@article {pmid42967602,
year = {2026},
author = {Aguilar-Dominguez, P and Colceriu, CM and Holland, TM and Lockhart, SN and Masdeu, JC and Neumann, LTV and Snyder, HM and Baker, LD and Bejanin, A and Landau, SM and Arenaza-Urquijo, EM},
title = {Association of neighborhood deprivation with Alzheimer's disease pathology, brain structure, and cognition by race and ethnicity, sex, and APOE ε4 status.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42967602},
issn = {1552-5279},
support = {//POINTER imaging grant/ ; //Fondo Investigación Sanitario/ ; CP20/00038//Instituto de Salud Carlos III/ ; PID2023-153362OB-I00//Ministerio de Ciencia e Innovación/ ; 23S06157-001//"Barcelona City Council-"la Caixa" Foundation Research and Innovation Grants/ ; AARG-22-923680/ALZ/Alzheimer's Association/United States ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alzheimer Disease/pathology/genetics/diagnostic imaging/ethnology ; *Apolipoprotein E4/genetics ; *Brain/pathology/diagnostic imaging ; *Cognition/physiology ; *Ethnicity/statistics & numerical data ; *Neighborhood Characteristics ; Positron-Emission Tomography ; Racial Groups ; Sex Factors ; Socioeconomic Disparities in Health ; United States ; White ; Hispanic or Latino ; },
abstract = {INTRODUCTION: We investigated associations of Area Deprivation Index (ADI) with Alzheimer's disease (AD) -related outcomes by biological and social factors in at-risk older adults.

METHODS: A total of 1880 U.S. POINTER participants with ADI and cognition (Preclinical Alzheimer's Cognitive Composite [PACC]) were included. 868 had amyloid, tau positron emission tomography (PET), white matter hyperintensities (WMH), and/or gray matter volumes. We conducted exploratory, linear regression models testing ADI interactions with sex, race and ethnicity, and apolipoprotein E (APOE) ε4, adjusting for age and education.

RESULTS: "White/European American" and "Hispanic/Latinx/Spanish" showed lower cognitive scores with higher ADI, while "White/European American" showed the highest cognitive scores across ADI levels. APOE ε4 carriers from high-ADI areas showed higher WMH and tau, and "Hispanic/Latinx/Spanish" from more deprived areas showed higher WMH. Females from moderate-ADI areas showed higher tau. Amyloid burden was higher among low-ADI APOE ε4 carriers.

DISCUSSION: Differential associations of ADI with AD-related outcomes across biological and social factors may reflect systemic health disparities and study design.},
}

Aged
Aged, 80 and over
Female
Humans
Male
*Alzheimer Disease/pathology/genetics/diagnostic imaging/ethnology
*Apolipoprotein E4/genetics
*Brain/pathology/diagnostic imaging
*Cognition/physiology
*Ethnicity/statistics & numerical data
*Neighborhood Characteristics
Positron-Emission Tomography
Racial Groups
Sex Factors
Socioeconomic Disparities in Health
United States
White
Hispanic or Latino

@article {pmid42967802,
year = {2026},
author = {Xu, X and Xu, X and Zhou, L and Wang, W and Ouyang, M and Zheng, J and Zhang, L},
title = {Construction of a robust fluorescent probe for the rapid evaluation of natural products' inhibition of Alzheimer's disease.},
journal = {Analytica chimica acta},
volume = {1426},
number = {},
pages = {346374},
doi = {10.1016/j.aca.2026.346374},
pmid = {42967802},
issn = {1873-4324},
mesh = {Animals ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Fluorescent Dyes/chemistry/chemical synthesis/pharmacology ; *Biological Products/chemistry/pharmacology/chemical synthesis/therapeutic use ; Mice ; PC12 Cells ; Peroxynitrous Acid/analysis/metabolism ; Rats ; Fluorescent Chemosensor Compounds ; Molecular Docking Simulation ; Optical Imaging ; },
abstract = {Peroxynitrite (ONOO[-]) is a key oxidative stress biomarker for Alzheimer's disease (AD), and elevated levels of ONOO[-] in the brain directly reflect the extent of oxidative stress-induced damage in AD. To enable in situ real-time monitoring of ONOO[-], this study designed and synthesized a ratiometric near-infrared fluorescent probe (BF) based on a D-π-A framework. The probe BF emits near-infrared fluorescence; upon interaction with ONOO[-], BF's intrinsic ICT is weakened, causing a blue shift in its emission and resulting in a red-to-green ratio change. When applied to PC12 cells and AD model mice, BF enables real-time ratiometric imaging monitoring of changes in ONOO[-] levels within the cells and the mouse brain. Furthermore, through molecular docking, neobavaisoflavone (with curcumin as a control) was screened as an intervention drug; BF successfully monitored the real-time dynamic downregulation of ONOO[-], and the signal recovery in the neobavaisoflavone group was superior to that in the curcumin group and the model group. This study established a rapid evaluation platform centered on real-time imaging with near-infrared ratiometric probes, which not only enables in situ dynamic monitoring of AD-related ONOO[-] but also provides an intuitive and reliable visualization method for the rapid assessment of the efficacy of anti-AD candidate drugs.},
}

Animals
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Fluorescent Dyes/chemistry/chemical synthesis/pharmacology
*Biological Products/chemistry/pharmacology/chemical synthesis/therapeutic use
Mice
PC12 Cells
Peroxynitrous Acid/analysis/metabolism
Rats
Fluorescent Chemosensor Compounds
Molecular Docking Simulation
Optical Imaging

@article {pmid42967904,
year = {2026},
author = {Corriveau-Lecavalier, N and Zhang, G and Botha, H and Barnard, LR and Wiste, HJ and Dicks, E and Gogineni, VR and Lee, J and Sintini, I and Senjem, ML and Schwarz, CG and Cogswell, PM and Johnson, DR and Gunter, JL and Kamykowski, MG and Graff-Radford, J and Ramanan, VK and Fields, JA and Machulda, MM and Stricker, NH and Boeve, BF and Lowe, VJ and Kantarci, K and Knopman, DS and Whitwell, JL and Josephs, KA and Petersen, RC and Jack, CR and Jones, DT and , },
title = {A model of brain function to predict tau across Alzheimer's disease and related disorders.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42967904},
issn = {2041-1723},
support = {U01 AG082350-01A1//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/physiopathology ; *tau Proteins/metabolism ; Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism/physiopathology ; Female ; Aged ; Male ; Aged, 80 and over ; Fluorodeoxyglucose F18 ; Machine Learning ; Carbolines ; Predictive Learning Models ; Neuroimaging ; },
abstract = {We developed a machine learning framework grounded in a computational model of brain function and FDG-PET imaging to predict Alzheimer's disease (AD)-type tau across AD and related disorders (ADRD). The model was trained on 1088 research participants spanning normal aging and ADRD with FDG-PET and flortaucipir-PET (FTP-PET). Validation was conducted in: (1) a longitudinal subset of the training cohort (n = 215), (2) Alzheimer's Disease Neuroimaging Initiative (n = 295), and (3) a heretogeneous clinical cohort (n = 264; n = 28 with FTP-PET). Results showed that the model accurately predicted FTP-PET when applied at the participant-level (R[2] ~ 0.34-0.71). It performed well in clinical scenarios, including classification of low versus high tau stages (79-95% accuracy) and prediction of tau in a heterogeneous clinical cohort without FTP-PET. These findings advance the understanding of the relationship between neurodegeneration and AD-type tau and provide a framework for estimating AD-type tau across ADRD.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/physiopathology
*tau Proteins/metabolism
Positron-Emission Tomography/methods
*Brain/diagnostic imaging/metabolism/physiopathology
Female
Aged
Male
Aged, 80 and over
Fluorodeoxyglucose F18
Machine Learning
Carbolines
Predictive Learning Models
Neuroimaging

@article {pmid42968018,
year = {2026},
author = {Simfukwe, C and An, SSA and Youn, YC},
title = {Eyes-open resting-state EEG microstate analysis using ratio-normalized parameters across four- and seven-class solutions in healthy controls, mild cognitive impairment, and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261501861},
doi = {10.1177/13872877261501861},
pmid = {42968018},
issn = {1875-8908},
abstract = {BackgroundResting-state EEG microstate analysis indexes large-scale network dynamics, yet the value of ratio-normalized temporal parameters under the eyes-open resting (EOR) condition remains unexplored across the cognitive decline continuum.ObjectiveTo examine whether ratio-normalized microstate parameters from four- and seven-class clustering solutions under EOR differentiate healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD).MethodsOne hundred and eighty participants (HC, MCI, and AD; n = 60 each) were recruited from a hospital-based cohort in an elderly Korean population. Resting-state EEG recorded under EOR was analyzed using MICROSTATELAB in EEGLAB. Absolute temporal parameters (duration, occurrence, coverage) and ratio-normalized forms (relative duration, relative occurrence) were compared using ANCOVA with age as covariate, false discovery rate (FDR) correction, and Bonferroni-corrected post-hoc comparisons.ResultsIn the four-class solution, three parameters reached nominal significance, none surviving FDR correction across the full set of 20 tests: coverage of Microstate B (visual network; F(2176) = 3.561, p = 0.030), relative occurrence of Microstate B (F(2176) = 5.281, p = 0.006), and relative occurrence of Microstate E (executive network; F(2176) = 3.816, p = 0.024). MCI showed higher visual and lower executive microstate engagement than AD (p ≤ 0.023); no contrast involving HC was significant. Absolute occurrence parameters were non-significant whereas their ratio-normalized counterparts were significant. The seven-class solution yielded no corrected effects.ConclusionsRatio-normalized EOR microstate parameters distinguished MCI from AD through visual and executive network engagement, with small-to-moderate effects and HC intermediate. The four-class solution outperformed the seven-class solution, contrasting with eyes-closed reports. As these analyses were exploratory and did not survive correction, confirmation in independent cohorts is required.},
}

@article {pmid42968096,
year = {2026},
author = {Zhang, ZY and Zhang, SS and Wang, SD and Cheng, K and Yi, WH and Li, ZW and Zhou, JN and Wang, XM and Wang, CW},
title = {Impact of heat-induced retrieval methods on silver staining for detecting senile plaques of Alzheimer's disease in human brain tissue sections.},
journal = {Diagnostic pathology},
volume = {21},
number = {1},
pages = {},
pmid = {42968096},
issn = {1746-1596},
support = {2022ZD0205202//STI2030-Major Projects/ ; KJ2021A0212//Anhui Province University Scientific Research Project/ ; 2021xkj008//Anhui Medical University Research Funding/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnosis ; *Plaque, Amyloid/pathology ; *Silver Staining/methods ; Hot Temperature ; *Brain/pathology ; Paraffin Embedding ; Tissue Fixation/methods ; Formaldehyde ; },
abstract = {BACKGROUND: Silver staining continues to serve as a critical technique for histological detection of pathological deposits, especially in the context of Alzheimer's disease (AD). In clinical research, paraffin-embedded sections are often stored for extended periods, and tissues may remain in formaldehyde for prolonged durations, both of which can lead to false-negative results. The objective of this study was to systematically evaluate whether heat-induced retrieval can enhance the efficacy and sensitivity of classical silver staining in these suboptimally preserved brain tissues.

METHODS: This study investigated the impact of heat-induced retrieval methods on silver staining efficacy in brain tissue. Three types of samples were examined: standard FFPE sections, tissues immersed in formaldehyde for 48 months, and paraffin‑embedded sections (initially fixed for 48 h in formalin, sections coated with paraffin and stored on slides) stored for seven years. Retrieval methods were performed using citrate-citric acid buffer, Tris-EDTA buffer, or proteinase K. Silver staining was conducted using three classical methods: Bielschowsky, periodic acid-methenamine silver (PAM), and Gallyas; untreated sections were used as controls.

RESULTS: Results showed that both citrate-citric acid and Tris-EDTA significantly increased the signal-to-noise ratio of senile plaques in Bielschowsky staining. This improvement facilitated better the detection of amyloid plaque details and density, with Tris-EDTA yielding higher sensitivity in long-stored paraffin sections. Proteinase K digestion did not enhance Bielschowsky staining results. None of the retrieval methods improved signal-to-noise ratio for senile plaques or neurofibrillary tangles with PAM or Gallyas.

CONCLUSIONS: These findings indicate that heat-induced retrieval methods with citrate or Tris-EDTA buffer, enabling more efficient silver ion reduction at specific targets in Bielschowsky. This work provides an experimental basis for optimizing silver staining protocols, which helps enhance diagnostic accuracy in neuropathological studies of AD and related disorders.},
}

Humans
*Alzheimer Disease/pathology/diagnosis
*Plaque, Amyloid/pathology
*Silver Staining/methods
Hot Temperature
*Brain/pathology
Paraffin Embedding
Tissue Fixation/methods
Formaldehyde

@article {pmid42968204,
year = {2026},
author = {Nicosia, FM and Miller, MJ and Hung, B and Pham, C and Lee, JA and Chesney, MA and Jacob, R and Hartmann, CW and Chao, L and Barnes, DE},
title = {Scaling a multimodal mind-body movement intervention for Veterans with dementia in VA nursing homes: A formative evaluation of the Preventing Loss of Independence through Exercise (PLIÉ) program.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500436},
doi = {10.1177/13872877261500436},
pmid = {42968204},
issn = {1875-8908},
abstract = {BackgroundPeople living with Alzheimer's disease and related dementias constitute a substantial proportion of residents in U.S. Veterans Health Administration nursing homes (Community Living Centers, CLCs). Non-pharmacologic interventions have demonstrated positive effects for people living with dementia (PLWD) but face implementation barriers in nursing homes. The Preventing Loss of Independence through Exercise (PLIÉ) program is an evidence-based multimodal mind-body movement program that supports quality of life and function for PLWD.ObjectiveTo identify potential facilitators and barriers that may impact implementation of PLIÉ in CLCs (PLIÉ-CLC) and inform the development of a remote staff training program.MethodsWe conducted a developmental formative evaluation using qualitative methods, guided by the Consolidated Framework for Implementation Research (CFIR). Semi-structured interviews with 30 CLC staff, directors, and VA health system leaders, explored perspectives on implementing PLIÉ-CLC. Data were analyzed using a template analysis approach.ResultsKey facilitators included PLIÉ's evidence base, adaptability, and alignment with person-centered care. Barriers included staffing constraints, workload demands, and limited accessible space. Participants emphasized the need for both synchronous and asynchronous training components to fit staff schedules and enhance feasibility.ConclusionsThis study highlighted the importance of adaptability and evidence-based support in implementing PLIÉ in VA nursing homes. The findings suggest that a flexible, remote training program incorporating both didactic and experiential learning may facilitate the scalability of PLIÉ. Understanding barriers and facilitators can inform strategies to improve the implementation of non-pharmacologic interventions for residents with dementia, ultimately enhancing care quality and outcomes in nursing homes.},
}

@article {pmid42968217,
year = {2026},
author = {Lee, E and Kim, K and Huo, M},
title = {Spousal Discrepancy in Perceived Importance of Care Needs Among Couples Managing Early-Stage Alzheimer's Disease.},
journal = {Research on aging},
volume = {},
number = {},
pages = {1640275261502783},
doi = {10.1177/01640275261502783},
pmid = {42968217},
issn = {1552-7573},
abstract = {This study examined discrepancies between persons living with dementia (PLWD) and their spousal caregivers in the perceived importance of PLWD's care needs, and how caregivers' dementia knowledge and empathy were associated with these discrepancies. Data were drawn from 65 couples managing early-stage Alzheimer's disease. PLWD self-reported the importance of their physical, psychological, and social needs, while caregivers provided proxy ratings. PLWD perceived addressing their physical needs as more important than did their caregivers, whereas both partners agreed on the importance of psychological and social needs. Caregivers' greater empathic concern was associated with smaller discrepancies in the perceived importance of physical needs; greater personal distress was associated with smaller discrepancies in social needs. Caregivers' dementia knowledge was positively associated with discrepancies in psychological needs only when relationship quality was lower. These findings highlight the importance of caregivers' emotional responsiveness and relational dynamics in caregiver interventions, expanding the focus beyond dementia knowledge.},
}

@article {pmid42968239,
year = {2026},
author = {Wang, X and Zhang, B and Ma, H and Shan, A and Lian, Q and Han, X and Xu, C and Yao, Q and Wen, B and Luan, H and Li, S and Cui, T and Lv, S and Sun, Q and Guo, J and Chen, R and Wei, C},
title = {Integrated clinical and transcriptomic analysis reveals miRNA-mediated mechanisms linking hearing loss to cognitive decline in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261501149},
doi = {10.1177/13872877261501149},
pmid = {42968239},
issn = {1875-8908},
abstract = {BackgroundHearing loss (HL) is a potent, modifiable risk factor for Alzheimer's disease (AD), but the underlying molecular mechanisms remain elusive. microRNAs (miRNAs) are potential key mediators given their roles in both neurodegeneration and auditory function.ObjectiveTo investigate whether peripheral blood miRNA profiles differ between AD patients with and without HL, and whether hsa-miR-6875-5p serves as a candidate molecular link.MethodsIn a case-control study of 41 AD patients (AD-HL n = 24, AD-non-HL n = 17), we performed neuropsychological assessments, plasma miRNA sequencing, target gene prediction, and external validation using public transcriptomic datasets.ResultsAD-HL patients showed significantly worse Montreal Cognitive Assessment and Auditory Verbal Learning Test delayed recall scores (p < 0.05). We identified 9 differentially expressed miRNAs, with hsa-miR-6875-5p being the most upregulated (3.29-fold, p = 0.041). Its predicted targets were enriched in synaptic plasticity-related pathways. External validation in AD brain datasets supported consistent upregulation of hsa-miR-6875-5p and downregulation of SYN1/PSD95. Validation in mouse cochlear datasets showed concordant expression trends for homologous miRNA and target genes. The absence of healthy control groups precludes determination of whether this miRNA signature is specific to AD-HL or a general feature of HL or AD.ConclusionsThis preliminary study identifies hsa-miR-6875-5p as a potential circulating biomarker linking HL to cognitive decline in AD. These findings are hypothesis-generating and require confirmation in larger cohorts, including healthy controls, and functional experiments.},
}

@article {pmid42968246,
year = {2026},
author = {Takanari, J and Goto, K and Misu, M and Shio, T and Fukuchi, Y and Homma, K and Fujii, H},
title = {Intake of ETAS[®] Improves Cognitive Function in Healthy Middle-Aged and Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial.},
journal = {Journal of nutritional science and vitaminology},
volume = {72},
number = {5},
pages = {415-423},
doi = {10.3177/jnsv.72.415},
pmid = {42968246},
issn = {1881-7742},
mesh = {Humans ; Double-Blind Method ; Female ; Male ; *Cognition/drug effects ; Aged ; Middle Aged ; Memory/drug effects ; Cognitive Enhancement ; *Plant Extracts/pharmacology/administration & dosage ; *Asparagus Plant/chemistry ; },
abstract = {As the aging population grows, the prevalence of dementia continues to increase, creating an urgent need for preventive strategies. ETAS, a standardized extract of Asparagus officinalis stem, has been shown to influence brain functions such as stress reduction and autonomic regulation. However, its specific effects on cognitive functions remain unclear. This randomized, double-blind, placebo-controlled trial investigated the effects of ETAS on cognitive function in healthy adults. Sixty-six adults aged ≥40 y with normal cognitive function (Japanese version of the Mini-Mental State Examination [MMSE-J] ≥24) were randomly assigned to receive 300 mg/d of ETAS or placebo for 12 wk. A comprehensive evaluation of cognitive function was conducted using Cognitrax, which includes various domains such as memory, attention, and visual information processing. Primary endpoint was the change in standardized score for composite memory, defined as the sum of verbal and visual memory scores, after continual intake of the test product for 12 wk. Sixty participants were included in the efficacy analysis. Compared with the placebo group, the ETAS group showed significantly greater improvements in composite memory score at 6 wk (difference: 12.8 points, p=0.006) and 12 wk (difference: 9.0 points, p=0.048). No adverse events related to ETAS were reported. These findings suggest that ETAS may help maintain and enhance memory function in healthy adults and individuals with suspected mild cognitive impairment. Clinical Trial No.: UMIN000048006.},
}

Humans
Double-Blind Method
Female
Male
*Cognition/drug effects
Aged
Middle Aged
Memory/drug effects
Cognitive Enhancement
*Plant Extracts/pharmacology/administration & dosage
*Asparagus Plant/chemistry

@article {pmid42968295,
year = {2026},
author = {Yang, L and Zeng, J and Ding, Y and Li, L},
title = {Dry, but not wet, age-related macular degeneration increases Alzheimer's disease risk: Findings from a multidimensional analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261502863},
doi = {10.1177/13872877261502863},
pmid = {42968295},
issn = {1875-8908},
abstract = {BackgroundAge-related macular degeneration (AMD) and Alzheimer's disease (AD) share pathophysiological features along the eye-brain axis, but epidemiological, molecular, and causal evidence has not been systematically integrated.ObjectiveTo determine whether AMD, particularly its dry subtype, is causally associated with AD by integrating global epidemiological, bibliometric, molecular, and genetic evidence.MethodsWe analyzed Global Burden of Disease 2021 data, performed a bibliometric analysis, explored shared molecular targets using GeneCards and STRING, and conducted bidirectional two-sample Mendelian randomization (MR) using genome-wide association study summary statistics.ResultsFrom 1990 to 2021, AMD and AD prevalence rose in parallel and peaked in high socio-demographic index regions. Bibliometric analysis of 498 publications showed increasing attention to cellular senescence and MR. Bioinformatics identified 241 shared genes between dry AMD and AD, enriched in complement cascades, MAPK/PI3K-Akt signaling, and lipid metabolism. MR showed that dry AMD causally increased AD risk (OR = 1.14, 95% CI: 1.06-1.24, p = 0.0005), whereas overall AMD showed no causal effect and reverse causality was absent.ConclusionsDry AMD, but not AMD overall, is a causal risk factor for AD, providing genetic support for the eye-brain axis hypothesis. Shared pathways, particularly complement dysregulation, may inform risk stratification and therapeutic development.},
}

@article {pmid42968340,
year = {2026},
author = {Kurz, CI and Tegethoff, P and Hufnagel, A and Perneczky, R},
title = {Evaluating plasma phosphorylated tau217 for clinical rule-out of cerebral amyloid pathology: Evidence from a memory clinic cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500407},
doi = {10.1177/13872877261500407},
pmid = {42968340},
issn = {1875-8908},
abstract = {BackgroundPlasma phosphorylated tau 217 (pTau217) is a promising biomarker for Alzheimer's disease amyloid-β (Aβ) pathology, but cut-offs require validation.ObjectiveThe aim was to evaluate the diagnostic performance of plasma phosphorylated tau 217 for identifying cerebral amyloid pathology to reduce the need for more invasive or resource-intensive confirmatory testing by identifying individuals with a low likelihood of amyloid pathology.MethodsElecsys[®] pTau217 was evaluated in a memory clinic cohort using ROC analysis. Cut-offs were derived using sensitivity-weighted Euclidean distance and bootstrap resampling.ResultspTau217 discriminated Aβ-positive from Aβ-negative individuals (AUC 0.854). The cut-off was 0.169 pg/mL (95% CI 0.140-0.200), with 87.7% sensitivity and 77.0% specificity. Age and sex adjustment did not improve performance.ConclusionsThe threshold was consistent with previously reported low cut-offs, supporting potential rule-out utility; however, its sensitivity precludes stand-alone exclusion of Aβ pathology in memory clinic populations.},
}

@article {pmid42968523,
year = {2026},
author = {Kabbashi, S and Ahmed, M and Chetty, M},
title = {Beyond the Microbial Hypothesis: Shared Genetic, Osteoimmune and Vascular Mechanisms in the Oral-Brain Axis Linking Periodontitis and Alzheimer's Disease.},
journal = {The European journal of neuroscience},
volume = {64},
number = {9},
pages = {},
pmid = {42968523},
issn = {1460-9568},
support = {//South African Medical Research Council/ ; //University Research Chairs Program/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/immunology ; Animals ; *Periodontitis/genetics/metabolism/immunology/complications ; *Brain/metabolism/immunology ; Osteoprotegerin/metabolism ; },
abstract = {Periodontitis, a chronic inflammatory disease of the tooth-supporting tissues, is increasingly linked to Alzheimer's disease (AD), yet mechanistic accounts of this 'oral-brain axis' have been dominated by microbial translocation and the gingipain hypothesis. This review argues that the convergence between periodontitis and AD extends well beyond microbes, integrating shared genetic, osteoimmune and vascular-inflammatory mechanisms that are rarely considered together. Genetic susceptibility reaches beyond APOE ε4 to the osteoprotegerin (OPG) axis, with APOE ε4 linking the two conditions through impaired amyloid-β clearance, blood-brain barrier dysfunction and altered lipid handling. The OPG/RANK/RANKL system emerges as a bone-brain (osteoimmune) interface, in which OPG shows a dual-role paradox, reduced locally in periodontal bone loss yet elevated systematically in AD, while soluble RANKL displays neuroprotective properties. Because OPG acts as a decoy receptor for RANKL, we hypothesise that elevated OPG in AD limits RANKL-dependent microglial amyloid-β clearance. Endothelial dysfunction, reflected in circulating endocan, provides a shared vascular readout that is raised in both diseases and responsive to periodontal therapy. We propose that these genetic, microbial and vascular inputs converge on microglial priming and trained immunity, a unifying immunological node through which chronic peripheral inflammation may act during the decades-long preclinical phase of AD. Current evidence nonetheless remains predominantly associative, causality is unproven and mechanistic data rely heavily on animal models. The oral-brain axis is therefore best regarded as a promising yet still unproven framework in which osteoimmune and vascular pathways, and candidate biomarkers such as endocan, represent underexplored targets for future longitudinal and interventional research.},
}

Humans
*Alzheimer Disease/genetics/metabolism/immunology
Animals
*Periodontitis/genetics/metabolism/immunology/complications
*Brain/metabolism/immunology
Osteoprotegerin/metabolism

@article {pmid42968533,
year = {2026},
author = {Mohammadi, Y and Salehi, MS and Heidari, E and Ebrahimi, M and Ashjazadeh, N},
title = {Development, Optimization, and Physicochemical Characterization of Fluorescent Carbon Dot-Ginkgo biloba Extract Co-Loaded Niosomes for Future Neurological Disease-Relevant Evaluation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {11},
pages = {},
pmid = {42968533},
issn = {1755-5949},
mesh = {*Liposomes/chemistry ; Ginkgo biloba ; *Plant Extracts/chemistry/administration & dosage ; *Carbon Quantum Dots/chemistry ; Humans ; Animals ; Ginkgo Extract ; Cell Survival/drug effects ; Particle Size ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the major neurodegenerative diseases that affect the human brain and lead to memory loss. The present approaches to disease management have been relatively poor; the therapies provided do not arrest the disease process. This study aimed to develop and optimize dual-loaded niosomes containing Ginkgo biloba extract and CDOTs and to evaluate their physicochemical properties, formulation-level fluorescence, in vitro release, and preliminary cytocompatibility. The study did not assess blood-brain barrier transport, neuronal effects, Alzheimer's disease-specific mechanisms, or in vivo therapeutic efficacy.

RESULTS: Niosomes were prepared based on non-ionic surfactants and cholesterol for the encapsulation of Ginkgo and CDOTs. The response surface methodology (RSM) was used to optimize niosomal formulations through a Box-Behnken design. The formulations were evaluated for vesicle size, entrapment efficiency, and release profile. Field Emission Scanning Electron Microscopy (FESEM) research indicated that the average diameters of the free niosomes and CDOT@Ginkgo@Niosomes were 69.56 nm and 72.19 nm, respectively. HFF cell viability remained high at lower concentrations, whereas significant reductions in viability were observed at 10 and 50 μg/mL after 48 h, indicating concentration-dependent cytocompatibility. The formulation exhibited acceptable preliminary cytocompatibility at lower concentrations, whereas reduced viability was observed at higher concentrations. For both CDOT and Ginkgo, CDOT@Ginkgo@Niosomes showed a delayed release profile over 72 h, with near-complete release observed at the final time point.

CONCLUSIONS: CDOT@Ginkgo@Niosomes showed successful co-loading, preserved formulation-level fluorescence, delayed release, and acceptable cytocompatibility at lower concentrations in HFF cells. These findings support further formulation optimization and subsequent evaluation in disease-relevant neuronal, blood-brain barrier, and in vivo models. The present results do not demonstrate neuroprotection, diagnostic performance, blood-brain barrier transport, or the prevention or treatment of neurodegenerative disease.},
}

*Liposomes/chemistry
Ginkgo biloba
*Plant Extracts/chemistry/administration & dosage
*Carbon Quantum Dots/chemistry
Humans
Animals
Ginkgo Extract
Cell Survival/drug effects
Particle Size

@article {pmid42968820,
year = {2026},
author = {Klimova, B},
title = {Language Impairment in Alzheimer's Disease: An Updated Narrative Review of Digital Assessment, Social Interventions, and Medical Treatment, 2016-2026.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {633855},
pmid = {42968820},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/complications/therapy ; *Language Disorders/therapy/etiology ; Biomarkers ; },
abstract = {Language impairment is a core clinical manifestation of Alzheimer's disease (AD) that profoundly affects autonomy, decision-making, and social participation. Building upon the 2015 review by Kuca et al., this narrative review synthesizes empirical evidence from 2016 through 2026. A structured Web of Science Core Collection search retrieved 154 records. Following screening, 66 records were excluded and 88 full-text reports were appraised, of which 13 were consolidated, yielding 75 cited core empirical studies alongside foundational diagnostic, neuropathological, and trial benchmarks. Four main areas are synthesized. First, progressive linguistic decline across clinical stages is characterized, delineating typical amnestic AD dementia, mild cognitive impairment due to AD, and the logopenic variant of primary progressive aphasia (lvPPA), highlighting the necessity of biological amyloid and tau biomarker confirmation. Second, automated speech and natural language processing biomarkers have emerged as scalable tools predicting progression to dementia and detecting biological amyloid-beta positivity; however, real-world translation remains constrained by demographic bias, cross-linguistic variations, acoustic sensitivity, and privacy issues. Third, non-pharmacological interventions, including structured language stimulation and naming therapy, demonstrate measurable task-specific improvements; nevertheless, gains are largely restricted to trained items with minimal transfer to everyday discourse. Caregiver communication training programs reliably improve dyadic interactions and mitigate caregiver distress. Fourth, approved symptomatic drugs do not directly reverse language decline, and add-on memantine in the randomized ROMEO-AD trial produced no statistically significant language benefit over donepezil alone. Disease-modifying anti-amyloid antibodies offer biological intervention for biomarker-positive lvPPA, but pivotal trials lacked primary speech endpoints, establishing eligibility rather than demonstrated language recovery. Non-invasive neuromodulation remains preliminary and requires sham-controlled trials. Communication should be recognized as a distinct clinical outcome in trial designs, prioritizing standardized speech endpoints to assess disease-modifying therapies.},
}

Humans
*Alzheimer Disease/complications/therapy
*Language Disorders/therapy/etiology
Biomarkers

@article {pmid42969191,
year = {2026},
author = {Parker, MA and Klopack, ET and Johnson, AL and Guo, L and Parker, ES},
title = {Former versus current smoking among older adults living with Alzheimer's disease, related dementias, and cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500405},
doi = {10.1177/13872877261500405},
pmid = {42969191},
issn = {1875-8908},
abstract = {Smoking is a major modifiable risk factor for Alzheimer's disease and related dementias (ADRD), yet smoking status among older adults with ADRD or cognitive impairment, not dementia (CIND), remains poorly characterized. Using pooled 2010-2020 Health and Retirement Study data, we examined former versus current smoking among US adults aged ≥55 years with lifetime cigarette smoking. In weighted analyses of 13,595 participants, adults with CIND (AOR = 0.83, 95% CI: 0.74, 0.92) and ADRD (AOR = 0.80, 95% CI: 0.65, 0.99) had lower odds of former smoking than cognitively normal adults. Findings highlight the importance of understanding smoking cessation needs in cognitively impaired populations.},
}

@article {pmid42969271,
year = {2026},
author = {Ahn, J and Lee, MB and Kwon, OI and Rhee, HY and Jung, YJ and Kim, Y and Park, S and Ryu, CW and Lee, J and Jahng, GH},
title = {Conductivity-To-Tissue Volume Ratio: Imaging Biomarker for the Alzheimer's Disease Continuum.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261502814},
doi = {10.1177/15333175261502814},
pmid = {42969271},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/physiopathology ; Female ; *Magnetic Resonance Imaging/methods ; Male ; *Cognitive Dysfunction/diagnostic imaging/pathology/physiopathology ; Aged ; Cross-Sectional Studies ; Biomarkers ; *Hippocampus/diagnostic imaging/pathology/physiopathology ; *Cerebral Cortex/diagnostic imaging/pathology/physiopathology ; Prospective Studies ; Organ Size ; Middle Aged ; Electric Conductivity ; },
abstract = {While hippocampal volume and tissue conductivity are independent markers of neurodegeneration, their integrated diagnostic utility in Alzheimer's disease remains underexplored. This prospective cross-sectional study evaluated a novel conductivity-to-tissue volume ratio index across the Alzheimer's disease continuum. Overall, 110 participants-30 cognitively normal adults, 52 with amnestic mild cognitive impairment, and 28 with Alzheimer's disease-underwent magnetic resonance electrical properties tomography and 3D T1-weighted imaging. Three ratio indices were calculated from conductivity and regional tissue volume in the insula and hippocampus. After age adjustment, all indices showed a diagnostic gradient across groups. The insular conductivity-to-hippocampal volume ratio showed high discrimination for Alzheimer's disease dementia versus cognitively normal adults, with an area under the curve of 0.917. The indices correlated positively with age and negatively with K-MMSE2 (Korean version of Mini-Mental State Examination, version 2) scores. These findings suggest that conductivity-volume ratio indices may serve as biophysical imaging markers that amplify disease-related contrast across the Alzheimer's disease continuum.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/physiopathology
Female
*Magnetic Resonance Imaging/methods
Male
*Cognitive Dysfunction/diagnostic imaging/pathology/physiopathology
Aged
Cross-Sectional Studies
Biomarkers
*Hippocampus/diagnostic imaging/pathology/physiopathology
*Cerebral Cortex/diagnostic imaging/pathology/physiopathology
Prospective Studies
Organ Size
Middle Aged
Electric Conductivity

@article {pmid42969459,
year = {2026},
author = {François, G and Michalon, R and Tannou, T and Damier, P and Desmoulin, S and Lebouvier, T},
title = {Navigating the Challenges of Shared Decision-Making in Amyloid Immunotherapy for Alzheimer's Disease.},
journal = {European journal of neurology},
volume = {33},
number = {11},
pages = {},
pmid = {42969459},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/therapy/drug therapy ; *Decision Making, Shared ; *Immunotherapy/methods ; *Patient Participation ; Informed Consent ; },
abstract = {BACKGROUND: Anti-amyloid therapies (AATs), such as lecanemab and donanemab, represent a major therapeutic development for early Alzheimer's disease (AD). However, safety risks and uncertainties regarding long-term effects make treatment decisions complex. These decisions arise when patients remain legally capable of providing informed consent but may experience cognitive vulnerabilities affecting their ability to engage in complex decisions. Shared decision-making (SDM) is therefore particularly relevant, yet its implementation raises ethical and practical challenges.

METHODS: This position paper draws on a multidisciplinary reflection on decision-making, informed consent, and cognitive vulnerability in early AD and AATs. The authors, with expertise in neurology, geriatrics, law, and history, examined challenges to patient participation and developed a relational framework integrating SDM and supported decision-making.

RESULTS: Impairments in memory, insight, and executive function, together with cognitive biases, stigma, and the complexity of AAT-related information, may compromise patient participation despite preserved legal capacity. Formal capacity assessments and improved information delivery may address some difficulties but are unlikely to provide comprehensive support. We propose a relational framework involving assessment of patients' cognitive vulnerabilities, values, preferences, and informational needs; tailored information; and involvement of a patient-designated care partner to support information exchange, deliberation, and expression of preferences. Consent should be iterative, with safeguards to preserve autonomy and confidentiality, prevent coercion, and avoid excluding socially isolated individuals.

CONCLUSION: Combining SDM with supported decision-making may provide an ethical and practical framework for autonomous treatment decisions regarding AATs in early AD.},
}

Humans
*Alzheimer Disease/therapy/drug therapy
*Decision Making, Shared
*Immunotherapy/methods
*Patient Participation
Informed Consent

@article {pmid42969693,
year = {2026},
author = {Chen, Z and Chen, D and Zhang, J and Wang, C and Liu, J and Liang, Y and He, Q and Du, X},
title = {Iron Boride Nanostructures as Oral Acid-Responsive Hydrogen Donors for Alzheimer's Disease Therapy.},
journal = {Molecular pharmaceutics},
volume = {23},
number = {11},
pages = {5288-5304},
doi = {10.1021/acs.molpharmaceut.6c00223},
pmid = {42969693},
issn = {1543-8392},
support = {RCJC20210706092010008//Shenzhen Science and Technology Program/ ; 2025A1515011129//Natural Science Foundation of Guangdong Province/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; 82550005//National Natural Science Foundation of China (NSFC)/ ; W2512066//National Natural Science Foundation of China (NSFC)/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Hydrogen/chemistry/metabolism/administration & dosage ; Mice ; Male ; *Nanostructures/chemistry/administration & dosage ; Administration, Oral ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Brain/metabolism/drug effects/pathology ; Humans ; *Iron Compounds/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition with complex causes. Despite extensive research, effective disease-modifying treatment options remain limited. Recent studies have indicated that hydrogen molecule (H2) possesses therapeutic potential for AD, and it is of vital importance to enhance the bioavailability of H2 in the gastrointestinal tract based on the gut-brain axis. In this work, we develop iron boride nanostructures (FBN) as a novel acid-responsive hydrogen-releasing material with a high hydrogen release capacity to enhance the H2 delivery efficacy towards the gastrointestinal tract for AD treatment. In male 5×FAD and 3×Tg-AD mice, oral FBN administration generated H2 under gastric conditions and was associated with AD-like behavioral and pathological improvements, including improved learning and memory and attenuation of neuronal and synaptic damage. FBN treatment was associated with increased synaptophysin (SYP) expression and dendritic spine density. Additionally, FBN treatment was associated with reduced amyloid-beta (Aβ) accumulation and attenuated tau pathology, two key pathological features of AD. FBN treatment was also associated with increased expression of mitochondrial fusion-related proteins and improved mitochondrial morphology. Furthermore, FBN treatment increased antioxidant defense-related proteins and reduced apoptosis-related markers, suggesting a possible enhancement of neuroprotective responses. In addition, FBN treatment induced changes in gut microbiota-related metabolites, suggesting a possible contribution of the gut-brain axis. These findings provide valuable insight into the mechanisms underlying the protective effects of hydrogen against AD and support the development of hydrogen-based therapies for slowing or preventing disease progression.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Hydrogen/chemistry/metabolism/administration & dosage
Mice
Male
*Nanostructures/chemistry/administration & dosage
Administration, Oral
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Disease Models, Animal
Brain/metabolism/drug effects/pathology
Humans
*Iron Compounds/chemistry

@article {pmid42969705,
year = {2026},
author = {Hyvärinen, J and Todorovska, R and Palacios, MDP and Gynther, M and Afonin, A and Lehtonen, M and Auriola, S and Saveleva, L and Kanninen, KM and Fricker, G and Puris, E},
title = {Proteomics Reveals Blood-Brain Barrier Membrane Protein Remodeling in Amyloid-β Pathology.},
journal = {Molecular pharmaceutics},
volume = {23},
number = {11},
pages = {5848-5862},
doi = {10.1021/acs.molpharmaceut.6c00935},
pmid = {42969705},
issn = {1543-8392},
support = {//Alexander von Humboldt-Stiftung/ ; //Biocenter Finland/ ; //Alzheimer Forschung Initiative/ ; 362227//Research Council of Finland/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Proteomics/methods ; Mice ; *Alzheimer Disease/metabolism/pathology ; Humans ; Mice, Transgenic ; Endothelial Cells/metabolism ; Brain/metabolism/blood supply ; *Membrane Proteins/metabolism ; Disease Models, Animal ; Tandem Mass Spectrometry/methods ; Microvessels/metabolism ; Chromatography, Liquid ; },
abstract = {The protective function of the blood-brain barrier (BBB) is achieved by membrane proteins expressed in the endothelial cells of brain microvessels, such as tight junction proteins, receptors, and transporters, which regulate the passage of solutes, including nutrients, drugs, and metabolites. In Alzheimer's disease (AD), characterized by the accumulation of amyloid-β (Aβ) plaques, BBB dysfunction has been widely reported. However, quantitative information on Aβ-associated changes in the membrane proteome in the brain microvasculature remains limited. Here, we investigated the changes in abundances of membrane proteins playing roles in BBB function in the isolated brain microvessels of a mouse model mimicking human Aβ pathology, 5xFAD mice, versus corresponding wild-type (WT) mice using a state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS)-based data-independent acquisition (DIA) quantitative proteomics. In addition, we applied quantitative targeted absolute proteomics to evaluate the impact of Aβ1-42 on the absolute protein abundance of multiple transporters in an in vitro model of brain endothelial cells, hCMEC/D3. We identified changes in the protein abundance of numerous proteins involved in BBB integrity, including tight junction-associated proteins and proteins implicated in Aβ transport and clearance, in the brain microvasculature of 5xFAD mice. Furthermore, Aβ1-42 treatment altered GLUT1 protein abundance and the gene expression of SLC27A1 and SLC22A2 in hCMEC/D3 cells, which play roles in nutrient transport and drug disposition at the BBB. The present study provides novel insights into Aβ-associated molecular alterations in brain microvascular membrane proteins and advances our understanding of BBB changes in AD. The results may support the development of BBB-targeted therapeutic approaches and strategies for optimizing brain drug delivery in AD.},
}

Animals
*Blood-Brain Barrier/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*Proteomics/methods
Mice
*Alzheimer Disease/metabolism/pathology
Humans
Mice, Transgenic
Endothelial Cells/metabolism
Brain/metabolism/blood supply
*Membrane Proteins/metabolism
Disease Models, Animal
Tandem Mass Spectrometry/methods
Microvessels/metabolism
Chromatography, Liquid

@article {pmid42969854,
year = {2026},
author = {Wu, Y and Maurya, N and Yang, Y and Chen, W and Wang, G and Liu, Z and Hu, X and Zheng, WJ and Xu, Z},
title = {ADInteractome: discovering Alzheimer's disease-associated gene interactions from single-nucleus RNA-seq data through neural interaction states.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {6},
pages = {},
pmid = {42969854},
issn = {1477-4054},
support = {2451398//National Science Foundation/ ; 2450524//National Science Foundation/ ; 1UL1TR003167/NH/NIH HHS/United States ; 1UM1TR004906-01/NH/NIH HHS/United States ; 1R01AG066749/NH/NIH HHS/United States ; 1U24MH130988-01/NH/NIH HHS/United States ; 5R56AG069880-02/NH/NIH HHS/United States ; W81XWH-22-1-0164//Department of Defense/ ; 1R01AR081280-01A1//Department of Defense/ ; 5R01AG074283-04//Department of Defense/ ; RP170668//Cancer Prevention and Research Institute of Texas/ ; RP210045//Cancer Prevention & Research Institute of Texas (CPRIT)/ ; RP260802//Cancer Prevention & Research Institute of Texas (CPRIT)/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Gene Regulatory Networks ; *Neural Networks, Computer ; *RNA-Seq ; Brain/metabolism/pathology ; Sequence Analysis, RNA ; *Epistasis, Genetic ; *Cell Nucleus/genetics/metabolism ; Single-Cell Gene Expression Analysis ; RNA, Small Nuclear/genetics ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid $\beta $ plaques and tau tangles, yet its molecular mechanisms remain elusive. Advances in single-nucleus RNA sequencing (snRNA-seq) have provided profound insights into the cellular heterogeneity of AD-associated brains. In this study, we introduce ADInteractome, an interpretable artificial intelligence framework designed to discover gene interactions associated with AD directly from the internal state of neural networks trained on the snRNA-seq data of brain cells. The method is based on the intuition that if a neural network can accurately classify cells from AD and non-AD donors based on their snRNA-seq data, then its internal interaction states, reflecting interaction patterns within the gene expression data, are informative for identifying biologically meaningful gene interactions. Applied to a large-scale snRNA-seq dataset from the Seattle Alzheimer's Disease Brain Cell Atlas, ADInteractome reveals cell-type-specific and AD-associated gene circuits supported by existing literature. The results were further supported by our virtual knock-out and knock-in experiments, a novel concept to probe our findings through a data-driven approach. Compared with traditional co-expression network methods, it achieves stronger enrichment for known AD-associated gene interactions and uncovers novel interaction patterns. These findings highlight the potential of interpretable AI approaches for elucidating complex molecular interactions in neurodegenerative disease.},
}

*Alzheimer Disease/genetics/metabolism
Humans
*Gene Regulatory Networks
*Neural Networks, Computer
*RNA-Seq
Brain/metabolism/pathology
Sequence Analysis, RNA
*Epistasis, Genetic
*Cell Nucleus/genetics/metabolism
Single-Cell Gene Expression Analysis
RNA, Small Nuclear/genetics

@article {pmid42970287,
year = {2026},
author = {Hsu, J},
title = {I'll Be Home in No Time.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.4008},
pmid = {42970287},
issn = {2168-6157},
}

@article {pmid42970288,
year = {2026},
author = {Xu, H and Bowblis, JR and Li, S and Pappadis, MR and Kuo, YF and Goodwin, JS},
title = {Racial and Ethnic Differences in Access to Alzheimer Special Care Units After Hospitalization.},
journal = {JAMA network open},
volume = {9},
number = {11},
pages = {e2643623},
doi = {10.1001/jamanetworkopen.2026.43623},
pmid = {42970288},
issn = {2574-3805},
mesh = {Humans ; Female ; United States ; Retrospective Studies ; *Alzheimer Disease/therapy/ethnology ; Aged ; Male ; *Hospitalization/statistics & numerical data ; Aged, 80 and over ; *Health Services Accessibility/statistics & numerical data ; Medicare/statistics & numerical data ; Hispanic or Latino/statistics & numerical data ; White People/statistics & numerical data ; Black or African American/statistics & numerical data ; *Healthcare Disparities/ethnology/statistics & numerical data ; *Nursing Homes/statistics & numerical data ; White ; *Ethnicity/statistics & numerical data ; Nursing Home Residents ; },
abstract = {IMPORTANCE: Older adults with dementia often need nursing home care after hospitalization.

OBJECTIVE: To examine whether Black and Hispanic patients have different access to Alzheimer disease special care units (ASCUs) after hospital discharge compared with White patients.

This was a retrospective cohort study of 100% Medicare fee-for-service claims from January 2018 to February 2020. Participants were Medicare beneficiaries with a prior diagnosis of dementia who were hospitalized or admitted to nursing homes from January 2018 to August 2019. Data analyses were performed from January to July 2026.

EXPOSURE: The race and ethnicity of a patient.

MAIN OUTCOMES AND MEASURES: The primary outcome was long-term care admission to a nursing home with an ASCU. An unadjusted logistic regression, an unadjusted 2-level (patient-hospital) model, and a multivariable 2-level model were conducted to assess racial and ethnic differences in long-term care admission to a facility with an ASCU and whether patient and hospital characteristics could explain the differences.

RESULTS: Of the 1 428 849 patients, 130 125 (9.11%) were Black, 77 868 (5.45%) were Hispanic, 1 164 829 (81.52%) were non-Hispanic White, 56 027 (3.92%) were of other races (American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander), 839 328 (58.74%) were female, and 1 075 171 (75.25%) were aged 75 years or older. A total of 122 654 patients (8.58%) became long-term care residents within 6 months of hospital discharge, and 19 313 patients (1.35%) were admitted to facilities with an ASCU. In the unadjusted logistic model, Black (relative risk [RR], 0.69; 95% CI, 0.65-0.73) and Hispanic (RR, 0.48; 95% CI, 0.44-0.53) patients had lower probabilities of long-term care admission in a facility with ASCU than White patients. After controlling for the clustering of patients in a hospital, the RR substantially increased to 0.94 (95% CI, 0.88-0.99) for Black patients and 0.78 (95% CI, 0.71-0.85) for Hispanic patients. Further controlling for patient and hospital characteristics slightly reduced these RRs. Disparities for Black patients (RR, 0.89; 95% CI, 0.84-0.95), but not Hispanic patients (RR, 0.93; 95% CI, 0.84-1.02), were also observed in the subcohort of Medicare beneficiaries who became long-term care residents.

CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that disparities in access to specialized dementia care occur mostly because patients from minoritized racial and ethnic groups are treated at hospitals with low rates of discharge to ASCUs. Efforts to improve dementia care access should focus on enhancing hospital discharge planning and addressing the extra barriers faced by female patients.},
}

Humans
Female
United States
Retrospective Studies
*Alzheimer Disease/therapy/ethnology
Aged
Male
*Hospitalization/statistics & numerical data
Aged, 80 and over
*Health Services Accessibility/statistics & numerical data
Medicare/statistics & numerical data
Hispanic or Latino/statistics & numerical data
White People/statistics & numerical data
Black or African American/statistics & numerical data
*Healthcare Disparities/ethnology/statistics & numerical data
*Nursing Homes/statistics & numerical data
White
*Ethnicity/statistics & numerical data
Nursing Home Residents

@article {pmid42970312,
year = {2026},
author = {Ali, U and Tan, R and Ding, S and Ji, S},
title = {PARP-CD38-Driven NAD[+] Loss in Immune Aging: An Emerging Mechanistic Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0890},
pmid = {42970312},
issn = {2152-5250},
abstract = {Immune aging is characterized by inflammaging, progressive immune decline, and compromised tissue surveillance. Although researchers have recognized an association between PARP hyperactivation and immune aging (emerging and context-dependent), a unifying framework for how PARP members beyond PARP1 orchestrate immune dysfunction via NAD[+] metabolism is lacking. We propose a context-dependent PARP-CD38-NAD[+]-inflammaging hierarchy. PARP1 is the most abundant nuclear PARP, responsible for 85-90% of nuclear PARP activity and dominant NAD[+] consumption under acute DNA damage; CD38, the principal NAD[+] glycohydrolase, is upregulated in inflamed aged tissues; NAD[+] is compartmentalized (cytosolic, mitochondrial) with distinct regulators (NAMPT, NMNAT1/2/3, SLC25A51). Recent human data challenge the universal NAD[+] decline hypothesis, showing that an 85% muscle NAD[+] reduction does not impair function, and whole-blood NAD[+] is age-invariant. Thus, NAD[+] decline is tissue- and compartment-specific; blood NAD[+] is not a reliable biomarker. Beyond PARP1, PARP2 (cardiomyocyte aging in mouse), PARP3 (intestinal aging), PARP16 (vascular aging), and PARP9/14 (Alzheimer's models) act as tissue-specific regulators, but their roles in human immune aging remain unquantified. PARP inhibitors and NAD[+] precursors show promise but face risks: genomic instability, hematopoietic toxicity, senescence promotion, and inconsistent efficacy. Unresolved questions, whether PBMC PARP activity predicts immune aging, sex differences, and whether partial inhibition reduces NAD[+] consumption without compromising DNA repair. By rethinking PARPs as context-dependent integrators, we provide a framework for immunogerontology.},
}

@article {pmid42970313,
year = {2026},
author = {Gong, Z and Xiang, Z and Xiang, L and Yuan, J},
title = {Exercise, Dynamic Functional Connectivity, and Sex in Alzheimer's Disease: A Hypothesis-Generating Framework for the Sex-Dependent Dynamic Reconstitution Model.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.1096},
pmid = {42970313},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is increasingly viewed as a disorder of large-scale brain network dynamics. Whether exercise-related changes in dynamic functional connectivity (dFC) reflect neural reorganization, vascular effects, or both remains uncertain, and most studies have not tested sex as a moderator. We propose the Sex-Dependent Dynamic Reconstitution Model (SDDRM) as a hypothesis-generating framework. Exercise may influence temporal flexibility (a dynamic connectivity metric) through partially sex-dependent pathways. In females, estrogen-BDNF signaling may potentiate medial temporal lobe (MTL) flexibility gains from aerobic exercise, but this possibility is constrained by menopausal status, age, menopausal hormone therapy (MHT; also known as hormone replacement therapy, HRT) exposure, and limited direct evidence. In males, structured exercise may preferentially influence default mode-frontoparietal coupling through IGF-1-related mechanisms. Evidence for these pathways is predominantly indirect and preclinical, and male and female pathways may overlap substantially. We outline four candidate, sex-stratified predictions: (1) sex may moderate exercise-related MTL flexibility changes, with menopausal status as an exploratory moderator; (2) dynamic flexibility changes may partially mediate cognitive improvement, with indirect pathway magnitudes compared using moderated mediation; (3) exercise cessation may produce different flexibility decay trajectories by sex; and (4) exercise modality may interact with sex. We emphasize dFC methodological caveats-including scan duration, motion, test-retest reliability, and neurovascular coupling-and distinguish biomarker-confirmed AD from MCI and cognitively unimpaired populations. This framework is intended to guide hypothesis-driven, sex-stratified research, not clinical exercise prescriptions.},
}

@article {pmid42970314,
year = {2026},
author = {Xu, J and Cao, Z and Liu, Y and Gao, A and Kong, Y},
title = {Fecal Microbiota Transplantation in Alzheimer's Disease: A Scoping Review of Human, Registry, and Preclinical Evidence.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0883},
pmid = {42970314},
issn = {2152-5250},
abstract = {Fecal microbiota transplantation (FMT) is being explored as a microbiota-directed intervention for Alzheimer's disease (AD), with evidence drawn mainly from preclinical studies. This scoping review mapped published human reports, registered trials and animal microbiota-transfer studies to inform FMT research in AD. Five human reports, eight unique registered trials and 34 animal studies were included. Four human reports concerned FMT administered for Clostridioides difficile infection (CDI). The remaining report was an uncontrolled five-patient pilot comprising two patients with AD, two with mild cognitive impairment (MCI) and one with frontotemporal dementia (FTD). It described maintained cognition in AD and FTD and improvement or maintenance in MCI. The published human studies were nonrandomized. Among the eight registered trials, two required AD biomarker confirmation and two specified donor-referenced engraftment outcomes. Among 30 animal studies assessing cognition, 24 reported positive findings and six mixed findings. Restriction to genetic/transgenic AD models reduced the positive proportion from 24/30 (80.0%) to 17/23 (73.9%). Cognition-specific randomization and blinding were reported in 16/30 (53.3%) and 4/30 (13.3%) studies, respectively. The evidence supports early-phase investigation, with attention to donor and product characterization, appropriate comparators, and separate measurement of engraftment, microbial function, systemic responses and AD outcomes. Safety data remain insufficient for patients with AD, particularly outside the CDI setting. FMT should remain investigational for AD.},
}

@article {pmid42970317,
year = {2026},
author = {Pourhadi, M and LeWitt, PA and Todi, SV},
title = {Ceruloplasmin in Disorders of the Nervous System.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0988},
pmid = {42970317},
issn = {2152-5250},
abstract = {Ceruloplasmin (Cp) is a multicopper ferroxidase that links copper handling, iron export, and redox homeostasis. Within the nervous system, these functions are critical because disruption of iron and copper balance can amplify oxidative stress, neuroinflammation, and neuronal vulnerability. Although Cp has long been studied as a circulating biomarker, most reports characterize it only by protein concentration, leaving its enzymatic and structural status comparatively unexplored. Here, we synthesize human literature on Cp across major neurological disorders, with attention to studies that assess Cp's ferroxidase activity, oxidation, fragmentation, and copper-binding state alongside its circulating levels. The evidence is by far most extensive in Alzheimer's and Parkinson's diseases, which together account for the majority of the reviewed literature: reduced ferroxidase activity, increased Cp oxidation, and altered non-Cp-bound copper are repeatedly linked to disease severity, regional iron accumulation, and biomarker-defined patient subgroups; in several studies, these alterations were independent of total Cp concentration. A smaller but growing body of evidence in amyotrophic lateral sclerosis, multiple sclerosis, essential tremor, and the cerebellar ataxias points to a related pattern of Cp-linked iron mishandling contributing to neuronal vulnerability. Preliminary findings from a few small studies in schizophrenia and a single study in obsessive-compulsive disorder further suggest that circulating Cp levels track systemic inflammatory and oxidative states in these conditions. From these investigations, a picture emerges where Cp's functional and structural integrity, rather than its abundance alone, is the more informative correlate of disease-relevant metal dyshomeostasis, most clearly demonstrated in Alzheimer's and Parkinson's diseases. Based on this body of work, we propose that future studies adopt combined assessments of Cp quantity and function to clarify disease-specific Cp signatures and to evaluate whether correcting Cp activity or copper/iron imbalance can improve outcomes.},
}

@article {pmid42970319,
year = {2026},
author = {Shin, J and Park, YJ and Lee, S and Kang, J and Lee, S and Lee, ES and Jung, HN and Ryoo, I and Chung, SJ and Eo, JS and Suh, SI and Oh, K and Koh, SB and Kang, SH},
title = {Baseline Physical Frailty Predicts Clinical Outcomes During Lecanemab Therapy in Early Alzheimer's Disease: A Prospective Real-World Cohort Study.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0978},
pmid = {42970319},
issn = {2152-5250},
abstract = {BACKGROUND: Physical frailty and sarcopenia are recognized as determinants of Alzheimer's disease (AD) progression, but their implications during anti-amyloid therapy remain unclear. We investigated their associations with longitudinal cognitive outcomes, treatment safety, tolerability, and plasma p-tau217 trajectories in patients with early AD receiving lecanemab.

METHODS: This prospective cohort included 187 patients with amyloid-positive early AD who initiated lecanemab at a tertiary memory clinic. Physical frailty was defined using the Short Physical Performance Battery (SPPB), and sarcopenia according to the 2019 Asian Working Group for Sarcopenia criteria. Logistic regression was used for infusion-related reactions (IRRs) and treatment discontinuation, whereas amyloid-related imaging abnormalities (ARIA) outcomes were evaluated using Firth penalized logistic regression because of the limited number of events. Longitudinal cognitive outcomes and plasma p-tau217 trajectories were analyzed using linear mixed-effects models.

RESULTS: SPPB-defined physical frailty and sarcopenia were associated with faster CDR-SB worsening (β = 1.52 and 1.40 points/year, respectively; both nominal p<0.001; both q<0.001). A greater decline in SNSB-D was observed in participants with SPPB-defined physical frailty (β=-11.36 points/year; 95% CI, -22.38 to -0.34; nominal p=0.044), although this association did not remain statistically significant after FDR correction (q=0.065). Neither exposure was associated with MMSE change. SPPB-defined physical frailty was associated with a higher risk of IRRs (adjusted odds ratio, 4.75; 95% confidence interval, 2.03-11.66; p<0.001), but was not associated with ARIA or treatment discontinuation. No differential plasma p-tau217 trajectories were detected according to baseline SPPB-defined physical frailty or sarcopenia status.

CONCLUSIONS: Baseline SPPB-defined physical frailty was associated with longitudinal clinical progression and IRRs during lecanemab treatment. These findings suggest that SPPB-defined physical frailty may represent a candidate prognostic marker of clinical outcomes during lecanemab therapy and warrant further validation in larger cohorts.},
}

@article {pmid42970657,
year = {2026},
author = {Ding, D and Yao, H and Yan, H and Huang, J and Zhang, R and Sun, H and Wu, T and Liu, Y},
title = {VR Scout for AD: An Immersive Virtual Reality System towards Early Screening of Alzheimer's Disease.},
journal = {IEEE transactions on visualization and computer graphics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TVCG.2026.3747520},
pmid = {42970657},
issn = {1941-0506},
abstract = {Alzheimer's Disease is a growing global health challenge, with early detection critical to effective intervention. Current screening methods such as biomarker detection and paper-based cognitive scales face limitations including cost, invasiveness, and cultural or age-related biases. In this work, we present a design and feasibility study of VR Scout for AD, an immersive virtual reality system specifically designed for the early screening of AD. The system comprises two scenario modules: a test-oriented module incorporating tasks adapted from clinically validated tools like the Montreal Cognitive Assessment and Color Trails Test, and a life-like module simulating daily activities to evaluate memory, attention, and executive function in a naturalistic environment. We conducted five iterative prototyping sessions with neurologists and older adults with and without cognitive decline, collecting qualitative feedback and System Usability Scale scores. Through repeated revisions, we improved system accessibility, usability, and comprehensiveness. The final version received a score of 91.9, indicating excellent usability and strong user acceptance. Our findings suggest that VR Scout is a promising, user-friendly tool for scalable, non-invasive early AD screening.},
}

@article {pmid42970748,
year = {2026},
author = {Esteller-Gauxax, D and Pérez-Millan, A and Sarto, J and Guillén, N and Puey, R and Collet-Romà, T and Comas-Albertí, A and Borrego-Écija, S and Canasto, P and Martín-Sobrino, I and Massons, M and Bosch, B and Rigol, A and Patricio, V and Juncà-Parella, J and Fernández-Villullas, G and Alcón, D and García, RR and Rondán, LN and Augé Fradera, JM and Antonell, A and Falgàs, N and Tort-Merino, A and Lladó, A and Sánchez-Valle, R and Balasa, M},
title = {Plasma P-Tau217 and NfL Longitudinal Changes Across Neurodegenerative Diseases: Impact of α-Synuclein in Alzheimer Disease.},
journal = {Neurology},
volume = {107},
number = {10},
pages = {e218685},
doi = {10.1212/WNL.0000000000218685},
pmid = {42970748},
issn = {1526-632X},
mesh = {Humans ; *tau Proteins/blood ; Female ; *alpha-Synuclein/blood/metabolism ; *Alzheimer Disease/blood ; Male ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Aged ; Longitudinal Studies ; Prospective Studies ; *Neurodegenerative Diseases/blood ; Disease Progression ; Phosphorylation ; Aged, 80 and over ; Lewy Body Disease/blood ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma phospho-tau217 (p-tau 217) is a validated biomarker of Alzheimer disease (AD), and its longitudinal dynamics may reflect AD progression. Plasma neurofilament light chain (NfL) reflects axonal injury and neurodegeneration. Their trajectories may be modulated by concomitant proteinopathies such as α-synuclein (aSyn). We aimed to characterize longitudinal changes (36 months) in plasma p-tau217 and NfL across neurodegenerative and non-neurodegenerative cognitive disorders and to examine biomarker trajectories according to aSyn pathology status within AD.

METHODS: In this prospective single-center cohort, participants were recruited from a memory clinic in Barcelona, Spain. Participants were eligible if they had cognitive impairment because of neurodegenerative or non-neurodegenerative conditions between 2019 and 2022 and if baseline and 3-year follow-up blood samples were available. CSF AD biomarkers measured with Lumipulse and aSyn pathology assessed using real-time quaking-induced conversion assay were determined at baseline and used for patient diagnosis. Plasma p-tau217 and NfL were measured with Lumipulse at baseline and 36 months and analyzed as study outcomes. Between-group differences at longitudinal level were assessed using linear mixed-effects models.

RESULTS: A total of 223 participants were included: 92 AD-aSyn- (69.6 [5.6] years, 57.8% female), 15 AD-aSyn+ (69.1 [5.8] years, 53.3% female), 17 dementia with Lewy bodies (DLB)-AD- (70.9 [6.8] years, 23.5% female), 13 DLB-AD+ (age 72.3 [5.0] years, 30.8% female), 48 frontotemporal lobar dementia (FTD) (65.5 [8.8] years, 45.8% female), and 38 non-neurodegenerative cognitive impairment (NNCI) (65.3 [7.7] years, 35.9% female). At baseline, AD-aSyn+ and AD-aSyn- groups showed the highest plasma p-tau217, whereas DLB-AD+ showed intermediate levels and DLB-AD-, FTD, and NNCI the lowest. Over 36 months, AD-aSyn+ exhibited the steepest increase in p-tau217 (2.19 pg/mL; p < 0.001), whereas AD-aSyn- and DLB-AD+ showed smaller increases; DLB-AD-, FTD, and NNCI remained stable. For NfL, FTD and AD-aSyn+ had the highest levels at baseline and follow-up (both p < 0.001), with similar increases. AD-aSyn-, DLB-AD+, and DLB-AD- showed intermediate values with moderate increases, whereas NNCI displayed limited changes.

DISCUSSION: Plasma p-tau217 changes longitudinally in AD, and its trajectory is modulated by α-synuclein pathology. Patients with AD-aSyn+ show higher levels of NfL, similar to FTD, highlighting greater neuroaxonal injury. α-synuclein positivity identifies an AD-aSyn+ subgroup with steeper increases in p-tau217 and NfL, supporting biomarker-based stratification for prognosis and trial enrichment.},
}

Humans
*tau Proteins/blood
Female
*alpha-Synuclein/blood/metabolism
*Alzheimer Disease/blood
Male
*Neurofilament Proteins/blood
Biomarkers/blood
Aged
Longitudinal Studies
Prospective Studies
*Neurodegenerative Diseases/blood
Disease Progression
Phosphorylation
Aged, 80 and over
Lewy Body Disease/blood

@article {pmid42971085,
year = {2026},
author = {Song, J and Yue, H and Zhang, C and Jiao, J and Jiao, J},
title = {A background-suppressed CRISPR/Cas13a-HRCA biosensor for ultrasensitive miR-137 detection toward differential screening of Alzheimer's disease.},
journal = {Talanta},
volume = {314},
number = {},
pages = {130886},
doi = {10.1016/j.talanta.2026.130886},
pmid = {42971085},
issn = {1873-3573},
abstract = {Alzheimer's disease (AD) is associated with pathological changes that can occur years before the onset of clinical symptoms, highlighting the importance of sensitive biomarker detection for early diagnosis. Here, we developed a fluorescence biosensing platform based on CRISPR/Cas13a-assisted hyperbranched rolling circle amplification (CRISPR/Cas13a-HRCA) for the detection of the AD-related biomarker miR-137. A duplex composed of Linear-Bio and a Cas13a linker strand was first immobilized on streptavidin-coated magnetic beads to construct magnetic probes. In the presence of miR-137, the linker strand was displaced and released into solution through strand exchange and magnetic separation. The released linker activated the CRISPR/Cas13a system via complementary pairing with crRNA, leading to cleavage of the UUU site within the topological DNA reporter (TDR). The cleaved TDR subsequently initiated the HRCA reaction in the presence of Vent DNA polymerase and the P2 probe, generating abundant double-stranded DNA products for fluorescence readout using SYBR Green I. By combining CRISPR/Cas13a amplification, magnetic separation, and label-free fluorescence detection, the platform produced a fluorescence response to miR-137 over 10 fM-100 nM, with an LOD and LOQ of 1.77 and 11.11 fM, respectively. Recoveries ranged from 99% to 106%, with RSDs of 2.2-2.6% in aCSF. Furthermore, the method successfully distinguished cerebrospinal fluid samples from AD patients and healthy individuals, demonstrating its potential for AD-related miRNA analysis.},
}

@article {pmid42971292,
year = {2026},
author = {Ramin, F},
title = {Memory and Forgetting in Avicenna's Thought: A Philosophical-Medical Perspective on Alzheimer's Disease.},
journal = {Current problems in cardiology},
volume = {},
number = {},
pages = {103493},
doi = {10.1016/j.cpcardiol.2026.103493},
pmid = {42971292},
issn = {1535-6280},
abstract = {How historical medical and psychological concepts can be compared with contemporary formulations in the life sciences is a central question in the history and philosophy of the life sciences. This article examines this question through the concepts of memory and forgetting (nisyān) in Avicenna's Islamic thought and their relation to contemporary understandings of Alzheimer's disease. Using a historical-analytical method and a comparative approach, the study first reconstructs the structure of memory and the conceptual distinctions between nisyān and other forms of cognitive disorder in Avicenna's philosophical and medical works. It then considers these concepts in relation to four contemporary issues: the cognitive organization of memory, the relation between retention and retrieval, the implications of dysfunction in a single cognitive faculty for cognition as a whole, and the relationship between cognition, bodily conditions, and biological processes. The analysis shows that Avicenna situates memory within an organized system of cognitive faculties and relates its functioning to bodily conditions, whereas contemporary accounts explain memory through cognitive processes and neural and pathological mechanisms. The comparison therefore reveals neither an equivalence between historical concepts and contemporary diagnoses nor an absence of comparability, but differences in the levels and modes of explanation. The article argues that the historical study of memory and forgetting can illuminate how a common cognitive problem has been conceptualized and explained within different epistemic frameworks.},
}

@article {pmid42971333,
year = {2026},
author = {El-Far, SS and Abo-Saif, M and El-Sherbeni, SA and Ragab, AE and Ibrahim, SM},
title = {Phytochemical investigation and neuroprotective effect of Encephalartos kisambo Faden & Beentje: Regulation of SIRT1, lnc-MALAT1, and vimentin in mice.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107545},
doi = {10.1016/j.fitote.2026.107545},
pmid = {42971333},
issn = {1873-6971},
abstract = {The aim of this study is to conduct research about the phytochemical composition and neuroprotective potential of Encephalartos kisambo leaves. LC-ESI-MS/MS profiling of the methanolic extract putatively annotated 56 different compounds. Six compounds, namely β-sitosterol, 7,4',7'',4'''-tetra-O-methyl amentoflavone, kayaflavone, isoginkgetin, bilobetin, and amentoflavone were isolated and characterized by spectroscopical investigations using UV, 1D- and 2D-NMR, HPLC-ESI-MS, and HR-ESI-MS. The neuroprotective efficacy of the ethyl acetate and n-butanol fractions was evaluated in vivo using an aluminum chloride-induced neurodegeneration model. The ethyl acetate and n-butanol fractions exihibted significant cognitive improvement in the Morris water maze test. These fractions also enhanced catalase activity while markedly reducing malondialdehyde levels, indicating their ability to alleviate oxidative stress associated with dementia. Furthermore, treatment with the n-butanol fraction downregulated the expression of lnc-MALAT1 and vimentin while upregulating SIRT1, suggesting modulation of neuroinflammatory and apoptotic pathways. Histopathological examination revealed that co-administration of the n-butanol fraction with AlCl3 preserved the neuronal architecture in the cerebral cortex and CA2 region of the hippocampus. These findings highlighted E. kisambo as a promising source of neuroprotective agents with potential therapeutic relevance to help prevent Alzheimer's disease and manage its development.},
}

@article {pmid42971340,
year = {2026},
author = {Pan, Y and Yang, R and Xu, Y and Zhang, H},
title = {Disentangling Reproductive History and Parenthood in Late-Life Cognitive and Vascular Brain Health.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {107075},
doi = {10.1016/j.neubiorev.2026.107075},
pmid = {42971340},
issn = {1873-7528},
abstract = {Women bear a greater burden of Alzheimer's disease (AD), prompting interest in whether reproductive history contributes to late-life brain health. Yet parity, a count of live births, compresses biologically and socially distinct reproductive trajectories into a single measure. Current human biomarker studies provide little evidence that parity tracks amyloid-β or tau pathology. The clearest human evidence links adverse pregnancy outcomes (APOs), particularly hypertensive disorders of pregnancy (HDP), to later vascular brain injury and vascular dementia, supporting a life-course vascular framework that separates preconception susceptibility, pregnancy complications, and postpartum recovery. Mother-father comparisons further indicate that parenthood-related social exposures contribute to the observed associations. Obstetric history therefore has direct relevance to vascular risk assessment, whereas AD biomarker testing should follow established clinical and biomarker indications rather than parity. Future studies should pair exposure-resolved reproductive histories with serial postpartum phenotyping, vascular neuroimaging, and longitudinal AD biomarkers.},
}

@article {pmid42966516,
year = {2026},
author = {Fu, J and Liang, Z and Wang, F and Xiong, F and Wang, X and Sun, J and Zhan, J and Hu, K and Gao, H},
title = {Dendrobium officinale extract ameliorates Alzheimer's disease by modulating PI3K-AKT-mTOR pathway and autophagy-related processes: An integrated study combining feature-based molecular networking, network pharmacology and multi-omics.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122588},
doi = {10.1016/j.jep.2026.122588},
pmid = {42966516},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with limited effective treatments. Dendrobium officinale Kimura & Migo (D. officinale) has been traditionally used for dementia, but its active constituents and mechanisms remain unclear.

AIM OF THE STUDY: This study aimed to systematically characterize the chemical constituents of D. officinale extract (DOE) and elucidate its anti-AD mechanisms using an integrated pharmacological strategy.

MATERIALS AND METHODS: The chemical composition of DOE was analyzed using UHPLC-Q-TOF/MS combined with feature-based molecular networking (FBMN). Target prediction and pathway analysis were performed using a network pharmacology approach. Therapeutic effects were evaluated in 5×FAD mice using behavioral and histopathological assays. Mechanistic validation was further conducted using transcriptomics, proteomics, qRT-PCR, Western blotting, and molecular docking.

RESULTS: Sixty-five components were identified, with apigenin, naringenin, rutin and oxyresveratrol as major identified constituents. Integrated multi-omics and network pharmacology analyses highlighted the PI3K-AKT-mTOR pathway and autophagy-related processes as potential mechanisms underlying the anti-AD effects of DOE. In 5×FAD mice, DOE markedly improved cognitive deficits, alleviated hippocampal neuronal injury, reduced Aβ plaque deposition, and suppressed astrocytic and microglial activation. Mechanistically, DOE significantly downregulated the mRNA expression of Pi3k, Akt, and Mtor, reduced AKT and mTOR phosphorylation, and showed a trend toward decreased PI3K phosphorylation. DOE also reduced p62 accumulation and increased the LC3-II/LC3-I ratio, suggesting an improvement in autophagy-related processes. Molecular docking further demonstrated favorable binding affinities of major identified constituents toward key targets, particularly AKT1 and PIK3CA.

CONCLUSION: DOE ameliorates AD-related pathological changes, potentially through modulation of the PI3K-AKT-mTOR pathway and improvement of autophagy-related processes. These findings provide experimental evidence supporting the potential of D. officinale as a multi-target therapeutic candidate for AD.},
}

@article {pmid42966519,
year = {2026},
author = {Goetzl, EJ},
title = {Current development of therapeutic strategies for Alzheimer's disease.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2026.10.031},
pmid = {42966519},
issn = {1555-7162},
abstract = {Alzheimer's disease is an increasingly prevalent neurodegenerative cause of dementia. The prevailing model begins with neuronal deposits of beta-amyloid (Aβ42) (phase I), followed by intra-neuronal fibrillary tangles of p-tau (phase II) that recruit numerous effector pathways (phase III) leading to neuronal damage, synaptic loss and gliosis. Monoclonal anti-Aβ antibodies and tau substituent peptide-elicited anti-p-tau antibodies reduce brain loads of these pathogenic proteins. Anti-Aβ antibodies decreased cognitive loss by a mean of 26%, but anti-p-tau antibodies had no effect. Anti-p-tau antibodies were well-tolerated, but 30% of patients receiving anti-Aβ antibodies had brain areas of swelling and hemorrhages detected by imaging. Early studies of pharmacological alteration of phase III neuropathic effector mechanisms in humans and mouse models include inhibition of intersectin-1 to preserve mitophagy and synaptic vesicle recycling, melanin-concentrating hormone prevention of memory loss, chimeric (brain astrocyte) antigen-astrocyte reduction in Aβ load, PD-1 immune checkpoint inhibitor suppression of neuroinflammation, and reduction in oxidative stress by phytochemicals or MitoVitE. The many possible mechanisms of decreased resilience of neurons to effector attacks of Alzheimer's disease remain under investigation.},
}

@article {pmid42966893,
year = {2026},
author = {Gao, W and Gao, J and Su, X and Kong, X and Wei, X and Ding, T and Guo, T and Gao, S and Zhou, Y and Zhou, J and Zhao, H},
title = {Cross-Organ Multi-Omics Profiling of Systemic Alterations in 5xFAD Mice and Changes Associated with Huanglian Jiedu Decoction Treatment.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {},
doi = {10.1002/advs.78442},
pmid = {42966893},
issn = {2198-3844},
support = {CI2023C020YL//Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences/ ; CI2023E001TS09//Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences/ ; CI2026A04509//Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences/ ; 81974523//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic disorder involving metabolic abnormalities beyond the brain, but links between hepatic alterations and neuroinflammation remain unclear. We integrated behavioral, histopathological, transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses in male mice assigned to WT (n = 15), AD (n = 16), high-dose HLJDD (n = 16), low-dose HLJDD (n = 11), and donepezil (n = 10) groups and treated for 10 weeks. Longitudinal behavioral data were analyzed using repeated-measures models, and omics p-values were adjusted using the Benjamini-Hochberg FDR procedure. Cognitive impairment, glial activation, and neuroinflammation were accompanied by hepatic metabolic disturbances and alterations in insulin signaling and energy metabolism, implicating PPAR and PI3K/Akt-related processes. HLJDD, particularly at the high dose, improved behavioral and neuropathological outcomes and shifted abnormalities in TCA-cycle metabolites, amino acid neurotransmitters, and oxidative balance toward WT levels. To assess hepatocyte contributions to microglial inflammation, we established an AML12-BV2 conditioned-medium model with hepatocyte PPAR-γ knockdown. Conditioned medium from LPS/HLJDD-cotreated AML12 cells elicited lower inflammatory responses in BV2 cells than medium from LPS-treated hepatocytes. PPAR-γ knockdown attenuated this effect, supporting a hepatocyte PPAR-γ-dependent contribution to microglial regulation and further investigation of hepatic involvement in HLJDD-associated neuroprotection.},
}

@article {pmid42966930,
year = {2026},
author = {Paladino, J and Echols, H and Thacker, A and Gale, SA and Ramirez Gomez, L and Weizenbaum, E and Pu, CT and Ritchie, C and Shah, SJ and Lindenberger, E},
title = {Communication and shared decision-making for anti-amyloid therapy in early Alzheimer's disease: An exploratory qualitative study of real-world audio-recorded clinical encounters.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70343},
pmid = {42966930},
issn = {2352-8737},
abstract = {INTRODUCTION: Anti-amyloid therapies (AATs) for Alzheimer's disease (AD) offer modest slowing of cognitive decline but involve meaningful risks, burdens, and uncertainty. Decisions about AAT are preference sensitive and optimally guided by shared decision making (SDM), yet little is known about how these conversations unfold in real-world clinical practice.

METHODS: We conducted an exploratory qualitative content analysis of audio-recorded AAT counseling encounters in neurology clinics at two academic medical centers. Participants included neurology clinicians, patients with mild cognitive impairment or mild dementia due to AD, and care partners. We examined how clinicians presented options, benefits, risks, and burdens; elicited patient values and preferences; assessed understanding; and engaged patients and care partners.

RESULTS: We analyzed 10 encounters involving 9 patients and 5 clinicians; 8 patients had a care partner present. Encounters occurred at different stages of decision making, including pre-decision visits and visits in which a treatment decision was made. Clinicians consistently explained AAT mechanisms using action-oriented language, emphasized modest benefits, and discussed amyloid-related imaging abnormalities, magnetic resonance imaging monitoring as a safety net, and treatment logistics. However, communication framing varied. Some clinicians used optimistic framing that may have shaped treatment perceptions, while explicit discussion of not pursuing AAT as a valid option was rare. Open-ended exploration of values and goals varied and occurred more often in pre-decision encounters, whereas visits closer to treatment decisions focused on treatment selection and logistics. Assessment of treatment understanding ranged from open-ended teach-back, which revealed misunderstandings in some cases, to closed-ended checks. Clinicians also varied in how they balanced patient and care partner participation.

DISCUSSION: Although clinicians consistently addressed core medical information about AAT, variation in framing, values elicitation, teach-back, presentation of alternatives, and patient-care partner engagement may shape AAT decision making. Communication strategies that explicitly present options, connect potential outcomes to patient priorities, and reinforce understanding may support balanced, values-aligned SDM.},
}

@article {pmid42966961,
year = {2026},
author = {Alwithanani, NA},
title = {Bidirectional Interplay Between Periodontitis and Alzheimer's Disease: Mechanisms, Clinical Management, and Preventive Strategies.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e117264},
pmid = {42966961},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder, whereas periodontitis is a highly prevalent chronic inflammatory disease that may have important systemic consequences. Increasing evidence suggests a bidirectional relationship between periodontitis and AD, with periodontal inflammation potentially contributing to cognitive decline and neurodegeneration, while cognitive and motor impairment may simultaneously worsen oral hygiene and periodontal health. This narrative review synthesizes current evidence regarding the epidemiological association, potential biological mechanisms, clinical implications, and emerging preventive and therapeutic strategies linking the two conditions. Evidence indicates that periodontitis is associated with an increased risk of cognitive impairment and AD, although causality remains unproven. Proposed mechanisms include translocation of periodontal pathogens, particularly Porphyromonas gingivalis, systemic inflammation and neuroinflammation, blood-brain barrier disruption, oxidative stress, microbiome alterations, and effects on amyloid-β and tau pathology. In patients with AD, progressive cognitive impairment can compromise oral self-care and increase dependence on caregivers, contributing to periodontal deterioration. Early periodontal assessment, individualized treatment, caregiver-supported oral hygiene, regular maintenance, and interdisciplinary care may therefore be clinically beneficial. Emerging approaches targeting periodontal pathogens, gingipains, and the oral microbiome are promising but require stronger clinical validation. Overall, maintaining periodontal health represents a potentially modifiable component of comprehensive strategies for reducing the oral and systemic burden associated with AD.},
}

@article {pmid42966975,
year = {2026},
author = {Kujuro, Y and Saito, M and Maruko, M and Qian, E and Koh, H and Katai, H and Hattori, H},
title = {Spatial patterns of amyloid clearance after donanemab: A preliminary 12-month real-world amyloid PET study in Japanese patients with early Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70539},
pmid = {42966975},
issn = {2352-8729},
abstract = {INTRODUCTION: The regional pattern of amyloid clearance during donanemab treatment in routine practice is poorly characterized.

METHODS: We analyzed amyloid positron emission tomography (Centiloid, regional standardized uptake value ratio, visual reads) at baseline and 12 months in 18 donanemab-treated patients with early Alzheimer's disease.

RESULTS: Clearance was near-complete (removal 96%; 72% visually negative, i.e., full treatment-related amyloid clearance), although lower in the 2 early-onset (78%) than the 16 late-onset patients (98%). Higher baseline burden and older age predicted greater clearance (r = 0.88, P < .001; r = 0.60, P = .009, respectively). This held regionally (r = 0.82-0.91, all P < .001), with the posterior cingulate and precuneus clearing first. Clearance was independent of medial temporal atrophy and unrelated to 12-month cognitive change.

DISCUSSION: Donanemab cleared regional amyloid in proportion to its baseline distribution, with deposition-heavy regions clearing first and the temporal cortex retaining residual signal, independent of neurodegenerative stage and unrelated to short-term cognition.},
}

@article {pmid42967021,
year = {2026},
author = {Bao, X and García Pascual, B and Blakstad, E and Norgren, J and Abzhandadze, T and Zhu, N and Hoang, MT and Chatterjee, S and Scolamiero, M and Eriksdotter, M and Xu, H and Ptacek, SG},
title = {Mini-Mental State Examination trajectories across dementia subtypes in the Swedish Registry for Cognitive/Dementia Disorders and U.S. National Alzheimer's Coordinating Center.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70531},
pmid = {42967021},
issn = {2352-8729},
abstract = {INTRODUCTION: Mini-Mental State Examination (MMSE) trajectories are widely used to describe cognitive decline in dementia, but estimates may be sensitive to cohort structure, follow-up density, and modeling assumptions. We compared subtype-specific MMSE trajectories across two complementary longitudinal data resources.

METHODS: The analyzed data were from the Swedish Registry for Cognitive/Dementia Disorders (SveDem) and the U.S. National Alzheimer's Coordinating Center (NACC). Participants were included with at least two valid cognitive assessments separated by ≥ 90 days. The final cohorts included 30,115 SveDem participants and 33,429 NACC participants. Subtype-stratified regression-spline generalized additive mixed models and linear mixed-effects models were fitted with adjustment for demographic and clinical covariates.

RESULTS: Compared with NACC, SveDem participants were older (median age 79 vs. 72 years), had lower baseline MMSE scores (22.3 ± 4.2 vs. 26.5 ± 4.6), and had shorter follow-up (median 1.9 vs. 3.2 years; mean cognitive assessments 2.9 vs. 4.5). Shared dementia subtypes showed broadly similar relative decline patterns across cohorts. In regression-spline models, Alzheimer's disease showed faster estimated annualized decline than vascular dementia in both SveDem (-0.79 vs. -0.49 MMSE points/year) and NACC (-1.22 vs. -0.24 points/year). Lewy body dementias and frontotemporal dementia showed intermediate but less consistent patterns. Absolute decline estimates varied by model specification, particularly where later follow-up was sparse.

DISCUSSION: Relative subtype-specific MMSE decline patterns were broadly reproducible, whereas absolute long-horizon estimates required cautious interpretation. These cross-cohort reference patterns may support future dementia epidemiology studies using MMSE trajectories to compare subtypes, examine clinical factors or evaluate treatment-related associations.},
}

@article {pmid42967168,
year = {2026},
author = {Cao, S and Liu, T and Cheng, X and Tian, X and Wei, J},
title = {The "Invisible Killer" of Neurodegeneration: Mitochondrial Dysfunction in Neurodegenerative Disorders, Mechanisms, Emerging Pathways and Therapeutic Strategies.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {653025},
pmid = {42967168},
issn = {1178-7031},
abstract = {Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) place substantial burden on global public health. Mounting evidence identifies mitochondrial dysfunction as a central contributor to neuronal damage and progressive brain functional decline. As a narrative review, this work aims to dissect mitochondrial‑associated pathological features across these major neurodegenerative disorders, summarize under‑recognized emerging mechanisms, and highlight translational bottlenecks for mitochondrial‑targeted therapies. Mitochondria sustain neuronal survival by mediating oxidative‑phosphorylation‑driven energy production, biomolecule biosynthesis, calcium homeostasis, reactive oxygen species (ROS) metabolism, and apoptotic regulation. In PD, aggregated α‑synuclein (α‑syn) damages respiratory‑chain complex I, perturbs mitochondrial dynamics and blocks PINK1/Parkin‑dependent mitophagy. In AD, amyloid‑β together with hyper‑phosphorylated tau (p-Tau) impairs respiratory complex activity, axonal mitochondrial trafficking and mitophagic clearance. Mutant huntingtin induces multiple mitochondrial lesions in HD, while inflammation‑triggered oxidative stress secondarily compromises mitochondrial function in MS. Pathogenic mutations in ALS disrupt respiratory‑chain assembly, mitochondrial dynamics and mitophagy. Beyond classic mitochondrial defects including respiratory‑chain impairment, dynamic imbalance and defective mitophagy, emerging mechanisms such as mitocytosis, mitochondrial aminoacyl‑tRNA synthetase (mt‑aaRS) dysfunction and mitochondria‑associated membrane (MAM) disruption are discussed. Mitochondrial dysfunction drives neurodegeneration via energy exhaustion, aggravated oxidative stress, pathological protein aggregation and excessive neuronal apoptosis. We further recapitulate mitochondrial‑oriented therapeutic approaches including small‑molecule regulators, mitophagy activators, mitochondrial biogenesis promoters, gene‑editing strategies and mitochondrial transplantation. Notable translational obstacles remain, including limited blood‑brain‑barrier penetration of candidate drugs, narrow therapeutic time‑window post‑symptom onset, and prominent disease heterogeneity. By synthesizing basic experimental findings and pre‑clinical and clinical trial progress, this review provides updated insights into the pathogenesis of neurodegenerative diseases and facilitates the development of precise mitochondrial‑targeted therapeutic regimens.},
}

@article {pmid42967243,
year = {2026},
author = {Kartik, S and Rohilla, K and Pal, R},
title = {Targeting RIPK1-NF-κB crosstalk: A novel perspective on necroptosis in Alzheimer's Disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42967243},
issn = {1573-4978},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; *Necroptosis ; Signal Transduction ; *NF-kappa B/metabolism ; Animals ; Neurons/metabolism/pathology ; Apoptosis ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition characterised by gradual neuronal degradation, resulting in cognitive decline and memory loss. Multiple pathogenic mechanisms drive the progression of the disease, including amyloid-β (Aβ) and tau accumulation (neurofibrillary tangles), mitochondrial dysfunction, synaptic loss, chronic neuroinflammation, and neuro nal death. Neuronal loss in AD occurs through various forms of regulated cell death, including apoptosis, ferroptosis, pyroptosis, parthanatos, and necroptosis, each characterised by specific pathways and subsequent inflammatory consequences. Despite decades of focus on apoptosis and necrosis as the primary modes of neuronal loss, necroptosis has remained relatively understudied until recently. Necroptosis is a caspase-independent, inflammatory cell death pathway governed by the RIPK1-RIPK3-MLKL signalling axis. Activation of this pathway disrupts plasma membrane integrity, triggering the release of damage-associated molecular patterns (DAMPs) that sustain a self-propagating cycle of neuroinflammation and secondary neuronal loss. Crucially, RIPK1 signalling is closely linked to nuclear factor-[Formula: see text]B (NF-[Formula: see text]B), a principal modulator of inflammatory and cell-survival mechanisms. Although NF-[Formula: see text]B activation can facilitate neuronal survival under physiological conditions, its sustained activation in the AD brain promotes the synthesis of pro-inflammatory mediators, thereby accelerating neurodegeneration. This review discusses the emerging role of RIPK1-mediated necroptosis in AD and examines its functional interaction with NF-[Formula: see text]B signalling in driving neuroinflammation. Additionally, it examines emerging therapeutic strategies targeting the RIPK1-NF-[Formula: see text]B axis to alter disease progression and achieve disease-modifying potential in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
*Necroptosis
Signal Transduction
*NF-kappa B/metabolism
Animals
Neurons/metabolism/pathology
Apoptosis
Amyloid beta-Peptides/metabolism

@article {pmid42967355,
year = {2025},
author = {Dellafiore, F and Guardamagna, L and Casole, L and Modena, G and Diamanti, O and Nania, T},
title = {[The Process of Becoming a Caregiver to Patients with Advanced Alzheimer's Disease: A Constructivist Grounded Theory Study].},
journal = {Professioni infermieristiche},
volume = {78},
number = {3-4},
pages = {59-75},
pmid = {42967355},
issn = {0033-0205},
mesh = {Humans ; *Alzheimer Disease/nursing/therapy ; *Caregivers/psychology ; Grounded Theory ; Female ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; Italy ; },
abstract = {INTRODUCTION: Alzheimer's disease is an increasing public health issue with a substantial impact on caregivers, who are often family members. Approximately 600,000 people live with Alzheimer's disease in Italy. Managing patients with advanced disease poses considerable physical and psychological challenges for caregivers. This study explored the process of becoming a caregiver to patients with advanced Alzheimer's disease.

METHODS: A qualitative study based on constructivist grounded theory was conducted. Ten caregivers of patients with advanced Alzheimer's disease participated in 16 semi-structured interviews conducted between September and December 2023. Purposive sampling was followed by theoretical sampling until saturation was reached. Data analysis followed Charmaz's approach and included coding, constant comparison, and memo writing.

RESULTS: Four main categories emerged: changing daily life, feeling powerless, losing oneself, and sharing care with others. Caregivers reported social isolation, personal sacrifices, powerlessness in the face of disease progression, and difficulty maintaining a balance between caregiving and their own lives. These experiences had significant consequences for psychological and physical health. Support from hired caregivers provided partial relief and enabled participants to regain part of their daily lives.

DISCUSSION: The findings underline the profound impact of advanced Alzheimer's disease on caregivers and provide insights into the Italian context. They highlight the sense of responsibility that motivates family members to provide care and the importance of external support in improving caregivers' quality of life.

CONCLUSIONS: Becoming a caregiver to a patient with advanced Alzheimer's disease involves substantial sacrifices and challenges. The four categories demonstrate the need for appropriate healthcare and social support to strengthen caregiver resilience. Further studies are needed to develop more effective support strategies.},
}

Humans
*Alzheimer Disease/nursing/therapy
*Caregivers/psychology
Grounded Theory
Female
Male
Aged
Middle Aged
Aged, 80 and over
Italy

@article {pmid42967519,
year = {2026},
author = {Eiser, AR},
title = {Why Homocysteine Gets No Respect How That Adversely Impacts the Health of American Seniors.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2026.10.036},
pmid = {42967519},
issn = {1555-7162},
}

@article {pmid42967579,
year = {2026},
author = {Wang, Z and Lin, G and Fang, F and Yu, J},
title = {MRI-derived glymphatic-related composite captures brain and cognitive vulnerability associated with cardiovascular risk in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71961},
pmid = {42967579},
issn = {1552-5279},
support = {32371109//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Female ; Aged ; *Magnetic Resonance Imaging/methods ; Male ; *Glymphatic System/diagnostic imaging ; *Cardiovascular Diseases/diagnostic imaging ; *Brain/diagnostic imaging/pathology ; *Cognition/physiology ; Heart Disease Risk Factors ; Diffusion Tensor Imaging ; China ; },
abstract = {INTRODUCTION: We evaluated a multimodal magnetic resonance imaging (MRI)-derived glymphatic-related composite and examined its associations with cardiovascular risk, brain structural integrity, and cognition in older adults.

METHODS: Ninety-two participants were included in the baseline analyses and 68 in the 6-month reassessment analyses. Cardiovascular risk was estimated using the Prediction for ASCVD Risk in China 10-year atherosclerotic cardiovascular disease score. The glymphatic-related composite integrated six MRI-derived measures: choroid plexus volume, choroid plexus free-water fraction, diffusion tensor image analysis along the perivascular space index, blood oxygen level-dependent signal-cerebrospinal fluid coupling, basal ganglia perivascular spaces, and deep white matter perivascular spaces. Outcomes included cortical thickness in Alzheimer's disease (AD)-vulnerable regions, peak width of skeletonized mean diffusivity, and cognitive performance.

RESULTS: Higher cardiovascular risk was associated with lower glymphatic-related composite scores and lower cortical thickness in AD-vulnerable regions at baseline and the 6-month reassessment. Higher cardiovascular risk was also indirectly associated with poorer flanker task performance through the glymphatic-related composite at both assessments.

DISCUSSION: The MRI-derived glymphatic-related composite showed consistent associations with cardiovascular risk and cognitive vulnerability across repeated assessments and may serve as a summary measure of glymphatic-related MRI features in older adults.},
}

Humans
Female
Aged
*Magnetic Resonance Imaging/methods
Male
*Glymphatic System/diagnostic imaging
*Cardiovascular Diseases/diagnostic imaging
*Brain/diagnostic imaging/pathology
*Cognition/physiology
Heart Disease Risk Factors
Diffusion Tensor Imaging
China

@article {pmid42967588,
year = {2026},
author = {Sheets, KM and Curran, JM and Mielke, MM and Zeng, X and Karikari, TK and Sutphen, CL and Register, TC and Murray, AM},
title = {Chronic kidney disease and blood-based biomarkers of Alzheimer's disease: the brain in kidney disease study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71940},
pmid = {42967588},
issn = {1552-5279},
support = {U24AG082930/AG/NIA NIH HHS/United States ; R01 AG03755/AG/NIA NIH HHS/United States ; P30AG049638/AG/NIA NIH HHS/United States ; P30AG072947/AG/NIA NIH HHS/United States ; //Satellite Health Inc./ ; //Minneapolis Medical Research Foundation/ ; },
mesh = {Humans ; Female ; Biomarkers/blood ; *Alzheimer Disease/blood/complications ; *Renal Insufficiency, Chronic/blood/complications ; *tau Proteins/blood ; Aged ; Male ; Glomerular Filtration Rate/physiology ; Brain/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Reduced kidney function affects the levels of many Alzheimer's disease and related dementias (ADRD) blood-based biomarkers (BBMs). The extent to which kidney function is associated with serum levels of brain-derived tau (BD-tau), a novel BBM specific for Alzheimer's disease-type neurodegeneration, is unknown.

METHODS: ADRD BBMs were measured in stored serum samples from 443 BRain IN Kidney Disease study participants (mean age 68.9 years, 49% female).

RESULTS: Lower estimated glomerular filtration rate (eGFR; poorer kidney function) was inversely associated with levels of serum BD-tau: BD-tau 54.6 pg/mL (standard deviation [SD] 24.47) for eGFR < 15 mL/min/1.73 m[2], 34.16 [20.47] for eGFR 15 to 29, 22.89 [23.43] for eGFR 30 to 44, 16.76 [19.88] for eGFR 45 to 59, and 9.19 [9.05] for eGFR ≥60. Greater urine albumin-to-creatinine ratio (UACR; greater albuminuria) was positively associated with levels of serum BD-tau: BD-tau 39.84 pg/mL [SD 31.76] for UACR > 300 mg/g, 22.57 [21.59] for UACR 30 to 300, and 14 [10.72] for UACR < 30. These trends were consistent for all levels of cognitive impairment (CI; from no CI to severe CI) and persisted following adjustment for age, race, sex, and education. In contrast, associations of kidney function with the pTau217/BD-tau ratio were generally non-significant.

DISCUSSION: Kidney function needs to be considered when interpreting BD-tau levels.},
}

Humans
Female
Biomarkers/blood
*Alzheimer Disease/blood/complications
*Renal Insufficiency, Chronic/blood/complications
*tau Proteins/blood
Aged
Male
Glomerular Filtration Rate/physiology
Brain/metabolism
Middle Aged

@article {pmid42967596,
year = {2026},
author = {Sabt, A and Aboulthana, WM and Saleh, AM and Ibrahim, HAA and Saleh, A and Lei, X and Srour, AM},
title = {Design, Synthesis, and Biological Evaluation of Molecular Hybrids Incorporating Coumarin-Pyrazole-Linked Indolinone Derivatives With Antioxidant and Anti-Alzheimer Properties.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {11},
pages = {},
doi = {10.1002/cbdv.71900},
pmid = {42967596},
issn = {1612-1880},
support = {PNURSP2026R141//Princess Nourah bint Abdulrahman University Researchers/ ; //Princess Nourah Bint Abdulrahman University/ ; },
mesh = {*Coumarins/chemistry/pharmacology ; *Pyrazoles/chemistry/pharmacology ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; *Indoles/chemistry/pharmacology/chemical synthesis ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; Structure-Activity Relationship ; Acetylcholinesterase/metabolism ; Molecular Docking Simulation ; Humans ; Butyrylcholinesterase/metabolism/chemistry ; Molecular Structure ; Picrates/antagonists & inhibitors ; Biphenyl Compounds/antagonists & inhibitors ; Dose-Response Relationship, Drug ; },
abstract = {The increase in global life expectancy has resulted in a significant rise in the occurrence of Alzheimer's disease (AD), making it a critical public health burden. Therefore, there is an urgent need to create effective methods to prevent or slow down the progression of the disease. In this regard, fifteen previously reported hybrid molecules (7a-c, 10a-j, and 13a,b), combining 4-hydroxycoumarin and pyrazolyl indolin-2-one structures, were resynthesized and tested for their antioxidant and anti-Alzheimer properties. Several of these compounds showed moderate to strong biological activity. Among these, compound 7a demonstrated excellent antioxidant capacity (TAC = 80.65 mg gallic acid/g; IRP = 68.90 µg/mL) and impressive free radical scavenging abilities (DPPH = 5.33 µg/mL; ABTS = 4.59 µg/mL; NO = 6.76 µg/mL), comparable to the standard antioxidant ascorbic acid. Additionally, compound 7a demonstrated the robust inhibition of acetylcholinesterase (AChE) with an IC50 of 6.89 µg/mL, as well as potent inhibition of butyrylcholinesterase (BChE) (IC50 = 5.93 µg/mL). Molecular docking analyses of compound 7a revealed favorable binding interactions and stable conformations within the enzyme's active site, supporting its strong inhibitory effect. Overall, these findings indicate that this group of hybrid molecules offers a promising framework for developing new cholinesterase-targeting treatments for AD.},
}

*Coumarins/chemistry/pharmacology
*Pyrazoles/chemistry/pharmacology
*Antioxidants/pharmacology/chemistry/chemical synthesis
*Alzheimer Disease/drug therapy/metabolism
*Drug Design
*Indoles/chemistry/pharmacology/chemical synthesis
*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry
Structure-Activity Relationship
Acetylcholinesterase/metabolism
Molecular Docking Simulation
Humans
Butyrylcholinesterase/metabolism/chemistry
Molecular Structure
Picrates/antagonists & inhibitors
Biphenyl Compounds/antagonists & inhibitors
Dose-Response Relationship, Drug

@article {pmid42962668,
year = {2026},
author = {Santiago, JA and Rascol, O and Foltynie, T and Meissner, WG and Potashkin, JA and Gutierrez-Silva, JC and Shahrestani, MN and Wu, Y and Rundek, T and Haq, IU},
title = {Metabolic endotyping for mechanism-informed Alzheimer's and Parkinson's disease trials.},
journal = {Med (New York, N.Y.)},
volume = {},
number = {},
pages = {101336},
doi = {10.1016/j.medj.2026.101336},
pmid = {42962668},
issn = {2666-6340},
abstract = {Metabolically targeted therapies for Alzheimer's disease and Parkinson's disease have yielded mixed results despite convergent evidence implicating three interconnected axes of metabolic dysfunction: insulin signaling, cellular bioenergetics, and lipid-lysosomal biology. We argue that this pattern partly reflects a trial-design problem: therapeutics such as glucagon-like peptide 1 receptor agonists, terazosin, and stearoyl-CoA desaturase inhibitors generally have been tested in biologically unselected populations, with endpoints often distal to the targeted mechanism. We propose as a testable hypothesis that a metabolic endotype-a measurable, biomarker-supported pattern of metabolic dysfunction-spans subsets of both diseases and that failure to enrich for this endotype could dilute therapeutic signals in all-comer trials. We outline a modular four-tier framework integrating prodromal risk, metabolic vulnerability, pathway-specific confirmation, and mechanistic deep phenotyping to make Alzheimer's and Parkinson's disease trials more interpretable and therapeutically informative.},
}

@article {pmid42962966,
year = {2026},
author = {Santerre, M and Shcherbik, N and Sawaya, BE},
title = {The metabolic-brain axis: GLP-1 signaling, insulin resistance, and obesity pharmacotherapy in neurodegeneration.},
journal = {Metabolism: clinical and experimental},
volume = {},
number = {},
pages = {156810},
doi = {10.1016/j.metabol.2026.156810},
pmid = {42962966},
issn = {1532-8600},
abstract = {The intersection of metabolic disease and neurodegeneration represents one of the most consequential frontiers in translational neuroscience. Converging epidemiological, mechanistic, and pharmacological evidence supports a bidirectional metabolic-brain axis in which systemic insulin resistance, obesity, and chronic metabolic inflammation are associated with and may contribute to alterations in neuronal survival, synaptic plasticity, and neuroimmune homeostasis. GLP-1 receptor agonists, originally developed for glycemic control and weight management, have therefore been investigated as potential disease-modifying therapies across Alzheimer's disease, Parkinson's disease, and related neurodegenerative conditions through mechanisms including neuronal PKA activation, microglial NLRP3 suppression, mitochondrial biogenesis, and restoration of AQP4 perivascular localization that may contribute to glymphatic waste clearance. Direct human evidence for these CNS mechanisms remains limited or absent, with current support derived primarily from preclinical models and indirect human data, as detailed in Table 1, warranting dedicated investigation in the context of GLP-1 receptor agonism. Importantly, the two pivotal phase 3 programs designed to test this hypothesis in humans - EVOKE/EVOKE+ in early Alzheimer's disease and Exenatide-PD3 in Parkinson's disease - have both now reported, and neither demonstrated a statistically significant benefit on its primary clinical endpoint, despite favorable biomarker and epidemiological signals preceding these results. This review synthesizes current knowledge on brain insulin signaling, GLP-1 neurobiology, obesity-driven neuroinflammation, and the translational evidence for metabolic therapeutics in neurodegeneration, and uses the dissociation between mechanistic plausibility, epidemiological association, and null confirmatory trial results to identify critical knowledge gaps and translational barriers related to CNS target engagement, optimal dosing, and disease-modifying efficacy of GLP-1 receptor agonists. The review is organized into four major themes: brain insulin signaling, central GLP-1 biology, obesity-associated neuroinflammation, and the translational evidence supporting metabolic therapies for neurodegenerative disease.},
}

@article {pmid42963328,
year = {2026},
author = {Kim, D and Ho, BC and van Voorst, H and Liu, Y and Benzinger, TLS and Sha, S and Mormino, E and Henderson, VW and Zaharchuk, G},
title = {Deep learning-based prediction of regional brain Tau PET burden from MRI.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71911},
pmid = {42963328},
issn = {1552-5279},
support = {P30AG066515/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Magnetic Resonance Imaging/methods ; *tau Proteins/metabolism ; *Deep Learning ; *Brain/diagnostic imaging/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; Male ; Aged ; Predictive Learning Models ; Prediction Algorithms ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Regional tau is strongly associated with Alzheimer's disease (AD) symptoms, but tau positron emission tomography (PET) is not routinely available, limiting early risk stratification.

METHODS: We trained a deep learning model to predict regional tau PET standardized uptake value ratios (SUVRs) from magnetic resonance imaging (MRI) with and without basic demographics using public cohorts (Alzheimer's Disease Neuroimaging Initiative [ADNI], Open Access Series of Imaging Studies 3 [OASIS3-tau], Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study [A4], Harvard Aging Brain Study [HABS]). Mean absolute error (MAE), Pearson r, area-under-the-receiver-operating-curve (AUC), and comparison with cognitive testing were assessed in external test sets (SCAN, Stanford University).

RESULTS: The model achieved an MAE of 0.14 (95% confidence interval [CI]: 0.12-0.16) and r = 0.72 for an early uptake region (Braak I-IV), and an MAE of 0.14 (95% CI: 0.12-0.17) and r = 0.71 for a late uptake region (Braak V-VI). AUCs for binary tau positivity in these regions were 0.87 (95% CI: 0.83-0.90) and 0.88 (95% CI: 0.84-0.91), respectively.

DISCUSSION: Predicting regional tau burden from magnetic resonance imaging (MRI) is feasible and may enable scalable tau-informed clinical AD care.},
}

Humans
*Positron-Emission Tomography/methods
*Magnetic Resonance Imaging/methods
*tau Proteins/metabolism
*Deep Learning
*Brain/diagnostic imaging/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Female
Male
Aged
Predictive Learning Models
Prediction Algorithms
Aged, 80 and over

@article {pmid42963333,
year = {2026},
author = {Tariot, PN and Dickson, SP and Dwyer, J and Granda, C and Hughes, L and Karlawish, J and Linz, N and Nair, KV and Paulsen, R and Pawson, D and Perneczky, R and Schindler, SE and Scholler, E and Taylor, J and Tiede, B and Vradenburg, G},
title = {Expert perspectives on the design and communication of endpoints in Alzheimer's disease clinical trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71951},
pmid = {42963333},
issn = {1552-5279},
support = {//Bristol Myers Squibb/ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; *Clinical Trials as Topic ; *Endpoint Determination ; *Communication ; *Research Design ; },
abstract = {Disease-targeted therapies (DTTs) for Alzheimer's disease (AD) represent a major advance, yet challenges remain on how best to interpret and communicate their benefits. As clinical development increasingly targets the earliest stages of AD (before symptoms emerge and early symptomatic AD), there is a need for novel, complementary endpoints and improved communication of treatment benefits. The Global CEO Initiative on Alzheimer's Disease convened a multi-stakeholder working group to develop recommendations for improving the design and communication of endpoints in AD clinical trials. In the near term, communication can be improved by contextualizing treatment effects at the individual level, including framing benefits in terms of responder analyses and "time saved" over defined timeframes. In parallel, continued development of complementary endpoints is needed to enable more sensitive, scalable, and patient-centered measurements aligned with early intervention. These recommendations aim to support stakeholders in evaluating and communicating the meaningful benefits of current and emerging therapies.},
}

*Alzheimer Disease/therapy/drug therapy
Humans
*Clinical Trials as Topic
*Endpoint Determination
*Communication
*Research Design

@article {pmid42963335,
year = {2026},
author = {Moscoso Rial, A and Leuzy, A and Raket, LL and Villemagne, VL and Klein, G and Tonietto, M and Olafson, E and Smith, R and Schwarz, CG and Baker, S and Saad, ZS and Bullich, S and Lopresti, B and Sanabria Bohorquez, S and Domingues Kolinger, G and Lutz, O and Boada, M and Betthauser, TJ and Charil, A and Collins, EC and Collins, JA and Gunn, RN and Higuchi, M and Hostetler, E and Hutchison, RM and Iaccarino, L and Insel, PS and Irizarry, MC and Jack, CR and Jagust, WJ and Johnson, KA and Johnson, SC and Tissot, C and Vállez García, D and Salvadó, G and Stephenson, D and Marquié, M and Mathotaarachchi, S and Mintun, MA and Ossenkoppele, R and Huang, Q and Mao, X and Gnörich, J and Pappas, I and Petersen, RC and Chiotis, K and Rabinovici, GD and Rosa-Neto, P and Stephens, AW and Whittington, A and Carrillo, MC and Pontecorvo, MJ and Budd Haeberlein, S and Dunn, B and Kolb, HC and Tatton, N and Karten, Y and Brendel, M and O'Bryant, S and Xie, F and Rowe, CC and Hansson, O and Doré, V and , and , },
title = {Tau positron emission tomography harmonization using the CenTauR approach: General conversion equations, relevant cut-points, and external validation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71886},
pmid = {42963335},
issn = {1552-5279},
support = {//Food and Drug Administration (FDA) of the Department of Health and Human Services (HHS)/ ; U19 AG024904/NH/NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health/ ; },
mesh = {*Positron-Emission Tomography/methods/standards ; Humans ; *tau Proteins/metabolism ; Radiopharmaceuticals ; *Brain/diagnostic imaging/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Reproducibility of Results ; },
abstract = {INTRODUCTION: Tau positron emission tomography (PET) tracers differ in kinetics, binding properties, and quantification pipelines, complicating cross-study comparisons. The CenTauR approach provides a unified framework for harmonizing tau PET quantification across tracers.

METHODS: We defined a tracer-agnostic "Standard Method" using Statistical Parametric Mapping 12, standardized regions of interest, and harmonized acquisition parameters. Using data from five tau tracers-[[18]F]flortaucipir, [[18]F]MK-6240, [[18]F]PI-2620, [[18]F]RO948, and [[18]F]GTP1-we applied the Joint Propagation Model to derive linear equations converting regional standardized uptake value ratios into the tracer-independent CenTauR scale. Validation included independent cross-sectional, longitudinal, and test-retest datasets across multiple cohorts.

RESULTS: The CenTauR scale yielded highly consistent regional values across tracers, with strong cross-tracer agreement and robust performance in external validation cohorts. We also expressed clinically relevant cut-points and staging boundaries on the CenTauR scale.

DISCUSSION: The CenTauR approach enables harmonized, tracer-independent quantification of tau PET, supporting reproducibility across studies and improving interpretation in clinical research and multicenter trials.},
}

*Positron-Emission Tomography/methods/standards
Humans
*tau Proteins/metabolism
Radiopharmaceuticals
*Brain/diagnostic imaging/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Reproducibility of Results

@article {pmid42963336,
year = {2026},
author = {Pyun, JM and Park, YH and Shade, LMP and Fardo, DW and Kim, S and Nho, K and , },
title = {Polygenic risk scores for LATE-neuropathologic change: Implications for clinical utility.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71824},
pmid = {42963336},
issn = {1552-5279},
support = {AACSFD-24-1310485/ALZ/Alzheimer's Association/United States ; P30AG010133/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; R01AG081951//NIH/ ; R01LM012535/LM/NLM NIH HHS/United States ; U01AG072177/AG/NIA NIH HHS/United States ; U19AG074879/AG/NIA NIH HHS/United States ; //National Research Foundation of Korea/ ; RS-2024-00461936)//Korean government (Ministry of Science and ICT/ ; },
mesh = {Humans ; Genetic Risk Score ; Female ; Positron-Emission Tomography ; Male ; Aged ; Executive Function ; Aged, 80 and over ; *Alzheimer Disease/pathology/genetics/diagnostic imaging ; Disease Progression ; *TDP-43 Proteinopathies/pathology/genetics/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Cognitive Dysfunction/pathology/genetics ; Neuropsychological Tests ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Limbic-predominant age-related TDP-43 encephalopathy (LATE) exhibits clinical features resembling Alzheimer's disease (AD) and frequently occurs as a co-pathology, yet there are fewer biomarkers for LATE relative to AD.

METHODS: We calculated polygenic risk scores for LATE-neuropathologic change (LATE-PRS) and performed association analysis with neuropathology (N = 99) and longitudinal cognitive change rates (N = 538) in Alzheimer's Disease Neuroimaging Initiative participants aged ≥ 75 years, stratified by amyloid positron emission tomography (PET) positivity status.

RESULTS: LATE-PRS was significantly associated with pathologically confirmed LATE (odds ratio = 2.292, P = 0.002), independent of AD pathology. In cognitively impaired individuals, LATE-PRS was associated with faster executive function decline in PET-negative individuals (β = -0.002, P = 0.041), and faster memory (β = -0.002, P < 0.001) and executive function (β = -0.001, P = 0.035) decline in PET-positive individuals. In the overall sample, associations were significant only in the PET-negative individuals.

DISCUSSION: LATE-PRS may serve as a potential biomarker for LATE risk and cognitive progression.},
}

Humans
Genetic Risk Score
Female
Positron-Emission Tomography
Male
Aged
Executive Function
Aged, 80 and over
*Alzheimer Disease/pathology/genetics/diagnostic imaging
Disease Progression
*TDP-43 Proteinopathies/pathology/genetics/diagnostic imaging
*Brain/pathology/diagnostic imaging
Cognitive Dysfunction/pathology/genetics
Neuropsychological Tests
Longitudinal Studies

@article {pmid42963367,
year = {2026},
author = {Tian, J and Jia, K and Chen, Y and Wang, T and Guo, L and Swerdlow, RH and Du, H},
title = {Mitochondrial complex IV disruption is a detrimental pathology conferring ssusceptibility to alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42963367},
issn = {1476-5578},
support = {R01AG075108//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01AG059753//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P30 AG072973//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P30 AG035982//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; A20201159S//BrightFocus Foundation (BrightFocus)/ ; A2022036S//BrightFocus Foundation (BrightFocus)/ ; },
abstract = {Mitochondrial complex IV (CIV) is an integral part of the mitochondrial electron transport chain (ETC) and plays a pivotal role in maintaining mitochondrial function. In contrast to the long-standing recognition of its dysfunction in Alzheimer's disease (AD), the exact role of CIV deficit in the pathogenesis of this neurodegenerative disorder remains poorly defined. In this study, by incorporating clinical resources, mouse- and human-based models of AD risk, and a genetic approach to bypass defective CIV via the ectopic expression of alternative oxidase (AOX), we examined whether CIV deficits are a pathogenic driver of or a beneficial adaptation to AD-associated pathologies. Our results showed a clinicopathological association between neuronal CIV dysfunction and pathological characteristics of AD. Further experiments linked defective CIV to the development of mitochondrial dysfunction and synaptic loss in the tested mouse- and human-based models of AD risk. In addition, a reciprocal relationship between CIV dysfunction and amyloid pathology was determined. Lastly, a proteome-wide association study (PWAS) using genetic data from large-scale AD cohorts identified that downregulation of COX11, a crucial CIV assembly factor, confers susceptibility to AD risk. Collectively, our findings suggest that CIV dysfunction is a detrimental pathology contributing to AD-associated mitochondrial and neuronal damage. The dual role of CIV dysfunction, both as a consequence of and a contributor to amyloid toxicity in AD pathogenesis, further justifies the therapeutic potential of strategies targeting CIV deficits to diversify the tools for prevention and treatment of this neurodegenerative disorder.},
}

@article {pmid42963752,
year = {2026},
author = {Yang, X and Lyu, J and Wang, J and Quan, Y},
title = {Disentangling global atrophy burden from local structural patterns reveals clinically relevant heterogeneity in mild cognitive impairment.},
journal = {BMC neuroscience},
volume = {27},
number = {1},
pages = {},
pmid = {42963752},
issn = {1471-2202},
mesh = {Humans ; *Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid ; Atrophy/pathology ; Female ; Male ; Magnetic Resonance Imaging ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; Aged ; *Brain/pathology/diagnostic imaging ; Gray Matter/pathology/diagnostic imaging ; Aged, 80 and over ; White Matter/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous prodromal stage of Alzheimer's disease (AD). Imaging-based subtyping may conflate global neurodegenerative burden with local anatomical variation, limiting biological interpretability. We aimed to separate global atrophy burden from local structural patterns and assess their clinical relevance in MCI.

METHODS: Baseline ADNI-1 data from 731 participants were analyzed, including 205 cognitively normal individuals, 351 with MCI, and 175 with AD. A global atrophy index (GAI) was defined as the z-standardized ratio of TIV-adjusted whole-brain cerebrospinal fluid volume to TIV-adjusted gray matter plus white matter volume. Candidate regions were screened in the full CN-MCI-AD sample. Within MCI, regional measures were residualized against age, sex, education, and GAI to derive local residual structural features. Principal component analysis and unsupervised clustering were applied to identify imaging-based subtypes. Clinical associations were assessed using multivariable regression, and nested models evaluated the incremental explanatory value of continuous residual features beyond subtype labels.

RESULTS: GAI showed a clear gradient across cognitively normal, MCI, and AD groups. After adjustment for GAI, two local residual structural patterns were identified within MCI: a thalamic-striatal lower-residual subtype and a frontal-paralimbic lower-residual subtype. Compared with the thalamic-striatal subtype, the frontal-paralimbic subtype showed greater cognitive impairment and poorer daily functioning, with higher ADAS-Cog13 and FAQ scores after covariate adjustment. Associations with neuropsychiatric symptoms were weak. Continuous PCA-derived residual features provided additional explanatory value for ADAS-Cog13 and FAQ beyond subtype labels.

CONCLUSIONS: MCI heterogeneity is not explained solely by global atrophy. Local residual structural patterns were associated with cognitive and functional differences, and continuous residual features captured additional clinical information beyond discrete subtype labels. Separating global atrophy burden from local anatomical organization may improve interpretation of imaging heterogeneity in prodromal AD.},
}

Humans
*Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid
Atrophy/pathology
Female
Male
Magnetic Resonance Imaging
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
Aged
*Brain/pathology/diagnostic imaging
Gray Matter/pathology/diagnostic imaging
Aged, 80 and over
White Matter/pathology/diagnostic imaging

@article {pmid42964017,
year = {2026},
author = {Jing, Y and Li, D and Chen, L and Li, S and Yuan, X},
title = {miR-615-3p targets SESN2 to inhibit neuronal mitophagy in an in vitro Alzheimer's disease model by regulating the AMPK/ULK1 axis.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1873619},
pmid = {42964017},
issn = {1662-5099},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid-β accumulation, mitochondrial dysfunction, and neuronal injury. miR-615-3p is upregulated in AD, but its role in regulating mitophagy remains unclear.

METHODS: HT22 hippocampal neurons were treated with Aβ1-42 to establish an AD-like model. Gain-of-function and loss-of-function experiments were conducted to assess the roles of miR-615-3p and its target SESN2, which were identified through bioinformatics and dual-luciferase assays. Cell viability, apoptosis, oxidative stress, mitochondrial function, inflammatory responses, and mitophagy-related proteins were evaluated. The involvement of the AMPK/ULK1 pathway was also examined.

RESULTS: miR-615-3p overexpression significantly reduced cell viability and ATP levels while increasing apoptosis, Aβ accumulation, lactate dehydrogenase release, reactive oxygen species production, mitochondrial membrane potential loss, and inflammatory cytokine levels. Mitophagy markers, including LC3-II/LC3-I, Parkin, and PINK1, were elevated. Mechanistically, miR-615-3p downregulated SESN2 and inhibited AMPK/ULK1 phosphorylation. SESN2 overexpression reversed these effects, restoring mitochondrial function, reducing oxidative stress and inflammation, and improving cell survival.

CONCLUSION: miR-615-3p aggravates neuronal injury by targeting SESN2 and regulating mitophagy through the AMPK/ULK1 pathway, suggesting a potential therapeutic target for Alzheimer's disease.},
}

@article {pmid42964118,
year = {2026},
author = {Zhang, L and An, H and Ding, M and Yu, X and Yan, F and Gu, C and Li, X},
title = {Cross-sectional associations of Kidney deficiency, Phlegm-stasis, and Heat-toxin syndrome patterns with disease severity in Alzheimer's disease: an exploratory study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1763273},
pmid = {42964118},
issn = {1663-4365},
abstract = {BACKGROUND: Current Alzheimer's diagnostics lack integration with Traditional Chinese Medicine's syndrome differentiation framework, making it difficult to fully capture the clinical heterogeneity and multidimensional nature of the disease.

METHODS: This cross-sectional study analyzed 236 AD patients stratified by CDR into early-stage (n = 127), moderate (n = 66), and severe (n = 43) groups. Using the SHA-03-W1 diagnostic instrument and Tian Jinzhou Scale, patients were classified into three TCM syndrome patterns: Kidney essence deficiency (n = 87), Phlegm-stasis obstructing the orifices (n = 93), and Heat-toxin obstructing the collaterals (n = 56). Data collected included demographics, cognitive scores (MMSE, MoCA), activities of daily living (ADL), and plasma biomarkers (GFAP, NfL, p-tau181, p-tau217, Aβ42/40). Statistical analyses involved intergroup comparisons (Chi-square and Kruskal-Wallis tests), Spearman correlation analysis between dementia severity/TCM patterns and clinical measures, logistic regression to examine factors associated with disease severity, and exploratory ROC analysis to describe discriminatory performance within this development sample.

RESULTS: Across the three CDR-defined severity groups (n = 236), MMSE, MoCA, ADL and estimated symptom duration differed significantly (p < 0.05, q < 0.05). Dementia severity correlated strongly with MMSE (r = -0.779), MoCA (r = -0.785) and ADL (r = 0.742) (p < 0.001), and only weakly with estimated symptom duration (r = 0.384, p < 0.001). TCM syndrome distribution patterns differed across severity stages, with kidney essence deficiency being most prevalent in the early-stage group (48%), Phlegm-stasis in the moderate group (54.5%), and Heat-toxin in the severe group (60.5%). In multivariable multinomial logistic regression (reference: early-stage AD), MMSE and ADL scores were associated with AD severity (MMSE: moderate vs. early, OR = 0.844, 95% CI 0.774-0.921; severe vs. early, OR = 0.485, 95% CI 0.351-0.671; ADL: moderate vs. early, OR = 1.128, 95% CI 1.065-1.196; severe vs. early, OR = 1.280, 95% CI 1.150-1.425; all p < 0.001). Among TCM syndrome elements, Heat-toxin was associated with both moderate and severe AD (Moderate vs. Early-stage: OR = 1.177, 95% CI 1.046-1.324, p = 0.007; Severe vs. Early-stage: OR = 1.498, 95% CI 1.205-1.861, p < 0.001) and Phlegm-stasis with moderate AD only (OR = 1.198, 95% CI 1.079-1.329, p = 0.001). In an exploratory ROC analysis, single indicators showed modest discriminatory performance for Heat-toxin syndrome, with CDR (AUC = 0.709) > ADL (AUC = 0.690) > MMSE (AUC = 0.683), whereas AUCs for Kidney deficiency (≤0.633) and Phlegm-stasis (≤0.581) were close to chance. In a sensitivity analysis excluding participants with CDR 0.5 (n = 186), the cognitive, functional and Heat-toxin associations were essentially unchanged, but the Phlegm-stasis score was associated with both moderate and severe AD, with comparable effect sizes (Moderate vs. Early-stage: OR = 1.26, 95% CI 1.12-1.42, p < 0.001; Severe vs. Early-stage: OR = 1.25, 95% CI 1.02-1.54, p = 0.032), indicating that its restriction to moderate AD was not robust.

DISCUSSION: In this cross-sectional single-center sample, TCM syndrome distributions and scores differed across concurrent CDR-defined severity groups, with kidney essence deficiency predominating in early-stage AD (48.0%), Phlegm-stasis in moderate AD (54.5%), and Heat-toxin in severe AD (60.5%). Heat-toxin scores were associated with greater concurrent cognitive and functional impairment, whereas plasma biomarkers showed limited and inconsistent associations. These findings do not establish temporal syndrome transitions or validated diagnostic utility outside this development sample, but provide hypothesis-generating evidence for future prospective investigations.},
}

@article {pmid42964137,
year = {2026},
author = {Mole, SS and Dwivedi, PSR and Lobo, WL and Shastry, CS and Khanal, P},
title = {Trans-anethole attenuates streptozotocin-induced cognitive dysfunction by modulating oxidative stress and cholinergic activity.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1954658},
pmid = {42964137},
issn = {1663-9812},
abstract = {INTRODUCTION: Cognitive impairment is a neurological disorder defined as an inability to learn, think, judge, remember, and make decisions. The primary cause of chronic, age- related cognitive decline is Alzheimer's disease (AD), which is frequently studied as a representative model. The current therapies for AD provide only symptomatic relief, which necessitates the need for safer, multi-target treatments. Trans- anethole, the primary constituent of Illicium verum, Pimpinella anisum, and Foeniculum vulgare, is an aromatic molecule that possesses several pharmacological activities, including anti-inflammatory and antioxidant effects, which may have neuroprotective benefits.

METHODS: The current study integrated in silico, in vitro, and in vivo approaches to examine the neuroprotective potential of trans- anethole. In silico studies were carried out to find out the potential molecular targets and pathways associated with the effects of trans-anethole against AD- related cognitive dysfunction. Cytotoxicity, antioxidant activity, and cholinesterase inhibition were assessed in vitro on BV2 cells. Intracerebroventricular (ICV) administration of streptozotocin (STZ: 3 mg/kg) in rats induces an insulin-resistant brain state leading to progressive cognitive and memory impairment, a condition that closely relates to sporadic Alzheimer's disease. ICV-STZ-induced Wistar rats were used to assess the effect of trans- anethole on AD-related cognitive dysfunction through behavioral, biochemical, and histopathological assessments.

RESULTS: A total of 174 common targets were identified, enriching pathways including apoptosis, AGE-RAGE, TNF, and PI3K- Akt signaling. Stable interactions were observed in molecular docking and molecular dynamics simulations. Trans-anethole demonstrates moderate cholinesterase inhibition and antioxidant activity in BV2 cells. Comparing STZ- treated rats to disease control, trans-anethole at doses of 100 mg/kg and 400 mg/kg significantly reduced lipid peroxidation, restored antioxidant enzyme levels, and attenuated cholinergic dysfunction. Histopathological findings showed qualitative preservation of hippocampal neuronal morphology.

DISCUSSION: Overall, these findings suggest that trans-anethole may represent a potential neuroprotective preclinical candidate for further investigation in Alzheimer's disease-related cognitive dysfunction.},
}

@article {pmid42964287,
year = {2026},
author = {Wang, K and Goel, D and Shi, JM and Rodriguez, VJ and Brown, DS and Yoo, DW and Karkar, R and Saha, K},
title = {A Taxonomy of Mental Health and Technology Needs for Alzheimer's and Dementia Caregivers.},
journal = {Ageing international},
volume = {51},
number = {4},
pages = {47},
pmid = {42964287},
issn = {0163-5158},
abstract = {UNLABELLED: Family members caring for individuals with Alzheimer's disease and related dementias (AD/ADRD) provide the foundation of long-term care worldwide. In 2023, more than 11 million U.S. family and friends contributed 18 billion hours of unpaid care, often at the cost of their own physical and mental health. These informal caregivers-also referred as the "invisible second patients"-experience elevated rates of mental health problems. Yet research commonly reduces their complex psychosocial experiences to a single construct of caregiver burden, obscuring which specific needs are unmet or effectively supported. At the same time, digital and AI-enabled technologies are rapidly expanding, from smartphone apps and videoconferencing to sensor platforms and AI chatbots. However, the absence of shared frameworks across medicine, psychology, and technology research limits cumulative progress. This study introduces a Caregiver Mental Health and Technology Taxonomy that systematically links AD/ADRD caregiver needs with corresponding classes of technology-based interventions. Drawing from an interdisciplinary literature review and two qualitative studies with caregivers, the taxonomy identifies mismatches between caregiver priorities and existing technological support, highlights under-served domains such as relational strain and compassion fatigue, and proposes design directions for adaptive, responsive systems. The framework offers a shared vocabulary to guide clinicians, researchers, and technology designers in developing more person-centered and clinically grounded innovation in dementia care.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12126-026-09686-4.},
}

@article {pmid42964420,
year = {2026},
author = {Terman, SA},
title = {A newly defined substage of late-stage Alzheimer's disease, the "Dementia Gap": Can sedation to unconsciousness to relieve patients' intolerable suffering be moral?.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261460085},
doi = {10.1177/25424823261460085},
pmid = {42964420},
issn = {2542-4823},
abstract = {Advanced Alzheimer's disease is a terminal illness causing more intense, prolonged suffering than clinicians generally recognize. At least 500,000 Americans are trapped in the "Dementia Gap", a previously unidentified substage of advanced dementia. Patients lack capacity to voluntarily stop eating and drinking but can still eat and drink independently, making "dementia-specific" living wills ineffective until further disease progression requires assistance with oral feeding and hydrating. Additionally, patients experience "Non-Observable Suffering": inner emotional angst, inexpressible physical pain, and bi-directional suffering shared with loved ones. A dangerous non sequitur fallacy can lead casual observers to extrapolate peaceful inner states from withdrawn external behavior: "She's not suffering; she's just sitting there." To effectively relieve intolerable suffering, this article introduces "Moderate Anesthesia"-palliative sedation to unconsciousness modified to be clearly distinguishable from euthanasia. Cases demonstrate moral justification grounded in Sulmasy's "Reinvented Rule of Double Effect," "Parsimonious Direct Sedation," or the Principle of Proportionality. Two Dementia Gap patients the author treated are compared with two advanced cancer patients. Two withdrawn patients "awakened" through skillful interviewing, exemplifying this ethical warning: diligent efforts to detect and relieve non-observable suffering should precede implementing treatments of last resort. The article presents the "Three-Source Concordance" protocol using an illustrated patient decision aid and polling Patient Decision Committee members' substituted judgments to confirm the clinical appropriateness of implementing POLSTs that patients completed during advance care planning. A 42% cumulative lifetime dementia risk means many of us may reach the Dementia Gap. Launching the ARISE movement-Advocate by Recognizing and Investigating Suffering's (hidden) Existence-and convening expert panels to develop practice guidelines are moral imperatives.},
}

@article {pmid42964515,
year = {2026},
author = {Iulita, MF and Kolachalama, VB and Brugada-Ramentol, V and Harrison, J and Griffin, N and Benavides, GS and Vera-Campuzano, E and Minguillon, C and Alcolea, D and Mackintosh, L and Ward, L and Merino, AT and Balasa, M and Ishida, S and Rivera, OG and Calvet, MS and Robertson, J and Doecke, J and Mas, CP and Fallone, S and Charvat, M and Tarnanas, I and Jones, M and Streel, E},
title = {A multimodal digital NeuroMarker platform with composite and domain-level validity for identification of mild cognitive impairment: a cross-sectional study.},
journal = {EClinicalMedicine},
volume = {101},
number = {},
pages = {104266},
doi = {10.1016/j.eclinm.2026.104266},
pmid = {42964515},
issn = {2589-5370},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a clinically heterogeneous syndrome that can represent an early manifestation of neurodegenerative disease. Diagnosis relies on assessments that are difficult to scale, leaving many individuals unidentified.

METHODS: In this cross-sectional study conducted in the United States, Australia, and Spain between May 2022 and October 2024, 638 adults aged ≥ 50 years were classified as cognitively unimpaired (CU; n = 441) or MCI (n = 197) using Petersen/NIA-AA criteria. Participants completed a self-administered, tablet-based assessment (Altoida NeuroMarker Platform) integrating motor, speech, and augmented reality tasks. An XGBoost classifier was trained to distinguish CU from MCI. Diagnostic performance, test-retest reliability, and convergent validity were evaluated.

FINDINGS: Median assessment time was 13.8 min. Participants reported comfort with digital technology (67%), willingness to engage in cognitive screening (90%), and positive usability. Altoida's NeuroMarker differentiated MCI with ROC-AUC 0.90, 95% CI 0.88-0.92 and comparable performance in an independent cohort (ROC-AUC 0.87, 95% CI 0.80-0.93; n = 75). Cognitive composite and domain scores were lower in MCI than in CU. Classifier agreement across repeated assessments was κ = 0.60, and reliability of composite and domain scores was moderate-to-good (ICC 0.55-0.80). The composite score correlated with the Mini-Mental State Examination (MMSE) (r s = 0.40, p < 0.001) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Index (r s = 0.58, p < 0.001). The platform also showed convergent validity of cognitive domains (|r s| = 0.27-0.50, p < 0.001).

INTERPRETATION: A brief, self-administered multimodal assessment identified clinically adjudicated MCI and demonstrated convergent validity, test-retest reliability, and consistent performance in an independent cohort. Prospective studies should evaluate its implementation in real-world workflows.

FUNDING: Alzheimer's Drug Discovery Foundation; Altoida Inc.},
}

@article {pmid42964735,
year = {2026},
author = {Ghiasvand, K and Meftahi, GH},
title = {Black Myrobalan (Terminalia chebula) as a potential multitarget neuroprotective agent: Translational insights and future directions in neurodegenerative diseases.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102850},
doi = {10.1016/j.bbrep.2026.102850},
pmid = {42964735},
issn = {2405-5808},
abstract = {Myrobalan or Haritaki (Terminalia chebula Retz.) has been integrated into Ayurvedic, Unani, and even Tibetan medicine systems for over 2000 years. The "King of Medicines" has traditionally been used for diverse ailments such as digestive issues, wound healing, and general body strengthening. Now, modern medicine is focusing on the myrobalan's potential neuroprotective properties and its use in Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS) neurodegenerative disorders. These ailments are characterized by some combination of enduring oxidative damage, mitochondrial dysfunction, neuroinflammation, irregular protein aggregation, and progressive neuron cell death. Most of the current treatment options revolve around addressing the symptoms of the diseases, which is insufficient as the underlying disease continues to progress. There is an urgent need to devise therapies that work simultaneously on multiple disease pathways. Some of the noted secondary metabolites in T. chebula include hydrolyzable tannins like chebulinic and chebulagic acid as well as corilagin. Others occur as phenolic acids such as gallic and ellagic acid and flavonoids quercetin and kaempferol. Moreover, glycosides, sterols, and a wide range of alkaloids are also present. A number of these compounds are known to possess multifunctional biological properties like scavenging ROS, activating Nrf2/ARE signaling, downregulating pro-inflammatory mediators through blockade of NF-κB, and exerting protective effects on the mitochondria, as well as modulating apoptosis via Bcl-2 and caspases. T. chebula extracts and some isolated compounds have also been shown to improve cognitive function, reduce neuroinflammation, and protect dopaminergic neurons, and ameliorate neurotoxic effects of amyloid-β or α-synuclein through in vitro and in vivo animal studies. A review of the contributions from the phytochemistry, mechanism of action, preclinical, translational, and adjunctive applications of Terminalia chebula in neurodegenerative disease therapy is presented here.},
}

@article {pmid42964793,
year = {2026},
author = {Šišić, N and Barakovic, M and Edde, M and Théberge, A and Beaudoin, AM and Dumbia, M and Lapointe, E and Descoteaux, M and Magon, S and Gobbi, S},
title = {Agreement and longitudinal repeatability of established brain volumetry pipelines across healthy controls, multiple sclerosis, and Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1917471},
doi = {10.3389/fnins.2026.1917471},
pmid = {42964793},
issn = {1662-4548},
abstract = {INTRODUCTION: Brain volume estimates are increasingly used as longitudinal endpoints in neuroimaging studies and clinical trials, but outputs from different segmentation pipelines may not be interchangeable. In this study, we performed a version-specific comparison of six established brain segmentation pipelines across healthy controls (HC; n = 20), people with multiple sclerosis (MS; n = 19), and people with Alzheimer's disease (AD; n = 50).

METHODS: FreeSurfer v6, FreeSurfer v7.2, SAMSEG, FastSurfer v1, SIENAX/SIENA-XL, and CAT12 were evaluated. The primary aims were to quantify systematic offsets and inter-pipeline agreement in normalized baseline volume estimates, assess within-pipeline repeatability and longitudinal change-from-baseline concordance, and determine whether longitudinal processing reduced variability relative to cross-sectional processing. Gray matter, white matter, hippocampus, and thalamus were selected and normalized to intracranial volume. Agreement was assessed using intraclass correlation coefficients, while longitudinal change was evaluated using mixed-effects models and repeatability metrics.

RESULTS: Baseline volume estimates differed significantly across pipelines in 11 of 12 cohort-by-tissue comparisons (FDR-adjusted p < 0.001), with the largest pipeline-dependent offsets observed for grey matter, hippocampus, and thalamus. Inter-pipeline agreement was generally strong for white matter and lower for gray matter and subcortical structures (hippocampus and thalamus), particularly in pathological cohorts. Change-from-baseline models showed no significant Pipeline × Timepoint interactions after FDR correction, indicating broadly parallel longitudinal trajectories across pipelines after baseline normalization. However, significant pipeline main effects persisted in selected tissues, especially in AD and subcortical regions, indicating residual differences in the magnitude of estimated change. Longitudinal processing reduced within-subject variability in selected settings, particularly for FreeSurfer-derived hippocampal and thalamic estimates, but did not uniformly improve stability across all pipelines or tissues.

DISCUSSION: Together, these findings show that systematic offset, absolute agreement, longitudinal change magnitude, and short-interval repeatability represent distinct properties of volumetric pipelines and vary by tissue, cohort, and processing mode. Longitudinal processing reduced variability but not uniformly, highlighting pipeline- and tissue-dependent differences relevant to the interpretation of longitudinal volumetric measurements.},
}

@article {pmid42964797,
year = {2026},
author = {Gaggi, NL and Hurwitz, B and Bernal, J and O'Brien, C and Ren-Fielding, C and Lofton, H and Chen, J and Saperstein, A and Lee, SH and Chang, YJ and Yates, KF and Fieremans, E and Osorio, R and Convit, A},
title = {Brain and Cardiometabolic Effects of Major Weight Loss in People With Obesity: Preliminary Cohort Findings.},
journal = {Obesity science & practice},
volume = {12},
number = {6},
pages = {e70191},
doi = {10.1002/osp4.70191},
pmid = {42964797},
issn = {2055-2238},
abstract = {OBJECTIVE: Given the overlap between obesity-related metabolic and vascular abnormalities and Alzheimer's disease (AD) risk factors, it is critical to determine whether weight loss improves brain and cardiovascular health. This study examined whether ≥ 40% excess-weight loss is associated with improvements in cardiometabolic risk, brain structure, and cognition.

METHODS: The study was a longitudinal study of individuals with obesity undergoing metabolic and bariatric surgery or medical/behavioral weight-loss treatment. Participants were classified at follow-up as weight-loss (WL; ≥ 40% excess-weight loss) or non-weight-loss (nWL; < 40%). All completed medical evaluations, structural MRI, and cognitive testing at baseline and 1 year.

RESULTS: At 1 year, the WL group exhibited improvements in BMI, HbA1C, inflammatory, metabolic, and lipid profiles. MRI-based volumetrics revealed increases in subcortical gray-matter volume and preservation of AD-vulnerable regions. Cognitive performance remained unchanged.

CONCLUSIONS: Achieving ≥ 40% excess-weight loss was associated with improvements in metabolic health and brain structure, including favorable subcortical volume increases. These findings underscore the potential of sustained weight reduction to mitigate risks linked to metabolic syndromes and neurodegeneration. Longer-term follow-up is warranted to determine whether continued metabolic improvements lead to detectable cognitive gains and additional brain-health benefits beyond 1 year.},
}

@article {pmid42964963,
year = {2026},
author = {Zhang, C and Liu, X and Fan, J and Li, W and Shi, J and Tian, M},
title = {Cerebellar Topological Alterations Across the Alzheimer's Disease Continuum.},
journal = {Psychiatry and clinical psychopharmacology},
volume = {36},
number = {4},
pages = {361-372},
doi = {10.65801/pcp.3523},
pmid = {42964963},
issn = {2475-0581},
abstract = {Background: Alzheimer's disease (AD) is characterized as a network disconnection syndrome. Despite evidence implicating the cerebellum in cognitive network integration, its associated electrophysiological network topology dynamics across the AD continuum remain unexplored. Methods: We enrolled 34 healthy controls (HC), 40 patients with mild cognitive impairment (MCI), and 30 AD patients in this study. Cortical and cerebellar signals were recorded with a whole-brain EEG cap, and weighted functional connectivity networks were constructed using the phase-locking value (PLV). Graph theory was used to analyze network topological metrics across the AD continuum, focusing on cerebellar nodes. Topological metrics were correlated with neuropsychological scores, and network-based statistics (NBS) identified differential connectivity patterns among groups. Results: Network changes were most prominent in the theta band, with additional alterations in the delta band. Both MCI and AD groups showed reduced small-world metrics, although small-world organization remained present. These groups also showed increased nodal centrality in the frontal, occipital and cerebellar regions (at CB1, CB2 and CBZ in MCI but only at CBZ in AD) but decreased in the central and temporal regions. NBS analysis identified selective theta-band reorganization of cerebello-cortical connectivity. An inverted U-shaped relationship was found between cerebellar nodal centrality and neuropsychological scale scores. Conclusions: The cerebellar theta rhythm may be a key pattern involved in cognitive processing, and the topological changes of the cortical-cerebellar network may represent candidate electrophysiological network markers across different AD stages. These markers may reflect stage-related differences in cerebellar function, shifting from compensation in MCI to decompensation in AD.},
}

@article {pmid42964993,
year = {2026},
author = {Blivet, G and Bertrand, C and Brauge, D and Delrieu, J and Touchon, J},
title = {Photobiomodulation as a regulator of neuroinflammation: mechanistic insights and therapeutic potential in brain disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1902491},
doi = {10.3389/fneur.2026.1902491},
pmid = {42964993},
issn = {1664-2295},
mesh = {Humans ; *Low-Level Light Therapy/methods ; *Neuroinflammatory Diseases/radiotherapy/metabolism ; Animals ; *Brain Diseases/radiotherapy/therapy/metabolism ; },
abstract = {Brain disorders, including neurodegenerative, neuropsychiatric, and cerebrovascular diseases, represent a growing global health challenge contributing to disability and mortality worldwide. Although these conditions differ in etiology and clinical presentation, accumulating evidence identifies neuroinflammation as a shared pathological mechanism. Involving microglial activation, astrocytic reactivity, cytokine dysregulation, oxidative stress, mitochondrial dysfunction, and blood-brain barrier disruption, it contributes to synaptic dysfunction, neuronal loss, and disease progression, yet therapeutic strategies targeting these processes remain limited. Photobiomodulation (PBM), the therapeutic application of low-intensity red to near-infrared light, has emerged as a neurotechnology capable of modulating biological pathways relevant to neuroinflammation. Preclinical studies suggest that PBM may influence mitochondrial activity through cytochrome c oxidase-mediated mechanisms, enhancing cellular metabolism while regulating reactive oxygen species, inflammatory signaling pathways, and tissue homeostasis. Through these effects, PBM may attenuate neuroinflammatory responses, regulate glial activation, and support neuroprotective processes across multiple neurological models. This narrative review examines evidence supporting neuroinflammation as a common denominator across major brain disorders and explores the biological rationale for PBM as a therapeutic strategy. It summarizes the cellular and molecular basis of PBM, its effects on neuroinflammatory pathways, and preclinical and clinical findings across brain disease models. Preclinical findings consistently support a multi-target anti-inflammatory effect, whereas clinical investigation remains at an early stage, with encouraging results in Alzheimer's disease and multiple sclerosis but mainly negative data on primary outcomes in Parkinson's disease and major depressive disorder. Further research is needed to optimize treatment parameters, clarify mechanisms of action, and determine clinical efficacy across disease contexts.},
}

Humans
*Low-Level Light Therapy/methods
*Neuroinflammatory Diseases/radiotherapy/metabolism
Animals
*Brain Diseases/radiotherapy/therapy/metabolism

@article {pmid42965095,
year = {2026},
author = {Cao, M and Leng, L and Liu, P and Fan, Z and Peng, G},
title = {Rapidly Progressive Alzheimer's Disease: Candidate Mechanisms and Diagnostic Challenges.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {638910},
doi = {10.2147/CIA.S638910},
pmid = {42965095},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/diagnosis/pathology ; Biomarkers/blood ; Disease Progression ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Magnetic Resonance Imaging ; },
abstract = {Alzheimer's disease (AD) usually follows a slowly progressive course, but some patients experience unusually rapid cognitive and functional decline. This clinical phenotype, commonly termed rapidly progressive Alzheimer's disease (rpAD), has no consensus definition; its status as a distinct biological entity remains unresolved, and its reported frequency depends strongly on operational criteria and referral settings. To synthesize current evidence, we conducted targeted literature searches (up to August 31, 2026) of clinical, neuropathological, and biomarker studies. This narrative review extends earlier overviews by integrating newer genetic, tau-seeding, and blood-biomarker findings with conflicting clinical evidence, while distinguishing candidate mechanisms from established diagnostic tools. Selected autopsy and biomarker studies suggest differences in amyloid-β and tau conformations, synaptic and mitochondrial proteins, neuroinflammatory responses, and concomitant pathologies; however, most data are associative, derive from small or selected cohorts, and do not establish rpAD as a discrete disease subtype. In practice, evaluation should confirm AD pathology while promptly excluding treatable causes and rapidly progressive mimics, particularly Creutzfeldt-Jakob disease (CJD), using established tools such as cerebrospinal fluid biomarkers, MRI, and PrP RT-QuIC. Cerebrospinal fluid, molecular imaging, structural MRI, and emerging blood biomarkers can provide supportive evidence, but no biomarker profile has been prospectively validated as an rpAD-specific diagnostic rule. Harmonized definitions and prospective, biomarker-stratified multicenter validation are required before candidate mechanisms or biomarkers can guide rpAD-specific interventions.},
}

Humans
*Alzheimer Disease/diagnosis/pathology
Biomarkers/blood
Disease Progression
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Magnetic Resonance Imaging

@article {pmid42965512,
year = {2025},
author = {Calderón-Garcidueñas, L and Cejudo-Ruiz, FR and Torres-Jardón, R},
title = {The olfactory bulb, prefrontal and anterior cingulate cortex are early pediatric targets for anthropogenic magnetic nanoparticles and their motion behavior under electromagnetic fields.},
journal = {Gaceta medica de Mexico},
volume = {162},
number = {2},
pages = {213-222},
doi = {10.24875/GMM.M26001158},
pmid = {42965512},
issn = {0016-3813},
mesh = {Humans ; *Electromagnetic Fields/adverse effects ; *Prefrontal Cortex/pathology ; *Olfactory Bulb/pathology ; Child ; *Gyrus Cinguli/pathology/drug effects ; Mexico ; *Magnetite Nanoparticles ; Male ; Female ; Microscopy, Electron, Transmission ; Spectrometry, X-Ray Emission ; Particulate Matter ; },
abstract = {BACKGROUND: Alzheimer's, Parkinson's, and fronto-temporal lobar degeneration neuropathology hallmarks are present in young urbanites exposed to fine particulate matter (PM2.5), ultrafine PM (UFPM), and nanoparticles (NPs). Metals associated with deteriorated automobile catalysts, diesel motor emissions, brake-pads dust, and electronic waste, including rare earth elements, are entering children's brains. Cognition deficits and brain structural and volumetric changes by magnetic resonance are documented in Metropolitan Mexico City (MMC) children.

OBJECTIVES: The objectives of the study are to identify ferromagnetic materials and their motion behavior upon exposure to magnetic fields 25-1,000 mT AC in 48 brain samples including olfactory bulbs, anterior cingulate, and prefrontal cortex.

MATERIAL AND METHODS: Using magnetophoresis, we identified small displacements and significant magnetic vector direction variations in magnetic particles. Transmission electron microscopy and energy-dispersive X-ray spectrometry identified the location and composition of the ferrimagnetic NPs.

RESULTS: MMC brain samples from 12 children 8.5 ± 7.6 years and 16 adults 39.2 ± 19.6 year showed ferrimagnetic NPs with magnetic motion behavior possessing organelle and soluble protein risk for neural damage, olfactory deficits, and neuropsychiatric burden, common early neurodegenerative manifestations.

CONCLUSION: Critical brain areas are damaged in early pediatric ages and neurodegeneration is in progress in MMC young urbanites at high risk of poor academic performance. Environmental MMC UFPM/NPs controls are needed.},
}

Humans
*Electromagnetic Fields/adverse effects
*Prefrontal Cortex/pathology
*Olfactory Bulb/pathology
Child
*Gyrus Cinguli/pathology/drug effects
Mexico
*Magnetite Nanoparticles
Male
Female
Microscopy, Electron, Transmission
Spectrometry, X-Ray Emission
Particulate Matter

@article {pmid42965578,
year = {2026},
author = {Kumar, A and He, Y and Kim, S and Hsu, FC and Meade, CS and Kiraly, DD and Strowd, R and Lesser, GJ and Deep, G},
title = {Longitudinal plasma protein profiling in glioblastoma patients using NULISAseq reveals treatment-associated changes across radiation and chemotherapy.},
journal = {Journal of neuro-oncology},
volume = {180},
number = {2},
pages = {},
pmid = {42965578},
issn = {1573-7373},
mesh = {Humans ; *Glioblastoma/blood/therapy/radiotherapy/pathology/drug therapy ; *Brain Neoplasms/blood/therapy/radiotherapy/drug therapy/pathology ; Female ; *Temozolomide/therapeutic use ; Male ; *Proteomics/methods ; *Biomarkers, Tumor/blood ; Longitudinal Studies ; Middle Aged ; Antineoplastic Agents, Alkylating/therapeutic use ; Chemoradiotherapy ; Aged ; Adult ; },
abstract = {PURPOSE: Glioblastoma (GBM) is the most aggressive primary brain tumor with poor outcomes despite surgery, radiotherapy (RT), and temozolomide (TMZ). Monitoring relies on imaging, which is confounded by pseudoprogression and provides limited molecular insight. Circulating biomarkers may offer a minimally invasive approach to track disease and treatment effects.

METHODS: We performed targeted longitudinal proteomic profiling of plasma from post-surgery GBM patients (n = 11) at baseline (pre-radiotherapy (RT)), after RT with concomitant TMZ, and after adjuvant TMZ, alongside healthy controls (n = 15), using the NULISAseq CNS panel covering 131 proteins related to neurodegeneration, neuroinflammation, and vascular health. Differential expressions were assessed using volcano plots, hierarchical clustering, paired statistical comparisons and longitudinal trends analysis.

RESULTS: At baseline, GBM plasma showed elevated markers of neuroaxonal and glial injury, extracellular matrix regulators, and inflammatory signaling compared to controls. Several established neurodegeneration and Alzheimer's disease- related biomarkers were also higher in GBM plasma versus controls. Following radiotherapy and concomitant TMZ, cytokines including IL10, IL5, and IL33 increased, indicating systemic immune activation, while BDNF showed a modest decline. Adjuvant TMZ treatment attenuated radiotherapy-induced cytokine elevations and reduced neuronal injury markers, suggesting therapy-driven reduction of inflammatory and neurodegenerative signals. Longitudinal analysis confirmed dynamic shifts in specific proteins across baseline, radiotherapy, and TMZ phases.

CONCLUSION: High-sensitivity plasma proteomics suggested therapy-induced changes in CNS-specific and immune markers in GBM, highlighting candidate biomarkers that can be further developed for real-time monitoring of treatment response. These findings suggest candidate circulating markers that may complement imaging for monitoring disease biology and therapeutic response, and warrant validation in larger cohorts.},
}

Humans
*Glioblastoma/blood/therapy/radiotherapy/pathology/drug therapy
*Brain Neoplasms/blood/therapy/radiotherapy/drug therapy/pathology
Female
*Temozolomide/therapeutic use
Male
*Proteomics/methods
*Biomarkers, Tumor/blood
Longitudinal Studies
Middle Aged
Antineoplastic Agents, Alkylating/therapeutic use
Chemoradiotherapy
Aged
Adult

@article {pmid42965647,
year = {2026},
author = {Van Skike, CE and DeRosa, N and Galvan, V and Hussong, SA},
title = {Correction to: Rapamycin restores peripheral blood flow in aged mice and in mouse models of atherosclerosis and Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11357-026-02609-w},
pmid = {42965647},
issn = {2509-2723},
}

@article {pmid42965704,
year = {2026},
author = {Labonte, J and Miner, AE and Groh, JR and Montoliu-Gaya, L and Tripodis, Y and Aparicio, HJ and Turk, KW and Budson, AE and Farrer, L and Goldstein, LE and Qiu, WQ and Mez, J and McKee, AC and Zetterberg, H and Stein, TD and Gobom, J and Ashton, NJ and Alosco, ML},
title = {Leveraging immunoprecipitation mass spectrometry and neuropathology to identify the clinical value of different blood tau species in Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42965704},
issn = {1432-1459},
support = {P30AG072978/AG/NIA NIH HHS/United States ; 1UL1TR001430//BU-CTSI/ ; #2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; AF-1032107//Alherimerfonden/ ; 22HLT07//European Partnership on Meterology/ ; 2025-373//Stiftelsen för Gamla Tjänarinnor/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/pathology ; Female ; Male ; Cross-Sectional Studies ; Biomarkers/blood ; Mass Spectrometry/methods ; Aged ; Immunoprecipitation ; Phosphorylation ; Aged, 80 and over ; *Brain/pathology ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Advances in plasma-based assays have allowed for the study of several tau and p-tau epitopes. P-tau217 has emerged as one of the most robust markers of Alzheimer's disease (AD) pathology. Despite their strong diagnostic performance, plasma tau biomarkers require further validation to clarify their clinical utility.

OBJECTIVE: To investigate the associations between a panel of phosphorylated and non-phosphorylated tau species measured in antemortem plasma and clinical features of autopsy-confirmed AD.

METHODS: Cross-sectional data from 123 participants from the BU ADRC who had antemortem blood draws and brain donation following death. Participants completed neuropsychological testing during life as part of their National Alzheimer's Coordinating Center-Uniform Data Set (NACC UDS) evaluation. AD neuropathology was diagnosed using NIA-Reagan criteria. Time interval between testing at last visit and autopsy ranged from 0 to 12 years, mean = 5.54 years. Raw neuropsychological test scores were used for analysis. Sample size ranged from 65 to 91 across the tests. Plasma samples were analyzed using immunoprecipitation mass spectrometry (IP-MS) for phosphorylated tau species (p-tau-181, 199, 202, 205, 217, 231) and non-phosphorylated tau (195-209, 212-221) peptides. Two ratios were analyzed, p-tau217/tau212-221 and p-tau205/tau195-209.

RESULTS: 123 participants took part in this study, 55 (44.7%) female, and 6 (4.9%) Black/African American. The mean (SD) age at blood draw was 78.17 (8.55). The strongest association between plasma biomarkers with neuropsychological test outcomes was observed with the ratio p-tau217/tau212-221 (b = - 0.564-0.404, plow-high = 0.00-0.18), followed by p-tau217 (b = - 0.478-0.377, plow-high = 0.00-0.28), both significantly correlating with six of the eight neuropsychological measures (p < 0.05). Followed by the ratio p-tau205/tau195-209 (b = - 0.513-0.356, plow-high = 0.00-0.55), p-tau205 (b = - 0.365-0.226, plow-high = 0.00-0.44), then p-tau231 (b = - 0.319-0.237, plow-high = 0.02-0.62). Fewer significant relationships and weaker effect sizes were observed among the other biomarkers. The effect sizes of the ratio p-tau217/tau212-221, followed closely by p-tau217 on neuropsychological test outcomes, were observed to be the most similar to the effect sizes of autopsy-confirmed AD (b = - 0.564-0.393).

CONCLUSIONS: Plasma p-tau217 and p-tau ratios were comparable to autopsy-confirmed AD in predicting clinical outcomes of AD. This study highlights the promise and potential utility of plasma biomarkers for symptom monitoring.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/pathology
Female
Male
Cross-Sectional Studies
Biomarkers/blood
Mass Spectrometry/methods
Aged
Immunoprecipitation
Phosphorylation
Aged, 80 and over
*Brain/pathology
Neuropsychological Tests

@article {pmid42965717,
year = {2026},
author = {Kaur, A and Goel, RK},
title = {Revealing Pharmacological Target for Comorbid Epilepsy in Alzheimer's Disease: Neurochemical Insights from STZ Mice.},
journal = {Neurochemical research},
volume = {51},
number = {6},
pages = {},
pmid = {42965717},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/metabolism/chemically induced/drug therapy/complications ; *Epilepsy/metabolism/drug therapy/chemically induced ; Streptozocin/toxicity ; Mice ; Male ; Oxidative Stress/drug effects/physiology ; Maze Learning/drug effects ; Acetylcholinesterase/metabolism ; Brain/metabolism/drug effects ; Kindling, Neurologic/drug effects ; Pentylenetetrazole ; },
abstract = {Despite growing evidences of shared neurochemical alterations linked to comorbid epilepsy in AD, effective unified therapeutic strategies remain lacking. Thus, the present investigation was designed to identify shared neurochemical changes associated with lowered convulsive threshold in STZ (streptozotocin) model of AD-type dementia to pharmacologically address this comorbidity. Swiss albino mice were injected STZ (3 mg/kg, ICV) to induce AD-like pathology. On day 22nd, STZ mice were divided into two groups: one group served as AD control (STZ) and another group (STZ + PTZ) received PTZ (35 mg/kg) kindling to assess the reduced epileptogenesis threshold while naïve served as negative control. One more group was involved as epileptic control (PTZ). All groups underwent behavioral assessment using elevated plus maze, novel object recognition test and radial arm maze. Mice were euthanized on day 48th to collect the brain samples. The brain homogenate was used to assess redox status (GSH, TBARS and ROS), acetylcholinesterase (AChE) activity, amyloid and tau protein expression, histological alterations for specific disease pathology. As well as for neurochemical analysis to assess the shared neurochemical targets associated with comorbid epilepsy in AD. STZ mice were subjected to PTZ kindling exhibited significant greater seizure severity. The kindled status achieved by the sixth injection of PTZ, indicating reduced epileptogenic threshold. Behavioural results indicated significant cognitive impairment in STZ + PTZ treated mice compared with naive mice in EPM, NORT and RAM test. Significantly increased oxidative stress and cholinergic dysfunctions observed in STZ + PTZ mice. Neurochemical analysis revealed augmented excitatory neurotransmitter levels, along with declined glycine, GABA, taurine and arginine in STZ + PTZ mice. Moreover, reduced levels of monoamines and their metabolites reflect cognitive deficits in STZ and STZ + PTZ mice. This increased susceptibility to seizures was accompanied by significantly increased oxidative stress and excitatory neurotransmission in STZ + PTZ mice. Collectively, these observations suggest that AD related neurodegeneration may predispose to epileptogenesis further aggravate neurochemical changes. Our findings suggest that taurine, arginine and monoamines may serve as a shared neurochemical target for comorbid epilepsy in AD-type dementia.},
}

Animals
*Alzheimer Disease/metabolism/chemically induced/drug therapy/complications
*Epilepsy/metabolism/drug therapy/chemically induced
Streptozocin/toxicity
Mice
Male
Oxidative Stress/drug effects/physiology
Maze Learning/drug effects
Acetylcholinesterase/metabolism
Brain/metabolism/drug effects
Kindling, Neurologic/drug effects
Pentylenetetrazole

@article {pmid42965728,
year = {2026},
author = {Watkinson, B and Bast, T and Williams, S and Bourgade, K and Garcia-Rates, S and Hasan, S and Greenfield, S},
title = {Intracerebral Administration of a Novel, Bioactive Peptide Induces a Biochemical Profile in Rat Brain Reminiscent of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {6},
pages = {},
pmid = {42965728},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/metabolism/chemically induced/pathology ; Male ; *Brain/drug effects/metabolism/pathology ; Rats ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Peptides/administration & dosage ; Injections, Intraventricular ; Acetylcholinesterase/metabolism ; *Peptide Fragments/administration & dosage ; },
abstract = {Alzheimer's disease (AD) presents a great unmet clinical need, but the much needed replication of the characteristic neuropathology in animal models has had limited success. Here, we provide in vivo evidence that T30, a bioactive peptide posited to drive AD, can induce in the rat brain a biochemical profile resembling AD pathology. Bilateral microinfusions of T30 into the medial septum/vertical diagonal band were administered twice a week for three weeks in rats. Although there was no effect on locomotor activity, novel object recognition and watermaze delayed-matching-to-place performance, T30 infusion reduced weight growth in the rats. Post mortem immunohistochemistry showed that T30 increased the AD biomarkers amyloid beta and phosphorylated tau in the cortex, hippocampus, and midbrain. Significant neuronal loss, indicated by reduced NeuN[+] staining, was observed in brain tissue pooled from neocortex, hippocampus and midbrain. Further analysis showed a strong correlation between the 14mer T14, the active component of T30, and levels of its parent molecule acetylcholinesterase. However, this correlation only applied to protein levels, not enzymatic activity, suggesting independence from cholinergic transmission. Together, these findings support a non-cholinergic, peptide-driven mechanism by which T30 contributes to Alzheimer's-like neurodegeneration.},
}

Animals
*Alzheimer Disease/metabolism/chemically induced/pathology
Male
*Brain/drug effects/metabolism/pathology
Rats
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Peptides/administration & dosage
Injections, Intraventricular
Acetylcholinesterase/metabolism
*Peptide Fragments/administration & dosage

@article {pmid42965774,
year = {2026},
author = {Takahashi, R and Ikegami, S and Iseki, C and Nakajima, M and Oishi, K and Ishii, K},
title = {Anatomical VOI-based assessment of the three DESH components in probable idiopathic normal pressure hydrocephalus.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42965774},
issn = {1867-108X},
abstract = {PURPOSE: To evaluate whether anatomical volume-of-interest (VOI) thresholds derived from a SINPHONI-2 reference cohort could provide standardized component-wise quantification of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in a separate clinical cohort.

MATERIALS AND METHODS: Thresholds were derived from 61 SINPHONI-2 cases using a prespecified mildest-case rule and applied without re-optimization to 33 participants with probable idiopathic normal pressure hydrocephalus (iNPH), 26 with Alzheimer disease, 18 with progressive supranuclear palsy, and 20 normal controls. DESH metric-S summed binary positivity for ventriculomegaly, Sylvian fissure enlargement, and tight high-convexity and medial sulci; DESH metric-I was defined as (Sylvian fissure volume + lateral ventricular volume)/high-convexity and medial sulcal volume. Evans index and callosal angle were evaluated as conventional imaging measures.

RESULTS: For iNPH versus pooled non-iNPH, DESH metric-S had an area under the curve (AUC) of 0.958 (95% CI, 0.921-0.990), sensitivity of 97.0% (84.7-99.5%), and specificity of 92.2% (83.0-96.6%). DESH metric-I had an AUC of 0.995 (95% CI, 0.983-1.000), sensitivity of 100.0% (89.6-100.0%), and specificity of 93.8% (85.0-97.5%).

CONCLUSION: Anatomical VOI-based measures provided standardized component-wise quantification of DESH morphology. DESH metric-S retained the status of each component, whereas DESH metric-I provided a continuous summary. Because DESH contributed to probable-iNPH classification, the observed discrimination reflects concordance with a DESH-supported classification rather than independent diagnostic accuracy for iNPH. External validation, including cohorts spanning incomplete/non-DESH morphology and treatment-response outcomes, is required before clinical or prognostic use.},
}

@article {pmid42966047,
year = {2026},
author = {Devi, B and Jangid, K and Temgire, P and Kumar, N and Thareja, S and Kumar, P and Kumar, V},
title = {Computationally driven design and validation of piperazine-bridged phthalimide derivatives as multifunctional agents against Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {321},
number = {Pt 3},
pages = {119417},
doi = {10.1016/j.ejmech.2026.119417},
pmid = {42966047},
issn = {1768-3254},
abstract = {A multi-target-directed ligand (MTDL) strategy has been proposed as an effective approach for treating complex multifactorial neurological disorders like Alzheimer's Disease. A 3D-QSAR pharmacophore model of piperazine derivatives against AChE was developed and validated (R[2] = 0.99 and Q[2] = 0.91). The best pharmacophore hypothesis model (AHR_1) was used to screen an in-house generated library of 188 phthalimide-piperazine derivatives, followed by structure-based virtual screening against the targeted enzymes. The docking scores of the identified eleven hit molecules were found to be better than the standard inhibitors, and MD simulations confirmed the stability of the compound-target complexes. As a proof of concept, the top hits were synthesized in the laboratory and evaluated for their inhibitory potential. Compound VPT-2 displayed IC50 values of 0.897 μM against AChE and 0.519 μM against MAO-B, while VPT-5 showed IC50 values of 3.45 μM against AChE and 1.074 μM against MAO-B, respectively. VPT-2 and VPT-5 inhibited Aβ1-42 self-aggregation significantly by 43.27 % and 43.28 %, respectively at a concentration of 20 μM, after 48 h. Additionally, an MTT assay using SH-SY5Y cells confirmed the safety of both the lead compounds up to 20 μM. Both compounds exhibited neuroprotective effects against 6-OHDA-induced neurotoxicity and significantly reduced intracellular ROS levels by 80-90 % at 5 μM. Thus, in this drug design strategy, CADD is integrated with in vitro experimental validation for the identification of phthalimide-piperazine derivatives as promising multi-target drug candidates for the treatment of Alzheimer's disease.},
}

@article {pmid42966163,
year = {2026},
author = {Gao, C and Shi, R and Jiang, X and Chai, H and He, X},
title = {Immunometabolic dysregulation of reactive microglia and astrocytes in neurodegenerative diseases: Mechanistic insights and therapeutic implications.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126237},
doi = {10.1016/j.jns.2026.126237},
pmid = {42966163},
issn = {1878-5883},
abstract = {Neurodegenerative diseases (NDDs) are increasingly understood as multifactorial disorders characterized by intertwined pathological processes, in which metabolic dysfunction may act as a critical and potentially disease-amplifying contributor to the proteinopathy-driven pathological cascade. Despite growing recognition that microglial and astrocytic metabolism governs central nervous system tissue damage-repair homeostasis, intercellular metabolic crosstalk between glia and neurons remains insufficiently synthesized across major NDDs. This review delineates how core metabolic pathways, including glycolysis, mitochondrial respiration, lipid processing, and amino acid transport, shape glial reactivity in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We highlight glial metabolic reprogramming, a proposed theoretical framework arising from severe glial metabolic dysregulation. Within this framework, persistent pathological stress may drive reactive glia to sequester local energy substrates in excess, which is hypothesized to trigger bioenergetic failure in neighboring neurons. Broad-spectrum anti-inflammatory agents show poor clinical performance because they only block cytokine outputs rather than reverse glial metabolic exhaustion. Therapeutic efforts should therefore shift toward restoring glial metabolic flexibility. Cell-type-specific metabolic reprogramming, instead of pan-metabolic suppression, may circumvent systemic adverse effects. Precision strategies targeting such intercellular metabolic imbalance could provide promising cell-resolved metabolic avenues to retard NDD progression.},
}

@article {pmid42966413,
year = {2026},
author = {Li, C and Zhang, M and Xia, H and Zhi, X and Wang, N and Guo, J and Wang, K and Wang, L and Wang, X and Zhang, W},
title = {Reduced BNIP1 impairs autophagosome-lysosome fusion in hippocampal neurons and contributes to Alzheimer's disease pathology.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112186},
doi = {10.1016/j.brainresbull.2026.112186},
pmid = {42966413},
issn = {1873-2747},
abstract = {BNIP1 (BCL2‑interacting protein 1) belongs to the soluble N‑ethylmaleimide‑sensitive factor attachment protein receptor (SNARE) family. Statistical screening based on the Gene Expression Omnibus (GEO) dataset GSE48350 reveals reduced BNIP1 expression in patients with Alzheimer's disease (AD), suggesting that BNIP1 is a potentially key regulatory protein for investigating AD pathogenesis. In this study, we detected BNIP1 protein levels in APP/PS1 transgenic mice and APP‑overexpressing HT22 hippocampal neuronal cells, screened key interacting proteins of BNIP1 via mass spectrometry, and further performed gain‑ and loss‑of‑function assays using overexpression plasmids and small interfering RNA (siRNA) to verify the protein function of BNIP1. Our findings indicate that, in these experimental models, reduced BNIP1 expression contributes to AD‑related pathological alterations by impairing autophagosome‑lysosome fusion. Restoration of BNIP1 expression enhances Rab5b‑mediated Rab7 recruitment and consequently ameliorates autophagosome‑lysosome fusion. This study suggests that reduced BNIP1 expression is involved in AD‑related pathological alterations.NIP1 (BCL2-interacting protein 1) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family. Statistical screening based on the Gene Expression Omnibus (GEO) dataset GSE48350 reveals reduced BNIP1 expression in Alzheimer's disease (AD) patients, which renders BNIP1 a potentially key regulatory protein for investigating AD pathogenesis. In this study, we detected BNIP1 protein levels in APP/PS1 transgenic mice and APP-overexpressing HT22 hippocampal neuronal cells. Mass-spectrometry analysis was performed to screen key interacting proteins of BNIP1. Gain- and loss-of-function experiments were further conducted using overexpression plasmids and small interfering RNAs (siRNAs) to verify the protein function of BNIP1. Our findings indicate that decreased BNIP1 may act as an important contributing factor mediating AD-associated autophagosome-lysosome fusion defects in these experimental models. Restoration of BNIP1 expression enhances Rab5b-mediated Rab7 recruitment and consequently ameliorates aberrant autophagosome-lysosome fusion. This study suggests that BNIP1 serves as a potentially key regulatory protein for mechanistic research into Alzheimer's disease.},
}

@article {pmid42966482,
year = {2026},
author = {Li, J and Wang, Y and Liu, Y and Ji, Y and Lu, P and Yang, W and Zhang, S},
title = {Nanomedicine for Alzheimer's Disease: A Stage-Matched Framework Integrating Pathological Network Modulation, Blood-Brain Barrier Delivery, and Clinical Translation.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109709},
doi = {10.1016/j.phrs.2026.109709},
pmid = {42966482},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) remains one of the most difficult neurodegenerative disorders to treat. Therapeutic failure is driven mainly by two barriers: the multifactorial pathological network of AD and the limited access of most therapeutics to the brain imposed by the blood-brain barrier (BBB). Conventional symptomatic drugs and emerging antibody-based therapies provide clinical benefit, but they do not fully address the interacting processes involving amyloid-β (Aβ) accumulation, Tau pathology, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic impairment. In this review, we discuss nanomedicine as an integrated platform for AD intervention. We summarize the major pathological nodes that provide targets for nanomedicine-based therapy and discuss BBB structure and transport mechanisms. We then compare polymeric, inorganic, carbon-based, lipid-based, protein-based, nucleic acid-based, and biomimetic platforms in terms of delivery function, intrinsic bioactivity, pathological modulation, and translational risk. Assisted brain-delivery strategies are also discussed, including focused ultrasound-mediated BBB modulation and intranasal nose-to-brain delivery. We then review clinical-stage AD nanomedicine candidates and summarize the key barriers to their translation. This review integrates stage-dependent pathology, BBB transport, and nanoplatform properties. It proposes a stage-matched framework for preclinical, mild symptomatic, and moderate-severe AD. At each stage, the framework matches active pathological nodes with feasible BBB transport strategies, carrier features, and administration routes. It may guide the development of mechanistically defined, reproducible, and clinically testable nanomedicines.},
}

@article {pmid42966483,
year = {2026},
author = {Liu, D and Li, P and Gao, Q and Liu, B and Li, W and Liu, X},
title = {SIRT1 Signaling in Alzheimer's Disease: Regulation of Mitochondrial Biogenesis and Therapeutic Implications.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109713},
doi = {10.1016/j.phrs.2026.109713},
pmid = {42966483},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is one of the leading causes of dementia worldwide. Its pathological features include Aβ deposition, Tau hyperphosphorylation, and impaired neuronal energy metabolism, accompanied by persistent oxidative stress. As a nicotinamide adenine dinucleotide (NAD[+])-dependent deacetylase, sirtuin 1 (SIRT1) is a central regulator of mitochondrial biogenesis. This review systematically examines the emerging roles of SIRT1 in regulating these pathological processes in AD, with a particular focus on its regulation of mitochondrial biogenesis. It also delineates the complex regulatory mechanisms governing SIRT1, including NAD[+]-metabolism-dependent regulation, protein interaction-dependent regulation, post-translational modifications such as ISGylation and nitrosylation, and non-coding RNA-mediated post-transcriptional regulation. In addition, the coordinated influence of upstream activators and downstream effectors is discussed. Impairment of SIRT1-mediated mitochondrial biogenesis may exacerbate neuronal energy deficits and oxidative stress in AD, thereby increasing susceptibility to neurodegeneration. This review further elucidates the molecular mechanisms underlying the SIRT1-mitochondrial biogenesis axis. By integrating upstream activating signals with downstream effectors, SIRT1 creates a permissive regulatory environment for peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-driven, mitochondrial transcription factor A (TFAM)-mediated mitochondrial biogenesis, thereby facilitating quality-controlled renewal of the mitochondrial network. In addition, this review discusses the potential value of dynamic biomarker monitoring following therapeutic targeting of the SIRT1 pathway and summarizes current challenges and future intervention strategies. Targeting SIRT1-mediated mitochondrial biogenesis may provide a promising avenue for the development of novel therapeutic strategies for AD.},
}

@article {pmid37703428,
year = {2024},
author = {Hirata, K and Matsuoka, K and Tagai, K and Endo, H and Tatebe, H and Ono, M and Kokubo, N and Oyama, A and Shinotoh, H and Takahata, K and Obata, T and Dehghani, M and Near, J and Kawamura, K and Zhang, MR and Shimada, H and Yokota, T and Tokuda, T and Higuchi, M and Takado, Y},
title = {Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease.},
journal = {Annals of neurology},
volume = {95},
number = {1},
pages = {104-115},
doi = {10.1002/ana.26797},
pmid = {37703428},
issn = {1531-8249},
support = {JP22dk0207063//Japan Agency for Medical Research and Development/ ; JP19dm0207072//Japan Agency for Medical Research and Development/ ; JP22dk0207055//Japan Agency for Medical Research and Development/ ; JP21zf0127004//Japan Agency for Medical Research and Development/ ; JP19H01041//Japan Society for the Promotion of Science/ ; JP21K18268//Japan Society for the Promotion of Science/ ; },
abstract = {OBJECTIVE: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD.

METHODS: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [[11]C]PiB and [[18]F]florzolotau, respectively. Myo-inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography.

RESULTS: Myo-inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo-inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo-inositol and lactate levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p < 0.05). Significant correlations were noted between myo-inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05).

INTERPRETATION: We found high myo-inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo-inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2024;95:104-115.},
}

@article {pmid37787094,
year = {2024},
author = {Sadlon, A and Takousis, P and Ankli, B and Alexopoulos, P and Perneczky, R and , },
title = {Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function.},
journal = {Annals of neurology},
volume = {95},
number = {1},
pages = {195-206},
pmid = {37787094},
issn = {1531-8249},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: Debate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative.

METHODS: Participants were classified using the ATN (amyloid, tau, neurodegeneration) classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, analysis of covariance models identified differences in cerebrospinal fluid (CSF) levels of amyloid β1-42, phosphorylated tau 181 (ptau181), total tau (t-tau), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analyzed. Linear mixed effect models examined longitudinal changes.

RESULTS: The study included 995 individuals, with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non-Alzheimer pathophysiology and chronic pain showed increased CSF levels of t-tau and sTREM2. Chronic pain was associated with increased tumor necrosis factor α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid-positive and neurodegeneration-negative chronic pain patients showed higher memory function cross-sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group.

INTERPRETATION: Our study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm these findings. ANN NEUROL 2024;95:195-206.},
}

@article {pmid42957394,
year = {2026},
author = {Veziroglu, E and Nikpanah, M and Farhadi, F and Kalbi, D and Hensley, C and McConathy, J},
title = {PET for Evaluation of Neurologic Diseases: Part one: Neurodegenerative Diseases.},
journal = {Radiologic clinics of North America},
volume = {64},
number = {6},
pages = {1023-1037},
doi = {10.1016/j.rcl.2026.07.008},
pmid = {42957394},
issn = {1557-8275},
mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; *Positron-Emission Tomography/methods ; Radiopharmaceuticals ; Fluorodeoxyglucose F18 ; Brain/diagnostic imaging ; },
abstract = {This review of PET for evaluation of neurological diseases is divided into two parts; part one examines the clinical use of positron emission tomography (PET) in neurodegenerative diseases. FDG-PET can identify characteristic patterns of cerebral metabolism and help distinguish among neurodegenerative disorders. Amyloid and tau PET have expanding diagnostic and theranostic roles in Alzheimer's disease, including assessment of disease-specific pathology and treatment eligibility. FDOPA-PET evaluates presynaptic dopamine synthesis and supports assessment of Parkinson's disease and other parkinsonian syndromes. Combined with structural imaging and clinical evaluation, PET can improve diagnostic confidence, refine prognosis, and inform treatment decisions.},
}

Humans
*Neurodegenerative Diseases/diagnostic imaging
*Positron-Emission Tomography/methods
Radiopharmaceuticals
Fluorodeoxyglucose F18
Brain/diagnostic imaging

@article {pmid42957517,
year = {2026},
author = {Li, J and Lin, T and Long, Z and Lin, J and Gao, F and Shen, Y},
title = {Endothelial BACE1 impairs insulin signaling to drive cerebral small vessel disease and stroke.},
journal = {Science bulletin},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.scib.2026.10.030},
pmid = {42957517},
issn = {2095-9281},
abstract = {Cerebral small vessel disease (CSVD) is a major cause of stroke and dementia, yet its molecular etiology remains incompletely understood, and no disease-modifying therapies are currently available. Here, we identify a non-canonical pathogenic mechanism linking β-secretase 1 (BACE1), a therapeutic target for Alzheimer's disease, to vascular insulin resistance. BACE1 was upregulated in the cerebral endothelium of patients with hypertensive arteriopathy and cerebral amyloid angiopathy. The upregulated endothelial BACE1 cleaved the β-subunit of insulin receptor (INSR), disrupting the INSR-Akt-endothelial nitric oxide synthase (eNOS) signaling axis required for vascular homeostasis. This disruption occurred early in disease progression in a relevant rodent model of CSVD, the stroke-prone spontaneously hypertensive rat fed a high-salt diet. Treatment with the clinical BACE1 inhibitor elenbecestat (E2609) restored endothelial function, ameliorated cerebrovascular pathology, and significantly reduced stroke incidence. INSR blockade abolished these protective effects, supporting an INSR-dependent mechanism. These findings identify an intersection between neurodegenerative and metabolic pathways in the vasculature and suggest that BACE1 inhibitors, previously abandoned in Alzheimer's disease treatment, may have therapeutic potential for stroke prevention and CSVD therapy.},
}

@article {pmid42957617,
year = {2026},
author = {Abdolmaleki, M and Gaynor, LS and Liu, D and Hohman, TJ and Gifford, KA and Zetterberg, H and Jefferson, AL and Bolton, CJ},
title = {Improving the Diagnostic Accuracy of Plasma Alzheimer's Disease Biomarkers With Objective and Subjective Cognitive Screening.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70565},
pmid = {42957617},
issn = {2328-9503},
support = {AACSF-24-1294323/ALZ/Alzheimer's Association/United States ; IIRG-08-88733/ALZ/Alzheimer's Association/United States ; F32-AG076276/AG/NIA NIH HHS/United States ; K23-AG084850/AG/NIA NIH HHS/United States ; K24-AG046373/AG/NIA NIH HHS/United States ; P20-AG068082/AG/NIA NIH HHS/United States ; R01-AG034962/AG/NIA NIH HHS/United States ; R01-AG056534/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Blood-based biomarkers are increasingly used to identify Alzheimer's disease (AD) pathology and may play an important role in early disease screening and participant selection for clinical trials. However, their performance across stages of cognitive impairment remains unclear. This study examined whether plasma biomarkers differ in their ability to predict amyloid pathology by performance on cognitive screening measures.

METHODS: Participants were older adults from the community-based Vanderbilt Memory and Aging Project (N = 154; mean age = 72 ± 6 years; 37% MCI). Plasma phosphorylated tau (p-tau)231 and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa technology. Amyloid positivity was defined by cerebrospinal fluid β-amyloid 42/40 ratio < 0.072. Objective cognitive impairment was defined as ≤ 26 on the Montreal Cognitive Assessment; cognitive complaints were assessed by a single-item self-report. Logistic regression and stratified ROC analyses evaluated associations between biomarkers and amyloid status, with area under the ROC curve (AUC) values compared using DeLong's test.

RESULTS: Forty-seven percent of participants were amyloid positive. Higher plasma p-tau231 was associated with increased odds of amyloid positivity (OR = 1.18, p < 0.001; AUC = 0.73). Discriminative accuracy was significantly higher among individuals without subjective cognitive concerns (AUC = 0.85) than among those individuals with concerns (AUC = 0.67; p = 0.02). Plasma GFAP was also associated with amyloid positivity (OR = 1.01, p < 0.001; AUC = 0.75) and showed greater accuracy among participants with objective cognitive impairment (AUC = 0.82) compared to unimpaired individuals (AUC = 0.63; p = 0.03).

CONCLUSIONS: Plasma p-tau231 and GFAP were associated with amyloid pathology, but their diagnostic accuracy varied by cognitive screening results, highlighting the value of integrating brief cognitive assessments when interpreting blood-based biomarkers.},
}

@article {pmid42957639,
year = {2026},
author = {Lista, S and Emanuele, E and Cuperlovic-Culf, M and Mahdi, A and Singh, V and López-Ortiz, S and Khoramipour, K and Merino-País, M and Minoretti, P and Cisale, GY and Heslegrave, A and Imbimbo, C and Sancesario, GM and Bendlin, BB and Imbimbo, BP and Zetterberg, H and Santos-Lozano, A},
title = {Artificial intelligence applications in microbiota-gut-brain axis research: Implications for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500124},
doi = {10.1177/13872877261500124},
pmid = {42957639},
issn = {1875-8908},
abstract = {Alterations in the gut microbiota (GM) are increasingly implicated in Alzheimer's disease (AD) pathogenesis through the microbiota-gut-brain axis (MGBA), influencing neuroinflammation, amyloid-β deposition, and tau aggregation. The inherent complexity of microbiota data necessitates artificial intelligence (AI) and machine learning (ML) to identify novel biomarkers and therapeutic targets. In this narrative review, we examined AI applications in AD-related GM research, including metataxonomic and metagenomic approaches. AI methods facilitate microbial signature identification and enterotype characterization associated with AD progression, enable multi-omics integration clarifying molecular pathways linking GM dysbiosis to neurodegeneration, support predictive modeling for early AD detection, and inform personalized MGBA-targeted interventions. Employed techniques include classical ML (e.g., random forests) for taxonomic classification, deep learning (e.g., neural networks) for complex pattern recognition, and explainable AI for identifying key bacterial taxa and metabolic functions. Significant challenges persist regarding methodological standardization, larger longitudinal cohorts, and ethical considerations in clinical applications. Future priorities include developing interpretable models, integrating longitudinal multi-omics data to establish causality, and validating AI-derived insights for precision AD prevention and treatment. AI uniquely enables high-dimensional, non-linear analyses that advance understanding of microbiome-brain interactions, though clinical translation requires rigorous validation and interdisciplinary collaboration.},
}

@article {pmid42957774,
year = {2026},
author = {O'Leary, K},
title = {A small-molecule TREM2 agonist for Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/d41591-026-00055-x},
pmid = {42957774},
issn = {1546-170X},
}

@article {pmid42957838,
year = {2026},
author = {Abaresh, S and Ivantsova, E and Parmar, MS},
title = {Glymphatic Dysfunction as a Multisystem Pathway Linking Systemic Health Conditions to Alzheimer's Disease: Mechanisms, Risk Factors, and Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42957838},
issn = {1559-1182},
mesh = {Humans ; *Glymphatic System/pathology/metabolism/physiopathology ; *Alzheimer Disease/therapy/physiopathology/metabolism/pathology ; Animals ; Risk Factors ; *Health ; },
abstract = {The glymphatic system is a glia-associated perivascular pathway involved in cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and the transport and clearance of neurotoxic metabolites, including amyloid-β (Aβ) and tau, from the central nervous system. Growing evidence suggests that alterations in glymphatic and perivascular clearance are associated with Alzheimer's disease (AD) pathology and may contribute to the accumulation of neurotoxic proteins and neurodegeneration. This review examines the role of the glymphatic system in AD and explores how aging, sleep disturbances, hypertension, ischemic heart disease, high-fat diet, diabetes, and gut microbiome dysbiosis impair glymphatic transport. A recurring mechanism across experimental models is the loss of perivascular AQP4 polarization, while vascular, metabolic, and inflammatory conditions may converge on related perivascular and neurovascular processes that impair CSF-ISF exchange and solute handling. Neuroimaging studies using markers such as DTI-ALPS, perivascular space burden, and free-water measurements provide evidence of alterations in glymphatic-related and perivascular processes in AD and demonstrate associations with amyloid deposition, neurodegeneration, and cognitive decline. Furthermore, glymphatic dysfunction may interact with neuroinflammation and tau pathology, creating a self-reinforcing cycle that accelerates disease progression. Emerging therapeutic strategies, including continuous theta-burst stimulation, positive airway pressure therapy for obstructive sleep apnea, pharmacological enhancement of AQP4 function, and nutritional interventions, have shown potential in experimental and early translational studies to influence glymphatic-related processes and may mitigate AD-related pathology. Collectively, current findings suggest that glymphatic and perivascular clearance pathways may represent an important link between systemic health conditions and AD. Because related pathways are implicated across multiple systemic conditions, interventions targeting glymphatic and perivascular dysfunction may have broader relevance to brain health, but their clinical effects remain to be established.},
}

Humans
*Glymphatic System/pathology/metabolism/physiopathology
*Alzheimer Disease/therapy/physiopathology/metabolism/pathology
Animals
Risk Factors
*Health

@article {pmid42957873,
year = {2026},
author = {Carron, C and Noë, S and Vanderlinden, G and Koole, M and Schramm, G and Van Laere, K},
title = {Effects of motion and white matter hyperintensities on reference region based [18]F-SynVesT-1 PET quantification in Alzheimer's disease and healthy volunteers.},
journal = {EJNMMI research},
volume = {16},
number = {1},
pages = {},
pmid = {42957873},
issn = {2191-219X},
support = {SAO-FRA 2021/0004//Internationale Stichting Alzheimer Onderzoek/ ; 1292326N//Fonds Wetenschappelijk Onderzoek/ ; C24M/22/031//KU Leuven/ ; },
abstract = {BACKGROUND: [18]F-SynVesT-1 is a PET tracer targeting synaptic vesicle protein 2A, a surrogate marker of synaptic density. Simplified quantification using pseudo-reference regions such as the centrum semiovale (CSO) or whole cerebellum (CER) has previously been validated in healthy volunteers and Alzheimer's disease. This study assessed how motion correction and white-matter hyperintensities (WMH) affect [18]F-SynVesT-1 quantification. We reconstructed [18]F-SynVesT-1 images for 40 healthy volunteers and 31 patients with Alzheimer's disease 60-90 minutes post-injection with 3 motion handling methods: no motion correction; 5 minute frame-based post-reconstruction coregistration and averaging, and a high-temporal-resolution data-driven motion correction applied during reconstruction. WMH were segmented from T2-FLAIR images and excluded from the CSO to generate lesion-corrected CSO regions. A region-based voxelwise partial volume correction was applied. SUV and SUVRCSO/CER were compared across motion- and lesion-handling methods and the effects on group differentiation were explored.

RESULTS: Data-driven motion correction during reconstruction improved visual image sharpness and increased SUV in high-binding cortical regions (median +0.3-1.0%, p≤0.001) while reducing SUV in the low-binding CSO (median -0.5%, p=0.001). Coregistering and averaging of frames only increased contrast when there was severe motion. The cerebellum was one of the least affected regions by motion correction (median SUV +0.4% with PETDDLM, p<0.001). WMH affected CSO SUV only when ≥25% of the region contained lesions and never affected the cerebellar SUV. SUVRCSO yielded better group differentiation than SUVRCER after accounting for motion and WMH. Individual patients' z-scores differed significantly in both directions depending on the use of SUVRCSO or SUVRCER (e.g. mean absolute difference of 1.00± 0.82 in the precuneus).

CONCLUSION: Data-driven motion correction during reconstruction reduced the impact of head movements and attenuation mismatches, improving image contrast and quantitative accuracy. SUVRCER was less sensitive to motion and WMH than SUVRCSO, indicating greater robustness. When motion and WMH effects were controlled, SUVRCSO provided slightly better group differentiation than SUVRCER. These findings suggest that CSO may be preferred for group comparisons in well-controlled datasets, while the cerebellum represents a more robust reference region in the presence of motion or substantial WMH burden. The study was registered on ClinicalTrials.gov (NCT05384353), first posted on 20 May 2022.},
}

@article {pmid42957970,
year = {2026},
author = {Mendes, AJ and Boccalini, C and Ribaldi, F and Pievani, M and Peretti, D and Garibotto, V and Chincarini, A and Frisoni, GB and , },
title = {APOE ε4 gene dose drives a canonical and predictable topography of amyloid deposition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71935},
pmid = {42957970},
issn = {1552-5279},
support = {//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI (Department of Defense)/ ; //National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering/ ; //AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research/ ; 320030_185028/SNSF_/Swiss National Science Foundation/Switzerland ; 320030_182772/SNSF_/Swiss National Science Foundation/Switzerland ; 20030_169876/SNSF_/Swiss National Science Foundation/Switzerland ; 320030_220269/SNSF_/Swiss National Science Foundation/Switzerland ; //Association Suisse pour la Recherche sur la Maladie d'Alzheimer, Fondation Segré, Ivan Pictet, Race Against Dementia Foundation, Fondation Child Care, Fondation Edmond J Safra, Fondation Minkoff, Fondazione Agusta, McCall Macbain Foundation, VELUX Foundation, Schmidheiny Foundation/ ; Ricerca Corrente 2025-2027//Italian Ministry of Health/ ; },
mesh = {Humans ; *Apolipoprotein E4/genetics ; Female ; Positron-Emission Tomography ; Male ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism ; Aged ; *Brain/diagnostic imaging/metabolism/pathology ; *Gene Dosage ; Heterozygote ; *Amyloid/metabolism ; *Amyloid beta-Peptides/metabolism ; Genotype ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Apolipoprotein E ε4 (APOE ε4) carriership is associated with higher amyloid burden in Alzheimer's disease (AD), but whether it constrains the spatial predictability of amyloid deposition at the individual level remains unknown.

METHODS: We analyzed voxel-wise amyloid positron emission tomography data from 781 amyloid-positive individuals across two independent cohorts (Alzheimer's Disease Neuroimaging Initiative and Geneva Memory Center), spanning the full clinical continuum. Individual topographic similarity to canonical AD amyloid maps and within-group spatial homogeneity were assessed via voxel-wise correlations and linear regression adjusted for age, sex, and global amyloid burden.

RESULTS: APOE ε4 carriers exhibited amyloid distributions more aligned with canonical AD topographies than non-carriers (p < 0.001), with a clear gene-dose effect on within-group spatial homogeneity: Homozygotes showed the highest inter-subject consistency, followed by heterozygotes and non-carriers. Effects were robust across tracers, clinical stages, and cohorts.

DISCUSSION: APOE ε4 gene dose constrains the spatial predictability of amyloid accumulation, informing genotype-stratified approaches in anti-amyloid trials.},
}

Humans
*Apolipoprotein E4/genetics
Female
Positron-Emission Tomography
Male
*Alzheimer Disease/genetics/diagnostic imaging/metabolism
Aged
*Brain/diagnostic imaging/metabolism/pathology
*Gene Dosage
Heterozygote
*Amyloid/metabolism
*Amyloid beta-Peptides/metabolism
Genotype
Aged, 80 and over

@article {pmid42957973,
year = {2026},
author = {Liu, J and Xiao, BW and Mai, X and Wang, YC and Fei, Y and Wang, Y and Hou, SX},
title = {ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71926},
pmid = {42957973},
issn = {1552-5279},
support = {82450108//National Natural Science Foundation of China/ ; 32370739//National Natural Science Foundation of China/ ; 32271510//National Natural Science Foundation of China/ ; 2023YFA1800202//National Key R&D Program of China/ ; 2024YFA1306000//National Key R&D Program of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism ; Humans ; Ubiquitination ; *Ubiquitin Thiolesterase/metabolism/genetics ; Mice ; Disease Models, Animal ; Drosophila ; *Drosophila Proteins/metabolism/genetics ; Phosphorylation ; *Tauopathies/metabolism/pathology ; },
abstract = {INTRODUCTION: Hyperphosphorylated Tau accumulation drives neurodegeneration in Alzheimer's disease (AD), but mechanisms linking impaired Tau ubiquitination to disease progression remain incompletely defined.

METHODS: We integrated Drosophila RNAi screening, human AD datasets, cellular assays, and mouse tauopathy models to evaluate arrestin domain-containing 4 (ARRDC4) in Tau pathology. ARRDC4-dependent regulation of Tau ubiquitination was examined using proteomics, proximity labeling, co-immunoprecipitation, BiFC, domain mapping, genetic suppression, and small-molecule interference.

RESULTS: ARRDC4 was upregulated in AD-relevant human and animal datasets and correlated with Tau burden. ARRDC4 overexpression promoted Tau phosphorylation, self-association, seeded aggregation, secretion, and inflammatory activation. Mechanistically, ARRDC4 brought Tau and USP14 into proximity, suppressing Tau ubiquitination. Genetic ARRDC4 deficiency or pharmacological disruption of the ARRDC4-USP14 interface restored Tau ubiquitination and ameliorated Tau pathology, neuroinflammation, neuronal injury, and behavioral deficits across cellular, Drosophila, and mouse models.

DISCUSSION: ARRDC4 is a regulator of Tau proteostasis and a potential therapeutic target for Tau-associated AD pathology.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism
Humans
Ubiquitination
*Ubiquitin Thiolesterase/metabolism/genetics
Mice
Disease Models, Animal
Drosophila
*Drosophila Proteins/metabolism/genetics
Phosphorylation
*Tauopathies/metabolism/pathology

@article {pmid42957985,
year = {2026},
author = {Hu, P and Zhang, M and Wei, X and Xiao, S and Li, B and Liu, K and Su, G and Han, B and Shi, X and Wei, C and Sun, J and Zhang, Z and Han, Z and Shen, L},
title = {Total salvianolic acids protect APP/PS1 mice from Alzheimer's disease by attenuating neuroinflammation through hippocampal lipid regulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498369},
doi = {10.1177/13872877261498369},
pmid = {42957985},
issn = {1875-8908},
abstract = {BackgroundTotal salvianolic acids (TSA) have been shown to exert neuroprotective effects in cognition-associated behavioral tests in APP/PS1 mice in our previous research; however, research on TSA-mediated modulation of hippocampal lipid metabolism remains limited.ObjectiveThis study elucidated the therapeutic mechanisms underlying prophylactic TSA administration by integrating lipidomic profiling and demonstrating TSA-induced neuroprotection through suppression of hippocampal neuroinflammation in APP/PS1 mice.MethodsTen 3.5-month-old APP/PS1 mice and ten age-matched wild-type mice received intraperitoneal saline injections as the disease model and healthy control groups. Another twenty APP/PS1 mice were allocated to two TSA treatment groups (30 mg/kg/day and 60 mg/kg/day). After fifteen weeks of intervention, memory performance was assessed using the Y-maze test. Hippocampal Aβ, IBA1, and GFAP protein expression levels were quantified by western blotting. Targeted UHPLC-MS/MS was used for quantitative detection of hippocampal lipid biomarkers.ResultsThe 60 mg/kg TSA group exhibited improved memory in Y-maze tests, with elevated spontaneous alternation rate (p < 0.05) and arm entries (p < 0.01). The latency to enter the novel arm was significantly reduced at both doses of TSA (p < 0.01). TSA at 60 mg/kg reduced hippocampal inflammation markers IBA1 (p < 0.05), GFAP (p < 0.05), and Aβ (p < 0.01) in APP/PS1 mice. Lipids revealed significant changes in 41 lipid species after TSA treatment. TSA suppressed the levels of glycerides, sterol lipids, and free fatty acids while increasing glycolipids including monogalactosyldiacylglycerols. TSA also regulated sphingomyelins by reducing acyl chain-modified PCs and increasing phosphatidylserines.ConclusionsThis study reveals TSA's preventive potential against Alzheimer's disease by modulating inflammation-associated lipid metabolism in APP/PS1 mice.},
}

@article {pmid42958309,
year = {2026},
author = {Kurz, C and Leonhardt, S and Hufnagel, A and Wizemann, S and Deutelmoser, H and Menzel, P and Perneczky, R},
title = {A prospective observational study measuring the stability of plasma pTau181 using the Elecsys Phospho-Tau (181P) plasma immunoassay for early detection of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42958309},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood ; Immunoassay/methods ; Male ; Female ; Biomarkers/blood ; Aged ; Prospective Studies ; Early Diagnosis ; Phosphorylation ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Plasma tau phosphorylated at threonine 181 (pTau181) is a key blood-based biomarker that correlates with the burden of amyloid-beta (Aβ) pathology in Alzheimer's disease (AD). The Elecsys[®] Phospho-Tau (181P) Plasma (pT181p) immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) is intended for use as an aid in the early detection of Aβ pathology in adults ≥ 55 years presenting with complaints of cognitive decline and is Conformité Européenne-marked and approved for clinical use by the US FDA. Here, we evaluated the stability of plasma pTau181 measured using the pT181p immunoassay under different pre-analytical and storage conditions in samples from an intended-use population.

METHODS: Whole blood samples from individuals presenting at LMU Hospital with symptom severity ranging from subjective cognitive decline to moderate AD dementia were collected in three different tubes for plasma preparation (Li-Heparin, K2-EDTA, and K3-EDTA). These were transported under cooled (never frozen) conditions to the measurement site and processed within 6 h of collection. Plasma samples were stored at different temperatures for varying durations, and impact on plasma pTau181 recoveries was assessed.

RESULTS: Out-of-specification results not meeting pre-defined acceptance criteria observed in an initial cohort (n = 14), were found to be the result of buffy coat/erythrocyte contamination. Pre-analytical procedures were modified to prevent contamination during post-centrifugation plasma transfer. In samples from a separate cohort (n = 10), no instabilities were observed and acceptance criteria were met. After considering safety margins, analyte stability for all sample types was determined to be 2 days at 25 °C, 7 days at 4 °C, 12 weeks at -20 °C, and 16 weeks at -80°C; stability was also observed after one freeze/thaw cycle.

CONCLUSIONS: pT181p immunoassay measurements were stable and robust with respect to different sample handling procedures and storage conditions. These findings support implementation of the assay into routine, non-specialist healthcare settings to facilitate practical blood-based testing to rule out AD-related Aβ pathology.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood
Immunoassay/methods
Male
Female
Biomarkers/blood
Aged
Prospective Studies
Early Diagnosis
Phosphorylation
Middle Aged
Aged, 80 and over

@article {pmid42958401,
year = {2026},
author = {Cao, S and Chen, Y and Li, J and Li, Z and Liu, D and Zhong, L and Dong, X and Dai, J and Yin, H},
title = {Target-area dosimetry-guided photobiomodulation improves pathology and cognitive function in APPswe/PS1dE9 mice.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42958401},
issn = {1479-5876},
support = {2023-I2M-2-008//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; 2023YFB3609103//National Key Research and Development Program of China/ ; 62175261//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Low-Level Light Therapy ; *Cognition/radiation effects ; Monte Carlo Method ; Mice, Transgenic ; *Radiometry ; Alzheimer Disease/physiopathology/pathology/radiotherapy ; *Presenilin-1/metabolism ; Brain/pathology/radiation effects/physiopathology ; Mice ; Calibration ; Amyloid beta-Protein Precursor/metabolism ; },
abstract = {BACKGROUND: Photobiomodulation (PBM) has shown potential in Alzheimer's disease (AD) models, but substantial heterogeneity in irradiation parameters and the lack of intracerebral dose quantification have limited reproducibility and mechanistic interpretation. In transcranial PBM, surface power density does not reliably reflect energy delivery to brain targets due to wavelength-dependent tissue attenuation.

METHODS: We developed a target-area dosimetry- guided PBM framework by integrating Monte Carlo-based light transport modeling with inverse calibration for selected representative wavelength-target conditions. Based on these simulations, inverse calibration was performed for selected representative wavelength-target combinations, with 810 nm irradiation optimized for PFC-directed PBM and 1060 nm, 40 Hz pulsed irradiation optimized for HIPP-directed PBM. APPswe/PS1dE9 mice received region-oriented and comparative PBM treatments, followed by behavioral, pathological, and electrophysiological assessments.

RESULTS: Monte Carlo simulations revealed marked wavelength-dependent differences in intracerebral light distribution under identical surface irradiation. Inverse calibration supported the selection of region-specific irradiation parameters and highlighted the need to consider target-area light exposure rather than surface power alone. Among the tested irradiation conditions, PBM improved spatial learning and memory and modulated amyloid burden, neuroinflammatory responses, synaptic markers, and neural network activity. Among these treatments, combined hippocampal irradiation with 810 nm and 1060 nm light produced the most consistent overall responses, while 810 nm PFC irradiation also showed beneficial effects across several outcome measures.

CONCLUSIONS: These findings support target-area dosimetry as an important physical consideration for the design and interpretation of region-oriented PBM protocols in AD models. By integrating intracerebral light propagation modeling with biological evaluation, this study provides a methodological framework for improving PBM parameter selection and guiding future optimization of transcranial PBM interventions.},
}

Animals
*Low-Level Light Therapy
*Cognition/radiation effects
Monte Carlo Method
Mice, Transgenic
*Radiometry
Alzheimer Disease/physiopathology/pathology/radiotherapy
*Presenilin-1/metabolism
Brain/pathology/radiation effects/physiopathology
Mice
Calibration
Amyloid beta-Protein Precursor/metabolism

@article {pmid42958434,
year = {2026},
author = {Ma, L and Wang, Y and Goudey, B and Jin, L and Pan, Y},
title = {Neuropathological and vascular determinants of cerebral amyloid angiopathy risk: evidence from the NACC cohort.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42958434},
issn = {1758-9193},
support = {GNT2007912//National Health and Medical Research Council/ ; GNT2022203//NHMRC-AMED Dementia Collaborative Research Grant/ ; 23AARF-1020292//Alzheimer's Association USA/ ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/genetics/epidemiology ; Female ; Male ; *Brain/pathology ; Aged ; Cohort Studies ; Risk Factors ; *Alzheimer Disease/pathology/genetics/epidemiology ; Aged, 80 and over ; Frontotemporal Lobar Degeneration/pathology ; Lewy Bodies/pathology ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is strongly associated with Alzheimer's disease neuropathologic changes (ADNC), but its links with other brain pathologies remain unclear.

METHODS: We conducted a clinicopathological study of 3,267 participants from the National Alzheimer's Coordinating Center (NACC) cohort. Neuropathological evaluations included potential risk factors for CAA, such as ADNC, Lewy body pathology (LBP), frontotemporal lobar degeneration (FTLD), and other neuropathologies.

RESULTS: We found that ADNC and LBP were associated with increased odds of CAA, with the risk increasing according to ADNC severity and in cases of limbic/amygdala-predominant LBP. In contrast, FTLD, particularly the FTLD-TDP subtype, was inversely associated with CAA. Among other neuropathologies, CAA was positively associated with microinfarcts, arteriolosclerosis, white matter rarefaction, and hippocampus/cortical atrophy, but inversely associated with lobar atrophy and higher brain weight. In addition, APOE ε4 carriers with mixed ADNC, LBP, and FTLD exhibited the highest risk. Stronger associations between ADNC and CAA were observed in participants aged < 80 years and in males, whereas females demonstrated greater vulnerability to vascular- and atrophy-related correlates. Several neuropathology-CAA associations were also more pronounced among APOE ε4 carriers.

CONCLUSION: These findings highlight the interplay of neurodegenerative, vascular, sex, and APOE ε4 in CAA susceptibility, with implications for risk stratification.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/genetics/epidemiology
Female
Male
*Brain/pathology
Aged
Cohort Studies
Risk Factors
*Alzheimer Disease/pathology/genetics/epidemiology
Aged, 80 and over
Frontotemporal Lobar Degeneration/pathology
Lewy Bodies/pathology

@article {pmid42958467,
year = {2026},
author = {Dou, J and Zhu, Y and Du, Z and Zhang, G},
title = {LncRNA FBXL19-AS1 regulates the miR-650/ITGB3 axis to drive pathological progression in Alzheimer's Disease.},
journal = {Hereditas},
volume = {163},
number = {1},
pages = {},
pmid = {42958467},
issn = {1601-5223},
support = {Grant No. 2541ZF292//Baoding Science and Technology Program/ ; },
mesh = {Humans ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics/pathology ; *RNA, Long Noncoding/genetics ; Female ; *Integrin beta3/genetics ; Disease Progression ; Apoptosis ; Cell Proliferation ; Male ; Gene Expression Regulation ; Aged ; Amyloid beta-Peptides ; Cell Line, Tumor ; Cell Line ; DNA-Binding Proteins ; F-Box Proteins ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by complex and not yet fully understood pathological mechanisms. This study was designed to explore the molecular mechanisms of long non-coding RNA (lncRNA) FBXL19-AS1 in the pathological progression of AD.

METHODS: 110 AD patients and 110 healthy controls were recruited for this study. Relevant gene expression was measured using reverse transcription quantitative real-time PCR (RT-qPCR), and the diagnostic performance was assessed through receiver operating characteristic (ROC) curve analysis. AD cell models were established by treating SH-SY5Y and BV2 cells with amyloid β (Aβ)25-35. Cell proliferation was evaluated using the cell counting kit-8 (CCK-8) assay, cell apoptosis was analyzed by flow cytometry, and the secretion levels of inflammatory factors were determined via enzyme-linked immunosorbent assay (ELISA). A dual-luciferase reporter assay was performed to confirm the direct regulatory interactions.

RESULTS: In AD patients, the FBXL19-AS1 and integrin subunit beta 3 (ITGB3) expression were significantly elevated, whereas microRNA-650 (miR-650) expression was markedly reduced. FBXL19-AS1 showed certain diagnostic potential for AD, and its expression was negatively correlated with Montreal Cognitive Assessment (MoCA) scores. Following treatment with Aβ25-35, SH-SY5Y cells exhibited reduced proliferative capacity and increased apoptosis, while BV2 cells showed elevated levels of inflammatory factors. Additionally, Aβ25-35 treatment led to upregulated expression of FBXL19-AS1 and ITGB3, along with downregulated expression of miR-650. Knockdown of FBXL19-AS1 effectively reversed these effects. However, inhibition of miR-650 partially attenuated the changes induced by FBXL19-AS1 knockdown. Furthermore, knockdown of FBXL19-AS1 markedly reduced ITGB3 expression, whereas concurrent inhibition of miR-650 partially reversed this downregulatory effect.

CONCLUSION: FBXL19-AS1 appears to interact with and modulate miR-650, thereby affecting ITGB3 expression and potentially participating in the pathological progression of AD.},
}

Humans
*MicroRNAs/genetics
*Alzheimer Disease/genetics/pathology
*RNA, Long Noncoding/genetics
Female
*Integrin beta3/genetics
Disease Progression
Apoptosis
Cell Proliferation
Male
Gene Expression Regulation
Aged
Amyloid beta-Peptides
Cell Line, Tumor
Cell Line
DNA-Binding Proteins
F-Box Proteins

@article {pmid42958586,
year = {2026},
author = {Lee, S and English, AC and Peloso, GM and Bis, JC and Boerwinkle, E and Choi, SH and Heard-Costa, NL and Lin, H and Xia, R and Seshadri, S and Destefano, AL and Fornage, M and Sedlazeck, FJ},
title = {The impact of structural variation on Alzheimer's disease in the Alzheimer's disease sequencing project.},
journal = {Genome biology},
volume = {27},
number = {1},
pages = {},
pmid = {42958586},
issn = {1474-760X},
support = {U01-AG058589/AG/NIA NIH HHS/United States ; U01-AG058589, U01-AG052409, P30-AG066546/AG/NIA NIH HHS/United States ; U01-AG058589, U01-AG068221/AG/NIA NIH HHS/United States ; U01-AG058589, U01-AG052409, U01-AG070112/AG/NIA NIH HHS/United States ; U01-AG068221/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics ; Humans ; *Genomic Structural Variation ; Whole Genome Sequencing ; Linkage Disequilibrium ; },
abstract = {INTRODUCTION: Structural variants (SV), genomic alterations spanning more than 50 base pairs, can significantly impact gene expression and protein function. However, their contribution to Alzheimer's disease (AD) remains poorly understood. Leveraging a novel SV calling pipeline, we identified SVs with high accuracy in a diverse sample of the Alzheimer's Disease Sequencing Project (ADSP) and investigated the role of SVs in AD.

RESULTS: We analyze SVs in 16,841 individuals from ADSP whole genome sequencing data using BioGraph, a semi-assembly-based method that employs graph-based representation for accurate SV detection. We identify 456,644 high-quality SVs, 65% of which were novel. Of these, 272,728 SVs directly impact genes, including 86 AD-related genes. We perform association analyses within three ancestry groups, including 3,371 African (AFR), 6,327 European (EUR), and 2,126 Latin (LAT). We observe multiple deletions and insertions in moderate to high linkage disequilibrium with known AD loci, including TPCN1 and TMEM106B. In EUR, genome-wide association analysis identifies two significant low-frequency deletions associated with AD, located in introns of CCDC12 and CCDC88B, both encoding coiled-coil domain-containing proteins. Gene-based analyses further identify rare pathogenic SVs in several known AD genes, including PSEN1 in LAT and ABCA7 in AFR.

CONCLUSIONS: Using a novel graph-based SV calling pipeline, we identify high-quality SVs across a large and ancestrally diverse cohort. Our analyses reveal both common and rare SVs associated with AD. These findings provide valuable insights into the genetic architecture of AD, emphasizing the value of including diverse populations in AD genomic studies.},
}

*Alzheimer Disease/genetics
Humans
*Genomic Structural Variation
Whole Genome Sequencing
Linkage Disequilibrium

@article {pmid42958598,
year = {2026},
author = {Abd-ElRaouf, K and Murphy, DT and Cheong, LYT and Zeng, J and Lo, CH},
title = {The pathological roles of intrinsically disordered proteins in lysosomal acidification dysfunction in neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42958598},
issn = {2047-9158},
support = {Start-up grant//Syracuse University/ ; 25AARG-1375299//Alzheimer's Association Research Grant/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Lysosomes/metabolism/pathology ; *Intrinsically Disordered Proteins/metabolism ; Animals ; Autophagy/physiology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD) are characterized by the accumulation of intrinsically disordered proteins (IDPs), including amyloid-β (Aβ), tau, and α-synuclein (αSyn). These proteins disrupt neuronal homeostasis through toxic aggregation, impaired proteostasis, and progressive neurodegeneration, in part via dysfunction of the autophagy-lysosomal pathway (ALP). A central feature of this impairment is defective vacuolar-type (H[+])-ATPase (V-ATPase) function, leading to lysosomal deacidification and reduced degradative capacity. Pathological IDP species converge on V-ATPase through direct interactions with its subunits or by perturbing its assembly, while also exerting protein-specific effects, including lysosomal membrane destabilization, impaired hydrolase activity, and disrupted endolysosomal trafficking. These combined mechanisms create a reciprocal relationship between lysosomal dysfunction and IDP accumulation, in which impaired lysosomal degradation further promotes the persistence and aggregation of pathological IDP species. This review synthesizes current insights into the molecular interplay between IDPs and lysosomal acidification across AD, FTD, and PD, and highlights how these processes contribute to disease progression. We further discuss emerging therapeutic strategies aimed at restoring lysosomal function. These findings underscore lysosomal dysfunction as a common feature of IDP-driven neurodegeneration and a potential therapeutic target across these disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Lysosomes/metabolism/pathology
*Intrinsically Disordered Proteins/metabolism
Animals
Autophagy/physiology

@article {pmid42958736,
year = {2026},
author = {Saltiel, N and Howard, E and Lee, AJ and Moody, JN and Hayes, JP and , },
title = {Traumatic brain injury history moderates age-related episodic memory change in older veterans: the DOD-ADNI longitudinal cohort study.},
journal = {Brain injury},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/02699052.2026.2752523},
pmid = {42958736},
issn = {1362-301X},
abstract = {BACKGROUND: Traumatic brain injury (TBI) has been associated with increased risk of dementia and cognitive decline, but its relationship with age-related cognitive trajectories remains unclear. This study examined associations between TBI history and age-related changes in cognitive function in aging military veterans.

METHODS: Data from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD-ADNI) repository were used to evaluate whether TBI history moderates the relationship between age and longitudinal change in domain-specific cognitive performance. To investigate these relationships, this study utilized data from neuropsychological assessments collected at baseline and 12-month timepoints from a sample consisting of 203 Vietnam War veterans, 99% of whom were male, aged 60-84 years, with varying TBI histories.

RESULTS: Results revealed that TBI history moderated the association between age and change in episodic memory. Older age was associated with greater memory decline among individuals with TBI. No interaction effects were observed for executive functions or language.

CONCLUSIONS: These findings suggest that TBI history is associated with differences in age-related episodic memory change and highlight the importance of considering TBI history in studies of cognitive aging. Considering the modest proportion of variance explained by the interaction and homogeneous veteran sample, additional research is warranted.},
}

@article {pmid42959066,
year = {2026},
author = {Lin, D and Luo, Y and Qiu, X and Ye, P and Chen, R and Xu, W and Zheng, R and Fu, X and Fan, K and Chen, D and Yang, B and Chen, L and Ou, Q and Liu, X},
title = {Serum neuron-derived extracellular vesicle mitochondrial DNA as a potential biomarker for mild cognitive impairment due to AD.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1924123},
pmid = {42959066},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents the initial clinical manifestation, eventually evolving into the distinctive features of Alzheimer's disease (AD), making its early identification crucial. Notably, mitochondrial dysfunction is an early characteristic of AD. Neuron-derived extracellular vesicles (NDEVs) can cross the blood-brain barrier, and their mitochondrial DNA (mtDNA) can reflect intracerebral lesions, showing considerable potential. In this study, we investigated the alterations in mtDNA within serum NDEVs and evaluated their potential as early diagnostic biomarkers for MCI due to AD.

METHODS: A total of 42 MCI patients, 49 AD patients, and 57 age-matched cognitively unimpaired (CU) controls were enrolled. Serum NDEVs were enriched and characterized, and their mtDNA levels were quantified by qPCR. ROC curve was used to analyze diagnostic performance, and the integration of multimodal biomarkers was explored.

RESULTS: Serum NDEVs mtDNA levels were decreased in patients with AD-MCI, and a significant positive correlation was observed between serum NDEVs mtDNA levels and MMSE scores in MCI patients (r = 0.4864, P = 0.0407), and a similar association was observed in the AD group (r = 0.3857, P = 0.0469). In terms of diagnostic performance, serum NDEV mtDNA demonstrated outstanding discrimination between CU controls and AD subjects, achieving an area under the curve (AUC) of 0.965 (95% CI: 0.933-0.997), with 97.92% sensitivity and 89.09% specificity. Moreover, it also demonstrated moderate efficacy in differentiating early MCI from AD (AUC = 0.736, 95% CI: 0.629-0.842; sensitivity = 72.92%, specificity = 66.67%). In exploratory analyses of clinical and metabolic factors, serum NDEV mtDNA levels were positively correlated with HCY in MCI patients, while in AD patients, NDEV mtDNA levels were elevated in those with diabetes and positively correlated with TG. Notably, integrating NDEV mtDNA with established biomarkers, including p-Tau 217, GFAP, and APOE ε4 carrier status, significantly improved the accuracy of MCI detection, highlighting its value in multimodal biomarker strategies.

CONCLUSION: Serum NDEVs mtDNA levels were significantly reduced in patients with MCI and AD, suggesting strong potential as an early diagnostic biomarker for MCI due to AD.},
}

@article {pmid42959148,
year = {2026},
author = {Subih, O and Al Mustafa, WA and AlOmem, TA and Alrasheed, AM and Altunaiji, MS and Alhasan, AAM and Alshehri, AIA and Alshahrani, BM and Alharbi, RJM and Alshatti, AM and Al Mutairi, ME and Alkhaldi, SM and Bifari, IN},
title = {The association between diabetic retinopathy and cognitive impairment in patients with diabetes mellitus: a systematic review and meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1881602},
pmid = {42959148},
issn = {1664-2392},
mesh = {Humans ; *Diabetic Retinopathy/complications/epidemiology ; *Cognitive Dysfunction/epidemiology/etiology ; *Diabetes Mellitus/epidemiology ; },
abstract = {BACKGROUND: Diabetic retinopathy (DR) is a recognized microvascular complication of diabetes in which neurovascular and neurodegenerative mechanisms may also contribute. This systematic review evaluated the association between DR and cognitive impairment or dementia, including Alzheimer's disease and vascular dementia, using evidence from cross-sectional and longitudinal observational studies.

METHODS: We searched for relevant articles up to December 2025 from PubMed, Scopus, Web of Science, and Cochrane Library. Two independent reviewers extracted data from the selected studies, including baseline information and outcomes. All quantitative syntheses were conducted using R version 4.4.1.

RESULTS: Fourteen studies with reported study populations totaling 2,871,847 participants were included. Seven studies contributed to the crude dichotomous synthesis, which did not demonstrate a statistically significant association between diabetic retinopathy and cognitive impairment or dementia (OR 1.07, 95% CI 0.94-1.23; p=0.310; I[2]=52.3%). Seven studies contributed adjusted longitudinal estimates for incident dementia; diabetic retinopathy was associated with a higher incidence of dementia (HR 1.55, 95% CI 1.19-2.02; p=0.001; I[2]=97.8%; 95% prediction interval 0.65-3.68). Evidence concerning Alzheimer's disease and vascular dementia remained inconsistent.

CONCLUSION: Longitudinal evidence suggests that diabetic retinopathy is associated with a higher incidence of dementia, although substantial heterogeneity and the observational evidence base limit confidence in the pooled estimate. Evidence concerning Alzheimer's disease and vascular dementia remains inconclusive.

https://doi.org/10.17605/OSF.IO/YS462, identifier YS462.},
}

Humans
*Diabetic Retinopathy/complications/epidemiology
*Cognitive Dysfunction/epidemiology/etiology
*Diabetes Mellitus/epidemiology