care utilization between Medicare Advantage (MA) and Traditional Medicare (TM) beneficiaries, stratified by Alzheimer's disease and related dementias (ADRD) status.

STUDY SETTING AND DESIGN: Repeated cross-sectional observational analysis of community-dwelling Medicare beneficiaries aged ≥ 65 years continuously enrolled in MA or TM. Eight self- or proxy-reported binary utilization outcomes over a 12-month reference period were estimated by survey-weighted linear probability models stratified by ADRD status.

Secondary analysis of pooled 2018-2022 Medicare Current Beneficiary Survey (MCBS) public use files (N = 43,995: 974 TM and 954 MA with ADRD; 23,050 TM and 19,017 MA without ADRD), excluding beneficiaries entitled through disability or end-stage renal disease and records with missing covariates. Dual-eligible beneficiaries were retained and dual eligibility included as a covariate. Stabilized inverse probability of treatment weights multiplied by MCBS full-sample weights addressed non-random MA enrollment.

PRINCIPAL FINDINGS: Among beneficiaries with ADRD, seven of eight adjusted MA - TM differences were not statistically significant. Specialist visits were more common among MA beneficiaries with ADRD (5.2 percentage points; 95% CI, -0.1 to 10.2). Among beneficiaries without ADRD, MA was associated with lower outpatient hospital visits (-2.6; -3.7 to -1.6) and lower reported need for home health visits (-0.9; -1.5 to -0.3). Effect modification by ADRD status was significant only for specialist visits (interaction 6.3 percentage points; p = 0.004).

CONCLUSIONS: Adjusted health care utilization was broadly comparable between MA and TM for beneficiaries with ADRD, with the exception of higher specialist use in MA. Among beneficiaries without ADRD, MA was associated with lower outpatient hospital use. Plan-type differences were smaller and fewer for beneficiaries with ADRD.},
}

Humans
United States
Female
Aged
*Medicare Part C/statistics & numerical data
Male
Cross-Sectional Studies
*Patient Acceptance of Health Care/statistics & numerical data
*Dementia/epidemiology/therapy
*Medicare/statistics & numerical data
Aged, 80 and over
Propensity Score
Alzheimer Disease