@article {pmid42167944,
year = {2026},
author = {Demina, A and Casey, D and Amaral, S and Fabus, MS and Béjot, Y and Trojak, B},
title = {Protocol for a living systematic review of randomised controlled trials on the clinical efficacy of transcranial pulse stimulation in neurological and psychiatric conditions.},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e117329},
doi = {10.1136/bmjopen-2026-117329},
pmid = {42167944},
issn = {2044-6055},
mesh = {Humans ; Systematic Reviews as Topic ; Randomized Controlled Trials as Topic ; *Mental Disorders/therapy ; *Transcranial Direct Current Stimulation ; Research Design ; *Nervous System Diseases/therapy ; Treatment Outcome ; *Alzheimer Disease/therapy ; },
abstract = {INTRODUCTION: Transcranial pulse stimulation (TPS) is a novel technology with therapeutic promise for Alzheimer's disease. Given its novelty and the rapidly evolving research in neurology and mental health using this technology, large randomised controlled trials are expected. Therefore, an independent and up-to-date synthesis of the available evidence is needed. In our effort to create a living systematic review of the clinical efficacy of TPS across various conditions, we aim to describe its methodology to ensure its transparency and scientific rigour. This protocol details the predefined methods related to search frequencies, updates to the review and quantitative synthesis.

METHODS AND ANALYSIS: We will only include randomised controlled trials involving clinically diagnosed populations and comparing active TPS to sham TPS. We will search MEDLINE, CENTRAL and Web of Science, as well as trial registries and grey literature. The principal searches in databases and trial registries will be rerun monthly, and new evidence will be integrated. Study selection, data extraction and risk-of-bias assessments will be performed independently and in duplicate. All relevant clinical outcomes measured with validated psychometric scales and tests will be collected. The relevance of a quantitative synthesis, the studies to be included in pairwise meta-analysis, appropriate scales, questionnaires and time points will be discussed by the research team annually. If a meta-analysis is conducted, we will use the standardised mean difference as the measure of effect size. We will assess our confidence in the cumulative evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

ETHICS AND DISSEMINATION: For this systematic review and meta-analysis, we will collect existing data without generating new datasets. Therefore, ethics approval or consent to participate is not required.We will publish our initial systematic review when a total of four randomised controlled trials across different health conditions using active TPS compared with sham TPS are available. At this stage of our project, we anticipate updating the living systematic review annually following the publication of the baseline review. We will conclude the living phase of the review when high certainty of evidence is achieved or if the topic loses its relevance.

CRD42024595947.},
}

Humans
Systematic Reviews as Topic
Randomized Controlled Trials as Topic
*Mental Disorders/therapy
*Transcranial Direct Current Stimulation
Research Design
*Nervous System Diseases/therapy
Treatment Outcome
*Alzheimer Disease/therapy

@article {pmid42168524,
year = {2026},
author = {Akagi, S and Sato, Y and Sakamoto, T and Minamisawa, M},
title = {Sequential co-extraction of gut microbial DNA and fecal polyamines enables integrated microbiome-metabolite profiling in an Alzheimer's disease mouse model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54312-7},
pmid = {42168524},
issn = {2045-2322},
support = {FTR-156//Translational Research Grant from Fujita Health University/ ; FTR-156//Translational Research Grant from Fujita Health University/ ; },
abstract = {Early, non-invasive biomarkers for Alzheimer's disease (AD) are urgently needed. Impaired polyamine metabolism, regulated by intracellular pathways and the gut microbiota, has been reported in postmortem brains of AD patients. Here, we developed a sequential co-extraction workflow (Method 10) that enables recovery of gut bacterial DNA and fecal free polyamines-putrescine, spermidine, and spermine-from the same small mouse fecal sample, allowing paired microbiome and metabolite profiling. Applying this workflow to an AD knock-in mouse model and age-matched controls at 8, 32, and 56 weeks revealed an early decrease in Lactobacillus abundance at 8 weeks accompanied by elevated spermidine levels (p < 0.05), while total fecal polyamine concentrations increased further in AD mice at 56 weeks. These findings suggest that integrated fecal microbiome-polyamine profiling may provide exploratory microbiota-polyamine signatures associated with AD progression.},
}

@article {pmid42168643,
year = {2026},
author = {Macedo, AC and Provost, K and Soucy, JP and Haeger, A and Therriault, J and Trudel, L and Rahmouni, N and Fernandez-Arias, J and Aumont, É and Lebrun, A and Chan, T and Hosseini, SA and Bezgin, G and Tissot, C and Servaes, S and Hall, B and Stevenson, J and Hopewell, R and Hsiao, CH and Triana-Baltzer, G and Kolb, HC and Benedet, AL and Massarweh, G and Klostranec, J and Vitali, P and Pascoal, TA and Rosa-Neto, P},
title = {Visual versus quantitative tau-PET Braak staging in Alzheimer's disease using [[18]F]MK6240.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42168643},
issn = {1619-7089},
support = {MOP-11-51-31; RFN 152985/NR/NINR NIH HHS/United States ; 159815/NR/NINR NIH HHS/United States ; 162303/NR/NINR NIH HHS/United States ; MOP-11-51-31-team 1//Consortium canadien en neurodégénérescence associée au vieillissement/ ; CFI Project 34874//Fondation Brain Canada/ ; 33397//Fondation Brain Canada/ ; FRQS//Fonds de Recherche du Québec - Santé/ ; 2020-VICO-279314//Fonds de Recherche du Québec - Santé/ ; 2024 VICO-356138//Fonds de Recherche du Québec - Santé/ ; https://doi.org/10.69777/324345//Fonds de Recherche du Québec - Santé/ ; https://doi.org/10.69777/356138//Fonds de Recherche du Québec - Santé/ ; https://doi.org/10.69777/312994//Fonds de Recherche du Québec - Santé/ ; 0000000158//Alzheimer Society Research Program/ ; },
abstract = {PURPOSE: The 2024 Alzheimer's Association Workgroup research framework designates tau proteinopathy (T2) as a key element for Alzheimer's disease (AD) staging, but optimal staging approaches have yet to be determined. Here, we compared visual and quantitative tau-PET-based Braak staging as candidate strategies to implement T2 biological staging in vivo.

METHODS: We included 140 participants from the TRIAD cohort who underwent [[1]⁸F]MK6240 tau-PET. Quantitative Braak staging (qBraak) was derived from regional SUVR thresholds, whereas visual Braak staging (vBraak) was independently performed by three nuclear medicine physicians using an adapted interpretation algorithm. Inter-rater and inter-method agreement were assessed using Cohen's and Fleiss' κ statistics. Associations with clinical severity, cortical thickness, plasma pTau217, and cortical tau extent were examined. Diagnostic performance for identifying amyloid-positive cognitively impaired individuals was evaluated.

RESULTS: vBraak demonstrated substantial to nearly perfect inter-rater agreement (κ = 0.65-0.93). Agreement between vBraak and qBraak was moderate when stages were treated categorically (κ = 0.51), but substantial when their ordinal nature was considered (weighted κ up to 0.73). Both strategies showed comparable associations with clinical severity and neurodegeneration. vBraak was more sensitive to amyloid-β-positive cognitive impairment and identified intermediate-stage involvement at lower global tau extent. Visual-quantitative discordant cases were primarily attributable to off-target binding or spatially heterogeneous tau patterns.

CONCLUSION: Both vBraak and qBraak staging provide complementary and largely concordant approaches for operationalizing T2 staging. Quantitative methods enable scalable, group-level analyses, whereas visual assessment remains essential for identifying atypical tau patterns and informing clinically relevant decision-making.},
}

@article {pmid42168722,
year = {2026},
author = {De Felice, M and Pascazio, A and Piccarducci, R and Germelli, L and Cirinciani, M and Fusi, J and Cintoli, S and Ulivi, M and Trincavelli, ML and Franzoni, F and Baldacci, F and Milazzo, P and Martini, C and Da Pozzo, E and Maestri, M and Bonanni, E},
title = {Mild Cognitive Impairment Associated with Obstructive Sleep Apnoea: A Pilot Study on Oxygen-Related Plasma Biomarkers and Network Analysis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42168722},
issn = {1559-1182},
mesh = {Humans ; *Sleep Apnea, Obstructive/blood/complications ; Pilot Projects ; *Cognitive Dysfunction/blood/complications ; Male ; *Biomarkers/blood ; *Oxygen/blood ; Female ; Aged ; Middle Aged ; Hypoxia-Inducible Factor 1, alpha Subunit/blood ; },
abstract = {Obstructive sleep apnoea syndrome (OSAS) is a breathing disorder frequently associated with mild cognitive impairment (MCI), a potential prodromal stage of Alzheimer's disease (AD). However, the mechanisms underlying MCI in OSAS remain unclear, making the identification of early biomarkers crucial. This pilot study investigates biochemical parameters related to oxygen disturbance and AD in OSAS patients with and without MCI (OSAS + MCI and OSAS-MCI, respectively) and explores their interplay through a network-based analysis. A total of 45 subjects (30 OSAS patients; 15 healthy controls) were enrolled, undergoing clinical assessment, polygraphy, and blood sampling. Compared to controls, OSAS patients exhibited increased apnoea-hypopnea index, oxygen desaturation index, and the percentage of cumulative time with oxygen saturation below 90% during total sleep time (T90). Notably, in the entire OSAS cohort, T90 positively correlated with HIF-1α levels, which were higher than controls, although not significantly. Interestingly, both T90 and HIF-1α were elevated in OSAS + MCI patients compared to OSAS-MCI, confirming a positive correlation between their levels. Regarding AD-related biomarkers, t-Tau and p-Tau181 levels were elevated in OSAS + MCI. AUROC analysis demonstrated that HIF-1α and t-Tau had fair discriminative ability, whereas p-Tau181 showed good differentiation between OSAS + MCI and OSAS-MCI. Finally, a network-based analysis suggested HIF-1α as possible candidate player in disease pathways, potentially interacting with Tau phosphorylation via GSK-3β. These findings recommend HIF-1α, t-Tau, and p-Tau181 as possible peripheral candidates for early MCI detection in OSAS, pointing out their possible involvement in the pathogenesis of cognitive impairment in OSAS pathology.},
}

Humans
*Sleep Apnea, Obstructive/blood/complications
Pilot Projects
*Cognitive Dysfunction/blood/complications
Male
*Biomarkers/blood
*Oxygen/blood
Female
Aged
Middle Aged
Hypoxia-Inducible Factor 1, alpha Subunit/blood

@article {pmid42168726,
year = {2026},
author = {Liu, Y and Qi, X and Liu, R and Xu, Z and Luo, H and Wu, B},
title = {Oral health, genetic susceptibility, and risk of dementia: a prospective cohort study of UK Biobank.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42168726},
issn = {2509-2723},
support = {R01AG089856/NH/NIH HHS/United States ; P30AG083257/NH/NIH HHS/United States ; P50MD017356/NH/NIH HHS/United States ; },
abstract = {Poor oral health and genetic susceptibility have each been linked to dementia risk, but their joint effects and subtype-specific associations remain unclear. To examine the independent and combined associations of oral health indicators and genetic susceptibility with incident dementia, we conducted a prospective cohort study using UK Biobank data. A total of 364,557 predominantly White European adults aged 38-73 years who were free of dementia at baseline (2006-2010) and had complete oral health and genetic data were followed for incident dementia through 2022. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), and interactions were evaluated. Over a median follow-up of 13.64 years, 7,553 participants developed all-cause dementia (ACD), including 3,277 Alzheimer's disease (AD) and 1,578 vascular dementia (VaD). Painful gums (HR 1.26, 95% CI 1.12-1.42) and denture use (HR 1.20, 95% CI 1.13-1.26) were associated with higher ACD risk, with comparable associations observed for AD and VaD. Toothache was associated with ACD (HR 1.24, 95% CI 1.11-1.39) and AD (HR 1.21, 95% CI 1.01-1.45) but not VaD. Dementia risk increased with the number of oral conditions. Higher genetic risk was independently associated with dementia, and moderate additive interactions were observed between oral health and genetic risk. These findings suggest that poor oral health was independently associated with higher risks of ACD, AD, and VaD and may amplify dementia risk among genetically susceptible individuals. Oral health may represent a potentially modifiable factor associated with dementia risk, but its causal role in dementia prevention should be tested in mechanistic and interventional studies.},
}

@article {pmid42168727,
year = {2026},
author = {Carpi, M and Afragola, AP and De Bartolo, M and Lopez, S and Bölükbaş, B and Del Percio, C and Henao Isaza, V and Lizio, R and Noce, G and Barjami, L and Carducci, F and Soricelli, A and Salvatore, M and Giubilei, F and Güntekin, B and Yener, G and Massa, F and Arnaldi, D and Famà, F and Pardini, M and Ferri, R and Lanuzza, B and Stocchi, F and Vacca, L and Coletti, C and Marizzoni, M and Taylor, JP and Hanoğlu, L and Yırıkoğulları, H and Frisoni, GB and Cuoco, S and Barone, P and Amboni, M and Cappiello, A and Bonanni, L and D'Anselmo, A and Biundo, R and Cauzzo, S and Fiorenzato, E and Antonini, A and D'Antonio, F and Bruno, G and Infarinato, F and Romano, P and Marziali, S and De Pandis, MF and Babiloni, C},
title = {Abnormal periodic and aperiodic resting-state electroencephalographic markers in Lewy body and Alzheimer's diseases with cognitive decline.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42168727},
issn = {2509-2723},
support = {B83C22002820006//Ministero dell'Università e della Ricerca/ ; B53C23002080006//Ministero dell'Università e della Ricerca/ ; 2022FJAXY8//Ministero dell'Università e della Ricerca/ ; PE00000006//Ministero dell'Università e della Ricerca/ ; 2010SH7H3F//Ministero dell'Università e della Ricerca/ ; GAP-101058516//HORIZON EUROPE Framework Programme/ ; PNRR-MAD-2022-12376415//Ministero della Salute/ ; PNRR-MCNT2-2023-12377423//Ministero della Salute/ ; PNRR-MCNT2-2023-12377357//Ministero della Salute/ ; },
abstract = {Lewy body disease (LBD) and Alzheimer's disease (AD) are the most common causes of cognitive decline and dementia and are associated with characteristic alterations in resting-state electroencephalographic (rsEEG) activity. This multicenter exploratory study investigated periodic and aperiodic rsEEG features in patients with cognitive decline due to Lewy body disease (LBCD) and Alzheimer's disease (ADCD), compared with cognitively unimpaired older adults (Nold), and examined the clinical relevance of these markers in LBCD. A total of 140 LBCD, 135 ADCD, and 118 Nold datasets from the PDWAVES archive underwent spectral parameterization to decompose rsEEG power spectra (1-30 Hz) into periodic peaks and aperiodic background activity. Both clinical groups showed a significant slowing of the individual alpha frequency (IAF), more pronounced in LBCD, along with reduced periodic alpha and beta power reflected in a lower vigilance index. The aperiodic exponent was elevated in both groups, and the aperiodic offset was also higher in LBCD, suggesting steeper spectral profiles consistent with increased inhibitory cortical tone. Within the LBCD group, poorer cognition was associated with higher low-frequency alpha power, whereas better cognition was predicted by higher high-frequency alpha power. A reduced vigilance index was associated with the presence of visual hallucinations, while no associations emerged for other symptoms. These findings suggest that combined periodic and aperiodic rsEEG features may provide relevant markers of altered vigilance regulation in LBCD. Future studies should evaluate whether these EEG markers can inform targeted interventions, such as neuromodulatory or audiovisual stimulation, to stabilize quiet-vigilance states and improve clinical outcomes.},
}

@article {pmid42168750,
year = {2026},
author = {Modi, JN and Taylor, AM},
title = {Investigating the Consequences of Aneuploidy in Cancer and Normal Tissue.},
journal = {Advances in experimental medicine and biology},
volume = {1509},
number = {},
pages = {403-422},
pmid = {42168750},
issn = {0065-2598},
mesh = {*Aneuploidy ; Humans ; *Neoplasms/genetics/pathology ; Animals ; Genomic Instability ; },
abstract = {Aneuploidy is an unbalanced number of chromosomes arising from errors during cell division. Under normal conditions, cells use highly precise mechanisms to accurately segregate chromosomes during mitosis and meiosis. Errors in this process lead to chromosome missegregation and result in aneuploid daughter cells. Aneuploidy causes dosage imbalances of hundreds of different genes, disrupting homeostasis and causing adverse effects like genomic instability, metabolic and proteotoxic stress, cell cycle defects, and apoptosis (Hosea et al. 2024). Aneuploidy is the leading cause of miscarriage and congenital birth defects (Nagaoka et al. 2012). Somatic aneuploidy is found at low levels in neuronal cells and has also been observed post-mortem in brains with neurological pathologies such as Alzheimer's. Tetraploidy, octaploidy, and some aneuploidies are widely observed in hepatocytes, though their significance is not clearly understood (Simonetti et al. 2019). Additionally, aneuploidy is a hallmark of cancer, as 90% of solid tumors are aneuploid with whole chromosome or chromosome arm alterations (Taylor et al. 2018). This chapter will explore the causes and consequences of aneuploidy and its potential therapeutic implications.},
}

*Aneuploidy
Humans
*Neoplasms/genetics/pathology
Animals
Genomic Instability

@article {pmid42168765,
year = {2026},
author = {Gogola, A and Minhas, D and Lopresti, B and Snitz, B and Reese, AC and Matan, C and Wu, M and Zeng, X and Saeed, A and Reis, S and Aizenstein, H and Ikonomovic, MD and Lopez, O and Karikari, T and Cohen, A and Villemagne, VL},
title = {Complex interplay of astrogliosis and pathology in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71520},
doi = {10.1002/alz.71520},
pmid = {42168765},
issn = {1552-5279},
support = {P50 AG005133/AG/NIA NIH HHS/United States ; R01 AG052446/AG/NIA NIH HHS/United States ; P01 AG025204/AG/NIA NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; *Gliosis/pathology ; Male ; Female ; Cross-Sectional Studies ; Aged ; Amyloid beta-Peptides/blood ; Glial Fibrillary Acidic Protein/blood ; tau Proteins/blood ; White Matter/pathology/diagnostic imaging ; Positron-Emission Tomography ; Hippocampus/pathology ; Magnetic Resonance Imaging ; Prodromal Symptoms ; },
abstract = {INTRODUCTION: We evaluated the effects of astrogliosis on Alzheimer's disease (AD) pathology, co-pathology, and symptoms.

METHODS: Cross-sectional data from 187 non-demented participants were processed to obtain measures of SMBT-1 standard uptake value ration (SUVR), plasma glial fibrillary acidic protein (GFAP), β-amyloid (Aβ), Centiloids (CL), tau (CenTauR), white matter hyperintensities (WMH), hippocampal volume (HV), and cognition. Linear regressions evaluated pairwise associations, linear regression interaction terms indicated moderating association, and causal mediation analysis evaluated mediating associations.

RESULTS: Astrogliosis was associated with CL (p < 0.01), neurodegeneration (0.05 < p < 0.1), and global cognition (p < 0.01). Moderation analyses revealed SMBT-1 SUVR had an attenuating interaction with CL in respect to CenTauR (β = -0.13, p = 0.0006) and memory impairment (β = 0.064, p = 0.05). Plasma GFAP had an attenuating interaction with CL in respect to CenTauR (β = -0.19, p = 0.00001).

DISCUSSION: Reactive astrogliosis is an early and important player in the AD development pathway by having an early attenuating effect against Aβ. More work is needed to further understand these complex associations.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
*Gliosis/pathology
Male
Female
Cross-Sectional Studies
Aged
Amyloid beta-Peptides/blood
Glial Fibrillary Acidic Protein/blood
tau Proteins/blood
White Matter/pathology/diagnostic imaging
Positron-Emission Tomography
Hippocampus/pathology
Magnetic Resonance Imaging
Prodromal Symptoms

@article {pmid42168776,
year = {2026},
author = {van Dyck, CH},
title = {Letter to the editor response for: "Schneider LS, Kennedy RE, Cutter G. Caution in interpreting disease-modification claims with lecanemab: selective reporting and causal inference. Alzheimer's & Dementia. 2026".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71485},
doi = {10.1002/alz.71485},
pmid = {42168776},
issn = {1552-5279},
}

@article {pmid42168777,
year = {2026},
author = {Aung, KZ and Nelson, PT and Ning, X and Wu, X and Tsuchiya, I and Karanth, S and Abner, EL and Fardo, DW and Katsumata, Y},
title = {GRN rs5848 variant associates with TDP-43 pathology and cancer in opposite directions.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag051},
pmid = {42168777},
issn = {1554-6578},
support = {P30 AG072946/GF/NIH HHS/United States ; R01 NS118584/GF/NIH HHS/United States ; RF1 AG082339/GF/NIH HHS/United States ; P01 AG078116/GF/NIH HHS/United States ; R01 AG076932/GF/NIH HHS/United States ; //University of Kentucky McCullers Scholar 2024/ ; },
abstract = {Epidemiologic studies have reported that cancer survivors have a relatively low risk of developing dementia, but the mechanisms underlying that inverse relationship are mostly unknown. The Granulin (GRN) gene single nucleotide variant rs5848 T allele is associated with increased risk of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-Aging). The T allele is also associated with lower expression of the cognate protein progranulin (PGRN), which is a mitogen implicated in neoplasia. We examined whether the rs5848 variant associated with LATE-NC/HS-Aging pathology and cancer in the same cohort. This study leveraged genotype data from the Alzheimer's Disease Genomics Consortium (n = 8121) and the Alzheimer's Disease Sequencing Project (n = 3231), with cancer history and neuropathology data drawn from the National Alzheimer's Coordinating Center. The rs5848 T allele was associated with higher odds of LATE-NC (p < 0.001) and was also associated with lower odds of cancer (p = 0.012). Established TMEM106B, APOE, and BIN1 risk alleles for Alzheimer's disease showed no associations with cancer, implying that the GRN-related associations could not be completely explained by selection bias in the study sample. The finding of a specific allele with opposite correlative impact on cancer risk and dementia-related pathology has potential therapeutic implications.},
}

@article {pmid42168780,
year = {2026},
author = {Lyu, X and Brown, CA and Duong, MT and Fischer, EP and McGrew, E and Irwin, DJ and Dickerson, BC and Nasrallah, IM and Shinohara, RT and Young, AL and Yushkevich, PA and Das, SR and Wolk, DA and , },
title = {Uncovering distinct spatiotemporal trajectories of T-N mismatch subtypes with likely co-pathology in Alzheimer's disease using event-based modeling.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71474},
doi = {10.1002/alz.71474},
pmid = {42168780},
issn = {1552-5279},
support = {//NIH/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Male ; Female ; Disease Progression ; Aged ; *tau Proteins/metabolism ; Positron-Emission Tomography ; Neuroimaging ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: In Alzheimer's disease (AD), tau-neurodegeneration (T-N) mismatch has been proposed to reflect non-AD processes such as transactive response DNA binding protein 43 kDa and vascular disease. We aimed to characterize the spatiotemporal trajectories of T-N mismatch that may reflect non-AD progression.

METHODS: We performed T-N regression on 710 Alzheimer's Disease Neuroimaging Initiative participants using cortical thickness and 18F-flortaucipir uptake across 20 cortical regions. SuStaIn, a data-driven phenotype discovery and staging algorithm, was applied to standardized T-N residuals in canonical (N∼T) and vulnerable (N > T) cases.

RESULTS: SuStaIn identified three vulnerable subtypes with distinct N > T progression patterns. The posterior and anterior subtypes displayed different, but progressively diffuse mismatch patterns, while the limbic subtype exhibited temporal-limbic progression. Subtypes and SuStaIn stages were associated with distinct clinical features. Their longitudinal trajectories aligned with SuStaIn inferred progression.

DISCUSSION: Findings support that T-N mismatch progression captures specific co-pathological processes.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Male
Female
Disease Progression
Aged
*tau Proteins/metabolism
Positron-Emission Tomography
Neuroimaging
Aged, 80 and over
Brain/pathology/diagnostic imaging

@article {pmid42168793,
year = {2026},
author = {Baniowska, MR and Mumford, P and Prestia, F and Stephan, P and Beament, M and Birling, MC and Lanzillotta, C and Ciafardini, L and Barone, E and Lau, G and Chevalier, C and Nahy, C and Messaddeq, N and Lestra, T and Wu, Y and Nalesso, V and Di Domenico, F and Wiseman, F and Herault, Y},
title = {Age-related behavioral and molecular landmarks in new mouse models for studying Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71498},
doi = {10.1002/alz.71498},
pmid = {42168793},
issn = {1552-5279},
support = {UKDRI-1014//UK Dementia Research Institute/ ; ARUK-SRF2018A-001//Alzheimer's Research UK/ ; 45U-4.IT//Istituto Pasteur-Fondazione Cenci Bolognetti/ ; RG1181642744DF59//Sapienza Università di Roma/ ; ANR-17-EURE-0023//Agence Nationale de la Recherche/ ; ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ANR-20-SFRI-0012//Agence Nationale de la Recherche/ ; ANR-10-IDEX-0002-02//Agence Nationale de la Recherche/ ; 848077//European Commission/ ; 2083//Fondation Jérôme Lejeune/ ; },
mesh = {*Down Syndrome/complications/genetics/pathology ; Animals ; *Alzheimer Disease/genetics/pathology/metabolism/complications ; *Disease Models, Animal ; Mice ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism/genetics ; Mice, Transgenic ; tau Proteins/metabolism ; *Behavior, Animal ; Male ; Mice, Inbred C57BL ; Amyloid Precursor Protein Secretases/metabolism ; },
abstract = {INTRODUCTION: Down syndrome (DS) is the leading genetic cause of intellectual disability and Alzheimer's disease (AD), with over 90% of individuals developing AD-related dementia (DSAD). The triplication of the APP gene on chromosome 21 drives early amyloid-β (Aβ) accumulation, but other Hsa21 genes also contribute to pathology. Current DSAD models are limited by species-specific Aβ differences.

METHODS: We developed and characterized two novel DSAD mouse models with partial humanization of Aβ.

RESULTS: These models exhibit early AD features: cognitive deficits, hyperactivity, altered novelty and risk responses, tau hyperphosphorylation, and endolysosomal dysfunction. Amyloid precursor protein (APP) processing shifts toward β-secretase, increasing CTF-β and altering Aβ dynamics. Aβ humanization modulates behavior, improving specific cognitive tasks but enhancing anxiety traits. Myelinosome formation and impaired autophagic flux further align these models with human AD pathology.

DISCUSSION: They offer valuable tools to investigate early DSAD mechanisms and therapeutic strategies, pending development of a fully humanized trisomic model.},
}

*Down Syndrome/complications/genetics/pathology
Animals
*Alzheimer Disease/genetics/pathology/metabolism/complications
*Disease Models, Animal
Mice
Humans
Amyloid beta-Protein Precursor/genetics/metabolism
Amyloid beta-Peptides/metabolism/genetics
Mice, Transgenic
tau Proteins/metabolism
*Behavior, Animal
Male
Mice, Inbred C57BL
Amyloid Precursor Protein Secretases/metabolism

@article {pmid42168823,
year = {2026},
author = {Pandey, R and Ruggiero, T and Andrews, B and Urbanc, B},
title = {Spontaneous Insertion of Aβ42 Dimers but Not Monomers into a Cholesterol-Rich Lipid Bilayer.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00942},
pmid = {42168823},
issn = {1948-7193},
abstract = {The leading Alzheimer's disease (AD) hypothesis posits that oligomers formed by amyloid β-protein (Aβ), in particular 42-residue-long Aβ42, interact with a cellular membrane, causing a cascade of events leading to neurodegeneration. The modes of Aβ42-lipid interactions are not well understood. Here, we use explicit-solvent all-atom molecular dynamics (MD) to demonstrate that Aβ42 monomers interact with lipids differently than Aβ42 dimers. In our simulations, lipids in the absence and presence of Aβ42 form a lipid bilayer with a cholesterol-rich domain, resembling a lipid raft. Whereas lipids stabilize the Aβ42 monomer structure, they partially destabilize Aβ42 dimers. Unlike monomers, which interact exclusively with solvent-exposed lipid tails on one side of a bilayer, dimers exhibit additional modes of interactions with lipids, including spontaneous insertion into the cholesterol-rich domain of a bilayer and carpeting, thereby disrupting the lipid bilayer structure. Our findings provide a mechanistic explanation for why Aβ42 monomers are nontoxic and reveal that Aβ42 oligomer-induced toxicity emerges already at the stage of Aβ42 dimer formation.},
}

@article {pmid42168828,
year = {2026},
author = {Xu, J and Meng, R and Zheng, W and Wu, Y},
title = {Aspiration Pneumonia as a Marker of a High Healthcare Utilisation Trajectory in Older Adults With Dementia: A Retrospective Cohort Study.},
journal = {Australasian journal on ageing},
volume = {45},
number = {2},
pages = {e70187},
doi = {10.1111/ajag.70187},
pmid = {42168828},
issn = {1741-6612},
mesh = {Humans ; *Pneumonia, Aspiration/mortality/diagnosis/therapy ; Retrospective Studies ; Aged ; Male ; Female ; Aged, 80 and over ; *Dementia/diagnosis/mortality/therapy/psychology ; Length of Stay ; Risk Factors ; Time Factors ; Age Factors ; *Patient Acceptance of Health Care ; Hospitalization ; },
abstract = {OBJECTIVES: To determine whether recorded aspiration pneumonia in older adults with dementia was associated with subsequent high inpatient use and to estimate its associations with all-cause mortality, any hospital admission and cumulative length of stay.

METHODS: This single-centre retrospective cohort study examined electronic medical records from a single tertiary hospital to identify 500 adults aged 65 years and older with Alzheimer's disease, vascular dementia or mixed dementia. Participants were followed for up to 36 months (median 20 months). Recorded aspiration pneumonia was analysed as an exposure available in the analytic dataset. Multivariable Cox, logistic and negative binomial models were adjusted for age, sex, dementia subtype, baseline dementia severity and baseline Mini-Mental State Examination (MMSE) score. Exact aspiration-event dates and clinically important domains including frailty, functional status, residence before admission, swallowing assessment, oral-health measures, medication burden and comorbidity burden were not available in the dataset.

RESULTS: Recorded aspiration pneumonia occurred in 24% of participants. After adjustment, the cohort-level mortality signal remained imprecise (HR 1.65, 95% CI 0.85-3.21). In contrast, aspiration pneumonia was independently associated with higher odds of hospitalisation (OR 2.02, 95% CI 1.29-3.16) and greater cumulative length of stay among those admitted (IRR 1.54, 95% CI 1.17-2.01).

CONCLUSIONS: In this dementia-specific cohort, recorded aspiration pneumonia was common and consistently associated with greater subsequent inpatient use. The findings support interpreting recorded aspiration pneumonia as a pragmatic clinical marker of heightened service dependence within a broader frailty and illness context and underscore the value of multidisciplinary review and anticipatory care planning after such events.},
}

Humans
*Pneumonia, Aspiration/mortality/diagnosis/therapy
Retrospective Studies
Aged
Male
Female
Aged, 80 and over
*Dementia/diagnosis/mortality/therapy/psychology
Length of Stay
Risk Factors
Time Factors
Age Factors
*Patient Acceptance of Health Care
Hospitalization

@article {pmid42168843,
year = {2026},
author = {Long, T and Satyal, S and Gao, J},
title = {Transcriptome graph transformer: a graph transformer-based unsupervised model for transcriptome data analysis.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-026-06458-4},
pmid = {42168843},
issn = {1471-2105},
support = {2400785//National Science Foundation/ ; },
abstract = {BACKGROUND: Rapidly growing transcriptomic datasets pose challenges for traditional analytical methods, which struggle with high dimensionality, heterogeneity, and nonlinear gene relationships. Existing deep learning models often require fixed-length inputs and fail to integrate biological network information.

METHODS: We introduce Transcriptome Graph Transformer (TGT), an unsupervised graph Transformer framework that constructs a heterogeneous gene-pathway graph using expression data, STRING interactions, and GO/KEGG/Reactome pathway annotations. TGT is pretrained with a masked-node prediction task and fine-tuned for disease classification, biomarker discovery, and zero-shot clustering of single-cell and spatial transcriptomics.

RESULTS: TGT achieves superior performance across Alzheimer's disease, cancer, acute kidney injury, and COVID-19 datasets, outperforming state-of-the-art baselines. The model generalizes well across platforms and yields biologically meaningful gene and pathway importance scores consistent with known disease mechanisms.

CONCLUSIONS: TGT provides an effective and generalizable approach for transcriptomic representation learning by integrating biological network knowledge with graph Transformer architectures. Its strong performance highlights its utility for broad transcriptomic applications and precision medicine.},
}

@article {pmid42169064,
year = {2026},
author = {Güzel, A and İncebacak, F and Issı, ES},
title = {Dementia subtype specification and cognitive evidence visibility in Turkish Court of Cassation decisions: a document analysis of 1,031 decisions (2005-2025).},
journal = {BMC medical ethics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12910-026-01480-w},
pmid = {42169064},
issn = {1472-6939},
abstract = {BACKGROUND: Dementia is frequently invoked in medico-legal contexts where questions of legal capacity, guardianship, testamentary validity, transactional validity, and criminal responsibility arise. Although subtype differentiation and cognitive assessment are central to clinical dementia evaluation, it remains unclear to what extent such clinically meaningful detail is visible in appellate judicial reasoning. This study examined the visibility of dementia subtype specification and cognitive evidence in decisions of the Turkish Court of Cassation (2005-2025), and examined the ethical implications of these textual patterns for transparency, accountability, and procedural fairness in judicial decision-making.

METHODS: We conducted a retrospective, cross-sectional, document-based analysis of publicly accessible Court of Cassation decisions. Using keyword-based searches ("demans," "bunama," and "Alzheimer"), 1,180 decisions were identified; after screening for legal relevance, 1,031 decisions were included. Each decision was coded across 15 variables, including dementia subtype specification, cognitive evidence visibility, legal context, and medical report source. Descriptive statistics were calculated for all variables. Temporal trends in dementia subtype visibility were analysed using logistic regression, supplemented by year-by-year distributional assessment and multivariable sensitivity modelling. A parallel logistic regression was also conducted for the broader binary outcome of any visible cognitive evidence (specific or non-specific; n = 104 events).

RESULTS: Dementia subtype information was explicitly specified in 46.4% of decisions (478/1,031; 95% CI, 43.3-49.5%), whereas 53.6% used only general or unspecified terminology. Alzheimer's disease was the most frequently reported subtype, appearing in 451 decisions (43.7% of the full sample; 94.4% of subtype-specified decisions). Subtype visibility increased significantly over time (OR = 1.062 per year; 95% CI, 1.034-1.091; p < 0.001). In contrast, visible cognitive evidence remained limited: 89.9% of decisions contained no reference to cognitive assessment, 9.8% included only non-specific references, and only 0.3% explicitly named the Mini-Mental State Examination (MMSE; 95% CI, 0.1-0.8%). No decision referred to the Montreal Cognitive Assessment (MoCA). Any visible cognitive evidence was present in 10.1% of decisions (104/1,031; 95% CI, 8.3-12.1%) and was highest in guardianship/restriction cases (19.7%). Temporal modelling of any visible cognitive evidence was associated with a statistically significant decrease over the study period (OR = 0.918 per year; 95% CI, 0.880-0.958; p < 0.001).

CONCLUSIONS: Dementia subtype specification became moderately more visible in appellate judicial reasoning over time, whereas the textual visibility of cognitive evidence remained limited. These findings concern the traceability of clinically relevant information within decision summaries rather than the adequacy of the underlying evidentiary process itself. Strengthening the structured reporting of diagnostic basis, relevant cognitive findings, and functionally relevant capacity-related findings in medico-legal documentation may support improved transparency and accountability in the translation of clinical evidence into legal reasoning.},
}

@article {pmid42169086,
year = {2026},
author = {Coraglia, F and Cecchetti, G and Rugarli, G and Spinelli, EG and Ghirelli, A and Pisano, S and Canu, E and Filippi, M and Agosta, F},
title = {Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02089-2},
pmid = {42169086},
issn = {1758-9193},
abstract = {BACKGROUND: Apolipoprotein E (ApoE) ε4 status informs risk stratification and safety management for anti-amyloid therapies, but genotyping typically requires dedicated procedures, longer turnaround times, and higher costs compared with automated laboratory assays. We evaluated an automated plasma approach for ε4 stratification based on proteotyping, the quantification of isoform-specific ApoE proteins to infer ApoE genotype.

METHODS: We retrospectively included 110 patients (mean age 67.82 ± 10.11 years, 49.1% female) of European ancestry with cognitive impairment across a broad diagnostic spectrum, including 68 AD-spectrum cases, 29 with subjective symptoms, and 16 with other etiologies. ApoE genotyping identified 57 ε4 non-carriers (51.8%), 44 heterozygous carriers (40.0%), and 9 homozygous carriers (8.2%). ApoE4 and total ApoE (PanApoE) were measured on Lumipulse and the ApoE4/PanApoE ratio (ApoE ratio) was derived.

RESULTS: The ratio showed excellent separation across genotypes in our cohort. For ε4 carrier identification, both the ratio and ApoE4 achieved an AUC of 1.00 (95% CI 1.00-1.00), whereas PanApoE showed poor discrimination (AUC 0.30, 95% CI 0.20-0.40), reflecting lower PanApoE levels in ε4 carriers. The ratio also accurately distinguished heterozygotes from homozygotes (AUC 1.00, 95% CI 1.00-1.00).

CONCLUSIONS: Automated plasma ApoE proteotyping mirrored genetic ε4 status. The ApoE ratio provided complete genotype separation, supporting its use for individual-level stratification. These findings should be interpreted cautiously considering the retrospective single-center design and the limited number of ApoE ε4 homozygotes, and require validation in larger, independent cohorts.},
}

@article {pmid42169160,
year = {2026},
author = {Ahn, J and Yun, J and Weiner, MW and Shin, D and Kang, H and Yim, S and Kim, S and Park, H and Jang, H and Chun, MY and Lee, EH and Kim, HJ and Na, DL and Kim, JP and Seo, SW and , },
title = {Longitudinal plasma p-tau217 as a marker for tracking progression and predicting cognitive decline in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02077-6},
pmid = {42169160},
issn = {1758-9193},
support = {RS-2020-KH106434//Korea Dementia Research Center/ ; RS-2025-02223212//Korea Health Industry Development Institute/Republic of Korea ; RS-2019-NR040057//National Research Foundation of Korea/ ; RS-2021-II212068//Institute of Information & Communications Technology Planning & Evaluation/ ; SMX1250081//Samsung Medical Center, Sungkyunkwan University/ ; 2024-ER1003-01//Korea National Institute of Health/ ; },
abstract = {BACKGROUND: Plasma phosphorylated tau217 (p-tau217) is a promising biomarker for Alzheimer's disease (AD) with strong cross-sectional concordance with beta-amyloid (Aβ) and tau pathology. However, its longitudinal behavior across disease stages and assay platforms, and its prognostic value for cognitive decline according to Aβ status, remain insufficiently characterized. This study aimed to evaluate stage- and assay-specific longitudinal changes in plasma p-tau217 and to determine their utility for predicting cognitive decline.

METHODS: We analyzed longitudinal data from 393 participants in the NA-ADNI, including cognitively unimpaired (CU) and cognitively impaired (CI) individuals. Plasma p-tau217 was measured using five assay platforms. Linear mixed-effects models were used to assess longitudinal biomarker trajectories, with time as the primary predictor and random intercepts and slopes. Aβ status and time-by-Aβ interactions were included to examine differential trajectories. Annualized biomarker changes were derived and related to longitudinal cognitive outcomes using models of Clinical Dementia Rating-Sum of boxes (CDR-SB) scores. Marginal R[2] values quantified the variance explained.

RESULTS: Plasma p-tau217 levels increased significantly over time across all assay platforms in both CU and CI groups (all q < 0.05). The largest standardized time effects were observed for the ALZpath-Simoa assay (βstd = 0.112 in CU; βstd = 0.100 in CI). Aβ + individuals showed steeper longitudinal increases than Aβ- individuals, with interaction effects ranging from βint = 0.102 to 0.164 in CU and from βint = 0.070 to 0.113 in CI. Annualized changes in p-tau217 were associated with cognitive decline in a stage- and assay-dependent manner. In CU, change in %p-tau217 measured by C2N-MS showed the strongest association with CDR-SB progression (β = 0.075, q < 0.001). In CI, absolute p-tau217 change measured by C2N-MS showed the strongest association (β = 0.238, q < 0.001), particularly among Aβ + individuals. Adding annualized change of other plasma biomarkers provided modest and stage-dependent improvements, with GFAP yielding the greatest incremental value in CI.

CONCLUSIONS: Longitudinal plasma p-tau217 is a robust marker of AD progression, but its optimal prognostic application depends on cognitive stage, Aβ status, and assay platform. These findings support stage-specific strategies for using serial plasma biomarkers in clinical monitoring and therapeutic trials.},
}

@article {pmid42169444,
year = {2026},
author = {Siciliano, G and Cillis, A and Clabassi, E and Ferrara, F and Chiriacò, MS and Turco, A and Loiola, C and Zecca, C and Dell'Abate, MT and Logroscino, G and Gigli, G and Malerba, F and Primiceri, E},
title = {Simultaneous Electrochemical Detection of NGF and proNGF Under Native Conditions Using Molecularly Imprinted Polymers: Toward Point-of-Care Diagnosis of Alzheimer's Disease.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e71262},
doi = {10.1002/adhm.71262},
pmid = {42169444},
issn = {2192-2659},
support = {PNRR-MR1-2023-12377571.//BIO-TEST - Circulating biomarkers and innovative device/ ; CUPB53C22004000006.//ALT-CAN - BaC HEAL ITALIA PNRR Mission 4 - Component 2Mission 4 - Component 2. Progetto/ ; PONARS01_00906//TITAN: Nano- tecnologie per l'ImmunoTerapia dei Tu0mori - FESR Programme PON "Ricerca e Innovazione"/ ; DGR n.2117 del 21/11/2018//"Tecnopolo per la medicina di precisione" (TecnoMed Puglia)/ ; CUP: B84I180 0 0540 0 02//"Tecnopolo per la medicina di precisione" (TecnoMed Puglia)/ ; Cod.T4-AN-01-CUP//Biotecnologia, Bioinformatica e sviluppo Farmaceutico. Piano operativo Salute: FSC 2014-2020.Traiettoria 4, Azione 4.1 - Cofinanziato dalla Regione Puglia; Fondo Ordinario Enti (FOE D.M 865/2019)/ ; F83C22001560003.//Biotecnologia, Bioinformatica e sviluppo Farmaceutico. Piano operativo Salute: FSC 2014-2020.Traiettoria 4, Azione 4.1 - Cofinanziato dalla Regione Puglia; Fondo Ordinario Enti (FOE D.M 865/2019)/ ; },
abstract = {In the brain, proNGF, the NGF precursor, is in a homeostatic equilibrium with its processing product, mature NGF. Dysregulation of the NGF/proNGF ratio has been associated with neurodegeneration in Alzheimer's disease (AD), positioning these neurotrophins as promising diagnostic biomarkers. Yet, their clinical validation as biomarkers has been hindered by the lack of analytical methods capable of discriminating and quantifying both isoforms under native conditions. Here, we introduce a dual electrochemical sensor based on Molecularly Imprinted Polymers (MIPs) that enables the simultaneous, selective, and label-free quantification of NGF and proNGF. The sensors were fabricated via electropolymerization of o-phenylenediamine on platinum microelectrodes, yielding highly specific recognition sites for each isoform. The MIP-based platform demonstrates remarkable selectivity, reproducibility, and isoform discrimination, achieving picomolar detection limits even for NGF, which is typically present at low concentration in cerebrospinal fluid (CSF). Validated on clinical CSF samples from AD and control patients, this system successfully quantifies both NGF and proNGF without antibodies or sample denaturation. To the best of our knowledge, this represents the first quantitative and simultaneous detection of NGF and proNGF under native conditions. This technology paves the way toward cost-effective, high-throughput, and point-of-care diagnostics for Alzheimer's and other neurodegenerative diseases.},
}

@article {pmid42169497,
year = {2026},
author = {Daoud, S and Taha, M},
title = {Developments in the design and therapeutic applications of GSK3β inhibitors.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/17568919.2026.2675873},
pmid = {42169497},
issn = {1756-8927},
abstract = {Glycogen synthase kinase-3β (GSK3β) has emerged as one of the most thoroughly validated therapeutic targets in modern drug discovery, with dysregulation implicated in neurodegenerative diseases, metabolic disorders, cancer, psychiatric conditions, and inflammatory pathologies. This review provides a comprehensive and critical overview of recent advances in GSK3β inhibitor design, encompassing ATP-competitive compounds, non-ATP-competitive modulators, covalent inhibitors, and targeted protein degradation strategies. We integrate computational approaches-including pharmacophore modeling, molecular dynamics simulations, and emerging artificial intelligence methods-with experimental validation, distinguishing this work from prior reviews. Therapeutic applications across Alzheimer's disease, type 2 diabetes, cancer, bipolar disorder, and inflammatory conditions are critically examined, with particular emphasis on clinical trial outcomes and translational challenges. We analyze why clinical translation has lagged, identifying insufficient CNS penetration, inadequate target engagement validation, and suboptimal patient selection as key factors, and provide recommendations for future development. Emerging directions including isoform-selective inhibition, context-dependent modulation, combination therapies, and biomarker-driven strategies are discussed. This review offers an integrated perspective on the GSK3β inhibitor landscape and outlines actionable opportunities for developing next-generation therapeutics.},
}

@article {pmid42169623,
year = {2026},
author = {Carbone, E and Scibetta, S and Cappella, M and Crestini, A and Perrone, F and Hallulli, M and Rosa, P and Rivabene, R and Maiolo, F and Simonelli, V and Ricceri, L and Di Bari, MA and De Luca, G and Vanacore, N and Lacorte, E and Piscopo, P},
title = {A systematic review on the effects of hypercaloric diet in animal models of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261448495},
doi = {10.1177/13872877261448495},
pmid = {42169623},
issn = {1875-8908},
abstract = {BackgroundAccording to several published studies, a hypercaloric diet (HD) could be considered a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To fully understand the molecular pathways involved, HD has been investigated in several animal models.ObjectiveThe aim of this systematic review (SR) is to provide an overview of recent published data on the effects of HD on animal models of AD to gain insight into the molecular mechanisms potentially involved and to highlight current knowledge gaps for future studies.MethodsStructured bibliographic searches were carried out on PubMed, the Cochrane Library, and ISI Web of Knowledge. The SR was conducted following the Cochrane Handbook and the PRISMA statement. Studies enrolling only wild-type models or not using standard diet (SD) as control were excluded, as were non-original publications. Included studies were assessed for risk of bias using SYRCLE's tool.ResultsA total of 77 studies met inclusion criteria. Most reported significant behavioral differences in HD-exposed mice (Morris Water Maze, Open Field, Y-maze), though with considerable variability due to protocol heterogeneity. A significant increase in tau and amyloid deposition was observed after HD exposure, and most studies reported negatively affected learning and memory. However, nearly half found no significant differences between HD and SD groups, likely reflecting heterogeneity in diet duration and type, animal age, and strain susceptibility. Methodological quality varied widely, with many studies omitting randomization, blinding, or sex-stratified analyses.ConclusionsDespite variability, evidence suggests HD worsens behavioral performance and increases tau and amyloid expression in mouse brain, representing a risk factor for dementia. More rigorous, standardized, and sex-balanced preclinical studies are needed, and findings support dietary interventions as early non-pharmacological strategies in AD prevention.},
}

@article {pmid42170105,
year = {2026},
author = {Bello, E and Long, K and Iwama, S and Steer, J and Cooper, SE and Alasoo, K and Kumasaka, N and Schwartzentruber, J and Panousis, NI and Bassett, AR},
title = {An Alzheimer's disease-associated common regulatory variant in a PTK2B intron alters microglial function.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115688},
pmid = {42170105},
issn = {2589-0042},
abstract = {Identifying and functionally validating the causal variants at genome-wide association study (GWAS) loci is very challenging and has only been achieved for very few variants. Here, we validate a single-nucleotide polymorphism (SNP) associated with increased Alzheimer's disease (AD) risk in an intronic enhancer of PTK2B, by engineering it into human induced pluripotent stem cells (hiPSCs). Upon differentiation to macrophages and microglia, the variant increases chromatin accessibility at the enhancer and binding of transcription factor CEBPB but causes only subtle effects on PTK2B or CLU expression. Nonetheless, this variant affects both the transcriptome and phenotype of the cells: interferon gamma-responsive genes are downregulated, secreted chemokine levels are reduced, and microglial chemotaxis is affected. We propose the variant acts by altering microglial reactivity, consistent with the established role of these cells in AD progression. This work demonstrates the power of isogenic hiPSC models for functionally validating GWAS-identified common regulatory variants.},
}

@article {pmid42170124,
year = {2026},
author = {Patel, D and Patel, T and Patel, PN},
title = {Integrative Analysis of Pharmacological and Non-pharmacological Interventions in Alzheimer's Dementia.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107386},
pmid = {42170124},
issn = {2168-8184},
abstract = {Alzheimer's dementia is a progressive neurodegenerative disorder in which cognitive decline, neuropsychiatric symptoms, and functional dependence emerge from a long preclinical and prodromal phase. Effective care increasingly requires an integrative approach: (1) disease-modifying pharmacology for selected patients early in the symptomatic course, (2) symptomatic pharmacotherapy for cognition and behavioral symptoms when benefits outweigh harms, and (3) non-pharmacological interventions that meaningfully affect quality of life, caregiver burden, safety, and functional outcomes across all stages. Recent advances, particularly anti-amyloid monoclonal antibodies, have reshaped early Alzheimer's treatment while raising new implementation challenges around biomarker confirmation, monitoring for amyloid-related imaging abnormalities (ARIA), and health-system capacity. Evidence also supports structured non-pharmacological strategies (e.g., cognitive stimulation, physical activity, caregiver programs, and environmental and behavioral approaches for agitation) as core therapies rather than "adjuncts." This narrative review synthesizes the evidence base and offers a practical, stage-based framework for combining pharmacological and non-pharmacological therapies, emphasizing person-centered goals, safety, feasibility, and equity.},
}

@article {pmid42170416,
year = {2026},
author = {Wang, J and Xia, K and Yang, D and Wu, J and Liu, L and Huang, Y and Shan, Q and Zhang, H and Wang, Y},
title = {Correction: Trends in mortality from Alzheimer's disease and related dementias with hyperlipidemia in the United States from 1999 to 2020-A CDC WONDER database study.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1856837},
doi = {10.3389/fneur.2026.1856837},
pmid = {42170416},
issn = {1664-2295},
abstract = {[This corrects the article DOI: 10.3389/fneur.2025.1705607.].},
}

@article {pmid42170457,
year = {2026},
author = {Qiu, G and Huang, Y and Wang, Q and Si, K and Xu, S and Yu, Y and Hu, P},
title = {The divergent effects of population aging: comparative analysis of the burden of Alzheimer's disease and other dementias in China and G20 countries, 1990-2050.},
journal = {American journal of translational research},
volume = {18},
number = {4},
pages = {3541-3558},
pmid = {42170457},
issn = {1943-8141},
abstract = {OBJECTIVES: Alzheimer's disease and other dementias (ADOD) pose a serious and escalating public health challenge globally, particularly in China. This study aimed to compare the ADOD burden between China and Group of 20 (G20) countries to inform targeted policy development.

METHODS: We assessed the burden of ADOD among adults aged 40 years and older in China and G20 countries during 1990-2021, using data from Global Burden of Disease 2021. Significant temporal trends were observed by joinpoint regression. Decomposition analyses estimated the effects of aging, population increase, and epidemiologic changes. Projections through the mid-century (2050) were derived using the autoregressive integrated moving average (ARIMA) models.

RESULTS: In 2021, China exhibited the highest age-standardized prevalence (900.82 per 100,000), incidence (151.47 per 100,000), and Disability-Adjusted Life Years (DALYs) (562.39 per 100,000) of ADOD among all G20 countries. During 1990-2021, China also experienced the most pronounced increases in these metrics (322.18%, 314.42%, and 272.71%). Aging was the primary driver of the ADOD burden growth in China. In contrast, aging played a dual role in G20 countries, with an adverse effect on the prevalence and incidence while remaining a contributory factor to deaths and DALYs.

CONCLUSION: Despite recent improvements, China faces a growing ADOD burden, largely propelled by population aging. This contrasts with the more complex role of aging in G20 countries, where aging shows a substantially mitigating effect on prevalence and incidence yet a persistent driving effect on deaths and DALYs. This underscores an urgent need for China to develop tailored strategies informed by experience from the G20.},
}

@article {pmid42170625,
year = {2026},
author = {Topal, M and Topal, F and Yilmaz, F and Bulut Atalay, E and Koçyiğit, ÜM and Güzel, E},
title = {Investigation of the enzyme-inhibitory, antibacterial, and anticancer properties of metal phthalocyanines.},
journal = {Turkish journal of chemistry},
volume = {50},
number = {2},
pages = {173-185},
pmid = {42170625},
issn = {1300-0527},
abstract = {In this study, the enzyme inhibitory, antibacterial, and anticancer activities of a phthalonitrile derivative and its metal phthalocyanines (Pcs; indium, zinc, copper, cobalt, and manganese; 1-6) were investigated. The cobalt and manganese Pcs were synthesized for the first time in this study. The inhibitory activities of the symmetric Pcs, which were expected to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) via their 4-(isopropylbenzyl)oxy substituents through host-guest interactions, were investigated. More selective inhibition of AChE than BChE was observed for these compounds. For AChE, CoPc was identified as the most potent inhibitor (IC50 = 14.81 nM), whereas for BChE, InPc was identified as the most potent inhibitor (IC50 = 56.35 nM). The Ki values indicated that most compounds exhibited competitive inhibition; copper phthalocyanine (CuPc) showed particularly strong inhibition against AChE (Ki = 3.08 nM ± 1.12), whereas the lowest Ki value against BChE was observed for MnPc (Ki = 25.98 ± 1.97 nM). Most compounds exhibited competitive inhibition; however, CuPc showed competitive inhibition toward AChE but a noncompetitive inhibition pattern toward BChE. Dual inhibition of AChE and BChE by these compounds may be promising for addressing cholinergic deficits associated with Alzheimer's disease. In addition, the acceptability of compounds 1-6 with respect to pharmacological drug-likeness criteria was assessed based on predicted absorption, distribution, metabolism, excretion (ADME) outcomes. In antibacterial tests, varying levels of inhibition were observed against selected bacterial strains. In anticancer assays, all compounds exhibited high cytotoxicity against the MCF-7 breast cancer cell line. Higher antiproliferative activity was observed for CuPc than for the other compounds. Morphological changes were induced in cancer cells by CuPc and MnPc. Overall, these compounds may have potential as enzyme inhibitors and as antibacterial and anticancer agents.},
}

@article {pmid42170779,
year = {2026},
author = {Beliraya, MN and Mallya, S and Prabhu, S},
title = {Predictive Analysis of Brain-Derived Neurotrophic Factor and Apolipoprotein E SNPs in Alzheimer's Pathogenesis.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e3806517},
pmid = {42170779},
issn = {2314-6141},
support = {//MAHE Seed Money Grant/ ; //Manipal Research Board Grant/ ; BT/INF/22/SP43065/2021//DBT-BUILDER/ ; 54/8/GER/2019-NCD-II//Indian Council of Medical Research/ ; },
mesh = {*Brain-Derived Neurotrophic Factor/genetics/chemistry ; *Alzheimer Disease/genetics/pathology ; Humans ; *Polymorphism, Single Nucleotide/genetics ; *Apolipoproteins E/genetics/chemistry ; *Genetic Predisposition to Disease ; Gene Frequency/genetics ; },
abstract = {BACKGROUND: Brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) are key regulators of neuronal function and cognitive health. Genetic variations in these genes, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), have been linked to Alzheimer's disease (AD). This study employs a computational approach to predict the potential functional impacts of nsSNPs in BDNF and APOE to explore their contributions to AD pathogenesis.

METHODS: A total of 3590 BDNF and 27,830 APOE SNPs were retrieved from the dbSNP database. Following quality filtering of coding region localization and minor allele frequency (≥ 0.001), 33 BDNF nsSNPs and 95 APOE nsSNPs underwent systematic analysis. Pathogenicity was assessed using SIFT and PolyPhen-2 algorithms, with functional impact evaluated via CADD scoring. Protein stability effects were predicted using MUpro and I-Mutant tools, and posttranslational modifications were analyzed via a GPS prediction system. Secondary structure alterations were assessed using GOR4, and three-dimensional structural models were generated through SWISS-MODEL with Ramachandran plot validation.

RESULTS: Three variants demonstrated concordant pathogenic predictions: rs1048218 (BDNF Q75H), rs7412 (APOE R176C), and rs769455 (APOE R163C). Protein stability analysis of these variants revealed consistent destabilization for rs1048218 (ΔΔG: -1.001 to -2.08 kcal/mol) and rs7412 (ΔΔG: -0.859 to -0.07 kcal/mol), whereas rs769455 showed conflicting predictions between algorithms. Posttranslational modification sites remained conserved across all the variants. Secondary structure analysis demonstrated minimal α-helix reduction (0.31%-0.81%) with compensatory random coil increases. Three-dimensional modeling revealed preserved overall protein folds despite localized structural perturbations, with acceptable model quality metrics (MolProbity scores ≤ 1.39, Ramachandran favored regions >91%).

CONCLUSION: In silico analysis suggested that certain nsSNPs in BDNF and APOE may negatively affect protein function and stability, despite preserved structural and posttranslational features. These computational predictions need further experimental validation to better understand their roles in AD pathogenesis.},
}

*Brain-Derived Neurotrophic Factor/genetics/chemistry
*Alzheimer Disease/genetics/pathology
Humans
*Polymorphism, Single Nucleotide/genetics
*Apolipoproteins E/genetics/chemistry
*Genetic Predisposition to Disease
Gene Frequency/genetics

@article {pmid42170819,
year = {2026},
author = {Abdi, H and Sanchez-Molina, D and Garcia-Vilana, S and Azizi, S and Rahimi-Movaghar, V},
title = {Progression of Cerebral Atrophy in Alzheimer's Disease and Its Consequences on Traumatic Brain Injury: Insights From Longitudinal MRI Studies.},
journal = {International journal for numerical methods in biomedical engineering},
volume = {42},
number = {5},
pages = {e70180},
doi = {10.1002/cnm.70180},
pmid = {42170819},
issn = {2040-7947},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/physiopathology ; *Brain Injuries, Traumatic/diagnostic imaging/physiopathology/pathology ; *Magnetic Resonance Imaging ; Atrophy ; Longitudinal Studies ; Finite Element Analysis ; Brain/pathology/diagnostic imaging ; Male ; Biomechanical Phenomena ; Disease Progression ; Aged ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cerebral atrophy that alters the brain's biomechanical response to external loading and may increase susceptibility to traumatic brain injury (TBI). This study aimed to quantify how varying degrees of AD-related atrophy affect intracranial dynamics under impact conditions and to compare these effects with those observed in normal aging. Three-dimensional finite-element head models were constructed in COMSOL Multiphysics, incorporating skull, cerebrospinal fluid (CSF), and brain tissue. Longitudinal MRI data informed annual volume-reduction rates of 0.5% (healthy aging), 1% (moderate AD), and 4% (severe AD) over a four-year period. Fluid-structure interaction (FSI) was employed to simulate dynamic interactions between the CSF and deformable brain tissue under a standardized blunt impact scenario. Key biomechanical metrics-relative brain-skull displacement and peak intracranial pressure-were recorded in frontal and occipital regions. At approximately 15.07% total volume reduction (severe AD), relative brain-skull displacement increased by 12.6% in the frontal region and 28.0% in the occipital region compared with healthy aging. Peak intracranial pressure decreased by 5.51% in the frontal region and 4.95% in the occipital region under severe atrophy, indicating enhanced energy absorption by the expanded CSF layer but greater overall brain motion. The amplified displacement patterns suggest elevated strain on bridging veins and a higher risk of subdural hematoma formation. Progressive brain atrophy in AD significantly modifies intracranial biomechanics under impact, underscoring the importance of accounting for neurodegenerative changes in TBI risk assessments. Incorporation of patient-specific viscoelastic properties-obtainable via Magnetic Resonance Elastography-into future models may further enhance predictive accuracy for vulnerable populations.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/physiopathology
*Brain Injuries, Traumatic/diagnostic imaging/physiopathology/pathology
*Magnetic Resonance Imaging
Atrophy
Longitudinal Studies
Finite Element Analysis
Brain/pathology/diagnostic imaging
Male
Biomechanical Phenomena
Disease Progression
Aged

@article {pmid42170857,
year = {2026},
author = {Javidnia, S and Roe, JM and Karhunen, V and Gill, D and Bell, S and Deak, JD and Levey, D and Kember, RL and Kranzler, HR and Cronjé, HT and Burgess, S and Gelernter, J and Ebmeier, KP and Topiwala, A},
title = {Opioid use disorder and dementia risk: evidence from observational and genetic analyses in diverse ancestry cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71418},
doi = {10.1002/alz.71418},
pmid = {42170857},
issn = {1552-5279},
support = {//NIH-NIDA/ ; //NIAAA/ ; 2101BX006482//U.S. Department of Veterans Affairs/ ; K01DA058807//Intramural Research Program, National Institute on Drug Abuse/ ; //UK Research and Innovation MRC/ ; 732592//Horizon 2020/ ; 2021079//University Grants Commission - South Eastern Regional Office/ ; //HDH Wills/ ; 225790/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; 216462/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; Genome-Wide Association Study ; *Opioid-Related Disorders/genetics/complications/epidemiology ; Male ; Female ; *Dementia/genetics/epidemiology ; Mendelian Randomization Analysis ; Magnetic Resonance Imaging ; White People/genetics ; Aged ; Genetic Predisposition to Disease ; Receptors, Opioid, mu/genetics ; Risk Factors ; Cohort Studies ; Middle Aged ; Polymorphism, Single Nucleotide ; White ; },
abstract = {INTRODUCTION: Opioid use disorder (OUD) may adversely affect brain health, but its role in dementia risk remains poorly understood.

METHODS: We investigated associations between OUD and dementia using observational data from 222,518 participants (European and African ancestry) in the Million Veteran Program and Mendelian randomization (MR) using genome-wide association study summary statistics from 6,066,918 individuals. Polygenic risk score (PRS) analyses were conducted in 229 opioid-naïve Lifebrain consortium participants with longitudinal magnetic resonance imaging data.

RESULTS: OUD was associated with increased risk of all-cause dementia (hazard ratio = 1.56, 95% confidence interval [CI]: 1.39 to 1.76), Alzheimer's disease, and vascular dementia. MR supported a potential causal link between genetic liability to OUD and dementia (inverse variance weighted odds ratio = 1.77, 95% CI: 1.43 to 2.19). Genetic variation in the μ-opioid receptor gene was also associated with dementia risk. No PRS associations were found with brain structure.

DISCUSSION: These findings suggest a potential causal role for OUD in dementia, implicating μ-opioid receptor pathways in neurodegeneration.},
}

Humans
Genome-Wide Association Study
*Opioid-Related Disorders/genetics/complications/epidemiology
Male
Female
*Dementia/genetics/epidemiology
Mendelian Randomization Analysis
Magnetic Resonance Imaging
White People/genetics
Aged
Genetic Predisposition to Disease
Receptors, Opioid, mu/genetics
Risk Factors
Cohort Studies
Middle Aged
Polymorphism, Single Nucleotide
White

@article {pmid42170924,
year = {2026},
author = {DeMeglio, M and De Biasi, ES and Breunig, P and Candlish, M and Sauerland, C and Günther, S and Kawase, H and Peguera, B and Bohnstaedt, C and Herms, J and Neubauer, A and Neher, JJ and Nilsson, PR and Hu, J and Hille, S and Müller, O and Acker-Palmer, A and Hammock, BD and Underhill, TM and Junek, S and Offermanns, S and Fleming, I and Hefendehl, JK},
title = {Soluble epoxide hydrolase drives neurovascular dysfunction in a model of amyloidosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag184},
pmid = {42170924},
issn = {1460-2156},
abstract = {Recent advances in anti-amyloid therapies for Alzheimer's disease have been promising, but they have also highlighted critical challenges, including increased vascular complications, such as amyloid-related imaging abnormalities. Emerging evidence suggests that the soluble epoxide hydrolase may be a promising therapeutic target due to the involvement of sEH-derived diols in inflammation, oxidative stress, and vascular destabilization. APPPS1 mice, a model of amyloidosis, were crossed with an inducible soluble epoxide hydrolase knock-out mouse line. The knock-out was induced before onset of amyloid deposition, and then the mice were analyzed using histological, molecular, and RNA sequencing techniques. Here, we identify astrocytic soluble epoxide hydrolase as a key mediator of vascular instability in amyloid pathology. Targeted astrocyte-specific deletion of soluble epoxide hydrolase in APPPS1 mice dramatically mitigated vascular changes, reducing the vascular amyloid burden by 67.95% and preserving VE-cadherin architecture. Importantly, vasomotion was markedly impaired in the Alzheimer's disease model and was preserved in soluble epoxide hydrolase-deficient animals. Transcriptomic profiling of vasculature in APPPS1xsEHΔAC mice revealed upregulated expression of genes critical for neurovascular protection. These findings identify soluble epoxide hydrolase as a central regulator of neurovascular dysfunction and underscore its therapeutic potential in increasing vascular stability in amyloidosis-associated diseases, such as Alzheimer's disease.},
}

@article {pmid42171457,
year = {2026},
author = {Li, R and Yang, J and Chai, W and Liu, H and Wang, X and Zhang, S and Cai, H and Wang, J and Guo, T and Han, Y},
title = {Diagnostic and Prognostic Utility of Plasma p-tau217 for Alzheimer's Disease in Chinese Elderly: Insights From the SILCODE Study With a Derived Threshold.},
journal = {European journal of neurology},
volume = {33},
number = {5},
pages = {e70618},
doi = {10.1111/ene.70618},
pmid = {42171457},
issn = {1468-1331},
support = {2022ZD0211800//STI2030-Major Projects/ ; 82327809//National Natural Science Foundation of China/ ; 2025HZGF02//the Construction Fund of Key Medical Disciplines of Hangzhou/ ; KYQD-ZR-21057//Initiative Funding of Hainan University/ ; //Education Funding from Mr Zhenhai Song and Mr Jinbo Yan/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood ; Female ; Male ; Aged ; Prognosis ; Biomarkers/blood ; Longitudinal Studies ; Aged, 80 and over ; Cross-Sectional Studies ; *Cognitive Dysfunction/blood/diagnosis ; Amyloid beta-Peptides ; Disease Progression ; China ; Asian People ; Phosphorylation ; East Asian People ; },
abstract = {BACKGROUND: Plasma phosphorylated tau 217 (p-tau217) has emerged as a promising Alzheimer's disease (AD) biomarker, yet its longitudinal associations with neurodegeneration and cognitive decline remain inadequately characterized in Chinese populations, and ethnicity-specific diagnostic thresholds are lacking for optimal clinical application.

METHODS: A total of 541 participants (402 cognitively unimpaired [CU]; 139 cognitively impaired [CI]) from the Sino Longitudinal Study on Cognitive Decline (SILCODE) cohort were enrolled. Cross-sectional and longitudinal associations of plasma p-tau217 with amyloid-β (Aβ) pathology, neurodegeneration, and cognition were evaluated. Diagnostic thresholds were derived using receiver operating characteristic analysis, and Cox regression assessed prognostic value for clinical progression.

RESULTS: Cross-sectionally, baseline p-tau217 was associated with greater Aβ burden, neurodegeneration, and poorer cognition in the whole cohort and CI group; in the CU group, associations were confined to amyloid measures. Longitudinally, accelerated p-tau217 accumulation was associated with faster neurodegeneration and cognitive decline in the whole cohort, with stage-dependent patterns: nominal associations with neurodegenerative markers in CU and prominent cognitive associations in CI. Plasma p-tau217 demonstrated high diagnostic accuracy for amyloid positivity (AUC = 0.891; cutoff: 0.529 pg/mL). Threshold-based stratification effectively differentiated individuals by Aβ burden, neurodegeneration, and cognitive trajectories. Elevated baseline p-tau217 predicted higher progression risk (Whole cohort: HR = 2.66 [1.28-5.53], p = 0.009; CU: HR = 2.44 [1.07-5.59], p = 0.034).

CONCLUSION: Plasma p-tau217 serves as a valuable diagnostic and prognostic biomarker for AD, even among CU individuals, and the ethnicity-specific threshold of 0.529 pg/mL enhances its clinical applicability for early detection and risk stratification in Chinese populations.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood
Female
Male
Aged
Prognosis
Biomarkers/blood
Longitudinal Studies
Aged, 80 and over
Cross-Sectional Studies
*Cognitive Dysfunction/blood/diagnosis
Amyloid beta-Peptides
Disease Progression
China
Asian People
Phosphorylation
East Asian People

@article {pmid42171655,
year = {2026},
author = {Mortazavi, N and Zubkov, M and Chylinski, D and Collette, F and Bastin, C and Maquet, P and Vandewalle, G and Talwar, P},
title = {Sleep arousals are associated with the polygenic risk for developing Alzheimer's disease and with cognitive change in healthy late middle-aged individuals.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag143},
pmid = {42171655},
issn = {1550-9109},
abstract = {STUDY OBJECTIVES: Sleep disturbances are increasingly recognized as early features of Alzheimer's disease (AD) neuropathology. Specifically, spontaneous arousals during sleep have been associated with the burden of Amyloid beta in the brain of healthy late middle-aged individuals. However, it remains unclear whether heterogeneity of arousals relates to genetic risk for AD in younger adults or to cognitive change later in life. Here, we evaluated the association between arousals, polygenic risk scores (PRS) for AD, and cognitive performance and change in healthy young and late-middle-aged individuals.

METHODS: We classified spontaneous arousals using in-lab EEG sleep recordings in 453 younger individuals (22±2.7y; 49 women) and 87 late middle-aged individuals (59.3±5.3y; 59 women) based on their association with sleep stage transitions and changes in muscle tone. We examined the associations between arousal types, AD-PRS, baseline cognitive performance and, in late middle-aged individuals, cognitive change over 2 and 7 years.

RESULTS: The prevalence of arousals associated with sleep stage transition was higher in late middle-aged vs. younger individuals. In late middle-aged but not younger individuals, transition arousals with muscle tone increases correlated with lower AD-PRS, better attentional performance and lower memory change over follow-ups, whereas transition arousals without muscle tone increases were linked to higher AD-PRS, poorer baseline attention, and greater memory change across follow-up periods.

CONCLUSIONS: The heterogeneity in spontaneous arousals during sleep may reflect their physiological intensity or underlying neural activation, and may indicate vulnerability to AD in late middle-aged individuals. The findings may help identify early markers of neurodegenerative risk.},
}

@article {pmid42171726,
year = {2026},
author = {Agrawal, L and Agrawal, PK and Agrawal, SS and Sonune, MS and Kadu, RK and Kulkarni, MB and Bhaiyya, M},
title = {AI-driven multimodal retinal imaging for early detection and risk stratification of vascular and neurodegenerative diseases.},
journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {42171726},
issn = {1435-702X},
abstract = {Systemic vascular and neurodegenerative disorders are important causes of disability and death worldwide, mainly because of the late stage of diagnosis and the high cost of current screening tools. Artificial intelligence (AI) and multimodal retinal imaging offer a non-invasive and viable approach for early risk stratification and longitudinal monitoring. This review highlights how changes in the retinal vasculature and nerve layers are markers of underlying pathophysiologies related to cardiovascular, metabolic, and neurological disorders. It gives an account of the critical retinal imaging modalities, such as fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), and more recently developed metabolic-sensitive imaging modalities, and how current AI approaches, such as deep learning, self-supervised learning, and multimodal fusion, can be leveraged for better risk stratification and decision support. Evidence from hypertension, stroke, coronary artery disease, diabetic complications, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cognitive impairment shows the potential for the retina to serve as a scalable biomarker for systemic health. However, there are still hurdles to be cleared, such as multicenter validation, prospective clinical trials, data fusion, and regulatory frameworks. In conclusion, AI-assisted retinal analysis may make way for early screening, better prevention, and more accessible precision healthcare.},
}

@article {pmid42159446,
year = {2026},
author = {Lee, WJ and Cho, K and Kim, GW},
title = {Integrated amyloid, neurodegeneration, and vascular biomarkers estimate the risk of dementia progression in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261445623},
doi = {10.1177/13872877261445623},
pmid = {42159446},
issn = {1875-8908},
abstract = {BackgroundProgression from mild cognitive impairment (MCI) to dementia arises from heterogeneous mechanisms involving Alzheimer's disease (AD) pathology and vascular factors.ObjectiveThis study aimed to develop a multimodal biomarker model to estimate the risk of dementia progression and to examine whether carotid atherosclerosis provides independent prognostic value, particularly in amyloid-β (Aβ)-negative MCI.MethodsWe retrospectively analyzed 300 individuals with MCI who underwent baseline [[18]F]florbetapir PET, structural MRI, carotid Doppler ultrasound, cognitive assessments, and APOE genotyping (2018-2021). Participants were followed for a total of 37 months to dementia based on longitudinal cognitive and functional decline, independent of follow-up amyloid PET findings. Aβ positivity was defined using Brain Amyloid Plaque Load criteria. Multivariable logistic regression and receiver operating characteristic analyses were performed.ResultsAmong 189 Aβ-positive individuals, 30.7% (n = 58) progressed to Aβ-positive AD dementia, while 9.0% (n = 10) of 111 Aβ-negative individuals developed non-AD dementia. Independent factors estimating Aβ-positive AD dementia included higher Aβ burden (OR 2.34, p < 0.001), smaller hippocampal volume (OR 0.71, p < 0.001), greater carotid plaque count (OR 1.45, p = 0.001), lower Mini-Mental State Examination (OR 1.11, p = 0.002), and APOE ε4 carriage (OR 1.82, p = 0.021). The integrated model showed excellent performance (AUC 0.903; 95% CI: 0.814-0.968). In Aβ-negative MCI, carotid plaque burden was the primary estimator of non-AD dementia progression.ConclusionsThe prominent prognostic role of carotid plaques in Aβ-negative MCI underscores the vascular contributions to non-amyloid cognitive decline and highlights the importance of evaluating both AD-related and vascular mechanisms in prodromal dementia.},
}

@article {pmid42159448,
year = {2026},
author = {Arnhardt, S and Singh, S and Steinebach, K and Fuchs, R and Diener, T and Gasser, D and Kornhuber, J and Freiherr, J},
title = {Color-modulated olfactory testing using RAPPIT: An innovative tool for early detection of cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449410},
doi = {10.1177/13872877261449410},
pmid = {42159448},
issn = {1875-8908},
abstract = {BackgroundOlfactory and visual processing are sensitive biomarkers for cognitive impairment; however, unimodal assessments may fail to capture early deficits in higher order cognitive integration. When sensory cues are mismatched, multisensory processing induces crossmodal conflict that requires inhibitory control, which is particularly vulnerable in early neurodegeneration.ObjectiveWe developed RAPPIT (Rapid, massively APPlicable Identification Test), a color-modulated olfactory test to assess multisensory interference as an early marker of cognitive decline.MethodsRAPPIT includes 16 physically presented odors, with a digital application for task control and response recording. Answer options are displayed on color backgrounds derived from the MONEX-40 color profile, either congruent or incongruent with the presented odors. A total of 163 participants from the German population completed the assessment. Odor identification accuracy, effects of color congruence (ΔE00), associations with cognitive performance (Montreal Cognitive Assessment, MoCA), hedonic ratings, and depressive symptoms were analyzed.ResultsOdor identification declined with age. Participants aged ≥ 60 years, a group at increased risk for neurodegenerative disorders including Alzheimer's disease, showed reduced performance under incongruent conditions. Performance exhibited a non-linear relationship with color difference (ΔE00), declining at mid-range values. Accuracy was significantly associated with MoCA scores. Hedonic ratings varied with color cues, while no associations were found with depressive symptoms.ConclusionsThese findings demonstrate that differences between congruent and incongruent odor-color conditions capture cognitively relevant interference effects beyond unimodal olfactory or visual performance, supporting the utility of this approach for early detection of cognitive impairment in older adults, in clinical and home settings.},
}

@article {pmid42159654,
year = {2026},
author = {Fernández-Lebrero, A and Jiménez-Balado, J and García-Escobar, G and Contador, J and Estraguès-Gázquez, I and Peraferrer-Montesinos, L and Suárez-Pérez, A and Manero-Borràs, RM and Beltrán, B and Gramegna, L and Campello, AR and Palacio-Gili, A and Grau, O and Suárez-Calvet, M and Ois, A and Puig-Pijoan, A and Navalpotro-Gómez, I},
title = {CSF Biomarker Profile of Cerebral Amyloid Angiopathy: Diagnostic Performance and Imaging Correlates in a Hospital-Based Neurology Cohort.},
journal = {European journal of neurology},
volume = {33},
number = {5},
pages = {e70613},
doi = {10.1111/ene.70613},
pmid = {42159654},
issn = {1468-1331},
support = {//Instituto de Salud Carlos III/ ; ERA-CVD_JTC2020-015//European Research Area Network on Cardiovascular Diseases/ ; },
mesh = {Humans ; Male ; Female ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/diagnosis/complications ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/complications/diagnosis ; tau Proteins/cerebrospinal fluid ; *Peptide Fragments/cerebrospinal fluid ; Cohort Studies ; Middle Aged ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer's disease (AD), complicating diagnosis in patients with cognitive impairment. The CSF biomarker profile of CAA remains poorly understood, particularly with AD co-pathology. We aimed to characterize CSF biomarkers in CAA, assess diagnostic accuracy, and examine associations with neuroimaging markers.

METHODS: We included 261 participants from a hospital-based cohort, recruited from memory clinic outpatients and neurology inpatients. Groups comprised healthy controls (HC, n = 35), CAA without AD co-pathology (CAA-nonAD, n = 27), CAA with AD co-pathology (CAA-AD, n = 30), and AD (n = 169). CSF Aβ40, Aβ42, p-tau181, and t-tau were quantified using automated immunoassays. Group differences were tested using ANCOVA adjusted for age and sex. ROC analyses with 10-fold cross-validation and bootstrapping assessed diagnostic performance. Associations between CSF biomarkers and CAA-related MRI markers were examined using ANCOVA.

RESULTS: Aβ40 concentrations were lower in CAA-nonAD and CAA-AD compared to AD and HC (p-valuebf < 0.05). Aβ42 was reduced in CAA-AD and AD versus HC, with no difference between CAA-nonAD and AD. p-tau181 and t-tau were elevated in AD and CAA-AD compared with CAA-nonAD and HC (p-valuebf < 0.05). Aβ40 showed the highest diagnostic accuracy for CAA (AUC = 0.73; 95% CI: 0.66-0.80), followed by Aβ42 (AUC = 0.71; 95% CI: 0.64-0.78). In AD patients, Aβ42 best discriminated coexisting CAA (AUC = 0.77). Higher CAA-SVD burden scores were associated with lower Aβ40 (p-valuebf < 0.05).

CONCLUSIONS: CSF Aβ40 and Aβ42 provide complementary diagnostic value for identifying CAA, both in isolation and with AD co-pathology. Reduced Aβ40 is associated with greater CAA-related vascular burden, supporting its role as a marker of vascular amyloid pathology.},
}

Humans
Male
Female
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/diagnosis/complications
*Amyloid beta-Peptides/cerebrospinal fluid
Aged
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/complications/diagnosis
tau Proteins/cerebrospinal fluid
*Peptide Fragments/cerebrospinal fluid
Cohort Studies
Middle Aged
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid42159858,
year = {2026},
author = {Rong, W and Xu, J and Li, B and Li, Y and Xu, Y},
title = {Single-cell atlas reveals the key role of pro-inflammatory IREB2[+] microglia subsets in the microenvironment of Alzheimer's disease.},
journal = {Clinical and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10238-026-02188-2},
pmid = {42159858},
issn = {1591-9528},
support = {U1904207//National Natural Science Foundation of China/ ; 2017YFA0105003//National Key Research and Development Program of China/ ; },
abstract = {Chronic neuroinflammation driven by activated microglia is a critical hallmark of Alzheimer's disease (AD) progression. Metabolic dysregulation, particularly iron metabolism, has been implicated in neurodegeneration, yet the role of iron-responsive element-binding protein 2 (IREB2) in AD-associated neuroinflammation remains poorly understood. We performed integrative analysis of single-cell RNA sequencing (scRNA-seq) data from AD brain tissues, using non-negative matrix factorization (NMF) and intercellular communication algorithms to map cellular landscapes. We identified microglial subpopulations and their inflammatory signaling. To experimentally validate the functional role of IREB2 in inflammatory responses, we conducted siRNA-mediated knockdown in the human neuroblastoma cell line SH-SY5Y, which serves as a neuronal model for assessing IREB2's effect on cytokine expression. Single-cell analysis revealed a distinct microglial subpopulation (IREB2[+] MC C1) that is significantly expanded in AD. This subpopulation exhibits a hyper-inflammatory state, with enrichment of Toll-like receptor and IL-17 signaling pathways, and functions as a primary source of outgoing inflammatory signals (CCL3, CCL4). Furthermore, IREB2 knockdown in SH-SY5Y cells significantly suppressed the expression of key pro-inflammatory cytokines (IL6, IL-1β, and TNF-α), confirming that IREB2 positively regulates inflammation in neurons as well. IREB2 drives both microglial activation and neuronal inflammatory responses in AD, potentially via the NF-κB pathway. The IREB2[+] microglial subpopulation represents a specific pathogenic entity that orchestrates the inflammatory microenvironment. Targeting IREB2 may therefore offer a dual-pronged therapeutic strategy to mitigate neuroinflammation and slow AD progression.},
}

@article {pmid42159968,
year = {2026},
author = {Ollen-Bittle, N and Boesgaard, I and Roseborough, A and Frank, M and Zhang, Q and Pasternak, SH and Hammond, R and Whitehead, SN},
title = {Wasteosomes accumulate in periventricular white matter hyperintensities and exhibit complex relationships with mixed pathology, sclerotic index, and perivascular space.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70110},
doi = {10.1111/bpa.70110},
pmid = {42159968},
issn = {1750-3639},
support = {202104PJT-461038/CAPMC/CIHR/Canada ; RGPIN-2019-04742//Natural Sciences and Engineering Research Council of Canada/ ; //Kappa Kappa Gamma (KKG) Foundation of Canada/ ; },
abstract = {Corpora amylacea or "wasteosomes" are discontinuous lipid labyrinth structures that are polyglucosan rich, retain cellular waste and are thought to be of astrocytic origin. Wasteosomes localize around periventricular (PV) regions, perivascular spaces (PVS), and sub-pial regions; and their accumulation has been found to correlate with aging, vascular disorders, neurodegenerative diseases, and conditions that impair sleep. White matter hyperintensities (WMHs) are diffuse hyperintense areas seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans that represent damage to white matter. PV WMHs are known predictors of mild cognitive impairment, stroke, dementia and death. The relationship between wasteosome accumulation, PV WMHs, vascular pathology and PVS is currently unknown. For the first time, in a mixed diagnostic cohort of pathologically diagnosed: Alzheimer's disease (AD), cerebrovascular disease (CVD), mixed AD/CVD, and control tissue with no pathological diagnosis, we connected the histopathological wasteosome profile in periventricular brain sections in relation to 7T FLAIR-MRI confirmed PV WMHs, vascular sclerosis and PVS. Our results reveal wasteosomes accumulate in PV WMHs, are increased in proximity to large PV venules, and exhibit complex relationships with WMH severity, mixed pathology, sclerotic index and PVS. These findings provide novel insights into the pathophysiology underlying white matter injury.},
}

@article {pmid42160069,
year = {2026},
author = {Angus, DC and O'Connor, MB},
title = {A New Era in Dementia-Advances in Diagnostic Blood Tests, Novel Drugs, and the Power of Lifestyle Changes: A Healthy Dialogue With Gil Rabinovici.},
journal = {JAMA},
volume = {},
number = {},
pages = {e267539},
doi = {10.1001/jama.2026.7539},
pmid = {42160069},
issn = {1538-3598},
}

@article {pmid42160117,
year = {2026},
author = {Chen, H and Wang, T and Xia, K and Li, X and Yao, X and Huang, W},
title = {Emerging Nanoreactors for Precision Disease Treatment: From Principles to Biomedical Applications.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e73859},
doi = {10.1002/smll.73859},
pmid = {42160117},
issn = {1613-6829},
support = {BK20251864//Basic Research Program of Jiangsu/ ; 62288102//Natural Science Foundation of China/ ; //Disciplinary Fund of the School of Pharmaceutical Sciences/ ; 20250285//Nanjing Tech University Teaching Reform Project/ ; },
abstract = {Inspired by natural cellular compartments, nanoreactors are spatially confined nanostructures that precisely regulate chemical and biological reactions and act as high-performance catalytic nanocontainers. Multifunctional integration of these systems surmounts the inherent limitations of conventional therapeutic modalities. This review focuses on recent breakthroughs in organic and organic-inorganic hybrid nanoreactors, highlighting three core effects: (1) the spatial confinement effect, which elevates the reactant concentration, accelerates mass transfer, lowers activation energy, modulates electronic states, and boosts reaction rates by orders of magnitude; (2) the synergistic effect of active sites, which enables efficient cascade reactions via spatially segregated or hierarchical catalytic architectures; (3) the stimuli-responsive effect, which dynamically controls catalysis and cargo release under endogenous (pH, enzymes, ROS) or exogenous (light, temperature) cues. Typical nanoreactors (liposomes, polymeric micelles/vesicles, mesoporous silica, protein cages, and organic-inorganic hybrids) are systematically discussed regarding structural merits and biomedical applications in treating diabetes, rheumatoid arthritis (RA), chronic wound healing, cancer, and Alzheimer's disease (AD). Current challenges and future perspectives are also addressed. Intelligent nanoreactors are expected to offer immense potential for disease diagnosis and therapy.},
}

@article {pmid42160281,
year = {2026},
author = {, },
title = {Editorial Note: Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer's Disease with Plaques and Tangles.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349725},
doi = {10.1371/journal.pone.0349725},
pmid = {42160281},
issn = {1932-6203},
}

@article {pmid42160315,
year = {2026},
author = {Siegel, K and Cabán, M and Tran, E and Meng, A and Wetmore, JB and Ottman, R},
title = {Memory and thinking problems that aging Latinos in New York City would bring to a doctor's attention.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349635},
doi = {10.1371/journal.pone.0349635},
pmid = {42160315},
issn = {1932-6203},
mesh = {Humans ; *Hispanic or Latino/psychology ; New York City ; Middle Aged ; Female ; Male ; Adult ; *Memory Disorders/psychology/diagnosis ; *Aging/psychology ; *Thinking ; *Alzheimer Disease/diagnosis/psychology ; *Memory ; *Patient Acceptance of Health Care ; White ; },
abstract = {The number of individuals with Alzheimer's disease will grow dramatically in the coming decades. Early diagnosis benefits patients, caregivers and society, but depends heavily on afflicted individuals or their family members recognizing early symptoms as possible indications of a medical problem and seeking medical care. To examine the kinds of memory or thinking problems, Latinos ages 40-64 would seek medical care for, we analyzed data from 161 participants in a community-based study in northern Manhattan of the impact of receiving information about one's risk of developing late-onset Alzheimer's disease. Participants were asked whether experiencing each of 5 different memory or thinking problems multiple times over 2-3 months would make them seek medical care. Participants often offer a benign or normalizing attributions for symptoms. Disorientation was the most frequently endorsed problem. Considerations found to be associated with an inclination or disinclination to want to see a doctor about a symptom were identified. A better understanding of what Latinos would consider in deciding whether or not to bring different memory problems to a doctor's attention can help guide the development of educational interventions to encourage help-seeking and facilitate earlier diagnosis.},
}

Humans
*Hispanic or Latino/psychology
New York City
Middle Aged
Female
Male
Adult
*Memory Disorders/psychology/diagnosis
*Aging/psychology
*Thinking
*Alzheimer Disease/diagnosis/psychology
*Memory
*Patient Acceptance of Health Care
White

@article {pmid42160451,
year = {2026},
author = {Schwartz, M and Croese, T},
title = {Treating the immune system to repair the brain.},
journal = {Science translational medicine},
volume = {18},
number = {850},
pages = {eaeb1677},
doi = {10.1126/scitranslmed.aeb1677},
pmid = {42160451},
issn = {1946-6242},
mesh = {Humans ; *Brain/immunology/pathology ; *Immune System ; Alzheimer Disease/immunology/therapy ; Animals ; Neurodegenerative Diseases/therapy/immunology ; },
abstract = {Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.},
}

Humans
*Brain/immunology/pathology
*Immune System
Alzheimer Disease/immunology/therapy
Animals
Neurodegenerative Diseases/therapy/immunology

@article {pmid42160739,
year = {2026},
author = {Das, S and Rao Padubidri, S and K V, S and Shetty, KS and Jena, R and K R, H and Dehury, B and Pandurangan, AP},
title = {From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {3},
pages = {},
doi = {10.1093/bib/bbag231},
pmid = {42160739},
issn = {1477-4054},
mesh = {*Amyloid Precursor Protein Secretases/chemistry/metabolism/antagonists & inhibitors ; Humans ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Artificial Intelligence ; Drug Discovery ; *Computational Biology/methods ; *Drug Design ; },
abstract = {Advancements in computational biology are transforming the study of complex membrane proteins and their therapeutic targeting. The γ-secretase complex, a quintessential intramembrane protease implicated in Alzheimer's disease (AD) and more than 150 other substrates, provides a powerful exemplar to illustrate this transformative shift. Traditional γ-secretase inhibitors have been constrained by off-target toxicity, particularly through disruption of Notch signaling, underscoring the need for deeper mechanistic insights, now increasingly enabled by modern computational methodologies. We evaluate the computational strategies driving next-generation drug discovery of γ-secretase. Integrative modeling frameworks, informed by cryo-electron microscopy (cryo-EM) and biophysical data, have facilitated atomic-resolution reconstructions of γ-secretase dynamics and substrate recognition. All-atom molecular dynamics (MD) simulations, supported by enhanced sampling techniques such as umbrella sampling, steered MD, replica exchange, and Gaussian accelerated MD, have mapped conformational landscapes and elucidated molecular determinants of substrate selectivity. Structure-function mapping of familial AD mutations further demonstrates how computational modeling translates genetic variation into mechanistic understanding. Beyond structural modeling, the integration of artificial intelligence (AI) including deep generative models, machine learning-based activity prediction, and high-throughput virtual screening has created accelerated pipelines for discovering modulators predicted to reduce pathogenic amyloid beta (Aβ) production while preserving essential signaling pathways. These approaches demonstrate how computational methods increasingly serve as predictive and design-oriented engines in drug development. Using γ-secretase, this review highlights how state-of-the-art computational techniques, from integrative structural biology to AI-driven drug design, are reshaping the discovery of safer, more selective modulators with broader relevance across diseases requiring precise modulation of protein function.},
}

*Amyloid Precursor Protein Secretases/chemistry/metabolism/antagonists & inhibitors
Humans
Molecular Dynamics Simulation
*Alzheimer Disease/drug therapy/metabolism/genetics
*Artificial Intelligence
Drug Discovery
*Computational Biology/methods
*Drug Design

@article {pmid42160848,
year = {2026},
author = {Zheng, M and Yang, M and Su, W and Tian, L and Gao, W},
title = {Targeting microglia: A new strategy for the treatment of Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {418},
number = {},
pages = {578966},
doi = {10.1016/j.jneuroim.2026.578966},
pmid = {42160848},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.},
}

@article {pmid42160907,
year = {2026},
author = {Naomi, R and Al-Amin, M and Smykla, J and Rizman-Idid, M and Chong, TT and Murthy, JK and Zubairi, SI and David, P and Satriawan, H and Bakar, NA and Alias, SA},
title = {Network pharmacology and molecular docking of arctic Pseudogymnoascus australis compounds targeting ionotropic glutamate receptors for neuroprotection.},
journal = {Computational biology and chemistry},
volume = {124},
number = {Pt 1},
pages = {109126},
doi = {10.1016/j.compbiolchem.2026.109126},
pmid = {42160907},
issn = {1476-928X},
abstract = {Neurodegenerative diseases constitute a major public health burden, with neurotoxicity representing a critical pathogenic mechanism underlying Alzheimer's disease and Parkinson's disease. Current therapeutic approaches are primarily symptomatic and fail to prevent disease progression, highlighting the urgent need for neuroprotective agents that can modulate pathological pathways at their source. Natural fungal metabolites have emerged as promising sources of bioactive compounds with potential neuroprotective properties. This study investigates the neuroprotective potential of bioactive compounds derived from the Arctic fungus Pseudogymnoascus australis (P. australis) using an integrated in silico method. From 120 identified compounds, nine were selected based on favorable blood-brain barrier (BBB) permeability and pharmacokinetic profiles using ADMET 3.0 predictions. These included 2-aminohexadecanoic acid (AHA), 11-aminoundecanoic acid (AUA), and seven others, all exhibiting optimal drug-likeness (>0.83) and suitable CNS-targeting properties. Network pharmacology analysis identified 226 overlapping targets between the fungal compounds and neurotoxicity-associated genes. Nine hub genes (Gria1, Gria2, Gria4, Grik1, Grik2, Grin1, Grin2a, Grin2b, and Grin2c) were identified as critical nodes. Enrichment analyses revealed significant involvement in the neuroactive ligand-receptor interaction pathway, suggesting these compounds modulate ionotropic glutamate receptors. Molecular docking analysis showed strong binding affinities, with 78% of ligand-receptor complexes displaying RMSD values below 2.0 Å. AHA and Grik1 emerged as the most promising pair, with a docking score of -7.90 kcal/mol and excellent pharmacokinetic properties (drug-likeness: 0.462, BBB penetration: 0.985). Molecular dynamics simulations over 100 nanoseconds confirmed complex stability, with a mean RMSD of 2.45 Å and binding energies averaging -169.02 kcal/mol, demonstrating sustained ligand-protein interactions. These computational findings provide evidence that P. australis contains bioactive compounds capable of attenuating neurotoxicity through sustained modulation of glutamate receptors, with molecular dynamics validation supporting the thermodynamic stability and potential therapeutic relevance of these interactions.},
}

@article {pmid42160956,
year = {2026},
author = {Yan, Y and Hu, D and Kong, L and Li, K and Su, J and Wu, Y and Zhan, H and Zhang, H and Sun, Y and Dou, X and Huang, P and Zhou, J},
title = {Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100600},
doi = {10.1016/j.tjpad.2026.100600},
pmid = {42160956},
issn = {2426-0266},
abstract = {BACKGROUND: Anti-amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.

METHOD: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.

RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.

CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.},
}

@article {pmid42160959,
year = {2026},
author = {Wang, H and Long, Y and Tang, Y and Duan, L and Wang, Z and Zhang, S and Yin, Y and Zhou, J and Wu, W and Zhong, C},
title = {Identification of a CD44-dependent control of astrocytic autophagic activity in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100601},
doi = {10.1016/j.tjpad.2026.100601},
pmid = {42160959},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Despite extensive research, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. This study sought to identify robust molecular targets and cellular basis underlying AD progression.

METHODS: We performed a systematic analysis of cross-regional transcriptomic datasets from AD patients, integrating differential expression analysis across 14 Gene Expression Omnibus (GEO) datasets with cross-regional intersection mapping. Single-nucleus RNA sequencing (snRNA-seq) was employed to resolve cell-type-specific expression patterns. Furthermore, cellular communication analysis and functional enrichment of astrocyte-specific genes were conducted. The biological role of the identified candidate was validated in vitro using Aβ42 oligomer-treated primary astrocytes via siRNA-mediated knockdown and plasmid-driven overexpression, with autophagic activity assessed through LC3-II and p62 expression.

RESULTS: The transmembrane glycoprotein receptor CD44 was identified as consistently upregulated across AD-vulnerable brain regions, including the temporal cortex, frontal cortex, entorhinal cortex, and hippocampus. snRNA-seq analysis identified this upregulation primarily to astrocytes. Intercellular signaling analysis indicated that the CD44-SPP1 axis enhanced astrocyte-glial crosstalk. Functional enrichment analysis linked astrocytic CD44 to the modulation of autophagy pathways. In vitro experiments demonstrated that CD44 knockdown promoted autophagic activation (increased LC3-II and decreased p62), whereas CD44 overexpression suppressed autophagic activity.

CONCLUSION: Our findings establish CD44 as a pivotal regulator of astrocytic autophagy in AD, highlighting its potential as a novel therapeutic target.},
}

@article {pmid42161162,
year = {2026},
author = {, and Caligiore, D},
title = {Response to the Letter Regarding "Explainable machine learning on clinical features to predict and differentiate Alzheimer's progression by sex: Toward a clinician-tailored web interface".},
journal = {Journal of the neurological sciences},
volume = {487},
number = {},
pages = {126005},
doi = {10.1016/j.jns.2026.126005},
pmid = {42161162},
issn = {1878-5883},
}

@article {pmid42161225,
year = {2026},
author = {McNamara, O and Delany, T and Kwakowsky, A},
title = {Bumetanide as a potential treatment for neurodegenerative and neurodevelopmental disorders: A systematic review.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119533},
doi = {10.1016/j.biopha.2026.119533},
pmid = {42161225},
issn = {1950-6007},
abstract = {Neurological disorders represent a major global health burden, affecting an estimated 3.4 billion individuals worldwide. Bumetanide, a clinically approved loop-diuretic and antagonist of the Na[+] -K[+]-Cl[-] cotransporter NKCC1, has recently emerged as a candidate for repurposing in the treatment of neurological disorders. Disrupted excitation-inhibition balance, driven in part by depolarizing GABAA receptor signaling resulting from altered chloride homeostasis, has been implicated across multiple neurodegenerative and neurodevelopmental conditions. This systematic literature review evaluated preclinical and clinical evidence for the efficacy of bumetanide across a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, autism spectrum disorder, schizophrenia, tuberous sclerosis, fragile X syndrome, Down syndrome, and Angelman syndrome. Across in vivo and ex vivo models, bumetanide frequently restored hyperpolarizing GABAergic activity and attenuated behavioral and cognitive abnormalities, although translational relevance is constrained by limited central nervous system penetration following systemic administration. Clinical evidence mainly comes from autism spectrum disorder, where some studies have reported modest improvements in behavioral outcomes and measurable neurophysiological changes, although findings remain inconsistent. Collectively, these findings suggest that NKCC1 inhibition represents a mechanistically relevant but clinically unproven therapeutic strategy. Further research is required to clarify the cellular mechanisms underlying bumetanide responsiveness, optimize delivery to the central nervous system, and identify biomarkers to stratify patients most likely to respond to treatment.},
}

@article {pmid42161327,
year = {2026},
author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A},
title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag178},
pmid = {42161327},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.},
}

@article {pmid42161537,
year = {2026},
author = {Fernández-Romero, L and Díez-Cirarda, M and Delgado-Alonso, C and Cabrera-Martin, MN and González-Rosa, JJ and Sanz-Nieto, C and Pérez-Macías, N and Balugo, P and Gómez-Ruiz, N and Matias-Guiu, J and Portolés-Pérez, A and Matias-Guiu, JA},
title = {Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS).},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e112999},
doi = {10.1136/bmjopen-2025-112999},
pmid = {42161537},
issn = {2044-6055},
mesh = {Humans ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; *Aphasia, Primary Progressive/therapy ; Female ; Aged ; *Language Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Middle Aged ; },
abstract = {INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer's disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

METHODS AND ANALYSIS: The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke's Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

ETHICS AND DISSEMINATION: The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

TRIAL REGISTRATION NUMBER: NCT07158216.},
}

Humans
Double-Blind Method
*Transcranial Direct Current Stimulation/methods
*Transcranial Magnetic Stimulation/methods
*Aphasia, Primary Progressive/therapy
Female
Aged
*Language Therapy/methods
Male
Randomized Controlled Trials as Topic
Treatment Outcome
Middle Aged

@article {pmid42161560,
year = {2026},
author = {Wang, Y and Shi, J and Zhao, L and Kan, B},
title = {LncRNA OIP5-AS1 Is Involved in Alzheimer's Disease by Targeting miR-7-5p to Regulate Microglial Inflammation, Polarization, and Oxidative Stress.},
journal = {The Tohoku journal of experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1620/tjem.2025.J173},
pmid = {42161560},
issn = {1349-3329},
}

@article {pmid42161712,
year = {2026},
author = {Burke, E and Gunstad, J and Bond, D and Carroll, I and Crosby, R and Mitchell, JE and Heinberg, LJ and Steffen, K},
title = {Early changes in cognitive function following bariatric surgery: evidence for rapid improvement or practice effects?.},
journal = {Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.soard.2026.04.013},
pmid = {42161712},
issn = {1878-7533},
abstract = {BACKGROUND: Metabolic bariatric surgery (MBS) is associated with postoperative improvement in neuropsychological test performance and recent work raises the possibility that these gains may emerge within weeks of surgery. However, repeat testing across brief postoperative intervals introduces the possibility of measurement error that artificially increases test scores and distorts understanding of postoperative changes.

OBJECTIVE: Examine cognitive function prior to and 1-month following bariatric surgery.

SETTING: University Hospital.

METHODS: A total of 111 MBS participants completed the NIH Toolbox for the Assessment of Neurological and Behavioral Function test battery before and 1-month after MBS as part of a larger project.

RESULTS: Repeated measures analysis of covariance revealed improved cognitive test scores following both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), though reliability change metrics could not rule out contribution from practice effects. Receiver operating characteristic analyses revealed that lower preoperative body mass index (BMI) was associated with greater likelihood of true cognitive improvement post-MBS on the Pattern Comparison subtest of the NIH Toolbox (area under the curve = .65, 95% confidence interval .53-.76).

CONCLUSIONS: Though both RYGB and SG patients exhibited improved cognitive function 1-month postoperatively, the current results suggest these early gains should be interpreted cautiously as they may reflect more than just neurobiological factors. Preoperative BMI may predict cognitive trajectory post-MBS, though future research is needed to refine cognitive testing procedures with the goals of clarifying the timeline of neurological changes postoperatively and whether MBS may reduce risk of Alzheimer disease and other risk factors for cognitive decline.},
}

@article {pmid42161904,
year = {2026},
author = {Yang, Y and Jia, L and Xu, J and Wu, J and Huang, H and Yang, H and Qi, Z and Wang, Y and Yu, H and Wang, S},
title = {FBXW7α regulates amyloid pathology by mediating ubiquitination and degradation of BACE1 in Alzheimer's disease.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03159-y},
pmid = {42161904},
issn = {2058-7716},
support = {82201347//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {The dysregulation of proteostasis is a hallmark of Alzheimer's disease (AD), characterized by the accumulation of misfolded and aggregated proteins. Dysfunction of the ubiquitin-proteasome pathway is a major contributing factor to proteostasis imbalance. The E3 ubiquitin ligase, F-box and WD repeat domain-containing 7 (FBXW7), a key hub factor in AD, is significantly downregulated in AD patients. FBXW7 mediates the proteasomal degradation of tau and regulates the development of tau pathology. However, the effect of FBXW7 on β-amyloid pathology and the underlying mechanisms remain unclear. This study demonstrated that FBXW7α, the dominant FBXW7 isoform, was localized in both the cytoplasm and nucleus of neurons. Aging led to a decline in FBXW7α protein levels in the brain tissues of both wild-type and 5×FAD mice. Notably, the level of FBXW7 in the brain tissue of 5×FAD mice is significantly lower than that in wild-type mice after 6 months of age. FBXW7α interacted with BACE1 via the conserved phosphodegron motif and targeted BACE1 for degradation. FBXW7 knockdown diminished the ubiquitination of BACE1, impaired its proteasome-mediated degradation, and increased the accumulation of BACE1 in Golgi fractions. Additionally, restoration of FBXW7α in the hippocampus improved cognitive function and ameliorated amyloid pathology in 5×FAD mice. Our findings suggest that FBXW7α acts as a key regulator of amyloid pathology, and highlight FBXW7α as a promising potential therapeutic target for AD intervention.},
}

@article {pmid42161924,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Stage-dependent reorganization of amyloid PET region-symptom bipartite networks in drug-naïve, amyloid-positive Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04064-9},
pmid = {42161924},
issn = {2158-3188},
abstract = {Management of neuropsychiatric symptoms (NPS) is pivotal to care in Alzheimer's disease (AD), yet their alignment with amyloid topology may vary by stage. We examined whether the community (modular) structure of a brain-region-symptom co-occurrence network differs by clinical stage, testing the hypothesis that modular organization is more pronounced in earlier AD and becomes less segregated with increasing severity. In a cross-sectional retrospective cohort from a tertiary dementia clinic, we included 301 consecutive, drug-naïve patients with probable AD and amyloid-positive PET ([18]F-FC119S). Patients were stratified by Clinical Dementia Rating (CDR 0.5, n = 38; CDR 1.0, n = 107; CDR 2.0, n = 156). We built bipartite networks linking six cortical regions (bilateral frontal, temporal, parietal; PET positivity from automated SUVRs) to 12 Korean Neuropsychiatric Inventory (K-NPI) domains (presence = frequency × severity ≥ 1). Network density, community structure (Louvain modularity with 2000 within-symptom permutations), node strength/centralities, and stage-matched backbones were assessed. The pooled network was dense and non-modular. Stage-stratified analyses revealed significant modularity at CDR 0.5 only, with increasing density from CDR 0.5 to 2.0 and loss of community structure thereafter. Left temporal and left frontal cortices emerged as consistent regional hubs, while parietal contributions were minimal. On the symptom side, aggression and delusion carried the largest co-occurrence burdens, followed by disinhibition and anxiety; findings were robust across backbone and sensitivity analyses. These results support a stage-dependent reorganization from modest, symptom-specific modularity in early stage AD to diffuse, hub-centric coupling in later stages. Recognizing this transition may reconcile prior inconsistencies and inform clinical strategy: targeted, domain-focused interventions when modularity persists versus global stabilization as networks densify, with implications for enrichment and endpoint selection in NPS-focused trials.},
}

@article {pmid42161925,
year = {2026},
author = {Kim, DY and Kim, SM and Lee, C and Han, IO},
title = {O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08862-3},
pmid = {42161925},
issn = {2041-4889},
support = {RS-2024-00346770//National Research Foundation of Korea (NRF)/ ; },
abstract = {Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.},
}

@article {pmid42161970,
year = {2026},
author = {Seo, H and Terstege, DJ and Ren, Y and Liu, S and Goring, KR and Ahn, BY and Epp, JR},
title = {Dual platform spatial transcriptomics reveals parvalbumin interneuron subtype vulnerability in mouse models of Alzheimer's disease.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-73474-6},
pmid = {42161970},
issn = {2041-1723},
support = {190215//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Among the earliest regions affected is the retrosplenial cortex (RSC), where parvalbumin-expressing (PV +) interneurons are particularly susceptible to AD-related pathology. To understand the molecular alterations within these vulnerable neurons we employed a dual-platform spatial transcriptomics approach, integrating GeoMx Digital Spatial Profiler (DSP) and Xenium In Situ. We analyzed the transcriptomic profiles of PV+ and NeuN+ neurons in the RSC of female 5xFAD mice. We leveraged the individual strengths of each platform to generate a robust and comprehensive dataset. Using non-negative matrix factorization and k-means clustering, we identified disease-associated metagenes and examined their spatial distribution. Our analysis revealed distinct transcriptional subpopulations within PV+ interneurons, with specific metagenes differentially expressed in RSC. Dner, Gad1, and Pvalb exhibited significant down-regulation in TG mice, suggesting impairments in PV+ interneuron function and GABAergic signalling. Cross-validation between GeoMx DSP and Xenium In Situ as well as RNAscope and immunohistochemistry confirmed the reproducibility and robustness of these findings. This study provides insights into the heterogeneity and molecular vulnerabilities of PV+ interneurons in AD and demonstrates the power of integrating spatial transcriptomic platforms to uncover disease-associated neuronal subtypes and molecular markers.},
}

@article {pmid42162073,
year = {2026},
author = {Zamani, NISM and Hamezah, HS and Mediani, A and Ghazali, M and Sadikan, MZ and Jam, FA},
title = {Selective elimination of amyloid-β-induced senescent neuroblastoma cells by Moringa oleifera leaf extract.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-53311-y},
pmid = {42162073},
issn = {2045-2322},
support = {Fundamental Research Grant Scheme (FRGS/1/2024/SKK10/MUCM/02/1)//Ministry of Higher Education, Malaysia/ ; (MUCM-MRB/001/2024)//MUCM-MRB joint seed grant/ ; },
abstract = {Accumulation of senescent cells (SnCs) in the ageing brain contributes to Alzheimer's disease (AD) progression by secreting a senescence-associated secretory phenotype (SASP) that exacerbates neuroinflammation and neurodegeneration. Senolytic agents that selectively eliminate SnCs have emerged as a potential therapeutic strategy; however, safer natural alternatives remain underexplored. In this study, we aimed to investigate the senolytic potential of Moringa oleifera leaf extract (MOL) in an in vitro AD-senescence model using SH-SY5Y cells exposed to amyloid-β (Aβ1-42) oligomers. SH-SY5Y cells exposed to 20 µM Aβ oligomers exhibited a senescent phenotype, characterised by increased senescence-associated β-galactosidase (SA-β-gal) positivity and upregulated nuclear expression of p21, p16, and γH2AX. Treatment with 300 µg/mL MOL significantly reduced the number of cells expressing senescence-associated molecular markers and induced apoptosis in SnCs, while attenuating the secretion of pro-inflammatory SASP cytokines, including IL-8 and TNF-α. Overall findings suggest that MOL extract preferentially targets SnCs and mitigates SASP-associated inflammation. These results support the potential of MOL as a natural compound with senolytic activity and provide a foundation for further development into its therapeutic relevance in AD.},
}

@article {pmid42162258,
year = {2026},
author = {Otero, M and Carriel-Rubilar, FI and Hernandez, H and Cuadros, J and Condado, JG and Sainz-Ballesteros, A and Santamaria-Garcia, H and Legaz, A and Birba, A and Fittipaldi, S and Lopera, F and Ochoa-Gómez, J and Aguillon, D and González-Hernández, A and Bonilla-Santos, J and Gonzalez-Montealegre, RA and Yener, GG and Güntekin, B and Kıyı, İ and Aktürk, T and Yıldırım, E and Hanoğlu, L and Anghinah, R and Valdes-Sosa, PA and Garcia-Reyes, R and Escudero, J and Lopez, S and Whelan, R and Fernández, A and García, AM and Huepe, D and Soto-Añari, M and Herrera, E and Abasolo, D and Rubido, N and Clark, RA and El-Deredy, W and Cortes, JM and Parra, MA and Babiloni, C and Ibanez, A and Prado, P},
title = {Source-space EEG alpha activity reveals brain age gaps due to neurodegeneration and disparity.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10205-z},
pmid = {42162258},
issn = {2399-3642},
abstract = {Brain clocks are promising tools for evaluating brain health. However, most current methods rely on structural neuroimaging. Functionally based approaches remain scarce, especially for assessing age-related neurodegenerative diseases. This study examines whether the brain age gap (BAG), the difference between chronological and predicted brain age, reflects neurodegeneration when estimated from electroencephalographic resting-state (rsEEG) α-oscillations, a well-established marker of brain functional aging. It also explores whether α-based brain clocks reflect sociodemographic diversity and structural inequality. The BAG was computed using spectral descriptors of α-activity in the rsEEG source space of 1228 healthy participants, individuals with mild cognitive impairment (MCI), and patients with Alzheimer's disease or behavioral variant frontotemporal dementia, residing in 10 countries with varying levels of structural inequality. BAGs are increased in MCI and dementia groups, particularly in posterior cortical regions. Structural inequality emerges as the strongest predictor of BAG, surpassing cognition, education, and sex. The findings indicate that an α-oscillation-based brain clock provides a sensitive functional marker of brain aging, capable of capturing neurodegenerative processes as well as the impact of social disparities. This scalable, accessible approach to brain health shows promise for translational use and population-wide screening in underserved, resource-limited settings.},
}

@article {pmid42162264,
year = {2026},
author = {Renugadevi, K and Jayasankar, T},
title = {Retraction Note: Fusion of transfer learning models for detection of alzheimer's disease using bidirectional long short-term memory with equilibrium optimization algorithm.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41598-026-53577-2},
pmid = {42162264},
issn = {2045-2322},
}

@article {pmid42162276,
year = {2026},
author = {Liu, W and Wu, SA and Zhang, BX and Guo, SH and Li, L and Sun, W and Xiong, X and Nan, J and Wu, J and Zeng, L and Li, P and Cai, ZY and Ye, HF and Zhang, S and Nie, S and Li, B and Wu, D and Cheng, P and Qi, X and Fang, D and Chen, W and Zhang, Y and Chen, Q and Yang, ZH and Han, J and Mo, W},
title = {Tau aggregates cause reactivation of transposable DNA elements, leading to Z-RNA-ZBP1-mediated neuronal death.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42162276},
issn = {1546-1726},
abstract = {Once tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimer's disease being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting the neurotoxicity of tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in tau-related neurodegeneration (PS19 mouse model). Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from heterochromatin protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in individuals with Alzheimer's disease was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged (24-month-old) tau-transgenic mice, highlighting the therapeutic potential of ZBP1 inhibition to combat neurodegeneration in tauopathies.},
}

@article {pmid42162350,
year = {2026},
author = {Jansson, D and O'Boyle, R and Pedersen, TJ and Gino, E and Sevao, M and Vered, R and Suchland, KL and Zhou, B and Fame, R and Keil, SA and Braun, M and Iliff, J},
title = {Diurnal choroid plexus function in mice depends on sex, age, and amyloid-β status.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10335-4},
pmid = {42162350},
issn = {2399-3642},
support = {P30 AG066509/AG/NIA NIH HHS/United States ; },
abstract = {The adult choroid plexus (ChP) produces the majority of cerebrospinal fluid (CSF), yet little is known about the biological and physiological factors that regulate the ChP under healthy conditions. CSF physiology is regulated by sleep and/or time of day and alters with age and in Alzheimer's disease (AD), where sleep and circadian disruption often co-occur. We compare the transcriptome from mouse ChP in three conditions (young, aged, aged with amyloid β (Aβ) pathology) collected at day and night. In young mice, diurnal ChP gene expression changes are reflected in ontology pathways for protein stability and cell metabolism. In aged mice, these pathways shift to membrane transport and ion homeostasis, with diurnal regulation lost with Aβ pathology. ChP protein expression of ion co-transporter NKCC1 varies across diurnal timepoints with both age and sex and accompanies changes in CSF [K[+]]. Together, our work suggests an interplay between diurnal regulation of membrane transport in the ChP and CSF ion composition may shed light on the role of CSF dynamics in brain function and age-related pathological processes.},
}

@article {pmid42162446,
year = {2026},
author = {Megens, VR and Strandhagen, PW and Berntsen, EM and Müller, EG and Van Laere, K and Eikenes, L and Haberg, AK and , },
title = {The clinical Alzheimer's disease spectrum classified in the A/T/N framework with [18]F-Flutemetamol-Centiloid, [18]F-MK-6240-CenTauR, and [18]F-FDG-AD metaROI: a multicenter memory clinic observational study.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42162446},
issn = {1619-7089},
abstract = {PURPOSE: This study pioneers the ability of semi-quantitative A/T/N classification using combined [18]F-Flutemetamol (A), [18]F-MK-6240 (T) and [18]F-FDG (N) positron emission tomography (PET) tracers with binary classifications and standardised scales for Centiloid (A), CenTauR (T), and AD metaROI (N), to clinically describe subjects with Mild Cognitive Impairment (MCI) or Mild Dementia (MD) in Alzheimer's disease (AD).

METHODS: MCI (n = 45, mean age 71.0 ± 8.8, 40% female, MMSE 26.2) and MD (n = 44, mean age 70.1 ± 7.6, 48% female, MMSE 24.1) participants underwent PET with [18]F-Flutemetamol for amyloid-β, [18]F-MK-6240 tau and/or [18]F-FDG for neurodegeneration. Images were semi-quantified using Centiloid, CenTauR, and AD metaROI. Predefined cut-offs classified scans as positive (+) or negative (-), and standard uptake value ratio (SUVR) values semi-quantified A-burden, T-burden, and N-burden.

RESULTS: T+ was more frequent in MD (68%) than in MCI (44%). Among T+ , MD participants were more often A+ (39%) than MCI (27%). T-burden differed significantly between MCI and MD (W = 642, p = 0.004). Increasing A-burden, T-burden, and hypometabolism, reflected by lower N-burden were associated with worse performance in Norwegian validated revised mini-mental state-examination (MMSE-NR3) (p = 0.048, < 0.001, and 0.006, respectively), A-burden and N-burden with CERAD Word List Memory Test for immediate and delayed recall (CERAD) (p = 0.041), T-burden with CERAD Word List Memory Test for recognition (CERAD R) (p < 0.001), and N-burden with Clock-drawing test (CDT) (p = 0.023) and Controlled Oral Word Association Test (COWAT) (p = 0.025).

CONCLUSION: The A/T/N classification was most informative for A (+/-) and T (+/-) PET, with T-PET appearing to distinguish MCI from MD, while N-PET correlated most with cognitive impairment.},
}

@article {pmid42162487,
year = {2026},
author = {Singh, A and Denkinger, MN and Leuzy, A and Dieckhoff, K and Liu, J and Marques, TM and Monuki, E and Stark, C and Grill, JD and Hom, C and Sultzer, D and Doran, E and Lott, I and Wood, K and Gawronski, B and Gonzalez, L and Choudhury, P and Atri, A and Beach, TG and Serrano, GE and Sajjadi, SA and Van Keuren-Jensen, K and Reiman, EM and Head, E and Ashton, NJ},
title = {A plasma protein signature for cerebral amyloid angiopathy.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42162487},
issn = {1432-0533},
support = {U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; contract 211002//Arizona Department of Health Services/ ; contracts 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/blood/pathology/diagnosis ; Female ; Male ; Aged ; Biomarkers/blood ; Aged, 80 and over ; Middle Aged ; Alzheimer Disease ; Cohort Studies ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90% of individuals with Alzheimer's disease (AD) exhibit some level of CAA. Notably, in the new era of disease-modifying treatments for AD, CAA is a significant risk factor for amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-amyloid treatments. Therefore, there is great need for accessible, reliable and accurate in vivo biomarkers (e.g., blood-based) to improve antemortem identification of CAA that would improve risk stratification and reduce symptomatic ARIA. In this study, we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for exploratory biomarker quantification in antemortem plasma of participants with neuropathological assessments for CAA from the Banner Sun Health Research Institute Brain and Body Donation Program (N = 251) and independently validated in the University of California Irvine Alzheimer Disease Research Center cohort (N = 110). We evaluated the differential protein expression in antemortem plasma sample taken < 5 years (mean 1.76 ± 1.3) from death using a logistic regression model. We further compared multi-biomarker models and found that a combination of CRP, IL4, CCL11, NPY and PDLIM5, plus demographic covariates showed an area under the curve (AUC) of 0.90 (95% CI 0.86-0.94) to identify neuropathologically confirmed CAA in the discovery cohort. In our independent replication, the antemortem plasma signature performed better than the basic demographics model showing a potential to predict CAA. The exploration and validation in antemortem plasma indicate that a multi-analyte panel, when combined with in vivo blood biomarkers for AD pathology, may be capable of identifying the presence of CAA and could have an meaningful impact on the clinical evaluation of patients under the investigation for cognitive decline. Further developments in biomarkers for this condition are crucial so that CAA identification could inform treatment decisions by highlighting ARIA risk.},
}

Humans
*Cerebral Amyloid Angiopathy/blood/pathology/diagnosis
Female
Male
Aged
Biomarkers/blood
Aged, 80 and over
Middle Aged
Alzheimer Disease
Cohort Studies

@article {pmid42162490,
year = {2026},
author = {Romero-Flores, IS and Cuervo-Zanatta, D and Chavira, R and Sánchez-Valle, V and García-Mena, J and Perez-Cruz, C},
title = {Soluble Fiber Intake Restores the Estrous Cycle and Sex Hormone Alterations in APP/PS1 Female Mice.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01745-3},
pmid = {42162490},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is the most common form of dementia, with a higher prevalence in women than in men. It has been suggested that the decline in estrogen production after menopause may increase the risk of developing dementia. We have previously shown that transgenic female APP/PS1 mice, overexpressing APP and PS1 proteins, develop spontaneous gut dysbiosis with a consequent dysfunctional estrobolome leading to higher estradiol excretion rate compared to age-matched wildtype (WT) females. It has been demonstrated that soluble fiber intake restores gut microbiota dysbiosis, reduces anxiety and improves cognitive function in APP/PS1 male mice. Therefore, the aim of this study was to evaluate if the intake of soluble fiber can modify the gut microbiota composition, alleviating the estrobolome dysfunction, and restoring sex-hormone alterations in female APP/PS1 mice. We confirm that six-month-old APP/PS1 female mice develop a spontaneous gut dysbiosis, an estrobolome dysfunction, and lower oestrous cycle frequencies than their WT littermates. Soluble fiber intake modulates the gut microbiota composition and increases beta-glucuronidase activity in faecal samples associated with a restoration of estradiol and DHEA plasma levels. Additionally, consuming soluble fiber affects various bacterial metabolic pathways and enhances the production of butyrate and acetate. Improved memory and cognitive performance were also observed in female APP/PS1 mice that were fed fructans. Therefore, soluble fiber intake may represent a preventive strategy to mitigate the alterations associated with the onset of reproductive senescence and dementia in females.},
}

@article {pmid42162801,
year = {2026},
author = {Vilademunt, M and Çabas, I and Grieco, F and Carron, C and Sprenger, T and Larrieu, T and Cardinaux, JR and Toni, N},
title = {Astrocytes reduce microglial activation and enhance adult hippocampal neurogenesis in acute inflammation.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106814},
doi = {10.1016/j.bbi.2026.106814},
pmid = {42162801},
issn = {1090-2139},
abstract = {Adult hippocampal neurogenesis is a major process of neuronal plasticity involved in mood regulation and memory and is tightly regulated by the neurogenic niche that relays signaling from the periphery. Neuroinflammation is principally mediated by microglia and strongly impairs adult neurogenesis, but the contribution of astrocytes to this effect is unclear. In this study, we used in vitro and in vivo approaches to investigate the role of astrocytes in the microglial inflammatory response and its impact on adult hippocampal neurogenesis. In vitro, we found that astrocytes attenuated the response of microglia to Lipopolysaccharide (LPS) inflammatory stimulation, through both secreted factors and direct membrane-bound interactions, with secreted factors displaying the strongest effect. Furthermore, astrocytes rescued the inhibition of adult hippocampal stem cell proliferation by LPS-stimulated microglia. In vivo, the administration of astrocyte-conditioned solution (ACS), containing the astrocyte secretome, attenuated LPS-induced sickness and depressive-like behavior, microglial and astrocytic reactivity in the dentate gyrus and restored the number of neural intermediate progenitors. Together, these findings indicate that astrocytes modulate microglia response to inflammatory cues and highlight the astrocytic secretome as a potent anti-inflammatory and pro-neurogenic agent, with potential implications for neuroinflammation-associated conditions such as Alzheimer's disease and mood disorders.},
}

@article {pmid42162804,
year = {2026},
author = {Yu, R and Suraev, A and Shi, L and Martins, RN and Drummond, E and Kong, S and Bassett, K and Naismith, SL and Michaelian, JC},
title = {Stage-dependent dynamics of neuroinflammation across the Alzheimer's continuum.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106823},
doi = {10.1016/j.bbi.2026.106823},
pmid = {42162804},
issn = {1090-2139},
abstract = {Neuroinflammation is a core feature of Alzheimer's Disease (AD), but glial responses may evolve with disease progression. YKL-40 and GFAP reflect distinct astrocytic processes and may show differential relationships with pathology and cognition across the AD continuum. A total of 420 older adults underwent blood-based biomarker profiling (YKL-40, GFAP, pTau217, Aβ42/40, NfL) and neuropsychological assessment. Composite scores were derived for global cognition, memory, executive function, and processing speed. Linear regression interaction models investigated whether associations of glia markers with AD pathology or cognition differed with advancing disease, defined by plasma pTau217 status (negative < 0.4; positive > 0.6349 pg/mL) and clinical diagnosis (healthy controls [HC], subjective cognitive decline [SCD], mild cognitive impairment [MCI], AD). We observed stage-dependent relationships between YKL-40 and AD pathology. Higher YKL-40 was associated with greater pathology in cognitively unimpaired individuals (HC/SCD), but these associations progressively weakened in MCI and further in AD (pTau217: βinteraction = -0.230, p = 0.020; Aβ42/40: βinteraction = 0.003, p = 0.044). Similarly, the relationship between YKL-40 and pTau217 was dependent on AD likelihood (βinteraction = -0.218, p < 0.001); YKL-40 positively correlated with pTau217 in pTau-negative individuals (r = 0.208, p < 0.001), but negatively in pTau-positive individuals (r = -0.251, p = 0.025). In contrast, GFAP showed stable, monotonic positive relationships with all biomarkers across disease stages, with strengthening associations with poorer cognition, particularly memory and processing speed, at later stages. The findings suggest that astrocytic markers GFAP and YKL-40 exhibit distinct, stage-dependent relationships with AD pathology and cognition, underscoring key implications for biomarker interpretation and disease staging.},
}

@article {pmid42162832,
year = {2026},
author = {Xu, X and Wang, Q and Wang, L and Cheng, W and Li, F and Liu, H and Guo, Y},
title = {Indoleamine 2,3-dioxygenase 1 (IDO1) promoted the activation of inflammatory response in the brain tissue of Alzheimer's disease mice by regulating NF-κB pathway.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138635},
doi = {10.1016/j.neulet.2026.138635},
pmid = {42162832},
issn = {1872-7972},
abstract = {OBJECTIVE: To investigate the regulatory mechanism of IDO1 on brain tissue damage in Alzheimer's disease (AD) mice.

METHODS: APP/PS1 mice (AD model mice) and C57BL/6J mice were treated with IDO1 inhibitor 1-MT. Behavioral changes were assessed using the open field test, and histopathological changes were analyzed using HE staining, Nissl staining, and transmission electron microscopy. TUNEL staining and immunofluorescence were used to detect cell apoptosis and the expression of IDO1 and GFAP, respectively. Metabolomics was analyzed using liquid chromatography-mass spectrometry. An in vitro AD cell model was established, and inflammatory factor levels were measured using ELISA/qPCR, while NF-κB pathway activation was assessed using WB.

RESULTS: In vivo experiments showed that compared with the model group mice, 1-MT intervention improved behavioral abnormalities in AD mice, reduced hippocampal tissue damage, decreased neuronal apoptosis, and downregulated the expression of IDO1 and GFAP. In vitro experiments demonstrated that interfering with IDO1 could decrease the levels of IL-1β, TNF-α, and IL-6, reduce GFAP expression, and inhibit p65 phosphorylation.

CONCLUSION: Interfering with IDO1 can inhibit the NF-κB pathway, reduce the release of inflammatory factors, and improve brain tissue damage in AD mice.},
}

@article {pmid42162905,
year = {2026},
author = {Alamri, MA and Afzal, M and Pandey, SN and Afzal, O and Akela, MA and Rekha, A},
title = {Exosomal miRNA in cerebrospinal fluid as biomarkers for neurodegenerative disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121094},
doi = {10.1016/j.cca.2026.121094},
pmid = {42162905},
issn = {1873-3492},
abstract = {Cerebrospinal fluid protein biomarkers, such as the Aβ42/Aβ40 ratio, phosphorylated tau, and neurofilament light chain, have significantly advanced the diagnostic process for Alzheimer's disease. Nonetheless, these biomarkers face challenges in effectively distinguishing Alzheimer's disease from frontotemporal dementia or Parkinson's disease from dementia with Lewy bodies. This limitation arises from overlapping protein profiles and the variability inherent in immunoassay techniques. A complementary class of analytes is exosomal microRNAs in cerebrospinal fluid, where these non-coding RNAs are secreted by neurons, astrocytes, and microglia, are resistant to RNase degradation, and have a disease-specific expression pattern. This review critically evaluates the existing evidence of cerebrospinal fluid exosomal miRNAs as diagnostic biomarkers in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Exosome isolation techniques and detection platform characteristics were compared using RT-qPCR, droplet digital PCR, and small RNA sequencing. Pre-analytical factors, such as collection protocols, hemolysis contamination, freeze-thaw cycling, and circadian sampling variation, were assessed. miRNA profiling data based on disease stratification, receiver operating characteristic performance of the combinatorial panel, and strategies combining exosomal miRNAs with core cerebrospinal fluid proteins were synthesized. This article brings together disease-specific miRNA signatures, pre-analytical standardization needs, and diagnostic accuracy analyses in a translational model to fill the literature gap and form the basis for developing exosomal miRNA panels for rigorously validated clinical laboratory practice.},
}

@article {pmid42162939,
year = {2026},
author = {Barbosa-Carvajal, JP and García-García, M and Gómez Navarro, LF and Zubiri, V and Gelvez, N and López, G and Reyes, P and García-Cifuentes, E and Aguillón, D and Acosta-Uribe, J and Matallana, DL},
title = {Phenotypic diversity of frontotemporal lobar degeneration in two novel GRN variants from Colombia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71475},
doi = {10.1002/alz.71475},
pmid = {42162939},
issn = {1552-5279},
support = {//the National Institutes of Health/ ; //Intramural Research Program of the NIH/ ; R01 AG057234/AG/NIA NIH HHS/United States ; D43TW012455/TW/FIC NIH HHS/United States ; SG-20-725707/ALZ/Alzheimer's Association/United States ; //Rainwater Charitable foundation-Tau Consortium/ ; //the Bluefield Project to Cure Frontotemporal Dementia/ ; },
mesh = {Humans ; *Frontotemporal Lobar Degeneration/genetics/diagnosis/pathology ; *Progranulins/genetics ; Colombia ; Middle Aged ; Adult ; Male ; Phenotype ; Female ; Magnetic Resonance Imaging ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Pathogenic progranulin (GRN) variants are among the main genetic causes of frontotemporal lobar degeneration (FTLD). These variants have been predominantly reported in European cohorts, but their characterization in Latin America remains scarce. We describe two Colombian cases with novel GRN variants with amnestic and semantic syndromes leading to an initial diagnosis of Alzheimer's disease (AD).

METHODS: We conducted clinical, neuropsychological, neuroimaging, and genetic analysis. Biomarkers were included for one case.

RESULTS: At 42 years old, Case 1 presented a predominant amnestic profile and carried the GRN c.21G > A (p.Trp7*) variant. Case 2 debuted with a semantic impairment at 62 years old and was a carrier of GRN c.1098T > A (p.Cys366*) variant. Brain imaging revealed asymmetric temporal atrophy, and biomarkers supported diagnosis of FTLD.

DISCUSSION: GRN variants can mimic early-onset AD. An integrative approach including serial clinical, genetic, brain imaging, and biomarker analysis are essential for diagnosing Amnestic variants of FTLD in admixed genetic populations.},
}

Humans
*Frontotemporal Lobar Degeneration/genetics/diagnosis/pathology
*Progranulins/genetics
Colombia
Middle Aged
Adult
Male
Phenotype
Female
Magnetic Resonance Imaging
Brain/pathology/diagnostic imaging
Neuropsychological Tests

@article {pmid42162953,
year = {2026},
author = {Karthivashan, G and Wang, S and Wu, Q and Dahal, A and Li, X and Galleguillos, D and Sipione, S and Thinakaran, G and Kar, S},
title = {Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71348},
doi = {10.1002/alz.71348},
pmid = {42162953},
issn = {1552-5279},
support = {MOP-84480//CIHR/Canada ; PJT-175090//CIHR/Canada ; //Alzheimer Society of Alberta and Northwest Territories/ ; RF1AG077610//National Institute on Aging, National Institutes of Health/ ; RF1AG079141//National Institute on Aging, National Institutes of Health/ ; //Ballermann Translational Research Fellowship/ ; //SynAD postdoctoral fellowships/ ; },
mesh = {*Alzheimer Disease/pathology/drug therapy/metabolism ; Animals ; *Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology ; *Nanoparticles/administration & dosage ; Mice ; *Amyloid beta-Peptides/metabolism/drug effects ; Disease Models, Animal ; Male ; Mice, Transgenic ; Brain/pathology/metabolism/drug effects ; },
abstract = {INTRODUCTION: Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.

METHODS: We evaluated the effects of native PLGA in 8-month-old male 5xFAD mice via chronic intracerebroventricular (ICV) infusion using mini osmotic pumps. Cognitive function, amyloid level/burden, synaptic integrity, and neurodegenerative events were assessed along with transcript levels in brain tissues using bulk RNA sequencing (RNA-seq).

RESULTS: PLGA treatment reversed cognitive deficits, reduced Aβ levels/deposits, and attenuated neurodegenerative events. These effects were associated with modulation of Aβ production, oxidative stress, and lysosomal Aβ clearance. RNA-seq revealed transcriptional changes related to vesicle trafficking, immune activity, and redox regulation.

DISCUSSION: Native PLGA, by targeting different facets of the Aβ axis, offer unique therapeutic potential in treating AD-related pathology.},
}

*Alzheimer Disease/pathology/drug therapy/metabolism
Animals
*Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology
*Nanoparticles/administration & dosage
Mice
*Amyloid beta-Peptides/metabolism/drug effects
Disease Models, Animal
Male
Mice, Transgenic
Brain/pathology/metabolism/drug effects

@article {pmid42162956,
year = {2026},
author = {Li, ZJ and Yang, Z and Zhao, D and Qiu, YH and Wan, WY and Huang, ZK and Tian, L and Qi, RQ and Liu, HG and Chen, YH and Min, DY and Xu, XQ and Zhao, WD},
title = {Circulatory pro-CTSD binds brain endothelial LRP1 to trigger its lysosomal degradation leading to amyloid beta clearance deficit in Alzheimer's disease mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71494},
doi = {10.1002/alz.71494},
pmid = {42162956},
issn = {1552-5279},
support = {2023-BSBA-295//Joint Fund Project Doctoral Research Initiation Program of Liaoning Province/ ; 2023JH2/20200163//Science and Technology Funding Project for Supporting the High-Quality Development of China Medical University/ ; 32271203//National Natural Science Foundation of China/ ; 82174114//National Natural Science Foundation of China/ ; U23A20427//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Lysosomes/metabolism ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; *Brain/metabolism/pathology ; Disease Models, Animal ; *Endothelial Cells/metabolism ; Mice ; Humans ; Endocytosis ; },
abstract = {INTRODUCTION: Clearance of cerebral Aβ was primarily mediated by the brain endothelial transporters including LRP1. The regulatory mechanism of LRP1 expression remained unclear.

METHODS: LRP1 in brain endothelial cells treated with pro-CTSD were analyzed by western blot. Transgenic mice with high circulatory pro-CTSD (hCTSD[hi]) were generated to assess LRP1 levels and brain Aβ deposition by immunostaining and live-imaging. Internalization of pro-CTSD and its co-localization with LRP1 was analyzed using confocal and TIRF microscopy.

RESULTS: Circulatory pro-CTSD is increased in the AD models. hCTSD[hi] mice exhibited reduced endothelial LRP1 and impaired Aβ clearance. Soluble pro-CTSD bound the Cluster II domain of LRP1, triggering LRP1 endocytosis and lysosomal degradation. Crossing hCTSD[hi] mice with AD models increased brain Aβ deposition and exaggerated cognitive deficit.

DISCUSSION: Circulatory pro-CTSD triggered degradation of brain endothelial LRP1 to inhibit brain-to-blood Aβ clearance.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Lysosomes/metabolism
*Low Density Lipoprotein Receptor-Related Protein-1/metabolism
*Brain/metabolism/pathology
Disease Models, Animal
*Endothelial Cells/metabolism
Mice
Humans
Endocytosis

@article {pmid42162968,
year = {2026},
author = {Reyna, NC and Hamilton, DA},
title = {Effects of Corticotropin-Releasing Factor 1 Receptor Antagonism on In Vivo Dentate Gyrus Long-Term Potentiation in the TgF344-AD Rat Model of Alzheimer's Disease.},
journal = {Hippocampus},
volume = {36},
number = {3},
pages = {e70103},
doi = {10.1002/hipo.70103},
pmid = {42162968},
issn = {1098-1063},
support = {P20AG068077/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Long-Term Potentiation/drug effects/physiology ; *Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism ; *Dentate Gyrus/drug effects/physiopathology ; *Alzheimer Disease/physiopathology/drug therapy/pathology/genetics ; *Pyrroles/pharmacology ; *Pyrimidines/pharmacology ; Disease Models, Animal ; CRF Receptor, Type 1 ; Rats, Transgenic ; Male ; Rats ; Rats, Inbred F344 ; Excitatory Postsynaptic Potentials/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) is characterized by irreversible neurobiological deterioration and cognitive impairment. AD patients exhibit stress system abnormalities including upregulation of the corticotropin releasing factor type 1 receptor (CRF1) and elevated cortisol. Psychological distress increases the likelihood of AD diagnosis and hastens neurocognitive decline. Administration of the CRF1 antagonist, Antalarmin, reduces AD pathogenesis and anxiety-like behavior in models of AD. Motivated by these observations, the current study examined the potential contributions of CRF1 to altered synaptic plasticity in AD neuropathology and stress in the TgF344-AD rat model. In vivo electrophysiological recordings to assess long-term potentiation (LTP) in the perforant pathway to dentate gyrus synapses were performed in aged transgenic rats and wild-type (WT) controls (2-2.5 years). TgF344-AD rats had abnormal LTP measures of field excitatory post-synaptic potentials (fEPSP) and population spikes (PS). Treatment with Antalarmin did not alter LTP measures in TgF344-AD or WT rats. These observations indicate that LTP in TgF344-AD rats is reduced compared to WT rats and that acute treatment with a CRF1 antagonist did not rescue LTP deficits. Future research should further examine the mechanism of CRF1 in AD and implications of agonism or direct infusions of Antalarmin in vivo.},
}

Animals
*Long-Term Potentiation/drug effects/physiology
*Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism
*Dentate Gyrus/drug effects/physiopathology
*Alzheimer Disease/physiopathology/drug therapy/pathology/genetics
*Pyrroles/pharmacology
*Pyrimidines/pharmacology
Disease Models, Animal
CRF Receptor, Type 1
Rats, Transgenic
Male
Rats
Rats, Inbred F344
Excitatory Postsynaptic Potentials/drug effects/physiology

@article {pmid42163007,
year = {2026},
author = {Chatterjee, A and Alvarez, B and Sharma, RU and Jonson, C and Wilkins, HM and Pa, J and Swerdlow, RH and Goate, A and Yaffe, K and Andrews, SJ and , },
title = {Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's disease and Parkinson's disease using polygenic risk scores and Mendelian randomization.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71469},
doi = {10.1002/alz.71469},
pmid = {42163007},
issn = {1552-5279},
support = {P30AG072973//NIH-NIA/ ; R01AG078186//NIH-NIA/ ; ZO1 AG000534/NH/NIH HHS/United States ; R35AG071916/NH/NIH HHS/United States ; AARF-20-675804/ALZ/Alzheimer's Association/United States ; 23AARG-1023294/ALZ/Alzheimer's Association/United States ; R35AG071916/ALZ/Alzheimer's Association/United States ; //National Institute of Neurological Disorders and Stroke (NINDS)/ ; //Margaret "Peg" McLaughlin and Lydia A. Walker Opportunity Fund/ ; //University of Kansas Alzheimer's Disease Center/ ; AARF-20-675804/ALZ/Alzheimer's Association/United States ; 23AARG-1023294/ALZ/Alzheimer's Association/United States ; AG072973/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Parkinson Disease/genetics ; *Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; *DNA, Mitochondrial/genetics ; *Multifactorial Inheritance/genetics ; Genetic Predisposition to Disease ; DNA Copy Number Variations/genetics ; Risk Factors ; *Mitochondria/genetics ; Genetic Risk Score ; },
abstract = {INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with Alzheimer's disease (AD) and Parkinson's disease (PD). We integrated genetic correlation, polygenic risk scores (PRSs), and Mendelian randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWASs) distort these causal estimates.

METHODS: Using GWASs of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the Alzheimer's Disease Genetics Consortium (N = 27,383), and applied MR methods including latent heritable confounder-MR (LHC-MR).

RESULTS: Across the four mtDNAcn GWASs, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRSs showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk.

DISCUSSION: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.},
}

Humans
*Parkinson Disease/genetics
*Mendelian Randomization Analysis
*Alzheimer Disease/genetics
Genome-Wide Association Study
*DNA, Mitochondrial/genetics
*Multifactorial Inheritance/genetics
Genetic Predisposition to Disease
DNA Copy Number Variations/genetics
Risk Factors
*Mitochondria/genetics
Genetic Risk Score

@article {pmid42163019,
year = {2026},
author = {Qiang, Y and Luo, Q and Zhang, J and Ming, C and Chong, X and Huang, F and Gui, A and Wang, J and Yin, H and Ahmad, MZ and He, HF},
title = {Theanine: a phytochemical candidate for neural protection.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70740},
pmid = {42163019},
issn = {1097-0010},
support = {32102443//National Natural Science Foundation of China/ ; Jining Medical University: cx2024286//College Students' Innovative Entrepreneurial Training Plan Program/ ; cx2024286//Jining Medical University/ ; },
abstract = {Theanine, which accumulates in Camellia sinensis (L.) O. Kuntze, has demonstrated strong neuroprotective effects and other health benefits that have attracted attention. This paper reviews relevant literature published during the past 5 years, analyzing and summarizing studies focusing on the neuroprotective functions of theanine. By alleviating neuroinflammation, theanine exerts therapeutic effects on mental disorders caused by cumulative stress, ranging from mild sleep disturbances to depression induced by sleep deprivation. It has also demonstrated beneficial effects in delaying disease progression and promoting repair in age-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. This paper also reviews studies investigating the protective effects of theanine against organ dysfunction caused by nerve injury, as well as its synergistic effects with other phytochemical components in promoting neurological health. The potential mechanisms underlying the neuroprotective effects of theanine are considered from three perspectives: ferroptosis induced by oxidative stress in neuronal cells, the differentiation and development of neural stem cells (NSCs), and neural signal transduction pathways. Further investigations are needed to achieve a more rigorous and comprehensive understanding of theanine. © 2026 Society of Chemical Industry.},
}

@article {pmid42163170,
year = {2026},
author = {Moore, L and Lund, AE and Russell, C},
title = {Unawareness of deficits in mild cognitive impairment: a systematic review of its role in progression to Alzheimer's disease.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04884-8},
pmid = {42163170},
issn = {1471-2377},
abstract = {BACKGROUND: Reduced awareness or poor insight into cognitive abilities is a well-documented feature of Alzheimer's disease, yet its role in the earlier stages of cognitive decline-particularly in individuals with mild cognitive impairment (MCI)-remains less clear. Understanding whether diminished awareness in MCI is a predictor of progression to dementia is crucial, as it may help identify individuals who are at greater risk and who could benefit from timely support and intervention. This systematic review evaluates the evidence linking reduced awareness in MCI with an increased likelihood of conversion to dementia.

METHOD: Four electronic databases (CINAHL, Medline, Embase and PsychInfo) were systematically searched for all studies assessing awareness in individuals with MCI, which tracked their cognitive status over time. The protocol was registered with PROSPERO and PRISMA guidelines were followed. Inclusion criteria-studies must: Include participants with confirmed MCI diagnosis; Assess the relationship between awareness of cognitive and/or functional abilities and the development of dementia; Have longitudinal design; Be peer-reviewed. Exclusion criteria-studies must not: Be published in a different language to English; Include participants with comorbid neurological conditions; Include participants from the same cohort as another study; Use a case series design. Eleven studies were identified as fulfilling all criteria. Study quality was evaluated using the Critical Appraisal Skills Programme (CASP) checklist for cohort studies.

RESULTS: Six studies reported a statistically significant association between reduced awareness and conversion to dementia. Four studies found a trend toward significance, suggesting a possible link, but either did not test for significance or failed to reach it. Only one study found no association. Study quality was rated as high in five studies, moderate in two, and low in four. Notably, higher-quality studies were more likely to report significant associations. Due to substantial methodological variability across studies, a meta-analysis was not feasible.

CONCLUSIONS: Reduced awareness of memory impairment appears predictive of increased risk of progression from MCI to dementia. Assessing awareness-through informant reports and/or comparisons between subjective and objective cognitive measures-could help identify individuals at elevated risk. These individuals may benefit from closer monitoring to facilitate timely diagnosis and intervention.},
}

@article {pmid42163277,
year = {2026},
author = {Lee, HJ and Seok, J and Kang, S and Oh, S and Hwang, JW and Kim, YJ and Seo, J and Hoe, HS},
title = {The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03855-7},
pmid = {42163277},
issn = {1742-2094},
support = {RS-2024-00357857//NRF/ ; RS-2024-00343370//KDRC/ ; H0501-25-1001//NIPA/ ; 20190058//Whanin Pharm Co., Ltd/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2026-25492172//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.

METHODS: We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays.

RESULTS: BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807 administration downregulated IGF-1R phosphorylation, microgliosis/astrogliosis-related dynamics, and AKT/P38/STAT3 pathway. Notably, BMS-754807 treatment also diminished LPS-induced proinflammatory cytokine levels and STAT3/NF-κB signaling in human microglial models. Furthermore, BMS-754807 treatment decreased Aβ40/Aβ42 levels in hiPSC-derived AD neurons, and increased short-term spatial memory and reduced Aβ plaque accumulation by decreasing β-secretase (BACE1) activity in 5xFAD mice. Finally, in hiPSC-derived AD neurons and PS19 mice, BMS-754807 treatment significantly attenuated tau hyperphosphorylation, CaMKIIα phosphorylation, and tau-mediated astroglial activation.

CONCLUSIONS: Taken together, our results suggest that BMS-754807 exerts anti-inflammatory and potential disease-modifying effects by attenuating LPS/Aβ/tau-evoked glial activation and reducing Aβ and tau pathologies in both human cellular and mouse models of neuroinflammation and AD. Furthermore, BMS-754807 administration improved specific domains of cognitive function in vivo. These findings support pharmacological inhibition of IGF-1R as a potential therapeutic approach for neuroinflammation-associated diseases including AD.},
}

@article {pmid42163294,
year = {2026},
author = {Bao, R and Shi, W and Bao, H and Zhang, T and Li, X and Ding, W and , },
title = {Plasma p-tau217, p-tau181, and Aβ42 predict amyloid PET positivity in cognitively unimpaired adults.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02080-x},
pmid = {42163294},
issn = {1758-9193},
support = {GRK202510//Research Start-up Fund for High-level Talent at the Second Affiliated Hospital of Wannan Medical College/ ; GRK202511//Research Start-up Fund for High-level Talent at the Second Affiliated Hospital of Wannan Medical College/ ; 82501744//National Natural Science Foundation of China/ ; 2024-BSLH-047//Liaoning Provincial Natural Science Foundation Joint Funds Project/ ; LJ212510161032//Department of Education of Liaoning Province/ ; 2024AH040242//Major Scientific Research Project of the Anhui Province Department of Education/ ; EYR202306//High-level Talent Recruitment Program of Wannan Medical College/ ; },
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD) pathology in cognitively unimpaired individuals is critical for preclinical intervention. Plasma biomarkers, especially phosphorylated tau217 (p-tau217), are promising predictors of amyloid-β (Aβ) accumulation.

METHODS: In this cohort study, we analyzed data from cognitively unimpaired older adults in the A4 and LEARN studies (n = 1,407), comprising 452 participants with Aβ positron emission tomography (PET)-negative status and 955 participants with Aβ PET-positive status. We evaluated the accuracy of plasma biomarkers (p-tau217, p-tau181, Aβ42/40 ratio, and others) in predicting Aβ PET positivity using receiver operating characteristic analysis, comparing covariate-adjusted individual biomarker and biomarker-ratio models with a multivariable combined model integrating plasma biomarkers and covariates. (age, sex, apolipoprotein E [APOE] ε4 genotype).

RESULTS: Plasma p-tau217 showed the strongest individual association with Aβ PET status (area under the curve [AUC], 0.85). A combined model integrating p-tau217, p-tau181, Aβ42, age, sex, and APOE ε4 achieved the highest overall discrimination (AUC, 0.87), although the improvement over the covariate-adjusted p-tau217 model was modest.

CONCLUSIONS: Plasma p-tau217 showed the strongest individual performance for predicting Aβ PET positivity in cognitively unimpaired older adults. Adding other plasma biomarkers and clinical covariates provided a modest incremental improvement in classification performance. These findings support blood-based prescreening as a potential enrichment approach, while indicating that confirmatory amyloid assessment remains necessary when definitive Aβ status is required.},
}

@article {pmid42163351,
year = {2026},
author = {Soni, ND and Swain, A and Khokhar, SK and Wilson, NE and Nanga, RPR and Kumar, D and Bouche, E and Cao, Q and Haris, M and Wolk, DA and Lee, VM and Detre, JA and Reddy, R},
title = {An imaging biomarker to detect non-glucogenic shift in brain energy metabolism in Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08073-6},
pmid = {42163351},
issn = {1479-5876},
support = {P41EB029460/EB/NIBIB NIH HHS/United States ; RF1AG087306-01, R01AG071725, R01AG063869/AG/NIA NIH HHS/United States ; R01AG091760/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Cerebral glucose hypometabolism in Alzheimer's disease (AD) leads to enhanced metabolism of fatty acids (FAs) and branched-chain amino acids (BCAAs) as a compensatory mechanism. While there have been some [13]C labeled studies investigating the metabolism of FAs and BCCAs, their clinical translation is challenging. In this study, we investigated the potential of measuring neurometabolic perturbations through macromolecular signal at 0.9 ppm (MM09) in proton magnetic resonance ([1]H MR) spectrum. This signal represents a composite macromolecular signal with contributions from lipids and BCAA associated methyl resonances and may be sensitive to metabolic alterations occurring during glucose hypometabolism in AD.

METHODS: MM09 levels were measured from localized [1]H MR spectra in the hippocampus and thalamus/hypothalamus of male and female APP[NL-F/NL-F] (AD) mice. In addition, the levels of glutamate in these regions were also recorded as it is known to be reduced under glucose hypometabolism in AD. We further studied the metabolic association of MM09 with glutamate in Pearson correlation plots. To find the statistical significance of difference two-way ANOVA analysis with post-hoc Tukey HSD tests were used.

RESULTS: Male AD mice exhibited significantly reduced MM09 (15.42 ± 1.32 vs. 16.93 ± 1.15 mM; p = 0.008) and glutamate levels (15.27 ± 1.65 vs. 17.24 ± 1.21 mM; p = 0.004) in the hippocampus. Female AD mice did not show any changes in glutamate or MM09 levels. MM09 also showed a strong positive correlation with glutamate (R = 0.74; p < 0.0001).

CONCLUSION: The observed reductions in MM09 and glutamate in male AD mice are consistent with neurometabolic alterations associated with impaired glucose metabolism, whereas the absence of such changes in female AD mice may reflect sex-specific metabolic resilience. The strong association between MM09 and glutamate suggests that MM09 may capture neurochemical changes linked to metabolic adaptations in AD. Because the MM09 resonance occurs in a relatively uncrowded region of the [1]H MR spectrum, it may represent a promising spectroscopic marker for investigating metabolic shifts in AD and warrants further evaluation in clinical studies.},
}

@article {pmid42163381,
year = {2026},
author = {Xia, X and Clark, A and Brogaard, NJ and Mourer, A and Areovimata, A and Eriksdotter, M and Zetterberg, H and Kern, S and Skillbäck, T and Jönsson, L},
title = {Correction: Comorbidities predict institutionalization and mortality in biomarker-confirmed alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42163381},
issn = {1758-9193},
}

@article {pmid42163384,
year = {2026},
author = {Hsu, JL and Huang, SY and Wu, HC and Lin, KJ and Huang, KL and Huang, CC and Kim, S and Hsiao, IT},
title = {A clinically feasible framework to estimate tau pathology and clinical-biological discordance in the Alzheimer's disease spectrum.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02083-8},
pmid = {42163384},
issn = {1758-9193},
support = {MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; },
abstract = {BACKGROUND: Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer's disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer's Association (AA-2024) diagnostic framework, and to characterize clinical-biological discordance across the AD continuum.

METHODS: We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [[18]F]florbetapir amyloid PET, [[18]F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL > 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.

RESULTS: Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21-60 (6.1%) but increased in CL 61-100 (22.6%) and > 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical-biological discordance.

CONCLUSION: Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical-biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.},
}

@article {pmid42163385,
year = {2026},
author = {Deng, L and Yin, C and Zhou, X and Feng, C and Wu, J and An, X and Mi, J and Huang, L and Qin, D and Yu, L and Chen, T and Wu, A},
title = {Targeted degradation of aberrant Tau for the discovery of Pulsatilla chinensis in Alzheimer's disease.},
journal = {Chinese medicine},
volume = {21},
number = {1},
pages = {},
pmid = {42163385},
issn = {1749-8546},
support = {2024LZXNYDJ026//Joint Project of Luzhou Municipal People's Government and Southwest Medical University/ ; 81903829//Natural Science Foundation of Henan Province/ ; 2024YFHZ0361//Department of Science and Technology of Sichuan Province/ ; SKLKY2024B0006//State Key Laboratory of Traditional Chinese Medicine Syndrome/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by Tau aggregation, mitochondrial dysfunction, and oxidative stress, yet effective interventions targeting these pathological cascades remain limited. Therapeutic strategies that enhance autophagic and mitophagic clearance, attenuate Tau toxicity, and restore mitochondrial homeostasis are crucial for AD management.

METHODS: This study investigated the neuroprotective effects of Pulsatilla chinensis extract (PCE) in SH-SY5Y neuronal cells and Caenorhabditis elegans (C. elegans) models of Tauopathy. Autophagic flux was evaluated by GFP-LC3 puncta formation, LC3-II conversion, and p62 degradation. Mitochondrial function was assessed through reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and ultrastructural analysis. The roles of autophagy and mitophagy were examined using 3-methyladenine (3-MA) and the Parkin inhibitor AC220. In C. elegans, locomotion, Tau aggregation, oxidative stress, and mitophagosome formation were assessed, and pink-1 knockdown was used to confirm mitophagy dependence.

RESULTS: PCE significantly enhanced autophagic flux, decreased total and phosphorylated Tau (p-Tau Ser404) levels, and improved neuronal viability. It significantly reduced ROS accumulation, maintained MMP, and preserved mitochondrial morphology under both Tau overexpression and H2O2-induced oxidative stress. Inhibition of autophagy or Parkin-mediated mitophagy negated these protective effects. In C. elegans, PCE ameliorated neuromuscular dysfunction, suppressed Tau inclusions, and reduced oxidative injury, while the loss of pink-1 abolished its benefits, underscoring the critical role of mitophagy.

CONCLUSION: PCE exerts potent neuroprotective effects by promoting mitophagy, reducing Tau phosphorylation and aggregation, and restoring mitochondrial integrity. These findings reveal a novel mechanism linking mitochondrial quality control with Tau proteostasis and highlight PCE as a promising natural therapeutic candidate for AD.},
}

@article {pmid42163499,
year = {2026},
author = {Liu, M and Li, X and Fang, H and Miao, D},
title = {Development and validation of a novel single molecular immunology assay for detection of p-Tau181.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453031},
doi = {10.1177/13872877261453031},
pmid = {42163499},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) presents a major public health challenge. Current diagnostic methods for these disorders are often costly, invasive, and not widely accessible. The recently revised NIA-AA criteria highlight the potential of blood-based biomarkers as a promising non-invasive and cost-effective alternative for diagnosis.ObjectiveTo develop a novel single-molecule immunology assay specifically for the detection of phosphorylated tau at threonine 181 (p-Tau181) protein in blood samples.MethodsA novel single-molecule immunoassay targeting p-Tau181 was developed employing the Lychix Homebrew Kit. This new p-Tau181 assay underwent validation through the analysis of plasma samples from 98 clinically confirmed AD patients and 98 age-matched normal controls (NC), with the aim of assessing its effectiveness in differentiating between these two populations.ResultsInitially, the p-Tau181 immunoassay exhibited high nonspecificity and low discrimination between AD and NC plasma samples, with an AUC of 0.76. Further investigation revealed that false positive signals were caused by enzyme attachment to bead surfaces. By adjusting enzyme concentrations, reaction temperatures, and optimizing the sample diluent, it was ultimately discovered that salt concentration was the key factor in effectively minimizing false signals. With the optimized salt ion concentration, the refined p-Tau181 assay significantly improved its ability to distinguish AD from NC, achieving an AUC of 0.9313. The assay demonstrated improved sensitivity of 84.69% (76.27%-90.50%, 95% CI) and specificity of 87.76% (79.81%-92.85%, 95% CI).ConclusionsThe optimized single-molecule immunoassay p-Tau181 demonstrated significantly improved discrimination between AD and NC populations, underscoring its potential as a valuable diagnostic tool for AD.},
}

@article {pmid42163597,
year = {2026},
author = {Karim, A and Alturise, F and Alkhalifah, T and Khan, YD},
title = {predALZ: An Ensemble Learning Framework for Identifying Genetic Biomarkers in Familial Alzheimer's Disease.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501408301251214192633},
pmid = {42163597},
issn = {1873-5592},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a substantial genetic contribution, especially in the early-onset form. Mutations in genes like APP, PSEN1, and PSEN2 serve as crucial biomarkers, indicating a heightened risk of developing AD. Leveraging these genetic markers, we introduce predALZ, a prediction model designed to enhance early detection of familial AD through genomic sequence analysis.

METHODS: The model integrates data derived from genome-wide association studies (GWAS) and employs advanced feature encoding techniques to generate a robust representation of genomic patterns. A diverse ensemble of classifiers, namely XGBoost, Random Forest, LightGBM, and ExtraTrees, is employed to train the predALZ model, utilizing the generated feature vector for training.

RESULTS: The predALZ framework achieved 94% accuracy on an independent test set and approximately 96% accuracy in cross-validation for Alzheimer-related driver gene prediction. The ensemble model also yielded consistently high sensitivity, specificity, and Matthews correlation coefficient values, indicating stable and reliable classification performance.

DISCUSSION: The model's effectiveness was further rigorously validated through a comprehensive evaluation, using metrics such as accuracy, sensitivity, specificity, and Matthew's correlation coefficient. The study underscores the predictor's remarkable performance, consistently achieving 94% accuracy in an independent Test and ~96% in cross-validation.

CONCLUSION: These findings highlight predALZ's potential for application in predictive diagnostics and targeted therapeutic development for Alzheimer's disease.},
}

@article {pmid42163600,
year = {2026},
author = {Qasim, R and Tariq, Z and Ahmed, S and Raza, M and Khan, I and Zahra, R and Noor, A and Mehdi, BJ},
title = {Trends in Cerebrovascular Disease Mortality Among Alzheimer Patients in Older Adults Across the USA: A CDC Wonder Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050429545260402050204},
pmid = {42163600},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is the most common form of dementia, affecting more than 55 million individuals worldwide. Cerebrovascular Disease (CeVD) has been shown to co-exist with AD. This study aimed to shed light on this mortality trend to make a positive difference in improving patient care.

METHODS: Data were extracted from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database using CeVD as the underlying cause of death, and AD as a multiple cause of death, from 1999 to 2020 for older adults (≥ 65 years). The Age- Adjusted Mortality Rates (AAMRs) were calculated per 100,000 individuals, and trends were assessed using Joinpoint as the Average Annual Percentage Changes (AAPCs).

RESULTS: In total, 64,749 deaths were reported. The overall AAMR declined from 10.21 (1999) to 5.28 (2020). Females had higher AAMRs than males (7.75 vs. 5.59). Non-Hispanic White individuals had the highest AAMR (7.26), while the West region (8.57) and non-metropolitan areas (9.14) showed elevated rates. Vermont (11.81) and Washington (11.56) exhibited the highest death rates, in contrast to Nevada (3.08) and New York (3.25). Most deaths occurred in nursing homes, followed by medical facilities.

DISCUSSION: Mortality declined overall, attributed to advancements in healthcare and prevention, but significant disparities persist among women, non-Hispanic White populations, western, and rural regions. Limitations include potential death certificate misclassification. Future studies should further evaluate targeted interventions, such as community-tailored interventions, to enhance equity.

CONCLUSION: These trends showed significant spatiotemporal and demographic variation. Targeted interventions are required to mitigate fatalities, particularly in high-risk populations.},
}

@article {pmid42163660,
year = {2026},
author = {Yang, M and Dai, S and Li, S and Xu, Z and Chen, T},
title = {Involvement and Mechanisms of Aβ and Tau in the Neuroinflammatory Response of Alzheimer's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438314260228195840},
pmid = {42163660},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a common chronic neurodegenerative disorder, serving as the most prevalent cause of dementia among the elderly. The primary histopathological hallmarks of AD encompass senile plaques, induced by excessive deposition of extracellular β-amyloid (Aβ), and neurofibrillary tangles (NFT), resulting from excessive phosphorylation of intracellular Tau protein, leading to neuronal damage and loss. Numerous studies on AD patients and animal models have revealed the widespread presence of neuroinflammatory responses within the AD brain, emphasizing the pivotal role of neuroinflammation in the pathogenesis of AD, which is now widely recognized as one of the primary triggers of AD. Microglia, the resident macrophages in the brain and the first line of defense of the central nervous system, play a central role in neuroinflammation. In the pathogenesis of AD, microglia are considered a double-edged sword, exerting beneficial effects by clearing Aβ deposition while causing detrimental effects through the production of cytotoxic substances, leading to neuronal dysfunction. Although the precise role of neuroinflammation in the pathogenesis of AD remains incompletely elucidated, an increasing number of studies have revealed that pathological Aβ and Tau proteins are extensively involved in the neuroinflammatory process mediated by microglia activation in AD, exhibiting a complex interplay. Therefore, this article will provide a comprehensive review of the research progress on the relationship between Aβ or Tau proteins and neuroinflammation induced by microglia in AD, as well as its associated mechanisms.},
}

@article {pmid42163663,
year = {2026},
author = {Xu, H and Zhang, J and Wang, Y and Ma, G and Zhao, YJ},
title = {The Efficacy of Glucagon-like Peptide-1 Receptor Agonists on Different Cognitive Domains: A Meta-analysis of Randomized Controlled Trials.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X439787260312090015},
pmid = {42163663},
issn = {1875-6190},
abstract = {INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely studied for cognitive enhancement. However, their clinical efficacy remains inconclusive in patients with Alzheimer's disease (AD), Parkinson's disease (PD), and type 2 diabetes mellitus (T2DM). We therefore conducted a domain-specific meta-analysis to evaluate their cognitive effects.

METHODS: The PubMed, Web of Science, and Cochrane Library were searched for studies published up to January 2026. Eligible randomized controlled trials comparing GLP‑1 RAs to control groups, with baseline and post‑intervention cognitive scores, were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using a random‑effects model across six cognitive domains.

RESULTS: Eleven trials met the inclusion criteria. GLP-1 RAs demonstrated no significant benefit across all cognitive domains: pooled SMD for overall cognition was 0.03 (95% CI, -0.11 to 0.18; P =  0.64); memory, 0.21 (95% CI, -0.19 to 0.60; P = 0.30); attention, 0.23 (95% CI, -0.19 to 0.65; P =  0.28); executive function, 0.14 (95% CI, -0.28 to 0.56; P =  0.51); visuospatial ability, 0.04 (95% CI, -0.43 to 0.50; P =  0.88); and motor function, 0.20 (95% CI, -0.19 to 0.59; P = 0.31). Subgroup analyses by disease type and drug class also revealed no statistically significant differences.

DISCUSSION: Our findings suggest that the cognitive benefits of GLP‑1 RAs may be limited in patients with established disease. This may be attributable to irreversible neuropathological alterations in AD, PD, and T2DM patients, which hinder the translation of GLP‑1 RA-mediated neuroprotective actions into measurable symptomatic improvements. A key limitation of the present study is the relatively small sample size for several specific cognitive domains, which may affect the robustness of the results.

CONCLUSIONS: The available evidence from this meta-analysis does not support significant benefits across six cognitive domains with GLP‑1 RAs in patients with AD, PD, and T2DM. Future largescale trials with domain-specific assessments are needed to evaluate their potential in earlier disease stages or specific subgroups.},
}

@article {pmid42163677,
year = {2026},
author = {Tiwari, D and Mukherjee, A and Singh, S},
title = {Interplay of NMDAR and AMPAR in the Pathophysiology of Alzheimer's, Parkinson, ALS, Huntington's, and Epilepsy: An Update in Therapeutic Perspective.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X466249260418090832},
pmid = {42163677},
issn = {1875-6190},
abstract = {Glutamate-mediated excitotoxicity is a central driver of neurodegeneration and represents a shared pathogenic mechanism across neurodegenerative diseases and epilepsy, with N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-tors (AMPARs) occupying central roles in synaptic plasticity, Ca[2+] signalling, and neuronal survival. Dysregulation of these receptors disrupts the balance between pro-survival and pro-death pathways, accelerating neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lat-eral sclerosis (ALS), Huntington's disease (HD), and epilepsy. Disease-specific triggers converge on common patterns of receptor dysregulation, including a shift toward extrasynaptic NMDAR signal-ling and the pathological emergence of Ca[2+]-permeable AMPARs (CP-AMPAR), ultimately driving synaptic failure and neuronal loss. Although numerous NMDAR and AMPAR-directed modulators have demonstrated neuroprotective efficacy in preclinical models, clinical translation has been lim-ited by inadequate spatial, kinetic, and subunit selectivity, as well as adverse effects arising from the disruption of physiological glutamatergic transmission. In this review, we synthesize the literature published between June 1990 and March 2025 to develop an integrative framework that links recep-tor localization, downstream Ca[2+]-dependent signalling, astrocytic regulation, mitochondrial dys-function, and disease progression across these disorders. By critically evaluating both successful and failed therapeutic strategies, we provide insight into evident research gaps in the field and the neces-sity of addressing them to develop precise multi-target approaches at both the genetic and cellular levels as next-generation therapeutics. Such an approach would be essential to move beyond indis-criminate receptor blockade strategies, which have repeatedly proven ineffective over the decades, and towards a future of durable neuroprotection.},
}

@article {pmid42163678,
year = {2026},
author = {Jin, S and Liu, D and Ouyang, J},
title = {An Investigation of the Neurotoxic Mechanisms of Benzo[a]pyrene in Alzheimer's Disease Using an Integrated Approach of Network Toxicology and Machine Learning.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X447239260407111712},
pmid = {42163678},
issn = {1875-6190},
abstract = {INTRODUCTION: Benzo[a]pyrene (BaP) exposure is increasingly associated with the progression of Alzheimer's Disease (AD), yet the specific molecular links remain poorly understood. This study utilizes an integrated computational framework, combining network toxicology, machine learning, and molecular dynamics simulations, to identify core biomarkers and elucidate the potential pathological interplay between BaP and AD.

METHODS: We began our analysis by identifying the intersection of targets and then created a Protein-Protein Interaction (PPI) Network to identify hub genes. To ensure accuracy, we selected final core molecular targets from the intersection of three distinct types of machine learning algorithms. To validate diagnostic value, immune cell infiltration data analysis was performed using the GSE138260 dataset. Finally, we used molecular docking and 100 ns dynamics to assess how BaP interacts with the core molecular target.

RESULTS: We identified four proteins associated with BaP and AD: CASP3 (Caspase 3), HTT (Huntingtin), TH (Tyrosine Hydroxylase), and PARK7 (DJ-1). These proteins signal neuronal apoptosis and neuro-immune dysregulation due to their involvement in pathways associated with these processes. The Receiver Operating Characteristic (ROC) analysis demonstrated strong diagnostic properties for these targets. Molecular docking data also showed BaP as the main target, with TH binding with a value of -10.02 kcal/mol. The stability of this BaP-TH complex was further confirmed by 100 ns molecular dynamics simulations.

DISCUSSION: The research reveals TH's critical effect on BaP-induced neurotoxicity. We also identify the potential molecular mechanisms contributing to Alzheimer's disease pathology via environmental exposure.

CONCLUSION: This research identifies several significant molecular interactions between BaP and AD. One major molecular target for BaP interaction with AD is tyrosine hydroxylase (TH). Our findings here create an opportunity for the development of therapeutics for the treatment of AD cases caused by exposure to environmental toxins.},
}

@article {pmid42163688,
year = {2026},
author = {Malik, P and Singh, S},
title = {2DSDNN: A Novel Approach for Alzheimer's Disease Classification.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056368237251028221129},
pmid = {42163688},
issn = {1573-4056},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is one of the most prevalent types of dementia, which primarily impacts the elderly. Distinguishing AD stages has emerged as a significant challenge. The recent progress in neurological imaging techniques in conjunction with machine learning approaches has proved effective in identifying patterns in medical imaging. This can assist specialists in the early identification of AD.

METHODS: This paper proposes a skull-stripping algorithm to achieve precise image classification on MRI modalities. To achieve this, thresholding and morphological manipulations are executed beforehand on the T1 and T2 weighted MRI slides to eliminate extraneous tissues. Building on these segmentation results, a 2D Sequential Deep Learning Neural Network (2DSDNN) model is proposed that can effectively aid in improving the early detection of AD by utilizing 1,044 MRI scans from the ADNI dataset. 2DSDNN effectively distinguishes between types of Alzheimer's Disease for binary and multiclass classification tasks, providing superior performance over existing models.

RESULTS: Our technique achieves AD vs. CN classification accuracy, sensitivity, specificity, precision, recall, F1-score, and AUC of 98.03%, 99.04%, 97.03%, 98.00%, 99.20%, 98%, and 98.20%, respectively. The accuracy rate for AD vs. MCI classification is 95.03%, with a sensitivity rate, specificity rate, precision, recall, F1-score, and AUC of 97.07%, 94.91%, 96.0%, 97.01%, 96.0%, and 95.97%, respectively. The accuracy rate for CN vs. MCI classification is 94.05%, with sensitivity, specificity, precision rate, recall, F1-score, and AUC score of 94.21%, 94.21%, 95%, 97.01%, 96%, and 94.16%, respectively. The AD vs. MCI vs. CN classification achieved an accuracy of 97.20%, a sensitivity of 97.28%, a specificity of 95%, a precision of 97.32%, a recall of 96.13%, an F1-score of 96% and an AUC rate of 96.62%.

DISCUSSION: Compared with existing methodologies, our proposed 2DSDNN model, applied to T1- and T2-w MRI data, demonstrates a substantial enhancement in performance in the binary and multiclass classification of AD. The proposed skull-stripping algorithm, combined with Gaussian filtering and morphological manipulations, improves image segmentation, leading to more accurate classification of AD, MCI, and CN stages. Moreover, the use of T1 and T2 MRI modalities in a sequential deep learning framework allows superior performance in binary and multiclass classification tasks compared to traditional CNN and DNN models.

CONCLUSION: Our proposed model performed significantly better in binary and multiclass classification than existing contemporary techniques and could identify AD efficiently at an early stage.},
}

@article {pmid42163709,
year = {2026},
author = {Gao, C and Iles, MM and Bunce, D and Wu, B and Luo, H and Pavitt, S and Wu, J and Bishop, DT and Kang, J},
title = {Periodontal diseases and all-cause dementia risk: Genetic instrument analyses in half a million UK Biobank participants.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450558},
doi = {10.1177/13872877261450558},
pmid = {42163709},
issn = {1875-8908},
abstract = {BackgroundNumerous studies suggest that periodontal diseases might be associated with the development of dementia, but the causality is inconclusive.ObjectiveThis study aims to explore the casual effect of periodontal diseases on all-cause dementia.MethodsThe UK Biobank (UKB) data (n = ∼500,000) has been implemented, where participants were divided into two independent groups (2/3train and 1/3test). The exposure is the self-reported periodontal diseases, and the outcome is all-cause dementia measured by both clinical diagnoses based on ICD10 and ICD9 codes, and self-reported dementia. Four sets of genetic instruments were developed based on four different thresholds (main approach: p < 5 × 10[-8]; alternative approach I: p < 5 × 10[-6]; alternative approach II: p < 10[-4]; and alternative approach III: the best-fit p-value threshold calculated by polygenic risk score). The causal association between periodontal diseases and dementia was assessed by inverse-variance weighted (IVW), MR-Egger regression, weighted median, and mode-based estimate models.ResultsThe number of genetic instruments included in these four approaches varied from 3 to 1020, after passing the MR assumption checks. Most MR results suggested no causal association between periodontal diseases and dementia except the IVW model from main approach (coefficient beta: -0.816, 95% confidence interval, CI (-1.617, -0.015)) and the weighted median model from alternative approach II (beta: 0.077 95%CI (0.006, 0.149)) suggested potential causal relationship between periodontal diseases and dementia.ConclusionsThe results showed inconsistent evidence of causal link between periodontal diseases and dementia using UKB. Future studies are needed with clinically defined periodontal diseases to better understand the causal link.},
}

@article {pmid42163711,
year = {2026},
author = {Gabrielli, AP and Weidling, I and Lysaker, CR and Novikova, L and Ranjan, A and Wang, X and Wilkins, HM and Swerdlow, RH},
title = {An aging hallmark, Alzheimer's disease, and APOE nexus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452598},
doi = {10.1177/13872877261452598},
pmid = {42163711},
issn = {1875-8908},
abstract = {BackgroundThe commonality of Alzheimer's disease (AD) in the elderly suggests connections between aging and AD biology. APOE biology is also tied to AD.ObjectiveWe sought to link three aging hallmarks (loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing) to APOE biology.MethodsWe altered SH-SY5Y cell proteostasis directly via heat shock, integrated stress response inhibition (ISRIB), or autophagy inhibition (chloroquine), and indirectly by perturbing mitochondria (mtDNA depletion; oligomycin). We also exposed induced pluripotent stem cell-derived neurons to ISRIB and chloroquine. Conversely, we mitigated protein stress with rapamycin. We assessed intervention impact on APOE expression.ResultsIncreasing protein stress elevated and decreasing protein stress lowered APOE expression. In SH-SY5Y cells rapamycin blocked oligomycin-induced mTOR 2448 phosphorylation, Akt 473 phosphorylation, and APOE expression. In chloroquine-treated neurons rapamycin reduced mTOR phosphorylation and APOE expression.DiscussionProtein stress initiates APOE expression and facilitates mitochondrial dysfunction's impact on APOE by engaging the mTOR pathway. Our findings link aging and AD biology.},
}

@article {pmid42163712,
year = {2026},
author = {Clute-Reinig, N and Helfman, S and Lakis, J and Epstein, L and Niotis, K and Isaacson, R},
title = {Attitudes toward preventive neurology care: A cross-sectional survey study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452599},
doi = {10.1177/13872877261452599},
pmid = {42163712},
issn = {1875-8908},
abstract = {BackgroundUp to 45% of dementia cases due to Alzheimer's disease may be preventable, but implementation of risk-reduction programs have lagged in the United States.ObjectiveThe objective of this study was to understand whether belief in effectiveness, or interest in implementing risk-reducing interventions among healthcare consumers and providers are driving this lag.MethodsA survey was administered online using both directed and free-response questions. Directed questions were translated from Likert scales to numeric, while free-response questions were multi-operator coded and analyzed for themes.ResultsA total of 2054 full or partial responses were recorded; a majority of consumer respondents identified as White, Female, and between the ages of 51 and 79. Consumers were more interested in lifestyle than pharmaceutical interventions (Likert mean 4.5 versus 3.5, p < 0.0001), and were most interested in personalized risk reduction plans (mean 4.82, p < 0.001). Healthcare providers had higher belief in lifestyle interventions than pharmaceutical interventions (means 3.86 and 2.81, p < 0.0001), and they showed interest in medical education, referral networks, and blood biomarker testing (mean 4.15; 69%/58% of responses). Free response coding suggested that healthcare providers want to provide preventive neurology services but want guidance and education.ConclusionsBoth healthcare consumers and providers show interest in preventive neurology offerings. Our data suggest there is substantial demand for this type of care and that measures should be taken to increase clinical preventive neurology capacity.},
}

@article {pmid42163745,
year = {2026},
author = {Abdalla, EA and Fayed, AM and Hussein, MA and Abdel-Aziz, A and Mohamed, ZN},
title = {Multi-Target Neuroprotection of Salvia officinalis Aqueous Extract in a Scopolamine-Induced Model of Alzheimer's Disease: Comparative Efficacy Versus Donepezil.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128429239260312074215},
pmid = {42163745},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex, age-related, neurodegenerative disorder that involves cognitive deterioration, oxidative stress, and neuroinflammation. Symptomatic relief is limited with conventional treatments such as donepezil, sparking a significant interest in multi-target botanicals. We examined the neuroprotective effects of Salvia officinalis aqueous extract (SAGE) on a scopolamine-induced animal model of AD and the related molecular mechanisms regarding GABRA5α, GSK-3β, and pERK pathways.

METHODS: SAGE was characterized using phytochemical profiling and antioxidant assays. IC50 values were determined in vitro for inhibitor activity against GABRA5α and GSK-3β. In vivo experiments included assessment of behavior (Morris water maze), assays for oxidative stress and inflammation, gene expression studies by qPCR, and histopathology of hippocampal tissue. Efficacy versus donepezil was compared. Statistical significance was based on one-way ANOVA followed by Tukey's post-hoc test (p < 0.05) for robust comparisons between all treatment groups.

RESULTS: The SAGE had strong antioxidant abilities and was able to inhibit GABRA5α and GSK-3β in a target-specific way. SAGE treatment greatly enhanced spatial learning and memory, retained the redox equilibrium, decreased neuroinflammatory markers, and normalized AChE activity. Gene expression was found to modulate favourably for GABRA5α, GSK-3β and pERK. Histological findings confirmed neuronal preservation. In all parameters, SAGE was more effective than donepezil. The present findings demonstrated the therapeutic potential of SAGE's phenolics to mitigate oxidative cascades, including those suggested as contributing factors to AD pathology.

DISCUSSION: The superior multi-modal efficacy of SAGE over donepezil due to its phenolic-rich phytochemical profile and capacity to modulate oxidative, inflammatory, and neuronal pathways is demonstrated. This is encouraging, and additional studies should be conducted to investigate pharmacokinetics, mechanistic and clinical significance.

CONCLUSION: S. officinalis AE strongly protects the brain against scopolamine-induced AD-like neuropathology in a superior way over standard treatment via altered multi-targets. Its characteristics promote its further development as a natural therapeutic candidate for AD treatment. There are however constraints, such as nodescription of the pharmacokinetic profiling and no tau/Aβ quantification. Prospective studies with these endpoints and chronic dosing schedules should now address the issue of long-term effectiveness and safety.},
}

@article {pmid42164082,
year = {2026},
author = {Zhu, Y and Tu, Y and Ren, C and Ke, Y and Guo, Q},
title = {Correction: Elevated gonadotropins and risk of dementia in Chinese adults aged over 80: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1859014},
doi = {10.3389/fnagi.2026.1859014},
pmid = {42164082},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2025.1651723.].},
}

@article {pmid42164083,
year = {2026},
author = {Costa, CL and Araujo-Menendez, CEE and Lawrence, A and Mendoza, A and Tarraf, W and Stickel, AM},
title = {No associations between blood pressure and brain volumes in a convenience sample of Hispanic/Latino middle-aged and older adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729134},
pmid = {42164083},
issn = {1663-4365},
abstract = {BACKGROUND: High blood pressure (BP) is a known risk factor for dementia, but the relationships between BP and gross brain volumes are mixed and are understudied in groups who are at particularly high risk for dementia, such as Hispanic/Latino adults. Therefore, we aimed to investigate the relationships between BP and brain volumes, among Hispanic/Latino older adults.

METHODS: Participants included 122 cognitively healthy Hispanic/Latino late middle-aged and older adults ages (mean age = 73.48 years, SD = 7.32) from the National Alzheimer's Coordinating Center. Data were collected from 2005 to 2024 from 20 Alzheimer's Disease Research Centers. BP measures included systolic (SBP), diastolic (DBP), and pulse pressure (PP). Brain outcomes included total, hippocampal, gray matter, and white matter hyperintensity volumes. Covariates included age, sex, Hispanic/Latino heritage, hypertension, diabetes, hypercholesterolemia, body mass index, hypotensive status, and smoking status.

RESULTS: No BP measure was significantly associated with brain outcomes (all p > 0.05).

DISCUSSION: Overall, we found no relationships between BP measures and brain volumes in this sample of late middle-aged and older Hispanic/Latino adults. Our findings warrant longitudinal studies to better characterize the relationships between BP and other cardiovascular disease risk factors with brain health in this population.},
}

@article {pmid42164127,
year = {2026},
author = {Qi, J and Li, L and Duan, H and Sun, Y and Zhang, J},
title = {Integrating neuroimaging and plasma biomarkers to predict preclinical Alzheimer's disease progression.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1801239},
pmid = {42164127},
issn = {1664-2295},
abstract = {OBJECTIVE: To develop and validate a multimodal model integrating neuroimaging and plasma biomarkers for predicting the risk of cognitive progression in preclinical Alzheimer's disease (AD).

METHODS: This retrospective study enrolled 320 patients with Aβ-positive preclinical AD or AD-related mild cognitive impairment. Participants were randomly allocated into training and validation sets at a 7:3 ratio. In the training set, univariable analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariable Logistic regression were employed to identify core predictive variables. Subsequently, four machine learning models were constructed based on these variables. Model performance was evaluated using the area under the receiver operating characteristic Curve (AUC), calibration curves, and decision curve analysis. Interpretability was assessed using SHapley Additive exPlanations (SHAP) values.

RESULTS: The baseline characteristics were balanced between the training and validation sets. LASSO regression identified five core variables: Mini-Mental State Examination total score, Rey Auditory Verbal Learning Test delayed recall, normalized hippocampal volume, plasma phosphorylated tau181, and apolipoprotein E ε4 allele status. Multivariable analysis confirmed these as independent predictors (p < 0.01). The logistic regression model demonstrated robust predictive performance, achieving the highest area under the curve (AUC) in the independent validation set (0.818, 95% confidence interval: 0.703-0.933). Calibration and decision curve analyses conducted on the validation set indicated that the model was accurate and possessed clinical utility. SHAP analysis applied to the optimal model showed that normalized hippocampal volume was the most influential contributor to the predictions.

CONCLUSION: The developed multimodal model exhibits robust predictive performance and clinical utility. It may serve as a quantitative tool for individualized risk management in preclinical AD.},
}

@article {pmid42164258,
year = {2026},
author = {Podder, A and Liew, YJ and Cary, GA and Carter, GW and Uyar, A},
title = {Single-subject proteomic signatures in Alzheimer's disease reflect clinical phenotypes and distinguish asymptomatic from symptomatic cases.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70264},
pmid = {42164258},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) exhibits considerable inter-individual variability in clinical presentation, neuropathological burden, and underlying molecular processes. Conventional cohort-based analyses of omics molecular data often mask individual-level heterogeneity, limiting insights into precision therapeutic strategies. To address this challenge, we developed INdividual-level DIfferential GenOmics (INDIGO), a computational framework that quantifies molecular deviations for each individual relative to healthy controls, enabling subject-specific profiling of disease-associated alterations in proteomic data, with a framework that is readily applicable to other omics modalities.

METHODS: We applied INDIGO to dorsolateral prefrontal cortex (DLPFC) proteomic data from the Religious Orders Study and Memory and Aging Project cohort (N = 610). Protein-level deviations were aggregated into gene set activity scores for Kyoto Encyclopedia of Genes and Genomes pathways and curated AD Biodomain annotations. Functional alterations across AD and asymptomatic AD (AsymAD) individuals were evaluated and correlated with clinical metrics including apolipoprotein E (APOE) genotype, Braak stage, Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and Mini-Mental State Examination scores. Graph-based clustering was used to identify molecularly distinct subgroups based on shared patterns of functional dysregulation.

RESULTS: Limited overlap was observed between cohort-level differential expression analysis and INDIGO single-subject analyses. Individual deviations in various processes, including metabolic, immune, and epigenetic pathways, exhibited sex- and disease stage-specific patterns. Amyloid clearance and immune activation were strongly associated with APOE ε4 dosage, higher amyloid and tau burden, and cognitive decline, whereas upregulation of mitochondrial and synaptic modules correlated positively with preserved cognitive function. By linking individuals through concordant directional proteomic changes, we identified molecularly coherent subgroups that transcended conventional diagnostic boundaries and included both AD and AsymAD subjects. Each subgroup displayed distinct functional signatures defined by a unique set of key regulatory proteins.

DISCUSSION: These results demonstrate that single-subject omics profiling can resolve individual molecular signatures aligned with clinical and neuropathological variation in AD. By linking molecular heterogeneity with disease phenotypes, INDIGO provides a scalable framework for precision modeling and novel therapeutic target discovery.},
}

@article {pmid42164259,
year = {2026},
author = {Giorelli, M},
title = {Reframing Alzheimer's disease as a complex adaptive system: More than an amyloid beta-tau connection.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70256},
pmid = {42164259},
issn = {2352-8737},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, but simple models focusing on amyloid beta and tau only partially explain its variability and limited success in treatment. Evidence from systems biology, neuroimmunology, connectomics, and computational modeling supports viewing AD as a complex adaptive system, a multiscale network in which genetic, molecular, cellular, vascular, and environmental factors interact in complex, non-linear ways over time. In this perspective, disease paths develop from feedback-driven instabilities that spread across different levels, while resilience and compensatory mechanisms influence individual outcomes. This new understanding has important implications: diagnostic approaches should shift from static lesion biomarkers to longitudinal, multimodal measures of network states; treatments should combine pharmacological, metabolic, vascular, inflammatory, cognitive, and neuromodulatory strategies; and adaptive, model-informed algorithms should customize the timing and dosage to each patient's unique dynamics. Recognizing the complexity enables earlier detection of critical tipping points, targeted reinforcement of resilience, and personalized intervention plans, shifting AD care from late-stage, single-target methods to precision network medicine.},
}