@article {pmid43003089,
year = {2026},
author = {Sokolova, D and Puletti, F and Addington Ghansah, S and Georgiades, T and Zheng, Y and Wu, L and De Schepper, S and Lange, J and Ferreira, LSS and Sierksma, A and Rebejac, J and Crowley, G and Rueda-Carrasco, J and Geary, B and Nirujogi, R and Koutsiouroumpa, A and Muckett, P and Kittler, J and Gentry, M and Bourdenx, M and Freeman, OJ and Burden, JJ and Khakh, BS and Hong, S},
title = {An astrocyte-microglia MFG-E8 axis promotes synapse engulfment in early amyloid pathology.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.10.011},
pmid = {43003089},
issn = {1097-4199},
abstract = {Region-specific synapse loss is an early hallmark of Alzheimer's disease, yet the upstream signals that render synapses vulnerable remain unclear. In a mouse model of amyloidosis, we identify an early astrocyte state that emerges in vulnerable brain regions before widespread plaque deposition and overt gliosis. These astrocytes exhibit bulbous-looking perisynaptic processes enriched in p62 and glycogen, impaired autophagic flux and calcium signaling, and diminished astrocyte-synapse coverage. Rather than exhibiting increased synapse engulfment, bulbous astrocytes show elevated milk fat globule-epidermal growth factor 8 (MFG-E8) and are associated with increased local microglial synapse engulfment. Astrocyte-specific gain- and loss-of-function experiments demonstrate that astrocyte-derived MFG-E8 is required for microglial synapse engulfment and acts through microglial β3 integrin signaling. Astrocytic Mfge8 deletion reduces microglial engulfment and synapse loss across amyloidosis models and is associated with reduced amyloid pathology, gliosis, and cognitive impairment. Together, these findings define an astrocyte-microglia MFG-E8 signaling axis that contributes to region-specific synaptic vulnerability during early amyloid pathology.},
}

@article {pmid43003143,
year = {2026},
author = {Zhang, M and Zhang, H and Fu, B and Xu, D},
title = {Effects of Probiotics/Synbiotic Interventions on Cognitive Dysfunction in Alzheimer's or MCI: A Systematic Review and Meta‑Analysis of randomized controlled trials.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103442},
doi = {10.1016/j.arr.2026.103442},
pmid = {43003143},
issn = {1872-9649},
abstract = {OBJECTIVE: To systematically evaluate the effects of probiotics or synbiotics on cognitive function in individuals with mild cognitive impairment, Alzheimer's disease, and related cognitive decline.

METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to 20 September 2026. Randomized controlled trials comparing viable probiotics or synbiotics with placebo or usual care were included. Cognitive changes were pooled as standardized mean differences (SMDs) using a random-effects model. Subgroup, sensitivity, RoB 2, Egger, and GRADE assessments were conducted.

RESULTS: Ten trials involving 739 participants were included. Probiotics or synbiotics were associated with a possible improvement in cognitive function (SMD = 0.50, 95% CI: 0.19, 0.81; P = 0.002; Ι[2] = 76%). The approximate 95% prediction interval was -0.57 to 1.57. No statistically significant differences in treatment effects were detected between subgroups defined by disease category, intervention duration, intervention type, study-level mean age, strain composition, dosage, or cognitive instrument. The effect was numerically larger in studies with a mean age ≤ 70 years, but this difference was not significant (P = 0.17) and was sensitive to individual studies. Sensitivity analyses maintained the direction and statistical significance of the pooled effect. Egger's test showed no significant small-study effects (Z = 1.00, P = 0.318). The certainty of evidence was very low.

CONCLUSION: Probiotics or synbiotics may improve cognitive test performance, but the certainty of evidence is very low because of risk of bias, substantial heterogeneity, and imprecision. Exploratory subgroup analyses did not provide clear evidence that disease category, intervention duration, intervention type, study-level mean age, strain composition, dosage, or cognitive assessment instrument modified the treatment effect. Larger, well-designed randomized trials are needed.},
}

@article {pmid43003335,
year = {2026},
author = {Wang, C and Zhang, R and Lo, H and Wu, J and Song, L and Qu, L and Wang, H and Liu, M and Yun, X and Chen, X and Qu, Y and Tang, Y and Zhuang, G and Xiang, X and Ye, Z and Zhang, H and Ng, JPL and Wong, VKW and Tang, Y and Law, BYK},
title = {Tectoridin Attenuates Alzheimer's Pathology by Inhibiting Aβ Aggregation in 3xTg-AD Mice.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179540},
doi = {10.1016/j.ejphar.2026.179540},
pmid = {43003335},
issn = {1879-0712},
abstract = {BACKGROUND: Alzheimer's disease (AD) remains a major neurodegenerative challenge, necessitating the development of innovative, mechanism-targeted therapies.

PURPOSE: Tectoridin (Tec), an isoflavone from Belamcanda chinensis (L.) DC., was systematically investigated for its novel neuroprotective effects in AD to elucidate its therapeutic potential and molecular mechanisms.

METHODS: In vitro, western blotting, calcium assays, and flow cytometry were used to characterize Tec's impact on neuronal homeostasis. In vivo, the therapeutic efficacy of Tec was assessed in 3xTg-AD mice. Cognitive performance was evaluated via the Morris Water Maze, while pathological changes were analyzed through immunohistochemistry. RNA sequencing and experimental validation were performed to delineate regulatory pathways.

RESULT: Tec effectively inhibited Aβ aggregation and exhibited potent antioxidant activity. It maintained cellular homeostasis by mitigating Aβ-induced calcium overload, restoring ATP levels, and stabilizing mitochondrial membrane potential, ultimately preventing neuronal apoptosis. Furthermore, Tec treatment significantly ameliorated cognitive impairments in 3xTg-AD mice and markedly reduced cerebral Aβ plaque deposition. Mechanistic analysis revealed that Tec improves AD pathology by upregulating LRP1, thereby promoting the transmembrane transport and systemic clearance of Aβ.

CONCLUSION: This study confirms that Tec exerts significant neuroprotective effects in AD by inhibiting Aβ aggregation, reducing neuronal apoptosis and upregulating the expression of LRP1. The upregulation of LRP1 by Tec may enhance Aβ efflux from the brain, thereby contributing to the reduced Aβ pathology and subsequent neuroprotection observed in this study. In summary, tectoridin is a promising natural therapeutic for AD due to its high safety and multi-target mechanisms.},
}

@article {pmid43003587,
year = {2026},
author = {Pan, Z and Wang, Q and Feng, Q and Xu, H and Liu, W and Wang, P and Chen, G},
title = {Mn-doped dual-emission CdZnSe/Mn:ZnS quantum dots for self-calibrated ratiometric sensing of Alzheimer's disease biomarker.},
journal = {Analytica chimica acta},
volume = {1427},
number = {},
pages = {346394},
doi = {10.1016/j.aca.2026.346394},
pmid = {43003587},
issn = {1873-4324},
mesh = {*Quantum Dots/chemistry ; *Alzheimer Disease/diagnosis ; Zinc Compounds/chemistry ; Humans ; Sulfides/chemistry ; Manganese/chemistry ; *Amyloid beta-Peptides/analysis ; Biomarkers/analysis/blood ; *Biosensing Techniques/methods ; Cadmium/chemistry ; Selenium Compounds/chemistry ; Spectrometry, Fluorescence ; Aptamers, Nucleotide/chemistry ; Calibration ; Limit of Detection ; Fluorescent Chemosensor Compounds ; },
abstract = {BACKGROUND: Accurate detection of Alzheimer's disease (AD) biomarkers is critical for early identification, precise diagnosis, and timely therapeutic intervention. Nevertheless, conventional detection techniques rely on single-signal readout, which is susceptible to environmental interference and yields unreliable results in complex biological matrices. Therefore, developing reliable, sensitive and selective sensing platforms for AD biomarkers are highly desirable.

RESULTS: Herein, a self-calibrated ratiometric fluorescence aptasensor based on Mn-doped dual-emission CdZnSe/Mn:ZnS quantum dots (QDs) is constructed for detecting AD biomarker amyloid-β oligomers (AβO). Possessing two characteristic fluorescence peaks at 425 nm and 628 nm, CdZnSe/Mn:ZnS QDs act as dual self-calibrating references. CdZnSe/Mn:ZnS QDs and Ag NPs are modified at two termini of hairpin H1 (CdZnSe/Mn:ZnS QDs-H1-Ag NPs), quenching the 425 nm fluorescence (FL425 off and FL628 on). Upon AβO recognition, aptamer-functionalized magnetic beads convert AβO into released DNA strands (S). These S strands react with CdZnSe/Mn:ZnS QDs-H1-Ag NPs and black hole quencher 3-labeled H2 (H2-BHQ3) to trigger catalytic hairpin assembly (CHA) for signal amplification, quenching Mn-doped FL628 while restoring core FL425 and yielding an AβO-dependent FL425/FL628 ratiometric response. The aptasensor achieves a 5.2 fM detection limit and effectively distinguishes AD patients from healthy subjects, with results well consistent with standard diagnostic methods.

SIGNIFICANCE: This study demonstrates the great potential of intrinsic dual-emission Mn-doped QDs for self-calibrated ratiometric biosensing. By integrating magnetic beads-mediated signal transduction and CHA amplification, the aptasensor achieves high sensitivity and robust anti-interference performance toward AβO in clinical samples, providing a reliable analytical tool for early auxiliary diagnosis of AD.},
}

*Quantum Dots/chemistry
*Alzheimer Disease/diagnosis
Zinc Compounds/chemistry
Humans
Sulfides/chemistry
Manganese/chemistry
*Amyloid beta-Peptides/analysis
Biomarkers/analysis/blood
*Biosensing Techniques/methods
Cadmium/chemistry
Selenium Compounds/chemistry
Spectrometry, Fluorescence
Aptamers, Nucleotide/chemistry
Calibration
Limit of Detection
Fluorescent Chemosensor Compounds

@article {pmid43003805,
year = {2026},
author = {Leslie, S and Hicks, C and Norman, M and Zummach, D and McAiney, C},
title = {"I have Alzheimer's disease, it doesn't have me". Words of Wisdom From People Living With Dementia: A Secondary Qualitative Analysis.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261507124},
doi = {10.1177/14713012261507124},
pmid = {43003805},
issn = {1741-2684},
abstract = {Receiving a diagnosis of dementia can be an unsettling experience, often complicated by a lack of hope when seeking resources and support. While clinical guidance is important, peer-to-peer knowledge shared among people living with dementia can provide meaningful insight into ways to support one's well-being. The Wisdom Series was a three-part webinar series designed and offered by people living with dementia for people living with dementia. Led by a dementia advocate who lives with dementia, the series provided a platform for 17 individuals living with dementia across Canada to share their experiences and strategies for living well with dementia with others. A secondary qualitative data analysis was conducted with transcripts of the Wisdom Series webinars to understand participants' perspectives on well-being. Using thematic analysis, six themes were identified: (1) Knowing Yourself: Recognizing Abilities and Limits, highlighting the importance of adaptation and self-awareness; (2) Connecting with Meaningful Supports, focusing on relationships with peers, family, and animals; (3) Keeping your Mind and Body Nourished and Active, emphasizing cognitive, physical, and holistic approaches to health; (4) Finding Joy in Nature, illustrating emotional benefits of engaging with the natural environment; (5) Supporting Self and Others through Advocacy, describing participants' efforts to improve accessibility and awareness in their communities; and (6) Planning for the Future, encompassing advance care planning, medical assistance in dying, autonomy, and burden. In sharing their experiences and perspectives, the webinar panellists not only shared their wisdom but challenged deficit-based assumptions about dementia by demonstrating the agency, citizenship, and personhood of people living with dementia.},
}

@article {pmid43003833,
year = {2026},
author = {Madduri, AV and Ellis, RJ and Lakhani, CM and Bennett, DA and Patel, CJ},
title = {Single-cell machine learning uncovers genetically anchored, cell-type specific programs of Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43003833},
issn = {2041-1723},
support = {R01AG074372//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01ES032470//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; R01DK137993//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; Humans ; *Single-Cell Analysis/methods ; *Machine Learning ; Single-Cell Gene Expression Analysis ; Genome-Wide Association Study ; Quantitative Trait Loci ; Brain/metabolism/pathology ; Transcriptome ; Gene Expression Profiling ; Genetic Predisposition to Disease ; },
abstract = {Univariate differential expression analysis dominates single-cell transcriptomic studies of Alzheimer's disease, yet marginal testing alone cannot resolve multivariate disease-associated structure or distinguish clinical from neuropathological signatures. Here we introduce TriSCOPE, a framework integrating multivariate predictive modeling, donor-aware differential expression, and pseudotime inference, applied to six Alzheimer's disease snRNA-seq datasets comprising ~4.2 million nuclei from 627 donors. Across six major brain cell types and 41 subclusters, we identify cell-type-specific predictively expressed genes that are largely non-overlapping with differentially expressed genes, revealing disease-relevant signals invisible to univariate approaches. Conditional GWAS-eQTL colocalization anchors a subset of these predictively expressed genes to inherited Alzheimer's disease risk loci, including 27 genetically supported gene-cell type pairs (among them ARL17B, JAZF1) with no significant differential expression. Integration across all three analytical branches nominates high-confidence convergent programs including astrocytic stress markers (such as GFAP, MT2A), neuronal signaling genes (like RASGEF1B, LINGO1, NRG1), and microglial and oligodendrocyte regulators (including SYTL3, SPP1, APOD). Comparison of clinical and neuropathological models reveals cell-type-specific divergence between cognitive and pathological Alzheimer's disease signatures. Key predictively expressed genes including ARL17B, LINGO1, and APOE replicate across independent cohorts, with cross-cohort generalizability confirmed across all three analytical branches of TriSCOPE.},
}

*Alzheimer Disease/genetics/pathology/metabolism
Humans
*Single-Cell Analysis/methods
*Machine Learning
Single-Cell Gene Expression Analysis
Genome-Wide Association Study
Quantitative Trait Loci
Brain/metabolism/pathology
Transcriptome
Gene Expression Profiling
Genetic Predisposition to Disease

@article {pmid43003834,
year = {2026},
author = {Yan, T and Hou, X and Watzlawik, JO and Dickson, DW and Fiesel, FC and Springer, W},
title = {Serine-65 phosphorylated ubiquitin associates with soluble tau and seeding activity in Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43003834},
issn = {2041-1723},
support = {R56AG062556//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U54NS110435//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS085070//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 9AZ10//Florida Department of Health/ ; 25A11//Florida Department of Health/ ; 22A07//Florida Department of Health/ ; 26A09//Florida Department of Health/ ; P30AG062677//Mayo Clinic/ ; AARF-22-974258/ALZ/Alzheimer's Association/United States ; NIAP25-1446587/ALZ/Alzheimer's Association/United States ; AARF-22-973152/ALZ/Alzheimer's Association/United States ; NIAP25-1445722/ALZ/Alzheimer's Association/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; Humans ; Phosphorylation ; Female ; *Brain/metabolism/pathology ; Male ; *Ubiquitin/metabolism ; *Serine/metabolism ; Aged, 80 and over ; Aged ; Solubility ; },
abstract = {Tau propagation is a key driver of Alzheimer's disease (AD), yet selective markers of seeding-competent tau remain elusive. Ubiquitin phosphorylated at Serine-65 (pS65-Ub) is a PINK1-derived cellular stress signal that accumulates in AD with elevated tau pathology, but its relationship to tau seeding is unknown. Here, using postmortem brain tissue from female and male donors, we show that a subset of tau is covalently modified by pS65-Ub in AD brain. The pS65-Ub-associated tau population is elevated in AD and is enriched in soluble, high-molecular-weight, oligomeric, and hyperphosphorylated tau species. Across AD cases, soluble pS65-Ub-associated tau levels strongly correlate with tau seeding activity. Tau species isolated with pS65-Ub antibodies exhibit seeding activity, whereas removal of pS65-Ub-associated material markedly reduces seeding from AD brain extracts. Together, these findings identify pS65-Ub as a disease-enriched molecular feature of a seed-competent tau population and link cellular stress signaling with pathological tau propagation in AD.},
}

*Alzheimer Disease/metabolism/pathology
*tau Proteins/metabolism
Humans
Phosphorylation
Female
*Brain/metabolism/pathology
Male
*Ubiquitin/metabolism
*Serine/metabolism
Aged, 80 and over
Aged
Solubility

@article {pmid43003846,
year = {2026},
author = {Urbanek, A and Dear, AJ and Rhodes, DP and Garland, EF and Wareing, HE and Baker, HJ and Molenkamp, W and Zhang, R and Chen, G and Abelein, A and Bell, SM and Varela, JA and Michaels, TCT and Highley, JR and Meisl, G and Johansson, J and De, S},
title = {Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43003846},
issn = {2041-1723},
support = {MR/V023861/1//RCUK | Medical Research Council (MRC)/ ; MR/N013840/1//RCUK | Medical Research Council (MRC)/ ; 2594676//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; ARUK-PhD2024-010//Alzheimer's Research UK (ARUK)/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/genetics ; Humans ; Brain/pathology/metabolism ; Mice ; Plaque, Amyloid/pathology/metabolism ; Neurons/metabolism/pathology ; Disease Models, Animal ; Mice, Transgenic ; *Protein Aggregation, Pathological/metabolism/pathology ; *Peptide Fragments/metabolism/genetics ; Neuroglia/metabolism/pathology ; Female ; },
abstract = {Neurotoxic intermediates formed during amyloid-β (Aβ) aggregation are thought to drive Alzheimer's disease, yet their rarity and transient nature have obscured their identity and formation pathways in the human brain. Here, we combine super-resolution microscopy and single-molecule functional imaging with kinetic modelling to classify Aβ intermediates according to their membrane-disrupting activity and connect their damaging effects to the aggregation pathways that generate them. Applying this framework to recombinant Aβ42, an Alzheimer's knock-in mouse model and human Alzheimer's brain tissue, we find two functionally distinct intermediate populations present across all systems. They form through separate aggregation routes and differ in their neurotoxicity, abundance and susceptibility to inhibition. Both damage neurons and glia, but only one converts into plaques. Suppressing these intermediates pharmacologically in mice reduces plaque burden, attenuates astrogliosis and improves cognition. Our findings connect model systems with human pathology and identify intermediate formation pathways as actionable therapeutic targets across protein-misfolding disorders.},
}

*Alzheimer Disease/pathology/metabolism
Animals
*Amyloid beta-Peptides/metabolism/genetics
Humans
Brain/pathology/metabolism
Mice
Plaque, Amyloid/pathology/metabolism
Neurons/metabolism/pathology
Disease Models, Animal
Mice, Transgenic
*Protein Aggregation, Pathological/metabolism/pathology
*Peptide Fragments/metabolism/genetics
Neuroglia/metabolism/pathology
Female

@article {pmid43004046,
year = {2026},
author = {Rempe, MP and Voller, ME and Garrison, GM and Glesinger, RJ and Horne, LK and Hall, MC and Petts, AJ and Kress, KA and Carusi, OR and Volberding, LD and DeLuca, KR and John, JA and Springer, SD and Embury, CM and Johnson, CM and May-Weeks, PE and Spooner, RK and Wilson, TW},
title = {Glycemic control is differentially related to spontaneous cortical activity in patients on the Alzheimer's disease spectrum.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43004046},
issn = {2509-2723},
support = {R01-NS141729/NS/NINDS NIH HHS/United States ; R01-MH116782/MH/NIMH NIH HHS/United States ; S10-OD028751//NIH Office of the Director/ ; P20-GM144641/GM/NIGMS NIH HHS/United States ; },
abstract = {Diabetes is a major risk factor for developing cognitive impairment and studies have shown that poor glycemic control can increase this risk, but the neural mechanisms are poorly understood. Many studies have linked altered spontaneous cortical activity during the resting-state to Alzheimer's disease and other neurological conditions associated with cognitive impairment. Herein, we examine whether the strength of spontaneous activity during the resting-state is differentially related to glycemic control in 37 biomarker-positive participants on the Alzheimer's disease spectrum (ADS) and 43 cognitively normal aging adults. All participants completed resting-state magnetoencephalography (MEG), a blood draw to derive their level of glycemic control (i.e., A1C), and comprehensive neuropsychological assessment. Spontaneous activity was imaged in each of the canonical frequency bands (e.g., alpha) and probed for group differences in the relationship between neural activity and glycemic control. We found significant interactions between A1C and disease status (ADS vs. control) in the delta and alpha bands (p < 0.001). Specifically, delta power decreased with increasing A1C in the ADS group across a broad area of frontotemporal and inferior parietal cortices, while spontaneous alpha decreased with higher A1C in the control group across inferior frontal and temporal cortex. Importantly, delta activity in the superior frontal cortices mediated the effect of A1C on attention performance in the ADS group. In sum, these data suggest that the impact of glycemic dysregulation on spontaneous cortical activity may differ in those on the ADS compared with cognitively normal controls and that spontaneous delta may be critical for attention function.},
}

@article {pmid43004192,
year = {2026},
author = {Jian, Y and Shi, H and Hu, T and Zhou, S and He, X and Tao, D and Du, H and Zhou, J and Yao, Y and Shu, Z},
title = {Interpretable radiomics signature of the basal ganglia-thalamic circuitry for predicting PD-MCI: a multi-center study with external validation.},
journal = {BMC medical imaging},
volume = {26},
number = {1},
pages = {},
pmid = {43004192},
issn = {1471-2342},
support = {S2024018//the Medical Research Project of Sichuan Medical Association/ ; WJKY2024018//the Research Project of Health System of Longquanyi District/ ; },
mesh = {Humans ; Radiomics ; *Magnetic Resonance Imaging/methods ; *Cognitive Dysfunction/diagnostic imaging/etiology ; *Basal Ganglia/diagnostic imaging ; *Thalamus/diagnostic imaging ; Female ; *Parkinson Disease/diagnostic imaging/complications ; Retrospective Studies ; Male ; Aged ; Disease Progression ; ROC Curve ; },
abstract = {BACKGROUND: To develop and validate a T1-weighted imaging (T1WI)-based radiomic signature and integrate it with clinical features to construct a combined model for the early identification of cognitive decline in Parkinson's disease (PD).

METHODS: We retrospectively analyzed data from 233 PD patients, including 182 from the Parkinson's Progression Markers Initiative (PPMI) and 51 from the National Alzheimer's Coordinating Center (NACC). Based on baseline Montreal Cognitive Assessment (MoCA) scores, patients were classified into those with normal cognition (PD-NC) and those with mild cognitive impairment (PD-MCI). The PPMI cohort was randomly divided into training (n = 127) and test (n = 55) sets at a 7:3 ratio, while the NACC cohort served as an external validation set (n = 51). Radiomic features were extracted from T1WI of the bilateral basal ganglia (globus pallidus, putamen) and bilateral thalamus. After dimensionality reduction, a radiomic model was constructed. Independent clinical predictors were identified and integrated with the radiomic signature to establish a combined model. Model performance was evaluated using receiver operating characteristic (ROC) curves, confusion matrices, and F1-scores. SHapley Additive exPlanations (SHAP) was employed to interpret model outputs.

RESULTS: The radiomic model achieved area under the curve (AUC) values of 0.809, 0.777, and 0.776 in the training, test, and external validation sets, respectively. Multivariable regression identified the Geriatric Depression Scale (GDS) score (odds ratio [OR] = 1.41, P = 0.005) and resting tremor (OR = 4.11, P = 0.036) as independent predictors. The combined model incorporating these clinical factors with the radiomic signature yielded significantly improved AUCs of 0.848 (95% CI: 0.774-0.906), 0.796 (95% CI: 0.666-0.893), and 0.812 (95% CI: 0.628-0.925) across the three datasets, outperforming either model alone. Among the 13 retained radiomic features, texture features were predominant (69.2%). SHAP analysis confirmed that the Rad-score was the most influential predictor.

CONCLUSION: The combined model integrating T1WI-based radiomic features from the bilateral basal ganglia (globus pallidus, putamen)-thalamus with clinical characteristics demonstrates robust predictive capability for cognitive decline in PD. This approach offers valuable support for early intervention and precision management in clinical practice.},
}

Humans
Radiomics
*Magnetic Resonance Imaging/methods
*Cognitive Dysfunction/diagnostic imaging/etiology
*Basal Ganglia/diagnostic imaging
*Thalamus/diagnostic imaging
Female
*Parkinson Disease/diagnostic imaging/complications
Retrospective Studies
Male
Aged
Disease Progression
ROC Curve

@article {pmid43004376,
year = {2026},
author = {Zha, L and Xu, J and Zhu, X and Tu, Q and Zhong, C and Zhan, L and Zhang, M and Zhou, D and Wang, X and Wu, J and Hua, F and Guan, X},
title = {Rab GTPases and the Rabopathy framework: from synaptic trafficking to neurodegeneration via LRRK2-driven pathology.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {43004376},
issn = {2047-9158},
mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; *rab GTP-Binding Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Protein Transport/physiology ; *Synapses/metabolism/pathology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) show significant differences in their clinical manifestations, but they all seem to share a common upstream problem: malfunction in the membrane transport controlled by Rab GTPases. This review introduces the concept of Rabopathy, a framework that connects developmental synaptic maturation defects with late-onset protein aggregation. The LRRK2-Rab phosphorylation axis is emerging as a potential common amplifying mechanism across these disorders, with the strongest mechanistic support in PD and growing implications in AD and HD. When Rab substrates are excessively phosphorylated at specific sites, vesicular transport is impaired or arrested, leading to progressive depletion of the reserve pool of synaptic vesicles and the surface pool of receptors, and severe compromise of the autophagy-lysosome flux. The failure of distinct Rab sub-networks also produces disease-specific signatures, including Rab5-driven endosomal congestion in AD, Rab35-mediated α-synuclein secretion in PD, and Rab11/Rab7 trafficking collapse in HD. Restoration of Rab flux may be a therapeutic strategy for neurodegenerative diseases, which can be achieved through calibration of LRRK2 activity, modulation of selective Rab subtypes, and rescue of the trafficking network at the systems level.},
}

Humans
*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism
*rab GTP-Binding Proteins/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Animals
Protein Transport/physiology
*Synapses/metabolism/pathology

@article {pmid43004385,
year = {2026},
author = {Schöll, M},
title = {A pain in the Aß: a typographical plea to the amyloid community.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {43004385},
issn = {1758-9193},
}

@article {pmid43004463,
year = {2026},
author = {Christensen, A and Valencia-Olvera, AC and Xeros, H and Nguyen, ET and Lopez, M and Javaheri, R and Tai, LM and LaDu, MJ and Pike, CJ},
title = {Effects of sexual differentiation and APOE genotype on the development of Alzheimer-related pathology in female EFAD mice.},
journal = {Biology of sex differences},
volume = {17},
number = {1},
pages = {},
pmid = {43004463},
issn = {2042-6410},
support = {AG052374/NH/NIH HHS/United States ; AG069711/NH/NIH HHS/United States ; AG058068/NH/NIH HHS/United States ; AG058068/NH/NIH HHS/United States ; },
mesh = {Animals ; Female ; *Alzheimer Disease/genetics/pathology ; *Sex Differentiation ; Mice, Transgenic ; Genotype ; Male ; Mice ; *Apolipoprotein E4/genetics ; Sex Characteristics ; Brain/pathology/metabolism ; *Apolipoprotein E3/genetics ; Humans ; Amyloid beta-Peptides/metabolism ; },
abstract = {Apolipoprotein E ε4 genotype (APOE4), the most significant genetic risk factor for late-onset Alzheimer's disease (AD), is associated with sexually dimorphic effects whereby higher risks are generally observed in women. Sex differences can arise in part from developmental processes of sexual differentiation, which yield permanent sex-specific phenotypes that can impact adult trajectories and vulnerabilities to various conditions. We investigated the potential contributions of sexual differentiation to the female bias of APOE4 in driving AD pathogenesis. Specifically, using the EFAD transgenic mouse model of AD that includes knock-in of human APOE3 or APOE4, we examined the effects of experimental masculinization in perinatal female mice on adult patterns of AD-related pathology relative to control male and female mice. Both female sex and APOE4 genotype were associated with increased levels of β-amyloid pathologies. Masculinization resulted in expected systemic and neural phenotypes in adult animals. The effects of masculinization differed depending upon both outcome measure and APOE genotype. Intermediate phenotypes were the most common response to masculinization, though select aspects of AD-related endpoints, including the numbers of mature amyloid plaques, were reduced by masculinization of APOE4 female mice. These findings suggest that sexual differentiation in early life has modest effects on adult development of AD in females, a relationship that appeared stronger in the context of APOE4. The results complement prior work establishing roles of sex chromosomes and age-related depletion of sex hormones in the sexual dimorphisms characteristic of AD and provide new insights into the organizational actions of sex hormones and how these interact with APOE genotype.},
}

Animals
Female
*Alzheimer Disease/genetics/pathology
*Sex Differentiation
Mice, Transgenic
Genotype
Male
Mice
*Apolipoprotein E4/genetics
Sex Characteristics
Brain/pathology/metabolism
*Apolipoprotein E3/genetics
Humans
Amyloid beta-Peptides/metabolism

@article {pmid43004564,
year = {2026},
author = {Medina, G and MacKenzie, AE},
title = {The Role of DHA in PSD-95 Regulation and Postsynaptic Organization: Implications for Synaptic Function and Neurological Disorders.},
journal = {Journal of neurochemistry},
volume = {170},
number = {11},
pages = {},
doi = {10.1111/jnc.70571},
pmid = {43004564},
issn = {1471-4159},
support = {CFREF-2022-00007//Canada First Research Excellence Fund for the Brain (CFREF)/ ; },
mesh = {*Docosahexaenoic Acids/metabolism/pharmacology ; Humans ; Animals ; *Disks Large Homolog 4 Protein/metabolism ; *Synapses/metabolism/drug effects ; *Nervous System Diseases/metabolism/drug therapy ; *Neuronal Plasticity/physiology/drug effects ; *Post-Synaptic Density/metabolism/drug effects ; },
abstract = {Docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, plays a critical role in synaptic function by regulating membrane biophysical properties, neurotransmitter dynamics, and synaptic protein organization; as such, its therapeutic potential for synaptic disorders is an area of considerable research. Among DHA's effects on synapses is its modulation of postsynaptic density protein-95 (PSD-95), a key scaffolding protein essential for synaptic stability and plasticity. This review integrates current evidence linking DHA to changes in PSD-95 expression, synaptic localization, and interactions with glutamate receptors. Specifically, DHA incorporation into neuronal membranes alters lipid packing and membrane microdomain organization, which can influence receptor mobility and clustering. In parallel, DHA also engages intracellular signaling pathways, including protein kinase B (Akt)- and cAMP response element-binding protein (CREB)-associated signaling, which may contribute to PSD-95 synthesis, synaptic retention, and postsynaptic stabilization. Bioactive DHA metabolites, such as neuroprotectin D1 (NPD1) and N-docosahexaenoyl ethanolamide (DHEA; synaptamide), further influence synaptic function via receptor-mediated signaling at nanomolar concentrations. DHA deficiency disrupts synaptic architecture, impairing long-term potentiation (LTP) and cognitive function, while DHA repletion following deficiency can restore PSD-95 levels and selected measures of synaptic function. From a clinical perspective, DHA has shown potential to mitigate synaptic and behavioral deficits in neurodevelopmental disorders such as autism spectrum disorder (ASD) and Fragile X syndrome (FXS) and preserve synaptic integrity in neurodegenerative diseases, including Alzheimer's and Huntington's. However, clinical trials reveal variable outcomes, influenced by factors such as apolipoprotein E (APOE) genotype, dosing regimen, and baseline DHA status. Continued efforts to optimize bioavailability, incorporate genotype-stratified designs, and evaluate DHA metabolites are essential to advancing its translation from a nutritional supplement to a targeted neuromodulatory therapy for disorders characterized by postsynaptic dysfunction.},
}

*Docosahexaenoic Acids/metabolism/pharmacology
Humans
Animals
*Disks Large Homolog 4 Protein/metabolism
*Synapses/metabolism/drug effects
*Nervous System Diseases/metabolism/drug therapy
*Neuronal Plasticity/physiology/drug effects
*Post-Synaptic Density/metabolism/drug effects

@article {pmid43004651,
year = {2026},
author = {Shetty, S and Suvarna, V},
title = {Functionalized nanocarrier-based intranasal drug delivery of rivastigmine tartrate for enhanced brain exposure: a pharmacokinetic and biodistribution evaluation.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/20415990.2026.2760224},
pmid = {43004651},
issn = {2041-6008},
abstract = {AIMS: To develop and evaluate a polyethylene glycol (PEG)-functionalized multi-walled carbon nanotube (MWCNT)-based intranasal delivery system for rivastigmine tartrate (RT) to improve systemic exposure and brain delivery for Alzheimer's disease (AD).

MATERIALS AND METHODS: RT-loaded PEGylated MWCNTs were prepared, optimized using a 3[2] factorial design, and characterized for particle size, zeta potential, entrapment efficiency, morphology, in vitro release, ex vivo nasal permeation, pharmacokinetics, brain biodistribution, cytocompatibility, and neuroprotective activity.

RESULTS: The optimized formulation showed an entrapment efficiency of 90.92%, particle size of 176.7 nm, and zeta potential of -24.1 mV. Sustained drug release and efficient permeation across goat nasal mucosa were observed. Intranasal administration increased plasma exposure, producing approximately 5-fold higher relative bioavailability and a 4.1-fold increase in brain exposure compared with oral administration. In SH-SY5Y cells, the formulation reduced rotenone-induced oxidative stress and improved cell viability, indicating neuroprotective potential.

CONCLUSIONS: PEGylated MWCNT-mediated intranasal delivery enhanced rivastigmine bioavailability and brain exposure while demonstrating neuroprotective activity in vitro. These findings support further investigation of this nanocarrier platform as a strategy for brain-targeted delivery of rivastigmine.},
}

@article {pmid43004772,
year = {2026},
author = {Soni, J and Capucciati, A and Uttarkar, M and Monzani, E and Pezzoli, G and Cassidy, CM and Sulzer, D and Khairnar, A and Zecca, L and Zucca, FA},
title = {Neuromelanins: a link between brain aging and neurodegenerative diseases.},
journal = {Physiological reviews},
volume = {},
number = {},
pages = {},
doi = {10.1152/physrev.00036.2025},
pmid = {43004772},
issn = {1522-1210},
abstract = {Neuromelanins (NMs) accumulate in large amounts in catecholaminergic neurons of the substantia nigra (SN) and locus coeruleus (LC), which selectively degenerate in Parkinson's disease (PD) and Alzheimer's disease (AD). Lower amounts of NMs are also present in other human brain regions. NMs are contained in specialized autolysosomes with lipid bodies, proteins, and metals. Their structure, synthesis, functions, and cellular localization differ from those of melanins in non-nervous tissues. Purified NMs have a complex structure, are composed of melanic moieties, lipids, proteins, and inorganic components, and are insoluble. NMs can exert either a protective or toxic role depending on cellular context. NMs synthesis is driven by cytosolic catecholamines and is a protective process, as it removes excess cytosolic catechols that would otherwise trigger neurotoxicity. NMs can bind reactive/toxic metals, forming stable and non-toxic complexes, thereby playing a neuroprotective role. However, NMs released from degenerating neurons in PD and AD activate microglia, which release reactive species and proinflammatory factors, thereby exacerbating neuroinflammation and neurodegeneration. The major histocompatibility complex class I is present within NM-containing organelles of SN and LC neurons and can bind antigens, presenting them on the neuronal membrane. Subsequently, CD8[+] T-cells may target catecholaminergic NM-containing neurons, contributing to neurodegeneration. The loss of NM-containing neurons in PD and AD causes a decrease of NMs concentration within the SN and LC, which can be visualized using magnetic resonance imaging (MRI). NM-sensitive MRI of the SN and LC is increasingly being used for the diagnosis and treatment monitoring of neurodegenerative and psychiatric disorders.},
}

@article {pmid43004896,
year = {2026},
author = {Li, C and Leitner, D and Liang, Z and Yakovishina, V and Ibrahim, M and Faustin, A and Wisniewski, T and Wadghiri, YZ and Ge, Y and Zhang, J},
title = {Short T1 Fraction as a Marker of Myelin Content: Evidence From Postmortem MRI and Histology.},
journal = {Magnetic resonance in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/mrm.70656},
pmid = {43004896},
issn = {1522-2594},
support = {P30 AG066512//National institutes of Health in the United States/ ; R01 AG077422//National institutes of Health in the United States/ ; R01 HD074593//National institutes of Health in the United States/ ; R01 NS108491//National institutes of Health in the United States/ ; R13 AG067684//National institutes of Health in the United States/ ; RF1 NS11041//National institutes of Health in the United States/ ; U24 NS135568//National institutes of Health in the United States/ ; U24 NS141774//National institutes of Health in the United States/ ; RRID_SCR_017937//Preclinical Imaging Laboratory/ ; NIH/SIG 1S10OD018337-01//NYU Langone Health/NYU Grossman School of Medicine/ ; NIH/NCI 5P30CA016087//Laura and Isaac Perlmutter Cancer Center Support/ ; NIH P41 EB017183//NIBIB Biomedical Technology Resource Center/ ; },
abstract = {PURPOSE: To investigate the short-T1 fraction as a potential biomarker of white matter myelin integrity, using myelin histology as ground truth.

METHODS: Multi-inversion-time MRI data were acquired from four postmortem brain specimens from donors with Alzheimer's disease on a clinical 3T scanner, and from five dissected tissue blocks containing white matter hyperintensities (WMHs) on a preclinical 3T system. Short-T1 fraction maps were generated using inverse Laplace transform to isolate short-T1 components and were compared with T2-based myelin water imaging metrics through joint T1-T2 correlation analysis. Short-T1 fraction maps from the tissue blocks were further compared with myelin histology. In addition, in vivo short-T1 fraction data were acquired from five participants, including four healthy male volunteers (35.4 ± 12.1 years) and one 71-year-old female participant with moderate white matter microangiopathy and WMHs, to demonstrate translational feasibility.

RESULTS: Postmortem MRI revealed reduced short-T1 fractions in WMHs. T1-T2 correlation analysis suggested that the short-T1 fraction was closely associated with the short-T2 (myelin water) component. Strong correlations were observed between short-T1 fractions and optical densities from both Luxol Fast Blue- and Myelin Basic Protein-stained histological sections, supporting the link between the short-T1 signal and myelin content. Preliminary in vivo findings also showed reduced short-T1 fraction within WMHs, consistent with the ex vivo observations.

CONCLUSION: The short-T1 fraction correlated with myelin content in postmortem brain white matter, supporting its potential as a biomarker of myelin integrity.},
}

@article {pmid43004989,
year = {2026},
author = {Sharma, R and Niranjan, N and Long, A and Sharma, R and Safieh, F and Kumar, P and Sund, P and Sellami, Z},
title = {Genome Editing of Mitochondrial Dysfunction in Neurological Disease: Progress and Translational Barriers.},
journal = {The Yale journal of biology and medicine},
volume = {99},
number = {3},
pages = {521-539},
pmid = {43004989},
issn = {1551-4056},
mesh = {Humans ; Animals ; *Gene Editing/methods ; *Mitochondria/genetics/metabolism/pathology ; *Nervous System Diseases/genetics/therapy ; *Mitochondrial Diseases/genetics/therapy ; DNA, Mitochondrial/genetics ; Neurodegenerative Diseases/genetics ; Translational Research, Biomedical ; },
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared mechanism across neurological disease. Specifically, impaired oxidative phosphorylation, oxidative stress, and mitochondrial DNA damage are factors in primary mitochondrial disorders and major neurodegenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, and amyotrophic lateral sclerosis. This review surveys the mechanisms driving mitochondrial dysfunction and evaluates the current landscape of gene-editing technologies developed to address them. We examine mitochondria-targeted editors and nuclear-targeted editors, examining the editing capability, delivery constraints, and off-target risk of each. Heteroplasmy-shifting nucleases currently offer the strongest in vivo evidence for mtDNA-directed therapy, while base editors extend correction to homoplasmic mutations at the cost of a narrower editing scope and off-target editing. Nuclear editing platforms avoid the mitochondrial gRNA import barrier entirely, allowing current technologies to achieve the most progress toward functional, behavioral rescue in animal models. Across all platforms, delivery efficiency, off-target specificity, and translation from rodent to primate models remain unresolved barriers to clinical application. Gene editing for mitochondrial dysfunction is highly creditable as a precision therapy for genetically defined disease subsets, including primary mitochondrial disease and other neurodegenerative disorders with a known nuclear driver, rather than as a universal strategy for sporadic neurodegeneration, where mitochondrial dysfunction arises from multifactorial and poorly localized causes.},
}

Humans
Animals
*Gene Editing/methods
*Mitochondria/genetics/metabolism/pathology
*Nervous System Diseases/genetics/therapy
*Mitochondrial Diseases/genetics/therapy
DNA, Mitochondrial/genetics
Neurodegenerative Diseases/genetics
Translational Research, Biomedical

@article {pmid43005006,
year = {2026},
author = {Uzakov, U and Anvarkhonov, A and Azizakhon, A},
title = {Mechanisms of Mitochondrial DNA Leakage as Primary Upstream Catalysts for NLRP3 Inflammasome Activation in Neurodegenerative Pathology: A Systematic Review.},
journal = {The Yale journal of biology and medicine},
volume = {99},
number = {3},
pages = {600-616},
pmid = {43005006},
issn = {1551-4056},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *DNA, Mitochondrial/metabolism/genetics ; *Inflammasomes/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; Mitochondria/metabolism ; },
abstract = {Chronic neuroinflammation drives progressive neurodegenerative pathology, including Alzheimer and Parkinson diseases. While the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a central mediator of this response, its upstream, nonlinear activation mechanics remain poorly defined. Recent studies suggest that the translocation of damaged mitochondrial DNA (mtDNA) into the cytosol serves as a critical immunogenic catalyst bridging metabolic stress with inflammatory cascades. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines, a systematic review was conducted across PubMed, Embase, and Scopus for primary experimental studies. Eligibility focused on quantitative metrics of cytosolic mtDNA leakage and subsequent NLRP3 conformational assembly kinetics in neurodegenerative models. The data demonstrate that chronic oxidative stress and toxic protein aggregation induce mitochondrial outer membrane permeabilization via BCL2-associated X protein/BCL2 antagonist/killer 1 (BAX/BAK) macropores. The resulting efflux of oxidized mtDNA (8-OHdG) escapes cytoplasmic exonuclease degradation, binding directly to the leucine-rich repeat domain of NLRP3 to trigger enzymatic activation. This synthesis establishes that mtDNA leakage acts as a distinct, cooperative biochemical switch rather than a linear cascade. Characterizing these nonlinear threshold dynamics bridges clinical pathology with predictive systems biology, providing the quantitative parameters necessary to constrain advanced computational models of early-stage neurodegeneration.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*DNA, Mitochondrial/metabolism/genetics
*Inflammasomes/metabolism
Humans
*Neurodegenerative Diseases/metabolism/pathology/genetics
Animals
Mitochondria/metabolism

@article {pmid43005040,
year = {2026},
author = {Somaa, F and Khan, A and Kiyani, MM},
title = {Mitochondrial Dysfunction and Bioenergetic Failure at the Amyloid-Tau-Metal Interface: An Integrative Model of Alzheimer Disease Pathogenesis.},
journal = {The Yale journal of biology and medicine},
volume = {99},
number = {3},
pages = {405-425},
pmid = {43005040},
issn = {1551-4056},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Energy Metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Metals/metabolism ; Animals ; },
abstract = {Background Alzheimer disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, and metal dyshomeostasis. Emerging evidence suggests that mitochondrial dysfunction is a pivotal convergent event linking these hallmark pathologies, with bioenergetic failure emerging as a pivotal convergent driver of neurodegeneration rather than a downstream epiphenomenon. Objective This narrative review examines the mechanistic interplay between Aβ, tau, and transition metal ions in mediating mitochondrial dysfunction. We introduce the amyloid-tau-metal-mitochondria (ATMM) axis as a conceptual framework for understanding bioenergetic failure in AD and evaluate emerging therapeutic strategies targeting this integrative pathway. Key Findings Transition metals (copper, iron, zinc) catalyze Aβ aggregation and promote reactive oxygen species generation, damaging the mitochondrial membrane and impairing electron transport chain function. Aβ-heme complexes acquire peroxidase-like activity that sequesters heme from cytochrome c oxidase (Complex IV), amplifying respiratory failure. Tau hyperphosphorylation exacerbates energy deficits by disrupting axonal mitochondrial trafficking and promoting dynamin-related protein 1-mediated fragmentation. These constitute a self-reinforcing feedback loop-the ATMM cycle-culminating in a neuronal energy crisis and apoptosis. Conclusion Mitochondrial impairment represents a mechanistic hub in AD pathogenesis, integrating protein aggregation, metal dyshomeostasis, and oxidative stress into a unified neurodegenerative model. Mitochondria-targeted antioxidants, metal redistributing agents, and modulators of fission-fusion dynamics offer rational therapeutic avenues. Future efforts should prioritize validating mitochondria-centered biomarkers to facilitate early intervention and disease modification.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Mitochondria/metabolism/pathology
*Energy Metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
*Metals/metabolism
Animals

@article {pmid43005121,
year = {2026},
author = {Ghiamaty, Z and Akhlaghi, M and Jokar, S and Hafezi, H and Bavi, O and Sharifzadeh, M and Sabzevari, O and Shafiee Ardestani, M and Ghorbandaeipour, T and Asadi, M and Kiani, M and Roustaei, S and Ebrahimi, F and Beiki, D},
title = {Design and Evaluation of a Chalcone-Based Dimeric Scaffold Targeting Amyloid-Beta Plaques for Early Detection of Alzheimer's Disease: Synthesis, Radiolabeling, In Vivo Studies, and Integrated Molecular Docking and Dynamics Simulation.},
journal = {Advanced pharmaceutical bulletin},
volume = {16},
number = {2},
pages = {416-431},
pmid = {43005121},
issn = {2228-5881},
abstract = {PURPOSE: Amyloid-Beta (Aβ) plaque imaging can serve as a desirable tool for early detection of Alzheimer's disease (AD). This study presents a new dimer of a chalcone-based scaffold, [68Ga]Ga-DTPA[Ch-DE]2, as a potential radiotracer for Aβ plaques imaging.

METHODS: The synthesis of DTPA[Ch-DE]2 and its radiolabeling with gallium-68 were characterized using techniques such as 1H-NMR, mass spectrometry, HPLC, and instant thin-layer chromatography. Neurotoxicity of DTPA[Ch-DE]2 was evaluated using the MTT assay. The stability of radiotracer was tested in various buffer systems and human serum albumin (HSA). The binding affinity of the radiotracer to Aβ aggregations was evaluted on the brain sections from both normal and AD rat models. Positron emission tomography-computed tomography (PET/CT) of brain imaging and Thioflavin S staining characterized the AD model. Biodistribution studies and PET/CT scans were performed on normal and AD rats. Computational studies also were conducted.

RESULTS: [68Ga]Ga-DTPA[Ch-DE]2 was synthesized with over 93% radiochemical purity. It showed high stability in various buffer systems and HSA after 2 hours. The binding assay revealed strong affinity to Aβ42 aggregations. Biodistribution studies and PET/CT imaging indicated favorable brain uptake: 0.54% ID/g and 0.59% ID/g at 2 minutes in normal and AD rats, respectively. Computational studies indicated that DTPA[Ch-DE]2 binds specifically to the Aβ fibrils while maintaining the receptor's architectural integrity. In vivo studies show that [68Ga] Ga-DTPA[Ch-DE]2 has good brain uptake and retention in AD rats compared with normal.

CONCLUSION: Thus, results suggest that [68Ga]Ga-DTPA[Ch-DE]2 could be a promising radiotracer for Aβ targeting and early diagnosis of AD.},
}

@article {pmid43005271,
year = {2026},
author = {Wang, X and Zhang, BW},
title = {Extracellular vesicles and Alzheimer's disease: hotspots, trends, and future directions-a tri-database bibliometric analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1951959},
pmid = {43005271},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease is a neurodegenerative disorder marked by progressive cognitive decline. The pathogenesis of AD is complex, and effective methods for early diagnosis and treatment are currently lacking. Extracellular vesicles, which are key mediators of intercellular communication, significantly influence the onset and progression of AD. Consequently, a systematic review of this field is essential.

METHODS: This study utilized the WoSCC and Scopus databases to gather English "Articles" and "Reviews." Following duplicate removal via Python, bibliometric methods systematically analyzed research hotspots and frontiers concerning extracellular vesicles in Alzheimer's disease. The analysis encompassed publication trends, countries, institutions, authors, journals, keywords, and references. Concurrently, the PubMed database was searched to verify the robustness and consistency of the analysis results.

RESULTS: This study conducted a bibliometric analysis of 2,626 articles, with 1,614 articles from PubMed used for consistency verification. The findings indicate a continuous rise in research interest in this field. Key areas of focus include emerging pathological mechanisms, peripheral blood biomarkers, targeted drug delivery, miRNA, and clinical trials. Cross-database verification confirmed a strong consistency in publication trends, countries, institutions, and authors, with a significant overlap of keywords and prominent research hot spots.

CONCLUSION: This study demonstrates a shift in the research focus on Extracellular vesicles within Alzheimer's disease from single-pathology investigations to exploring multiple mechanisms. Their significance in precise diagnosis and targeted therapy is increasingly evident. However, clinical trials remain limited. Future efforts should prioritize enhancing clinical validation and standardizing isolation techniques.},
}

@article {pmid43005312,
year = {2026},
author = {Chu, YY and Wang, BY and Qu, CY and Lan, Y and Wang, LY and Mao, M},
title = {Gastrodia elata in neurological disorders: a systematic review of anti-inflammatory mechanisms and cross-disease therapeutic potential.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1967946},
pmid = {43005312},
issn = {1663-4365},
abstract = {BACKGROUND: Neuroinflammation serves as a common pathological substrate across various neurological disorders, including neurodegenerative diseases, cerebrovascular diseases, and neuroimmune conditions. Key pathogenic mechanisms underlying these disorders include aberrant microglial activation, sustained release of pro-inflammatory cytokines, and dysregulation of critical signaling cascades, particularly the NLRP3 inflammasome, NF-κB, and Nrf2/HO-1 pathways, all of which collectively contribute to progressive neuronal damage and functional decline.

OBJECTIVES: This review aims to systematically evaluate the preclinical evidence for the neuroprotective effects of Gastrodia elata Blume and its major bioactive constituents-gastrodin, parishin, p-hydroxybenzyl alcohol, and G. elata polysaccharides-in the treatment of Parkinson's disease, Alzheimer's disease, acute ischemic stroke, vascular dementia, and epilepsy, with a particular focus on their modulation of inflammation-related signaling pathways.

METHODS: A comprehensive literature search was performed in PubMed, Web of Science, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang databases from inception to May 2026. Original studies investigating G. elata or its components in animal or cellular models of the aforementioned diseases and reporting inflammatory mechanisms were included.

RESULTS: G. elata and its active constituents regulate multiple neuroinflammation-associated signaling pathways, including Nrf2/HO-1, NF-κB/NLRP3, JAK2/STAT3, and MAPK, thereby suppressing inflammatory responses. Mechanistically, these effects are primarily manifested as: (1) inhibition of microglial M1 polarization and consequent reduction of pro-inflammatory cytokine release; (2) blockade of inflammation-induced neuronal death through suppression of ferroptosis, pyroptosis, and apoptosis; (3) enhancement of Nrf2 nuclear translocation, leading to upregulation of antioxidant enzymes and attenuation of oxidative stress-mediated inflammation (e.g., ROS-driven cascades); and (4) modulation of the gut microbiota-brain axis to reduce both peripheral and central low-grade chronic inflammation.

CONCLUSION: Despite certain limitations in the existing evidence, this review clearly identifies future research priorities, including investigation of non-gastrodin active components, causal validation using gene-knockout models, and development of brain-targeted delivery strategies. These findings provide a valuable reference for the mechanism-guided development of neuroprotective agents derived from G. elata.},
}

@article {pmid43005395,
year = {2026},
author = {Jiang, C and Krivinko, J and Sweet, RA and Deng, Y and Ezigbo, U and Huang, R and Kofler, J and Wang, L},
title = {Comparative functional and cognitive trajectories following second-generation antipsychotic initiation among long-term care residents with Alzheimer disease: A target trial emulation study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70347},
pmid = {43005395},
issn = {2352-8737},
abstract = {INTRODUCTION: Real-world evidence comparing the functional and cognitive outcomes associated with commonly prescribed second-generation antipsychotics (SGAs) in long-term care (LTC) residents with Alzheimer disease (AD) is limited.

METHODS: We emulated target trials using linked LTC Data Cooperative and Medicare data. A total of 17,766 eligible new users initiating risperidone, quetiapine, olanzapine, or aripiprazole were compared under an intention-to-treat framework using inverse probability of treatment weighting and weighted generalized estimating equations. Outcomes were 12-month trajectories of Activities of Daily Living (ADL) and Brief Interview for Mental Status (BIMS).

RESULTS: ADL trajectories were similar across SGAs. In BIMS trajectory, quetiapine was associated with a modestly greater decline (β = -0.203, 95% confidence interval [CI] -0.380 to -0.027) compared with aripiprazole. Age modified several comparative treatment effects, particularly for BIMS. Findings were consistent across sensitivity analyses.

DISCUSSION: Long-term functional and cognitive outcomes were broadly comparable across commonly prescribed SGAs. Age-related heterogeneity in comparative treatment effects warrants further investigation.},
}

@article {pmid43005418,
year = {2026},
author = {Zhao, Y and Liu, M and Zhou, Y and Cui, M and Cai, N and Wang, H and Liu, G and Sun, H and Kong, X and Zhao, P},
title = {Chronic neuropeptide S treatment improves sleep architecture and reduces Aβ-related pathology in APP/PS1 mice.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1825666},
pmid = {43005418},
issn = {1664-2295},
mesh = {Animals ; *Neuropeptides/pharmacology/administration & dosage ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism/complications/drug therapy/genetics ; Mice ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; Hippocampus/metabolism/drug effects ; Disease Models, Animal ; *Sleep Wake Disorders/drug therapy/etiology ; *Sleep/drug effects ; Hypothalamus/metabolism/drug effects ; Peptide Fragments ; Wakefulness/drug effects ; },
abstract = {BACKGROUND: Sleep disturbances frequently occur in Alzheimer's disease (AD). Although neuropeptide S (NPS) promotes wakefulness through the widely expressed NPS receptor (NPSR), its role in AD-related sleep dysregulation is unclear.

AIMS: To investigate the effects of chronic NPS administration on AD-related sleep disturbances beyond its acute wake-promoting effects.

METHODS: NPSR expression was examined in the hypothalamus and hippocampus of APPswe/PS1dE9 (APP/PS1) mice, a double-transgenic mouse model of AD. Mice received intracerebroventricular NPS (1 nmol/day) for 14 days. Sleep-wake states were classified as wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Sleep architecture and amyloid-β (Aβ)-related pathology were assessed in mice. Cell-associated Aβ levels, extracellular signal-regulated kinase (ERK) phosphorylation, and autophagy-related proteins were examined in BV2 cells. Sleep responses to subsequent intracerebroventricular Aβ₁-₄₂ administration were examined in NPS-treated APP/PS1 mice.

RESULTS: APP/PS1 mice had lower NPSR protein levels in the hypothalamus and hippocampus than wild-type (WT) controls. Compared with saline-treated APP/PS1 mice, NPS-treated mice showed increased NREM sleep, reduced wakefulness, and lower Aβ-related pathology. Changes in sleep amounts were most evident during the light phase. Subsequent Aβ₁-₄₂ administration increased wakefulness and reduced NREM sleep mainly during the dark phase. It also shortened NREM episodes during the light phase. In BV2 cells, NPS altered cell-associated Aβ levels and increased ERK phosphorylation. NPS treatment was also associated with higher LC3B-II and lower p62 levels. SCH772984 attenuated the NPS-associated changes in autophagy-related proteins and cell-associated Aβ.

CONCLUSION: Chronic NPS administration improved sleep architecture and reduced Aβ-related pathology in APP/PS1 mice. The BV2 findings suggest possible involvement of ERK signaling and autophagy-related processes in cellular Aβ handling.},
}

Animals
*Neuropeptides/pharmacology/administration & dosage
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Alzheimer Disease/pathology/metabolism/complications/drug therapy/genetics
Mice
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Male
Hippocampus/metabolism/drug effects
Disease Models, Animal
*Sleep Wake Disorders/drug therapy/etiology
*Sleep/drug effects
Hypothalamus/metabolism/drug effects
Peptide Fragments
Wakefulness/drug effects

@article {pmid43005441,
year = {2026},
author = {Amon, KK and Huang, C and Fleischmann, HH and Correia, S and Kiselica, AM},
title = {Comparing criteria for objective cognitive staging in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70527},
pmid = {43005441},
issn = {2352-8729},
abstract = {INTRODUCTION: Individuals with preclinical Alzheimer's disease may develop objective subtle cognitive decline (OSCD) as they transition between the cognitively unimpaired and mild cognitive impairment stages. Selection of individuals with OSCD into clinical trials may provide enrichment for participants likely to benefit from treatment. We examined how choice of operational criteria for OSCD impacted clinical staging.

METHODS: We analyzed data from 6154 older adults in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease clinical trial to evaluate differences in clinical categorization rates by operational approach, as well as interactions with sex, race, and ethnicity.

RESULTS: Multinomial generalized estimating equation models yielded significant differences in clinical categorization rates: Interview-based methods led to the lowest proportion of individuals categorized with OSCD, cognitive screeners yielded the highest proportion, and multi-test neuropsychological methods provided a balance. These main effects were moderated by significant interactions with sex and race/ethnicity.

DISCUSSION: Choice of OSCD criteria will have significant impacts on trial sample makeup.},
}

@article {pmid43005453,
year = {2026},
author = {Duehring, JA and Feldman, HH and Salmon, DP and Edland, SD},
title = {Statistical efficiency of outcome measures for secondary prevention trials in Alzheimer's disease: Evidence from the A4 trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70344},
pmid = {43005453},
issn = {2352-8737},
abstract = {INTRODUCTION: Secondary prevention trials targeting preclinical Alzheimer's disease (AD) require clinical outcome assessments (COAs) that are sensitive to subtle decline that might be found in the cognitively unimpaired population typically enrolled in these trials. The recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) trial is an opportunity to explore the performance of commonly applied COAs in the preclinical AD population.

METHODS: The performance of COAs was compared using power calculations informed by data from the placebo arm of the A4 trial alone (N = 583), and through a cross-cohort analysis incorporating data from participants in the companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study (N = 538). Outcomes included the Preclinical Alzheimer's Cognitive Composite (PACC), the Clinical Dementia Rating Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Instrument (ADL-PI), and the Cognitive Function Instrument (CFI).

RESULTS: The PACC and its component neuropsychological tests did not meaningfully decline over the first 168 weeks of the trial, compromising their utility as trial endpoints. In contrast, the CDR-SB and the ADL-PI declined monotonically. Based on the progression observed in A4 alone, a trial using the CDR-SB endpoint would require a fraction of the participants required for a commonly used neuropsychological endpoint.

DISCUSSION: These findings help inform the selection of clinical endpoints for secondary prevention trials, and highlight potential limitations of cognitive performance tests in the earliest stages of AD. We found that practice effects on the PACC and its component tests were present despite the use of alternating test forms, reducing the effectiveness of these instruments in this population and motivating future exploration of the effectiveness of alternate clinical endpoints.},
}

@article {pmid43005456,
year = {2026},
author = {de Oliveira, RM and Nalvarte, I and González, A},
title = {Editorial: Glucose metabolism in brain and neurodegenerative diseases: multifactorial effects.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1991548},
pmid = {43005456},
issn = {1663-4365},
}

@article {pmid43005510,
year = {2026},
author = {Ali, AE and Otranen, HM and Lehtonen, JV and Courtney, MJ and Pentikäinen, OT and Postila, PA},
title = {In Silico Assessment of SYNGAP1 Missense Variant Pathogenicity.},
journal = {Human mutation},
volume = {2026},
number = {},
pages = {8234670},
pmid = {43005510},
issn = {1098-1004},
mesh = {Humans ; *Mutation, Missense ; *ras GTPase-Activating Proteins/genetics/chemistry ; *Computational Biology/methods ; Computer Simulation ; Machine Learning ; Models, Molecular ; Protein Conformation ; },
abstract = {SynGAP, a critical regulator at the postsynaptic density, is associated with Alzheimer's disease, tumorigenesis, and most notably, SYNGAP1-related disorders (SRD), which manifests as autism, epilepsy, and cognitive impairment. SRD is likely primarily caused by SynGAP missense (SGM) variants, whose pathogenicity is difficult to confirm experimentally. To address this issue, a wide range of structure- and/or sequence-based as well as machine learning- and deep learning-based in silico predictors were benchmarked against clinically annotated SRD data. Folding stability calculations (e.g., Foldetta) and deep learning methods ESM1b and AlphaMissense showed the highest prediction accuracy under default settings. Applying optimized nondefault thresholds, especially with AlphaMissense, could further improve predictor performance. The predictions exhibited a strong structural pattern: Pathogenic variants were highly enriched within defined structural domains, particularly the GAP and PH domains, whereas variants located in nondomain and nonmotif regions were predominantly predicted to be benign. The verified phosphosites and predicted phase separation impacting variants occupy matching sections, including the protein's N-terminal region and the vicinity of putative SH3-binding motif in the disordered regions. Thus, these regions collectively could act as phase separation-promoting segments, complementing the protein's trimerization-coupled coiled-coil domain. Finally, the SynGAP Missense (SGM) server was presented to support SynGAP variant assessment. The SGM server integrates a Data Table with top-performing predictors, a 3D Viewer for structure-level assessment and AI-generated lay summaries for all variants arising from single-base substitutions, including those not yet observed in public databases.},
}

Humans
*Mutation, Missense
*ras GTPase-Activating Proteins/genetics/chemistry
*Computational Biology/methods
Computer Simulation
Machine Learning
Models, Molecular
Protein Conformation

@article {pmid43005539,
year = {2026},
author = {Jiang, S and Kong, L and Bai, X and Yang, M and Ding, J and Wang, Y and Fan, W and Yan, Y and Pu, C and Zhang, N},
title = {Apigenin promotes neuronal norepinephrine release via GPR30/PLCβ1-Ca[2+]-Syt1 signaling to enhance astrocytic lactate and exert neuroprotection in D-galactose-induced cognitive impairment.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1979963},
pmid = {43005539},
issn = {1663-9812},
abstract = {OBJECTIVE: AD, a prevalent neurodegenerative disorder clinically defined by progressive cognitive impairment, is pathologically featured by early dysfunction of the locus coeruleus, depletion of noradrenergic (NE) neurons, and dysregulated astrocytic glycogen metabolism, which collectively compromise patients' daily functioning. Although Api, a common phytoestrogen, has shown therapeutic efficacy in diverse diseases, its role and mechanism in AD remain unexplored.

METHODS: To address this gap, we evaluated the protective effects of Api against D-gal-induced cognitive deficits through behavioral and histomorphological assessments. Untargeted metabolomics was performed to profile metabolic alterations in the locus coeruleus (LC), complemented by targeted metabolomics focusing on specific pathways. Putative targets were predicted by molecular docking and verified via cellular thermal shift assay (CETSA), while molecular biology approaches were adopted to elucidate the underlying signaling cascades.

RESULTS: Api significantly ameliorated D-gal-induced cognitive impairment and increased hippocampal NE and lactate levels with enhanced neuronal activity. Metabolomics indicated that Api regulates energy metabolism pathways including TCA cycle, amino acid metabolism, glycolysis/gluconeogenesis, and glutathione metabolism. Specifically, Api elevated NE and lactate in the LC. GPR30 was identified and validated as the key target via molecular docking and CETSA, showing strong binding affinity. Mechanistically, Api activates GPR30 on noradrenergic neurons to regulate PLCβ1-Ca[2+]-Syt1 signaling, promoting NE release, which in turn drives astrocytic glycogenolysis and lactate production, thereby relieving neuronal energy deficits.

CONCLUSION: Collectively, this study not only clarifies the PLCβ1-Ca[2+]-Syt1-dependent mechanism of Api in aging-related cognitive impairment, but also highlights NE and lactate elevation as a promising therapeutic approach.},
}

@article {pmid43005561,
year = {2026},
author = {Tang, L and Li, XY and Ran, Z and Qin, ZZ and Chen, SY and Zhang, MM and Zhou, LY and Wang, WJ and Chen, L},
title = {Microglia in Alzheimer's disease: from pathogenic mechanisms to therapeutic targeting.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1952810},
pmid = {43005561},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/immunology/therapy/etiology ; *Microglia/immunology/metabolism/pathology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Inflammasomes/metabolism ; Molecular Targeted Therapy ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by β-amyloid (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, vascular injury, and metabolic dysregulation. Recent advances in single-cell, spatial, and multi-omics transcriptomics have substantially reshaped our understanding of microglia, shifting the field from the classical M1/M2-like polarization dichotomy toward a model of state-dependent functional heterogeneity. Distinct subpopulations-including disease-associated microglia, lipid-associated microglia, interferon-responsive microglia, and senescence-associated microglia are now mechanistically linked to Aβ clearance, tau propagation, complement-mediated synaptic pruning, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and immunometabolic reprogramming. Central to this regulatory network are the TREM2-ApoE axis, complement cascades, NLRP3 inflammasome, mitochondrial dysfunction, and aberrant lipid/iron metabolism, which largely contribute to AD progression. In parallel, the clinical deployment of anti-Aβ monoclonal antibodies such as lecanemab has ushered in the era of disease-modifying therapy; however, limited efficacy and the occurrence of amyloid-related imaging abnormalities underscore that Aβ removal alone is insufficient to halt disease evolution completely. In this review, we systematically synthesize the evolving landscape of microglial states and their pathogenic contributions, and we further evaluate current therapeutic avenues, including microglia-targeted strategies, anti-Aβ antibody combination regimens, non-pharmacological interventions, and peripheral immunomodulation. We also compare these microglial mechanisms with those in multiple sclerosis to highlight shared neuroimmune modules and disease-specific features. Our goal is to provide a valuable updated reference for accurate molecular subtyping and multi-target combination therapy in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology/immunology/therapy/etiology
*Microglia/immunology/metabolism/pathology/drug effects
Animals
Amyloid beta-Peptides/metabolism
Inflammasomes/metabolism
Molecular Targeted Therapy

@article {pmid43005575,
year = {2026},
author = {Liu, X and Zhang, X and Su, Y and Guan, G and Luo, X and Zhang, P},
title = {Brain insulin resistance and microglial immunometabolic dysregulation in neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {2002283},
pmid = {43005575},
issn = {1663-4365},
abstract = {Brain insulin resistance (BIR) is increasingly recognized as a contributor to the development and progression of neurodegenerative diseases rather than simply a metabolic abnormality. In the central nervous system, insulin signaling is involved in neuronal survival, synaptic plasticity, energy metabolism, and protein homeostasis. Increasing evidence suggests that impaired brain insulin signaling is associated with Alzheimer disease (AD), Parkinson disease (PD), and other neurodegenerative conditions, although the mechanisms linking BIR to persistent inflammation and neuronal injury remain incompletely understood. Microglia, the principal innate immune cells of the central nervous system, integrate metabolic and immune signals and may therefore provide an important link between impaired insulin signaling and chronic inflammation. BIR may disrupt insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) signaling and promote nuclear factor-kappa B (NF-κB) activation, mitochondrial dysfunction, oxidative stress, impaired mitophagy, and lysosomal and lipid metabolic disturbances. These changes may promote activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, inflammatory mediator release, excessive phagocytosis, and synaptic dysfunction. In turn, persistent microglial inflammation may further impair insulin signaling, forming a reciprocal feedback loop that sustains pathological changes. This review summarizes the mechanisms linking BIR to microglial immunometabolic dysfunction and discusses potential therapeutic strategies targeting metabolic and inflammatory pathways in neurodegenerative diseases.},
}

@article {pmid43005605,
year = {2026},
author = {Hu, M and Esmaeeli, S and Stolzenburg, L and Milkovich, B and Jouni, M and Nyamugenda, E and Hammond, RK and Reinhardt, P and Bahnassawy, L and Gasparini, L and Waring, JF and Vasanthakumar, A},
title = {New insights on bridging integrator 1 protein isoforms as a risk increasing gene in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937726},
pmid = {43005605},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial, age-associated neurodegenerative disorder that leads to progressive declines in cognition, memory, and the capacity for independent daily living. Genome-wide association studies (GWAS) have identified Bridging Integrator 1 (BIN1) as one of the strongest and most reproducible genetic risk factor for AD, which we replicated in our GWAS by proxy (GWAX) analysis on UKBiobank data. However, the mechanism by which BIN1 impacts AD risk is largely unknown and our work aims to uncover the underlying mechanism.

METHODS: We generated human induced pluripotent stem cell (hiPSC)-derived neuronal and microglia cell models to evaluate cell-type specific BIN1 isoform expression using droplet digital polymerase chain reaction (ddPCR). We then extended our analysis to a Phase 2 AD clinical trial in which we evaluated the association of BIN1 isoform expression with the BIN1 genotype status.

RESULTS: Our data indicated that BIN1 isoform expression patterns shifted with the differentiation of hiPSC into neurons or microglia. We also found that the SNP rs35103166 is associated with the expression of the microglia-specific BIN1 isoforms.

CONCLUSION: We demonstrate that BIN1 genotype is associated with isoform expression, which differs between neurons and microglia, enabling evaluation of disease-specific isoform effects. Given the strong association of BIN1 with susceptibility to AD, exploring the mechanisms of BIN1 genetic variants and their impacts on cell-type specific expression could serve as a valuable resource for novel drug discovery.},
}

@article {pmid43005608,
year = {2026},
author = {Wang, J and Chen, W and Zhang, Z},
title = {Comparative efficacy and safety of quetiapine versus other atypical antipsychotics for behavioral and psychological symptoms in Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1887284},
pmid = {43005608},
issn = {1664-0640},
abstract = {BACKGROUND: The management of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) remains a significant challenge. While atypical antipsychotics are used, their comparative efficacy and safety, particularly for quetiapine, are not well-established within a homogeneous AD population. This meta-analysis aimed to directly compare the efficacy and safety of quetiapine versus other active pharmacological agents (primarily risperidone and olanzapine) for BPSD specifically in patients with AD.

METHODS: A systematic search of PubMed, Embase, Cochrane Library, Web of Science, CNKI, and WanFang databases was conducted up to March 15, 2024, for randomized controlled trials (RCTs). The primary efficacy outcome was treatment failure (lack of clinical improvement). Safety outcomes included specific adverse events. Data were pooled using random-effects models to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: Twenty-five RCTs involving 2143 participants were included. The pooled analysis of 16 studies (n=1384) demonstrated that quetiapine was associated with significantly lower odds of treatment failure compared to other atypical antipsychotics (OR 0.66, 95% CI 0.49 to 0.89, P = 0.006). In pre-specified subgroup analyses, quetiapine showed significant superiority over risperidone (OR 0.50, 95% CI 0.33 to 0.75, P = 0.0009) and a non-significant trend favoring quetiapine over olanzapine (OR 0.90, 95% CI 0.58 to 1.38, P = 0.62). Regarding safety, quetiapine was associated with a substantially and significantly lower risk of extrapyramidal symptoms (EPS) (OR 0.17, 95% CI 0.09 to 0.33, P<0.00001). No significant differences were found for other common adverse events such as somnolence, dizziness, or constipation.

CONCLUSION: This meta-analysis suggests that quetiapine may offer a potential efficacy advantage for alleviating BPSD in patients with AD, particularly when compared to risperidone, while demonstrating comparable overall effectiveness to other atypicals. Its most distinguishing feature is a substantially lower risk of extrapyramidal symptoms. Interpretation of these findings must be tempered by the moderate risk of bias in constituent trials, the necessary harmonization of disparate efficacy metrics, and the scarcity of long-term safety data. Quetiapine may serve as a neurologically better-tolerated option when non-pharmacological strategies are insufficient, pending careful, time-limited use.},
}

@article {pmid43005718,
year = {2026},
author = {Kaufman, EJ and Smukowski, SN and Gudsnuk, K and Course, MM and Valdmanis, PN},
title = {Alzheimer Disease Risk Variants at ABCA7 Tag Tandem Repeat Length.},
journal = {Neurology. Genetics},
volume = {12},
number = {6},
pages = {e200456},
pmid = {43005718},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: ATP-binding cassette subfamily A member 7 (ABCA7) variants are a well-established genetic risk factor for Alzheimer disease (AD). This risk includes increased length of a variable number tandem repeat (VNTR) with a ∼25bp repeat motif in intron 18 of ABCA7. We sought to examine VNTR length, exact internal sequence composition, and correlation with genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) in AD.

METHODS: Three hundred and seven ABCA7 alleles based on long-read sequencing were evaluated from the 1000 Genomes Project. Short read sequences from 7,968 cases and 6,792 controls were evaluated from the AD Sequencing Project (ADSP). RNA sequencing data from 130 cases and 253 controls from the Religious Orders Study/Memory and Aging Project were used to identify alternative splicing at ABCA7.

RESULTS: We found that the top AD GWAS SNPs at ABCA7 tag tandem repeat length in an allele-specific manner. Homozygous carriers of the rs3764650 risk allele average 87 copies of the ABCA7 VNTR compared with 65 repeat copies in heterozygous individuals and 53 copies in individuals homozygous for the reference allele. This effect was specific to samples of European descent because rs3764650 had no correlation with repeat length in samples of African ancestry in 1000 Genomes Project samples. Nevertheless, an African-specific sentinel GWAS variant (rs115550680) is adjacent to the 25bp VNTR. In ADSP samples, we found that tandem repeat length was significantly associated with rs3764650, rs78117248, and rs4147929 regardless of affection status. ABCA7 repeat length was associated with aberrant splicing leading to mRNAs with premature termination codons.

DISCUSSION: Converging lines of genetic and functional evidence implicate ABCA7 VNTR length as a potential risk factor for AD.},
}

@article {pmid43005833,
year = {2026},
author = {Mohammadi, S and Sharbafshaaer, M and Pirozzi, MA and Trojsi, F and Ghaderi, S and Iturria-Medina, Y and Fereshtehnejad, SM},
title = {White matter hyperintensities and amyloid pathology in cognitively unimpaired aging: topographical, microstructural, and network-level evidence.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {2005174},
pmid = {43005833},
issn = {1663-4365},
abstract = {The frequent coexistence of white matter hyperintensities (WMHs) and β-amyloid (Aβ) pathology in cognitively unimpaired older adults complicates interpretation of vascular and neurodegenerative imaging findings. This narrative review synthesizes topographical, microstructural, and network-level evidence in cognitively unimpaired aging, distinguishing biomarker-characterized samples from supportive mixed or symptomatic cohorts. WMHs have heterogeneous etiologies. Posterior and some periventricular patterns are associated with cerebral Aβ in several cohorts, but lobar location and distance from the ventricles are overlapping classifications, and vascular associations are not confined to frontal or deep lesions. Independent and additive cognitive associations are more consistently reported than interactions. Longitudinal executive-function interactions reported in a dissertation and related abstract remain preliminary and non-independent. Some longitudinal studies associate baseline Aβ with subsequent WMH accrual, but findings are not uniform and do not establish causation. APOE-related findings vary with age, population, and amyloid burden. Diffusion MRI detects tissue abnormalities beyond visible lesions, although microstructural and disconnectome measures require prospective validation before they can improve individual prognosis. Anti-amyloid trial evidence identifies MRI safety considerations; effects on chronic WMH progression remain uncertain.},
}

@article {pmid43005927,
year = {2026},
author = {Adnan Azeez Aboomaima, W and Hasan Burhan, A and Aziz Abu Omaima, HA and Mahmoudi, A},
title = {Isoform-Selective and Context-Dependent Modulation of Nitric Oxide Synthase by Cannabidiol: A Mechanistic Review of Preclinical Evidence in Neurological and Neuropathic Disorders.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {650304},
pmid = {43005927},
issn = {1178-7031},
abstract = {Nitric oxide (NO), produced by nitric oxide synthase (NOS) isoforms, plays a dual role in the central nervous system. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has shown promise as a neuroprotective and anti-inflammatory agent. This narrative review examines the complex interactions between CBD and NOS isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) variants, and discusses how these may contribute to its neuroprotective and analgesic properties. Preclinical evidence, primarily from cellular and animal models, indicates that CBD can reduce excessive NO production, particularly by inhibiting iNOS in neuroinflammatory conditions. However, the effects of CBD on nNOS are context-dependent and cannot be characterized simply as inhibitory: while CBD may attenuate pathological nNOS-mediated excitotoxicity in some models, nNOS-derived NO is also required for CBD-induced analgesia in certain neuropathic pain models, where nNOS activation and downstream NO signaling contribute to antinociception. The strongest preclinical evidence supports CBD-mediated suppression of pathological iNOS expression and NO production in neuroinflammatory conditions. The effects of CBD on nNOS are context-dependent and cannot be characterized simply as inhibitory: while CBD may attenuate pathological nNOS-mediated excitotoxicity in some models, nNOS-derived NO is also required for CBD-induced analgesia in certain neuropathic pain models, where nNOS activation and downstream NO signaling contribute to antinociception. Similarly, evidence for eNOS-mediated vascular benefits in the CNS remains preliminary and largely derived from peripheral studies, and cerebrovascular eNOS effects require further investigation. We review the potential therapeutic implications of these interactions in neurological conditions such as Alzheimer's disease, multiple sclerosis, depression, and neuropathic pain. The review also addresses antioxidant and anti-nitrosative benefits of CBD, pharmacokinetic challenges, and research gaps, including the need for clinical trials with biomarkers to validate NOS-related findings. By integrating molecular, preclinical, and translational perspectives, this review provides insights into the context-dependent and isoform-selective modulation of NOS by CBD, emphasizing that the strength of evidence varies by isoform, with iNOS and nNOS modulation being better established than eNOS-related effects.},
}

@article {pmid43006157,
year = {2026},
author = {Xiao, S and Wu, L and Qiao, W and Yue, R and Guo, X and Li, C and Tang, Y and Ye, J},
title = {HDAC7 Scaffolds GSK3β-Tau Interaction to Drive GSK3β Activation and Tau Pathology.},
journal = {Aging cell},
volume = {25},
number = {11},
pages = {},
pmid = {43006157},
issn = {1474-9726},
support = {82101493//National Natural Science Foundation of China/ ; 2025A1515012551//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; },
mesh = {Animals ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Histone Deacetylases/metabolism/genetics ; *tau Proteins/metabolism ; Humans ; Mice ; Phosphorylation ; *Tauopathies/metabolism/pathology ; Neurons/metabolism ; Acetylation ; Alzheimer Disease ; },
abstract = {Intraneuronal accumulation of hyperphosphorylated tau is a pathological hallmark of Alzheimer's disease (AD) and related tauopathies. Although dysregulation of both histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β) has been implicated in tau pathogenesis, whether and how they functionally interact to drive tau pathology remains unclear. Here, we identify HDAC7 as a critical scaffold that promotes GSK-3β-tau complex formation, leading to GSK-3β activation and tau hyperphosphorylation in a tauopathy mouse model. HDAC7 is selectively upregulated in human tau-bearing neurons. Neuronal overexpression of HDAC7 exacerbates tau hyperphosphorylation and cognitive deficits, accompanied by increased GSK-3β kinase activity and protein levels both in vivo and in vitro. Mechanistically, HDAC7 scaffolds the direct interaction between GSK-3β and tau independently of its deacetylase activity. Formation of the HDAC7-GSK3β-tau complex enables tau to promote GSK-3β acetylation at lysine 15, which in turn stabilizes GSK-3β protein and enhances its kinase activity. Conversely, neuronal deletion of HDAC7 reduces GSK-3β protein levels and kinase activity, attenuates tau hyperphosphorylation, restores synaptic integrity, and rescues cognitive deficits in hTau-expressing mice. Together, our findings propose a novel mechanism by which HDAC7 scaffolds GSK3β-tau interaction to drive sustained GSK-3β activation and tau pathology, highlighting reducing HDAC7 as a potential therapeutic strategy for AD and other tauopathies.},
}

Animals
*Glycogen Synthase Kinase 3 beta/metabolism
*Histone Deacetylases/metabolism/genetics
*tau Proteins/metabolism
Humans
Mice
Phosphorylation
*Tauopathies/metabolism/pathology
Neurons/metabolism
Acetylation
Alzheimer Disease

@article {pmid43006195,
year = {2026},
author = {Berruga, Y and Nanjundan, R and van Baelen, AC and Panek, S and Tonali, N and Dodero, VI and Garcia, AM},
title = {Peptide Self-Assembly: Insights From Functional Short Peptides, Amyloid-β, and Gluten Peptides.},
journal = {Journal of peptide science : an official publication of the European Peptide Society},
volume = {32},
number = {12},
pages = {},
doi = {10.1002/psc.70148},
pmid = {43006195},
issn = {1099-1387},
support = {RYC2023-042600-I//Agencia Estatal de Investigación/ ; PID2024-160195NA-I00//Agencia Estatal de Investigación/ ; PID2023-152323NB-I00//Agencia Estatal de Investigación/ ; SBPLY/24/180225/000086//Junta de Comunidades de Castilla-La Mancha/ ; 2025-GRIN-38471//Universidad de Castilla-La Mancha/ ; 2024_UNIVERS_12844//Universidad de Castilla-La Mancha/ ; ANR-22-CE92-0076-01//Agence Nationale de la Recherche/ ; DFG SE 609/20-1//Deutsche Forschungsgemeinschaft/ ; 43057848//Deutsche Forschungsgemeinschaft/ ; ANR-11-IDEX-003//PASREL (Université Paris-Saclay), France 2030 Programme/ ; COST Action CA23111 - SNOOPY//European Cooperation in Science and Technology/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Humans ; *Glutens/chemistry/metabolism ; *Peptides/chemistry ; Peptide Fragments/chemistry ; Amino Acid Sequence ; Alzheimer Disease/metabolism ; },
abstract = {In this perspective, we discuss how short peptides can be programmed through sequence design, stereochemistry, terminal modification, and external stimuli to form diverse supramolecular architectures. We then examine how similar molecular principles underlie disease-associated aggregation, focusing on early Aβ(1-42) assemblies in Alzheimer's disease and proteolysis-resistant gluten peptide nanostructures in gluten-related disorders. Attention is given to the detection, stabilization, and modulation of transient oligomeric species, which remain challenging but highly relevant to therapeutic and diagnostic targets. We further highlight how short functional peptides can be engineered to interfere with aggregation pathways in amyloid and nonamyloid aggregopathies, including diabetes-related amyloids, α-synuclein, and phenylalanine assemblies. Together, these examples illustrate the cross-applicability of concepts from supramolecular materials chemistry to molecular pathology. This perspective emphasizes that understanding peptide self-assembly at the molecular level is key to both exploiting and controlling its biological consequences.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Humans
*Glutens/chemistry/metabolism
*Peptides/chemistry
Peptide Fragments/chemistry
Amino Acid Sequence
Alzheimer Disease/metabolism

@article {pmid43006698,
year = {2026},
author = {Liang, EX and Li, QW and Liang, H},
title = {Chinese herbal medicine formulas for Alzheimer's disease: Evidence, mechanisms, and translational standards.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261505070},
doi = {10.1177/13872877261505070},
pmid = {43006698},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is defined biologically by amyloid and tau pathology. The emergence of biomarker-based diagnostic criteria, blood-based assays, and anti-amyloid therapeutic trials has substantially raised the evidentiary standard for all candidate AD interventions, including Chinese herbal medicine (CHM) formulas. However, CHM formula evidence for AD lacks critical appraisal and methodological standards. Thus, this review aims to: (1) critically evaluate the clinical, mechanistic, and translational evidence for oral or topical CHM formulas used in AD, specifically those selected according to Traditional Chinese Medicine (TCM) diagnostic; and (2) assess the methodological requirements necessary for credible development of such formulas in AD research. Preclinical studies suggest plausible effects of CHM formulas on amyloid-related pathways, tau phosphorylation, neuroinflammation, oxidative stress, and energy metabolism, but these findings remain hypothesis-generating rather than clinically validated. Most included studies relied on clinical diagnoses, likely encompassing mixed pathologies (e.g., vascular dementia, dementia with Lewy bodies, or depression-related cognitive impairment), rendering their results preliminary rather than confirmatory for biologically defined AD. Current evidence does not support CHM formulas as established therapies for AD. Future studies will require biomarker-confirmed diagnosis, rigorous formula quality control, prespecified TCM pattern stratification, clinically meaningful cognitive and functional endpoints, mechanistic target-engagement measures, and prospective safety and herb-drug interaction monitoring.},
}

@article {pmid43007416,
year = {2026},
author = {Schultzberg, M and Zhong, J},
title = {Resolution Failure in Alzheimer's Disease.},
journal = {Current topics in microbiology and immunology},
volume = {},
number = {},
pages = {},
pmid = {43007416},
issn = {0070-217X},
abstract = {Neuroinflammation is now recognized as an early and active driver of Alzheimer's disease (AD) rather than a secondary response to neurodegeneration. In the healthy brain, inflammation is terminated through specialized pro-resolving mediators (SPMs) which orchestrate a tightly regulated programme that restores tissue homeostasis. Ageing introduces early immune vulnerabilities such as altered microglial phenotypes, impaired efferocytosis, reduced SPM biosynthesis, and shifts in lipid substrate availability, all of which can weaken resolution capacity long before overt AD pathology emerges. In AD, these age-related deficits converge with disease-specific mechanisms: amyloid-β and tau pathology sustain NF-κB-and NLRP3-driven inflammatory signalling, impair microglial clearance, and disrupt SPM receptor-mediated pathways. Human post-mortem studies and cerebrospinal fluid (CSF) lipidomic profiling demonstrate reduced levels of several SPMs together with upregulated-but conceivably functionally uncoupled-SPM receptors, indicating an adaptive but insufficient response to ligand deficiency. SPMs or their analogues have been shown to restore phagocytosis, dampen inflammasome activation, stabilize the blood-brain barrier, and improve cognition in multiple AD models. These findings position resolution failure as a unifying mechanism linking ageing, innate immune dysregulation, and AD pathology. Therapeutic strategies aimed at restoring resolution-through SPM supplementation, enhancement of endogenous SPM biosynthesis, or targeting of pro-resolving receptors-represent a promising, biologically coherent approach that acts not by suppressing immunity but by redirecting it towards effective clearance and neuronal protection.},
}

@article {pmid43007615,
year = {2026},
author = {Sakurai, R and Iwabuchi, Y and Shimizu, A and Bun, S and Kubota, M and Shimohama, S and Tezuka, T and Takahata, K and Tabuchi, H and Seki, M and Momota, Y and Yamamoto, Y and Shikimoto, R and Mimura, Y and Kurose, S and Watanabe, M and Takayama, T and Hoshino, Y and Hoshino, T and Suzuki, N and Morimoto, A and Osumi, A and Mimura, M and Ito, D and Jinzaki, M},
title = {Associations of plasma biomarkers and amyloid positron emission tomography with regional tau burden in Alzheimer's disease.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {43007615},
issn = {1867-108X},
support = {JP17pc0101006//Japan Agency for Medical Research and Development/ ; 16H06277//Japan Society for the Promotion of Science/ ; },
abstract = {PURPOSE: Amyloid positron emission tomography (PET) and plasma biomarkers are clinically established; however, their topographical relationship with regional tau burden remains unclear. We investigated whether amyloid PET and plasma biomarkers are associated with regional tau pathology, measured using second-generation tracer florzolotau ([18]F) PET, across the Alzheimer's disease (AD) continuum.

MATERIALS AND METHODS: This cross-sectional study enrolled participants who underwent biomarker assessment between September 2018 and May 2022. The primary outcome was the voxel-wise spatial correlation of florzolotau ([18]F) standardised uptake value ratio with amyloid PET centiloid and plasma biomarkers, assessed using age- and sex-adjusted whole-brain and region-of-interest (ROI) linear regression analyses, including multivariate models adjusted for amyloid PET centiloid.

RESULTS: The study included 92 individuals (mean age, 71 [standard deviation, 8.8] years; 46 men), comprising 40 amyloid-negative healthy controls, 10 patients with preclinical AD, 21 with mild cognitive impairment due to AD, and 21 with AD dementia. In initial analyses, regional tau uptake correlated widely with plasma amyloid-beta 42/40 (Aβ42/40) ratio, p-tau, and glial fibrillary acidic protein (GFAP). However, following multivariate adjustment for global amyloid burden, correlations for Aβ42/40 and GFAP were completely abolished. In contrast, plasma p-tau217, p-tau181, and neurofilament light chain (NfL) maintained significant amyloid-independent correlations with temporoparietal tau uptake, with p-tau217 uniquely retaining robust and extensive associations across the cortex.

CONCLUSION: Plasma p-tau217 is strongly associated with the spatial distribution and severity of tau burden independent of global amyloid burden. Measuring plasma p-tau217 holds significant potential for patient stratification and monitoring in the era of disease-modifying therapies.

TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000032027), registered 31 March 2018, prospectively registered (URL https//center6.umin.ac.jp/cgiopenbin/ctr_e/ctr_view.cgi? recptno=UMIN000032027). Japan Registry of Clinical Trials (jRCTs031180225), prospectively registered (URL https//jrct.niph.go.jp/enlatestdetail/jRCTs031180225).},
}

@article {pmid43007730,
year = {2026},
author = {Mandal, SM and Hoque, ME and Bandaru, P and Ghosh, G},
title = {A Hybrid Fluorescence-Optoelectronic Nanoscale Sensor for the Early Diagnosis of Tau Pathology.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.6c00511},
pmid = {43007730},
issn = {2379-3694},
support = {AG072487/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; AI163327//National Institute of Allergy and Infectious Diseases/ ; },
abstract = {Early detection of tauopathies is crucial for identifying disease onset and enabling effective management of disorders such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). Here, we present a highly sensitive and specific method for detecting early, non-fibrillar Tau oligomers before tangle formation. Among a series of synthesized quantum dots, only the nitrogen-phosphorus-doped carbon quantum dots (N,P-CQDs) demonstrated the desired specificity. These N,P-CQDs are derived from phosphoserine dimers linked through an unusual phosphate ester bond rather than a conventional amide bond. They are characterized as 3-7 nm in diameter and emit bright red fluorescence at 600 nm, enabling the specific detection of toxic oligomeric and fibrillar Tau species in vitro and in tau pathogenic brain tissues and cerebrospinal fluid (CSF). The N,P-CQD nanoprobe offers an advantage over conventional Thioflavin T staining because of its large 300-nm Stokes shift between excitation and emission, which minimizes background noise. The calculated fluorescence half-life (t1/2) was 1.66 μs, with a fluorescence decay time (τ) of approximately 3.0 μs, demonstrating the potential of the probe for ultrasensitive detection. The proposed integrated bio-opto-electronic platform, leveraging the specific and highly sensitive spectral response of N,P-CQD-functionalized nanoneedles to oligomeric tau aggregates, as determined in conjunction with biolayer interferometry (BLI), establishes a foundation for a real-time, minimally invasive future diagnostic tool for the detection of neurodegenerative disorders.},
}

@article {pmid43007767,
year = {2026},
author = {He, L and He, Z and Yu, Z and Bao, H and Zhang, Q and Duan, X and Wu, A and Li, J},
title = {Chirality-Functionalized Covalent Organic Frameworks for Enantioselective Neuroprotection with Restored Neuroactive Signaling in Alzheimer's Disease.},
journal = {ACS nano},
volume = {20},
number = {44},
pages = {29550-29563},
doi = {10.1021/acsnano.6c08616},
pmid = {43007767},
issn = {1936-086X},
support = {32025021//National Natural Science Foundation of China/ ; T2222021//National Natural Science Foundation of China/ ; 2023YFC2415700//National Key Research and Development Program of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Neuroprotective Agents/chemistry/pharmacology ; Stereoisomerism ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Humans ; Mice ; Mice, Transgenic ; Cysteine/chemistry/pharmacology ; *Nanoparticles/chemistry ; *Neuroprotection/drug effects ; Calcium/metabolism ; },
abstract = {Alzheimer's disease (AD) is driven by amyloid-β (Aβ) accumulation and a cascade of interconnected neurotoxic events, including oxidative stress, glutamate excitotoxicity, calcium dysregulation, and impaired neuroactive ligand-receptor signaling. To address the multifactorial nature of AD pathology, chiral d- or l-cysteine-functionalized covalent organic framework (COF) nanoparticles are developed as a multitarget nanotherapeutic platform. Both enantiomers effectively inhibit Aβ aggregation, scavenge reactive oxygen species, reduce extracellular glutamate levels, and attenuate calcium dysregulation. In parallel, d/l-Cys-COFs rescue compromised neuroactive ligand-receptor signaling, as evidenced by normalized expression of neuropeptide Y and brain-derived neurotrophic factor. In transgenic AD mice, d/l-Cys-COF treatment significantly improves memory and cognitive performance. Notably, the d-enantiomer affords superior neuroprotection through enhanced suppression of pathological intracellular calcium overload, whereas restoration of neuroactive ligand-receptor signaling remains chirality-independent. These findings identify chirality as a key design element for multitarget nanotherapeutics against AD, with enantioselective efficacy arising primarily from differential regulation of calcium dysregulation and shared restoration of neuroactive signaling contributing to the overall therapeutic benefit.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
*Neuroprotective Agents/chemistry/pharmacology
Stereoisomerism
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Humans
Mice
Mice, Transgenic
Cysteine/chemistry/pharmacology
*Nanoparticles/chemistry
*Neuroprotection/drug effects
Calcium/metabolism

@article {pmid43007869,
year = {2026},
author = {Soto-Faguás, CM and O'Niel, A and Saltonstall, E and Mueller, PA and Sanchez-Molina, P and Fedorov, LM and Woltjer, RL and Raber, J and Unni, VK},
title = {Mouse APOE Christchurch protects against Aβ-induced tau and α-synuclein aggregation.},
journal = {Cell reports},
volume = {45},
number = {11},
pages = {118301},
doi = {10.1016/j.celrep.2026.118301},
pmid = {43007869},
issn = {2211-1247},
abstract = {Apolipoprotein E (APOE) genotype alters the risk for Alzheimer's disease (AD) but also affects dementia risk in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recent evidence suggests that the APOE Christchurch (CC) mutation protects against AD, however, its effects on PD and DLB are unknown. We generated an APOE CC knock-in mouse to understand its effects on amyloid-β (Aβ), tau, and α-synuclein (α-syn) aggregation. APOE CC mice show increased plasma cholesterol and triglyceride levels, decreased Aβ and Aβ-induced tau pathology after intracortical AD-tau injection into 5xFAD mice but do not change Aβ or tau pathology in individual transgenic mouse models without injection. Interestingly, APOE CC reduces formation and spread of α-syn aggregation in the brain, peripheral-to-spinal cord spread, and directly increases binding affinity to α-syn compared to APOE WT. Our study emphasizes the remarkable protective effects of a point mutation in murine APOE against Aβ-induced tau and α-syn aggregation.},
}

@article {pmid43007886,
year = {2026},
author = {Kumar, R and Das Modak, S and Babu, MA and Sinha, S},
title = {Integrated molecular modeling and in vitro validation identify new acetylcholinesterase-inhibitory scaffolds among FDA-approved drugs.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/07391102.2026.2757693},
pmid = {43007886},
issn = {1538-0254},
abstract = {Acetylcholinesterase (AChE) inhibition remains a clinically validated strategy for the symptomatic management of Alzheimer's disease (AD). However, the limited long-term efficacy of currently available inhibitors continues to drive the search for new scaffolds, making drug repurposing an attractive strategy for accelerating drug discovery. Here, an integrated structure-guided workflow combining molecular docking, molecular dynamics (MD) simulations, MMGBSA binding free-energy analysis, dynamic interaction profiling, and in vitro enzyme inhibition assays was employed to investigate the AChE inhibitory potential of FDA-approved drugs. The docking study identified lumacaftor, olaparib, fexofenadine, and vibegron as the highest-ranked compounds, while MMGBSA predicted favourable binding energetics for lumacaftor, pemetrexed, olaparib, and cilostazol. MD simulations showed that most of the compounds remained favourably accommodated within the AChE active-site gorge while maintaining overall structural integrity of the enzyme. In vitro enzyme inhibition assays identified olaparib, cilostazol, and miconazole with the lowest measured IC50 values (2.86, 2.88, and 2.89 μM, respectively), while vibegron, irbesartan, pemetrexed, lumacaftor, and indomethacin also showed measurable inhibition. Fexofenadine showed 51.26 ± 4.81% inhibition at 20 μM, but its IC50 was not determined. Differences between computational predictions and experimental activity highlight the utility of computational approaches for compound prioritization rather than quantitative prediction of biological activity. Taken together, this study identified FDA-approved drugs with, to the best of our knowledge, previously unreported AChE inhibitory activity and provided mechanistic insights into AChE-ligand recognition. These compounds represent preliminary, experimentally supported AChE-interacting scaffolds for further biochemical, pharmacological, and in vivo investigation.},
}

@article {pmid43008775,
year = {2026},
author = {Barton, ME and Byrnes, W and van den Steen, B and van Tricht, H and Mesa, IR and Taiyari, K and Famodimu, O and Teng, E and Hains, AB and Bloemers, J and Maguire, RP and Ewen, C and Citron, M},
title = {Safety, tolerability, and efficacy of bepranemab in people living with prodromal-to-mild Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 2 trial.},
journal = {The Lancet. Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1474-4422(26)00357-1},
pmid = {43008775},
issn = {1474-4465},
abstract = {BACKGROUND: Tau aggregation is a defining feature of the pathophysiology of Alzheimer's disease and an appealing therapeutic target, yet tau-directed antibodies tested to date-primarily targeting N-terminal epitopes-have failed to slow tau progression or cognitive decline. Bepranemab targets the tau mid-region, predicted in cell-based assays to more effectively block neuron-to-neuron tau spread than anti-tau antibodies targeting the N-terminus. We aimed to investigate the safety and efficacy of bepranemab in slowing progression of tau pathology and clinical decline in people with prodromal-to-mild Alzheimer's disease.

METHODS: This double-blind, placebo-controlled, phase 2 trial recruited participants across 101 outpatient sites in Europe (eight countries), Canada, and the USA. Participants (aged 50-80 years) with prodromal-to-mild Alzheimer's disease were randomly assigned 1:1:1 (using an interactive response system) to intravenous bepranemab 45 mg/kg, bepranemab 90 mg/kg, or placebo (every 4 weeks for 76 weeks), stratified by diagnosis, apolipoprotein E ɛ4 carrier status, and symptomatic treatment use. The primary endpoint was change from baseline to week 80 in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) total score. Efficacy was assessed in the full analysis set (ie, all randomly assigned participants who received at least a partial dose of trial medication and had at least one valid post-baseline clinic visit and efficacy assessment). Safety was assessed in all randomly assigned participants who received at least a partial dose of the trial medication. No imputation was done for missing data. The trial is registered at ClinicalTrials.gov (NCT04867616) and is complete.

FINDINGS: Between Aug 24, 2021, and Oct 25, 2022, 466 participants were randomly assigned to bepranemab 45 mg/kg (n=154), bepranemab 90 mg/kg (n=155), or placebo (n=157) at 85 sites. Median age was 72·0 years (IQR 66·0-76·0), 259 (56%) were female, and 207 (44%) were male. In total, 460 participants were included in the full analysis set: bepranemab 45 mg/kg (n=152), bepranemab 90 mg/kg (n=152), and placebo (n=156). Least-squares mean CDR-SB total score change from baseline to week 80 was 2·15 in the bepranemab 90 mg/kg group and 1·85 in the bepranemab 45 mg/kg group versus 1·81 in the placebo group, with differences versus placebo of 0·34 (95% CI -0·09 to 0·78, p=0·12; 80% CI 0·06 to 0·63) for the bepranemab 90 mg/kg group and 0·04 (-0·40 to 0·47, p=0·87; -0·25 to 0·32) for the bepranemab 45 mg/kg group. Frequency of treatment-emergent adverse events with bepranemab was similar to the placebo group (139 [91%] with bepranemab 45 mg/kg, 140 [91%] with bepranemab 90 mg/kg, and 142 [90%] with placebo); no treatment-related neuroinflammatory safety signals were identified clinically or on brain MRI scans. There were adverse events leading to death in four (1%) participants in the combined bepranemab groups and six (4%) in the placebo group; none were considered related to the trial treatment.

INTERPRETATION: Treatment with bepranemab was associated with an acceptable safety profile. However, the primary endpoint was not met. Hypothesis-generating differences favouring bepranemab in tau PET and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale should be tested prospectively in trials powered for tau PET outcomes and stratified by baseline tau burden and apolipoprotein E ɛ4 status.

FUNDING: UCB.},
}

@article {pmid43008845,
year = {2026},
author = {Pei, K and Rossi, EA and Hill, D and Zhang, L and Markle, EM and Cordeiro, MF},
title = {Advances in Retinal Cellular Imaging: Towards Single-Cell Resolution and Functional Biomarkers.},
journal = {Progress in retinal and eye research},
volume = {},
number = {},
pages = {101542},
doi = {10.1016/j.preteyeres.2026.101542},
pmid = {43008845},
issn = {1873-1635},
abstract = {Retinal imaging has traditionally described tissue and layer level pathology, whereas direct assessment of individual cells in the living human retina has been limited by ocular aberrations, optical contrast and image analysis constraints. Adaptive optics (AO) has substantially changed this landscape by improving lateral resolution and enabling in vivo visualization of photoreceptors, retinal pigment epithelium (RPE), ganglion-cell-layer structures, immune cells and microvasculature. This review discusses human retinal cellular imaging across three major AO-enhanced platforms: flood-illumination adaptive optics (FIAO), adaptive optics optical coherence tomography (AO-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO). These modalities provide complementary capabilities, including rapid en face imaging, depth-resolved volumetric assessment and flexible confocal, non-confocal and fluorescence-based contrast. Recent progress is also being shaped by faster wavefront correction, wider-field acquisition, compressed multichannel imaging, sensorless AO and artificial intelligence (AI)-assisted reconstruction, segmentation and quantification. Beyond optical resolution, molecular labeling strategies are beginning to add biological specificity to retinal cellular imaging. Indocyanine green (ICG) supports AO-assisted assessment of RPE mosaic contrast, annexin V-based Detection of Apoptosing Retinal Cells (DARC) provides a molecular readout of retinal cell stress and apoptosis, and curcumin-based imaging has been explored as an experimental retinal amyloid marker in Alzheimer's disease. Together, these advances indicate a shift from high-resolution visualization alone towards cellular and molecular biomarkers of disease activity, progression and treatment response. Further translation will require standardized acquisition, robust automated analysis, multimodal validation and larger prospective studies across devices, disease populations and clinical sites.},
}

@article {pmid43008878,
year = {2026},
author = {Yang, S and Pei, Z and Lan, X and Lian, C and Liu, Y and Li, Z and Dang, G and Shi, X and Kang, H and Jiang, X and Chen, R and Guo, Y},
title = {Electroencephalography Neurophysiology Alterations in Association with Aβ and Tau Pathology Across the Symptomatic Stages of Alzheimer's Disease Continuum: A Cross-Sectional Study.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122341},
doi = {10.1016/j.neuroimage.2026.122341},
pmid = {43008878},
issn = {1095-9572},
abstract = {BACKGROUND: Amyloid-β (Aβ) and tau deposition drive Alzheimer's disease (AD). However, how these proteinopathies are linked to macroscopic neural activity alterations measured by electroencephalography (EEG) in symptomatic AD remains inadequately characterized. This study aims to investigate the associations between Aβ, tau, EEG neurophysiology, and cognition.

METHODS: We conducted a cross-sectional study of 73 MCI and AD participants, who underwent resting-state EEG, Aβ-PET, and tau-PET. EEG source analysis was performed to extract regional spectral power. Linear mixed-effects models were used to examine the associations of regional Aβ (quantified by SUVR), tau (binary classification), with EEG features, controlling for age, sex and education. Ordinary least squares (OLS) regression was applied to investigate the relationships of EEG spectral power and global Aβ burden with cognitive performance.

RESULTS: Elevated Aβ burden was associated with distinct regional spectral alterations. Specifically, higher Aβ SUVR was significantly correlated with increased theta power and decreased beta power in a subset of cortical regions. Tau positivity did not modulate the amyloid-theta association in any region, but attenuated the amyloid-beta association in a small set of parietal regions.

CONCLUSIONS: We identified a localized pattern of Aβ-related neurophysiological dysfunction across the symptomatic stages of AD continuum, characterized by theta increases and beta decreases, supporting a robust association between Aβ burden and cortical neural slowing. The findings highlight the value of source-localized EEG power as a sensitive indicator of Aβ-associated network dysfunction in AD and underscore the potential of source-localized EEG as a complementary, non-invasive biomarker for assessing pathological burden and informing diagnostic strategies in AD.},
}

@article {pmid43009006,
year = {2026},
author = {Liu, Y and Tian, K and Jiao, K and Wu, N and Ma, K and Shang, L and Du, M and Wang, Y and Wang, X and Lu, J and Zhang, J and Chen, B},
title = {Amyloid-β dimers bind to microglial TLR2 to induce early neuroinflammation and cognitive deficits in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.11.017},
pmid = {43009006},
issn = {1873-7544},
abstract = {Previous studies have shown that amyloid-β (Aβ) oligomers are implicated in the pathogenesis of Alzheimer's disease (AD). Aβ oligomers include various molecules with distinct characteristics, such as dimers and trimers; among these, Aβ dimers have been found to possess neurotoxicity. This study found that Aβ dimers can induce microglial proliferation, enhanced phagocytosis, and pro-inflammatory polarization in the mouse brain even before cognitive impairment occurs, and this effect was validated in vitro using BV2 cells. Mechanistically, Aβ dimers bind to the microglial receptor TLR2, activating the downstream NF-κB signaling pathway and upregulating the expression of inflammatory factors. Knocking down TLR2 significantly reverses the Aβ dimer-induced inflammatory response and alleviates microglial-mediated neuronal damage. Furthermore, repeated intracerebral injections of Aβ dimers lead to impaired learning and memory in mice, as well as loss of hippocampal neurons and synapses; these changes are independent of amyloid plaque deposition and tau protein hyperphosphorylation. In summary, Aβ dimers induce early neuroinflammation and cognitive deficits by binding to TLR2 on microglia, providing a new molecular target for early intervention in AD.},
}

@article {pmid43009032,
year = {2026},
author = {Kshirsagar, S and Alvir, RV and Pradeepkiran, JA and Ramasubramaniam, B and Hindle, A and Vijayan, M and Kumar, S and Reddy, AP and Reddy, PH},
title = {Urolithin A plus EGCG enhances mitophagy associated pathways, mitochondrial dynamics, and bioenergetic function in humanized amyloid-β knock-in mice.},
journal = {Mitochondrion},
volume = {},
number = {},
pages = {102237},
doi = {10.1016/j.mito.2026.102237},
pmid = {43009032},
issn = {1872-8278},
abstract = {Mitochondrial dysfunction and impaired mitochondrial quality control are increasingly recognized as important contributors to Alzheimer's disease (AD). Urolithin A is a mitophagy-promoting metabolite, whereas epigallocatechin-3-gallate (EGCG) has antioxidant, anti-inflammatory, and anti-amyloidogenic properties. In the present study, we evaluated the effects of urolithin A alone and in combination with EGCG on mitochondrial homeostasis in humanized amyloid-β knock-in (hAbKI) mice. Three-month-old hAbKI mice were treated with urolithin A (2.5 mg/kg) or urolithin A plus EGCG (25 mg/kg) by intraperitoneal injection three times per week for four months. At seven months of age, mitochondrial dynamics, mitochondrial biogenesis, mitophagy/autophagy-associated pathways, mitochondrial ultrastructure, ATP production, oxidative stress, synaptic and dendritic markers, glial and neuronal proteins, soluble Aβ40 and Aβ42 levels, and behavioral performance were evaluated. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis showed reduced expression of the mitochondrial fission genes Drp1 and Fis1 and increased expression of the fusion genes Mfn1, Mfn2, and Opa1 following treatment. Mitochondrial biogenesis-associated genes, including PGC1α, Nrf1 and TFAM, were also increased. These transcriptional changes were supported by immunoblotting analyses. Treatment further increased mitophagy- and autophagy-associated markers, including PINK1, Parkin, ATG5, LC3B, Beclin1, and BCL2. Transmission electron microscopy demonstrated increased mitochondrial length, reduced mitochondrial fragmentation. These changes were accompanied by increased mitochondrial ATP levels and reduced hydrogen peroxide and 4-hydroxynonenal levels. Both treatment regimens were also associated with increased synaptic and dendritic measures, reduced Iba1 and GFAP expression, increased NeuN levels, lower soluble Aβ40 and Aβ42 concentrations, and improved performance in several behavioral tasks. Across multiple mitochondrial and neuronal endpoints, the magnitude of the response was greater following combined urolithin A and EGCG treatment. These findings indicate that urolithin A modulates multiple components of mitochondrial quality control in hAbKI mice and that co-treatment with EGCG is associated with broader improvements in mitochondrial and neuronal homeostasis. Further studies are required to define the specific contribution of EGCG and to directly assess mitophagic flux and mitochondrial respiration.},
}

@article {pmid42999530,
year = {2026},
author = {Yildiz, M and Winstead, V and Jacob, A and Nemariam, A and Paul, N and Pickering, C},
title = {The Effect of Noncontingent Monetary Incentives in Recruitment Letters on Research Enrollment of Alzheimer's Disease and Related Dementia Caregiving Dyads: A Study Within a Trial (SWAT) Randomized Controlled Trial.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10818940/v1},
pmid = {42999530},
issn = {2693-5015},
abstract = {BACKGROUND Recruitment of persons living with Alzheimer's disease and related dementias (ADRD) and their family caregivers remains challenging. Although noncontingent monetary incentives are frequently used to increase research participation, little experimental evidence supports their effectiveness for recruiting ADRD caregiving dyads. We evaluated whether noncontingent monetary incentives included in mailed recruitment letters increased study response and enrollment. METHODS This Study Within A Trial (SWAT) randomized controlled trial identified 300 potential participants through the clinical data warehouse of a US academic health system using documented dementia diagnoses and recent healthcare utilization. Participants were randomized to receive a recruitment letter with no incentive (n = 103), a $5 noncontingent gift card (n = 93), or a $25 noncontingent gift card (n = 104). Individuals who did not directly respond received follow-up telephone outreach. Outcomes included response to the recruitment letter, eligibility, and study enrollment. RESULTS Twenty-two participants (7.3%) directly responded to the recruitment letter, and 31 (10.3%) ultimately enrolled. Response rates did not differ significantly across incentive groups (χ[2]=1.73, p=.420). Compared with no incentive, neither the $5 incentive (OR = 1.53; 95% CI, 0.47-5.35; p=.485) nor the $25 incentive (OR = 2.06; 95% CI, 0.70-6.81; p=.204) was significantly associated with response. Age and gender were also not associated with response. Follow-up telephone outreach resulted in additional enrollments but required substantial personnel resources. CONCLUSION In this trial, $5 and $25 noncontingent monetary incentives included in mailed recruitment letters did not produce a detectable improvement in response among ADRD caregiving dyads. The low response and enrollment rates, coupled with the personnel resources required for follow-up outreach, underscore the practical challenges of recruiting caregiving dyads. Experimental evaluation of scalable, caregiver-centered, and theory-driven recruitment strategies is needed to strengthen the evidence base for efficient ADRD research recruitment.},
}

@article {pmid42999580,
year = {2026},
author = {Ai, P and Wang, X and Shi, H and Wu, A and Wang, J},
title = {Identification of m5C-associated gene signatures in Alzheimer's disease and their relationship with immune infiltration.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {1087-1101},
pmid = {42999580},
issn = {2667-2421},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex genetic, epigenetic, and immune components. This study investigated m5C-associated gene-expression signatures in AD and explored their biological and immune-cell associations.

METHODS: Two GEO datasets (GSE132903 and GSE118553) were used for discovery, with GSE33000 and GSE122063 used for external expression assessment. Differential-expression, GO/KEGG enrichment, GSEA, protein-protein interaction, regulatory-network, CIBERSORTx, and ROC analyses were performed. Selected candidates were further examined by RT-qPCR in cortex and hippocampus from 4-month-old male 5 ×FAD mice and age-matched WT controls (n = 5 per group).

RESULTS: Five m5C-associated differentially expressed candidate genes (ZBTB4, MBD4, ZBTB33, NEIL1, and TDG) were identified. ZBTB4 showed reproducible expression differences across several human datasets, but its ROC AUC values (0.657, 0.605, and 0.569) indicated limited standalone discriminatory performance. Gene-immune-cell correlations were statistically significant but weak. In the 5 ×FAD model, Zbtb4 and Mbd4 mRNA levels were significantly reduced in both cortex and hippocampus compared with WT controls.

CONCLUSION: The integrated analyses identify candidate methylation/m5C-associated expression changes in AD and provide in vivo transcript-level corroboration for Zbtb4 and Mbd4. The ROC and immune-infiltration findings should be considered exploratory and do not establish clinical diagnostic utility or causal immune mechanisms.},
}

@article {pmid42999587,
year = {2026},
author = {Duan, D and Xu, S and Wu, K and Xu, M and Zhou, S and Yang, X and Guo, X and Yan, S and Yan, J and Yao, Q},
title = {Pomegranate Seed Oil Biologically Engineered Lactobacillus Extracellular Vesicles with Enhanced Yield and Brain Delivery via ApoE-Enriched Protein Corona.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {636377},
pmid = {42999587},
issn = {1178-2013},
mesh = {Animals ; *Plant Oils/chemistry/pharmacology ; *Pomegranate/chemistry ; Brain/metabolism ; *Extracellular Vesicles/chemistry/metabolism ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; *Apolipoproteins E/chemistry/metabolism ; Seeds/chemistry ; Rats ; },
abstract = {PURPOSE: The blood-brain barrier (BBB) is a major bottleneck for nanomedicine-based treatment of central nervous system (CNS) disorders. Lactobacillus-derived extracellular vesicles (LEV) are promising biocompatible nanocarriers, but their low production yield and limited BBB permeability hinder their development. We hypothesized that stimulation of Lactobacillus with pomegranate seed oil (PSO), or its nanoemulsion (PSO NE), could remodel the LEV membrane to simultaneously enhance vesicle production and brain accumulation.

METHODS: Lactobacillus was stimulated with PSO or PSO NE to generate engineered LEV. Lipidomic and proteomic analyses were performed to characterize membrane remodeling and plasma protein corona formation. Oleuropein (OL) was loaded into different LEV formulations, and their BBB permeability and brain accumulation were evaluated in vivo. The anti-amyloid β (Aβ) aggregation activity and biocompatibility of the engineered LEVs were also assessed.

RESULTS: PSO and PSO NE increased LEV production by approximately 3- and 5-fold, respectively, while markedly remodeling their membrane composition, with enrichment of phospholipids, triglycerides, and apolipoproteins. Upon exposure to plasma, the remodeled LEVs spontaneously acquired an apolipoprotein E (ApoE)-rich protein corona, facilitating BBB transport through low-density lipoprotein receptor (LDLR)-mediated transcytosis. Accordingly, OL-loaded LEV-PSO and LEV-PSO NE achieved 5-7-fold higher brain exposure than free OL, compared with only a 1.17-fold increase for conventional OL@LEV. Both native and OL-loaded LEVs inhibited Aβ aggregation, with OL-loaded formulations showing stronger activity. Repeated administration for 14 days demonstrated good biocompatibility and significantly increased BBB LDLR expression following LEV-PSO and LEV-PSO NE treatment.

CONCLUSION: PSO-mediated membrane engineering substantially improves LEV production and BBB transport through protein-corona modulation, providing a scalable and versatile platform for CNS drug delivery.},
}

Animals
*Plant Oils/chemistry/pharmacology
*Pomegranate/chemistry
Brain/metabolism
*Extracellular Vesicles/chemistry/metabolism
Blood-Brain Barrier/metabolism
Amyloid beta-Peptides/metabolism
*Apolipoproteins E/chemistry/metabolism
Seeds/chemistry
Rats

@article {pmid43000200,
year = {2026},
author = {Zhang, Z and Wang, K and Guo, X and Zhang, G and Jin, Y and Wang, Z},
title = {Chiral Materials for the Recognition and Inhibition of Amyloid-β Aggregation.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {},
doi = {10.1002/adhm.71957},
pmid = {43000200},
issn = {2192-2659},
support = {22474007//National Natural Science Foundation of China/ ; 22574009//National Natural Science Foundation of China/ ; KF2025021//State Key Laboratory of Natural and Biomimetic Drugs/ ; XK2025-05//Interdisciplinary Research Center of Beijing University of Chemical Technology/ ; buctrc202415//Fundamental Research Funds for the Central Universities/ ; },
abstract = {Abnormal aggregation of amyloid-β (Aβ) peptides is a central pathological event in Alzheimer's disease (AD), closely associated with neurotoxicity and disease progression. The development of molecules or materials with high selectivity and affinity toward Aβ aggregates constitutes an essential component for the early diagnosis and intervention of AD. Aβ peptides, composed of homochiral amino acids, undergo intermolecular β-sheet assembly to form supramolecular chiral aggregates, providing a structural basis for chirality-sensitive recognition. Therefore, chiral materials have attracted significant attention in Aβ aggregates recognition and regulation. Previous reviews have examined different types of chiral materials for the inhibition of Aβ aggregation, including chiral small molecules, amino acids, peptides, and various chiral interfaces or nanomaterials. The present review organizes reported chiral materials according to three intervention strategies for modulating Aβ aggregation: conformation-locking, self-assembly-induced remodeling, and multifunctional intervention. We summarize representative materials in each category, along with the corresponding design principles and modulation performance toward Aβ aggregation. Current challenges and potential directions for the development of chiral therapeutics for AD are also discussed.},
}

@article {pmid43000408,
year = {2026},
author = {Hovakimyan, A and Madoyan, H and Najarzadeh, Z and Chilingaryan, G and Petrushina, I and Mamikonyan, G and Lebedeva, E and Zaitsev, A and Mansour, K and O'Malley, TP and Gonen, S and Kniazev, R and Petrovsky, N and Grinberg, A and Alexander, RC and Schneider, LS and Ataullakhanov, R and Glabe, C and Ghochikyan, A and Agadjanyan, MG},
title = {A randomized, placebo-controlled, double blind Phase 1 trial of the Aβ vaccine, AV-1959R, in non-cognitively impaired participants: prelude for secondary preventive therapy in preclinical AD.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {43000408},
issn = {1750-1326},
support = {U01 AG060965//National Institutes of Health (NIH)/ ; U24 AG079683-01/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Double-Blind Method ; *Alzheimer Disease/prevention & control/immunology ; *Amyloid beta-Peptides/immunology ; Female ; Male ; Middle Aged ; *Alzheimer Vaccines/therapeutic use/immunology ; Adult ; Vaccination ; },
abstract = {BACKGROUND: Active immunotherapy targeting amyloid-β (Aβ) represents a promising strategy for preventing Alzheimer's disease (AD) in cognitively normal individuals at risk, referred to as the preclinical AD population. However, all Aβ vaccines tested so far in people with disease have faced significant challenges, primarily due to inadequate immunogenicity and insufficient antibody titers required to clear, reduce, or slow amyloid pathology. AV-1959R is a new generation MultiTEP-based Aβ vaccine specifically designed to overcome self-tolerance, provide broad T helper cell support, avoid the activation of Aβ-specific T cells, and elicit high levels of antibodies that selectively target pathological Aβ species in 100% of vaccinated individuals.

METHODS: We conducted a randomized, double-blind, placebo-controlled Phase 1 trial in 16 healthy adults aged 40-60 years. Participants received three intramuscular immunizations of AV-1959R (100-300 µg) or placebo formulated with Advax-CpG55.2 adjuvant (Day 1, Week 4, Week 14). Primary endpoints were safety and tolerability; secondary endpoints included humoral immunogenicity, antibody specificity, and isotype profiling. Antibody responses were assessed using validated ELISA and conformational Aβ microarray assays, and antibody kinetics were modeled to estimate durability.

RESULTS: AV-1959R was safe and well-tolerated, with no serious adverse events or ARIA observed. Adverse events were predominantly mild, transient injection-site reactions typical of adjuvanted vaccines. After receiving only two immunizations (priming), all vaccinated participants (12/12) developed antibody titers exceeding those reported for other Aβ vaccines in clinical trials. Induced antibodies selectively targeted pathological Aβ42 protofibrils and fibrils, with weaker binding to oligomers and minimal reactivity to monomers. Modeling based on priming and a single booster immunization predicts that antibody titers will remain 5 times above the baseline for approximately 1 year after priming, supporting an annual booster strategy. Vaccine-induced antibodies were of the IgG isotype and bound to amyloid plaques in human AD brain tissue.

CONCLUSIONS: AV-1959R combines a favorable safety profile with potent, selective, and durable anti-Aβ immunity. Its 100% responder rate, induction of high antibody titers, selective targeting of pathogenic Aβ species, and dosing regimen distinguish AV-1959R from all previously discontinued Aβ vaccines and several AD vaccines tested in Phase 1/2 trial with Alzheimer's and/or Down Syndrome individuals. These features classified AV-1959R as the top-tier, scalable immunogenic Aβ vaccine that can be safely used in the preclinical AD population with the evidence of amyloid pathology, with or without tau pathology, aiming to clear, reduce, prevent, or at least slow Aβ accumulation and the onset of Alzheimer's. The protocol for a planned Phase 2 preventive trial of AV-1959R under IND 30925-0004, has received IRB approval. Once initiated, the study will evaluate the vaccine's biological efficacy using established AD brain and blood biomarkers.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12624000737538; ClinicalTrials.gov NCT06831812.},
}

Humans
Double-Blind Method
*Alzheimer Disease/prevention & control/immunology
*Amyloid beta-Peptides/immunology
Female
Male
Middle Aged
*Alzheimer Vaccines/therapeutic use/immunology
Adult
Vaccination

@article {pmid43000457,
year = {2026},
author = {Massa, F and Lechiara, A and De Cesari, F and Pelagotti, V and Panza, A and Bozzo, G and Urbinati, M and Losa, M and Raffa, S and Mobilia, EM and Bozzano, FM and Visigalli, D and Lorenzini, L and Brugnolo, A and Girtler, N and Arnaldi, D and Schenone, A and Uccelli, A and Sambuceti, G and Morbelli, S and Pesce, G and Pardini, M},
title = {A CSF NPTX2-based residual metric captures prognostic heterogeneity within a proposed compensatory framework in prodromal Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {43000457},
issn = {1758-9193},
support = {PE0000006//Ministero dell'Università e della Ricerca/ ; 5x1000 2023//Ministero della Salute/ ; C13C23001070006//Ministero della Salute/ ; },
mesh = {Humans ; *C-Reactive Protein/cerebrospinal fluid ; Pentraxins ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis ; *Nerve Tissue Proteins/cerebrospinal fluid ; Female ; Aged ; Biomarkers/cerebrospinal fluid ; Male ; Retrospective Studies ; Disease Progression ; Prognosis ; Positron-Emission Tomography ; Fluorodeoxyglucose F18 ; Neurogranin/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Prodromal Symptoms ; Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; Brain/diagnostic imaging/metabolism ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: In Alzheimer's disease(AD), core CSF biomarkers incompletely predict clinical progression. Synaptic biomarkers may add prognostic information by capturing distinct biological dimensions, from synaptic injury to adaptive network function. Although correlated, neurogranin (Ng) is interpreted as a marker of post-synaptic injury, whereas neuronal pentraxin-2(NPTX2) is more closely related to circuit homeostasis. We tested whether CSF NPTX2 contains a specific component statistically associated with a putative adaptive network signal, interpreted within a hypothesized compensatory framework, using clinical progression and brain metabolism as convergent readouts.

METHODS: We retrospectively studied 104 patients with typical MCI-AD. CSF core AD biomarkers, NPTX2 and Ng were measured with commercial immunoassays. Early and late MCI stages were defined by proximity to dementia conversion (LMCI ≤ 2 years; EMCI > 2 years or stable). A residual NPTX2 measure(Res_NPTX2) was derived by regressing z-transformed NPTX2 on Ng, an index of AD burden based on tau/amyloid ratio, and age. Associations with MMSE and time-to-conversion were tested using linear and survival models. In all patients, brain [[18]F]FDG PET was analyzed with voxel-based methods to identify metabolic correlates of NPTX2 and Res_NPTX2 relative to AD-related hypometabolic regions.

RESULTS: Ng correlated strongly with NPTX2 (ρ = 0.67,p < 0.001). Res_NPTX2 was higher in EMCI than LMCI (p = 0.0006), associated with better baseline MMSE (p = 0.008), and predicted less MMSE decline over time (p = 0.002). During follow-up, 55/104 patients(52.9%) progressed to dementia. Higher Res_NPTX2 predicted lower progression risk (HR = 0.63,p = 0.007), including after accounting for baseline MMSE. Kaplan-Meier curves differed across Res_NPTX2 tertiles, with the strongest separation within 2 years (high vs. low: HR = 0.18,p = 0.008). On [[18]F]FDG PET, LMCI showed more marked left-sided posterior hypometabolism than EMCI. CSF NPTX2 and Res_NPTX2 were associated with distinct metabolic patterns centered on prominently left posterior parietal and right fronto-striatal regions, respectively.

CONCLUSIONS: In prodromal AD, CSF NPTX2 contains clinically relevant information beyond Ng and core biomarker burden. The proposed residualization approach provides a statistical strategy to isolate an NPTX2-related component associated with better cognition, lower short-term progression risk, and a precise right fronto-striatal metabolic signature. Within a hypothesized compensatory framework, this statistically isolated component may index a putative adaptive network capacity and help characterize clinically meaningful heterogeneity in early AD.},
}

Humans
*C-Reactive Protein/cerebrospinal fluid
Pentraxins
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis
*Nerve Tissue Proteins/cerebrospinal fluid
Female
Aged
Biomarkers/cerebrospinal fluid
Male
Retrospective Studies
Disease Progression
Prognosis
Positron-Emission Tomography
Fluorodeoxyglucose F18
Neurogranin/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Prodromal Symptoms
Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging
Brain/diagnostic imaging/metabolism
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Aged, 80 and over

@article {pmid43000458,
year = {2026},
author = {Lukkarinen, HEM and Luikku, AJ and Dougalis, AG and Pelkonen, A and Gomez-Budia, M and Abushik, P and Novosolova, N and Jäntti, H and Elomaa, AP and Kaipainen, A and Klimko, N and Walle, P and Jyrkkänen, HM and Danner, N and Piilonen, K and Firtser, NE and Immonen, A and Jääskeläinen, JE and Paterson, RW and Kahle, KT and Eide, PK and Macosko, E and Stevens, B and Julkunen, V and Solje, E and Takalo, M and Juopperi, SP and Kemppainen, S and Martiskainen, H and Lipponen, A and Hiltunen, M and Rauramaa, T and Malm, T and Leinonen, V},
title = {Live brain biopsy during CSF shunt surgery for precision diagnostics and multi-omic research.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {43000458},
issn = {1758-9193},
support = {338182//Research Council of Finland/ ; 339767//Research Council of Finland/ ; ADSF-24-1284326-C/ALZ/Alzheimer's Association/United States ; Strategic Neuroscience Funding of the UEF//Itä-Suomen Yliopisto/ ; },
mesh = {Humans ; *Cerebrospinal Fluid Shunts/methods ; *Brain/pathology/surgery ; *Hydrocephalus, Normal Pressure/surgery/pathology ; Multiomics ; Biopsy/methods ; Animals ; *Precision Medicine/methods ; Proteomics ; },
abstract = {Diagnostic testing and neurosurgical management involving CSF shunting in patients with idiopathic normal pressure hydrocephalus (iNPH) offers a unique, ethically sustainable opportunity to study the aging human brain. The common co-occurrence of neurodegenerative pathologies such as amyloid-β plaques and neurofibrillary tau tangles (NFT) provides a valuable window for research into the Alzheimer's disease-related mechanisms. Interindividual variability among iNPH patients enables investigation and validation of biomarkers and molecular mechanisms, opening possibilities for new treatments. In vitro techniques and culturing methods for living brain tissue expand the utility of samples for electrophysiological studies, drug testing, and examining genetic risk variants. Careful sectioning and processing are essential for high-quality samples with intact cells for functional analysis. A rigorous pipeline is also needed for preserving samples for transcriptomic, proteomic, and structural analyses, with emphasis on RNA integrity and tissue architecture for single-cell sequencing and spatial analysis. Here, we review the use of small cortical brain biopsies in neurodegenerative diseases research and diagnostics. Furthermore, we share our team's experience in acquiring and preserving living brain samples during iNPH CSF shunt surgeries, along with our protocols for resection, use, and preservation of biopsies for preclinical research. We highlight the potential of living human tissue for neuroscience, early neurodegenerative disease diagnosis, and targeted therapies.},
}

Humans
*Cerebrospinal Fluid Shunts/methods
*Brain/pathology/surgery
*Hydrocephalus, Normal Pressure/surgery/pathology
Multiomics
Biopsy/methods
Animals
*Precision Medicine/methods
Proteomics

@article {pmid43000671,
year = {2026},
author = {Bovolenta, P and Miaja, P and D'ambra, E and Martínez-Baños, M and Pereyra, G},
title = {SFRP1 as a therapeutic target in Alzheimer's disease: a druggable molecule involved in amyloid, synaptic, and inflammatory pathology.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2760107},
pmid = {43000671},
issn = {1744-7631},
abstract = {INTRODUCTION: Alzheimer's disease (AD), a leading cause of dementia worldwide, still lacks broadly effective disease-modifying therapies. Recent anti-amyloid monoclonal antibodies highlight both the promise and limitations of amyloid-only strategies. Secreted Frizzled-Related Protein 1 (SFRP1), a Wnt antagonist and endogenous inhibitor of the α-secretase ADAM10, has emerged as a glial- and choroid plexus-derived pathogenic factor promoting amyloidogenic APP processing and accumulation, neuroinflammation, and synaptic dysfunction.

AREAS COVERED: We review SFRP1 regulation of ADAM10-dependent non-amyloidogenic APP processing; its accumulation in amyloid plaques and cerebrospinal fluid of AD patients, independently corroborated by unbiased proteomic studies; its role as an astrocyte-to-microglia amplifier of neuroinflammation; its contribution to synaptic and cognitive decline in transgenic models; and its emerging link to APOEε4. We also discuss antibody- and small-molecule-based neutralization strategies, including pharmacodynamic and stage-dependent data defining its therapeutic window.

EXPERT OPINION: SFRP1 is a mechanistically validated, multifunctional target intersecting amyloid, inflammatory, and synaptic pathways upstream of plaque formation. Clinical translation requires sustained brain exposure without compromising safety, biomarker-guided early intervention, and management of systemic consequences from Wnt and ADAM10 de-repression. Addressing these challenges could establish anti-SFRP1 therapy as a complementary, mechanistically distinct AD treatment.},
}

@article {pmid43000884,
year = {2026},
author = {Alkhodair, Y and Smith, RJY and Helbling, C and DeMarco, ML},
title = {Rapid Apolipoprotein E ε4 Proteotyping for Alzheimer's Disease Anti-Amyloid Therapy Eligibility and Risk Assessment.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/cjn.2026.10688},
pmid = {43000884},
issn = {0317-1671},
abstract = {BACKGROUND: Anti-amyloid therapies for Alzheimer's disease (AD) are associated with amyloid-related imaging abnormalities (ARIA), with apolipoprotein E ε4 (APOE4) homozygosity conferring the highest risk. Given the new clinical need, novel plasma proteotyping assays may offer a rapid and high-throughput alternative to existing methods.

METHODS: We evaluated proteotyping performance against real-time polymerase chain reaction (PCR) genotyping in a cohort of 104 participants. Plasma samples were analyzed using apoE4 and total apoE assays on the Fujirebio Lumipulse G1200. APOE4 allelic status (non-carrier, heterozygote or homozygote) was determined from the apoE4-to-total apoE ratio. Analytical validation assessed precision, matrix interference and freeze/thaw stability.

RESULTS: Proteotyping correctly identified all non-carriers (n = 53) and all E4/E4 homozygotes (n = 6). Among 45 heterozygotes, 4 were misclassified as homozygotes, yielding 40% misclassification rate for homozygosity but 100% negative predictive value (NPV). Overall accuracy was 96.2%. The assay performed robustly in the presence of hemolysate and lipemia, with consistent results up to 4 freeze/thaw cycles.

CONCLUSION: Proteotyping reliably rules out E4/E4 homozygosity (100% NPV), enabling rapid eligibility screening for anti-amyloid therapies. Positive homozygosity results require confirmatory testing due to the potential for error. Among non-homozygous results, the assay discriminates E4 carriers from non-carriers, supporting ARIA risk stratification. As plasma phospho-tau217 testing is more commonly used, the ability to run plasma apoE4 testing on the same automated clinical immunoassay analyzer (and the same sample) enables a reflexive testing workflow, supporting more efficient treatment decision-making in the era of disease-modifying therapies.},
}

@article {pmid43000917,
year = {2026},
author = {Motamed, Z and Heutschi, D and Carine, G and Suter-Dick, L},
title = {Exosome-associated cargo is linked to familial Alzheimer's disease-associated phenotypes in vitro.},
journal = {Disease models & mechanisms},
volume = {},
number = {},
pages = {},
doi = {10.1242/dmm.052734},
pmid = {43000917},
issn = {1754-8411},
support = {NA//FHNW (School of Life Sciences)/ ; },
abstract = {The propagation of pathological proteins such as tau and amyloid-beta (Aβ) in Alzheimer's disease (AD) is poorly understood. Here, we developed a human-relevant in vitro conditioned medium (CM)-based model using human neural progenitor ReN cells carrying Familial AD (FAD) mutations in amyloid precursor protein (APP Sw/Lo) and presenilin 1 (PSEN1ΔE9). Healthy ReN-derived neurons and astrocytes treated with FAD-CM for nine weeks exhibited AD features, including cellular toxicity, neuro-glial alterations, and mitochondrial dysfunction. Exogenous Aβ42 further induced neuroglial and mitochondrial damage. Exosomes released by FAD cells and -to a lesser extent- by CM-treated healthy cells showed elevated Aβ42/40 ratios. Proteomic analysis also revealed that exosomes from FAD-cells carried a distinct content, including overrepresentation of proteins linked to inflammation, extracellular matrix remodelling, synaptic dysfunction, and Aβ processing, as well as Calmodulin-like protein 3. Moreover, exosomes were actively internalized by healthy cells through an actin-dependent mechanism. In summary, these findings support a model based on FAD-associated APP/PSEN1 mutations in which exosome-associated cargo alongside soluble and non-vesicular factors contribute to the transfer of AD-associated cellular phenotypes.},
}

@article {pmid43001167,
year = {2026},
author = {Li, L and Zhang, YB and Zhang, RZ and Xie, WT and Wang, Y and Zhao, YR and Wei, YT and Ma, C and Yan, XK},
title = {Glial Cell Mechanisms in Alzheimer's Disease Pathology and Progress in Biomarker Research.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {646472},
pmid = {43001167},
issn = {1176-6328},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in older adults and is increasingly recognized as a systems-level disease involving dynamic dysfunction and crosstalk among multiple glial cell populations. Microglia, astrocytes, and oligodendrocytes play distinct but interconnected roles across the AD continuum. Microglia respond to amyloid-β (Aβ) and tau pathology by adopting disease-associated phenotypes that contribute to neuroinflammation, complement-dependent synaptic pruning, and immunometabolic reprogramming. Astrocytes undergo reactive changes in response to pathological proteins and microglial inflammatory signals, thereby disrupting neurotransmitter homeostasis, energy and lipid metabolism, and neurovascular unit function. Oligodendrocytes and their precursor cells contribute through myelin injury, impaired remyelination, and reduced axonal metabolic support, potentially forming self-reinforcing loops with protein aggregation and glial inflammation. Unlike reviews focused primarily on individual glial cell types or isolated pathways, this review integrates glial state transitions, pathogenic mechanisms, measurable biomarkers, and disease progression within a unified framework. We summarize glia-related biomarkers reflecting cellular activation, inflammation, metabolic dysfunction, and myelin damage, and discuss their potential value for early detection, disease stratification, progression prediction, and therapeutic monitoring. Important knowledge gaps remain, including limited understanding of stage-specific glial heterogeneity, uncertain correspondence between peripheral or fluid biomarkers and central nervous system pathology, and insufficient standardization across cohorts and analytical platforms. Future studies combining longitudinal cohorts, single-cell and spatial multi-omics, and multimodal biomarker strategies are needed to clarify causal relationships between glial states and AD progression and to facilitate translation toward precision classification and stage-specific intervention. This integrative perspective positions glial biomarkers as measurable links between cellular pathology and clinical evolution, offering a framework for mechanism-based patient stratification and therapeutic development.},
}

@article {pmid43001175,
year = {2026},
author = {Guo, X and Guo, Z and Peng, T and Pan, J and Zhang, M and Ye, X and Wen, J and Liu, X and Li, Y and Lin, X},
title = {Integrated Machine Learning and Experimental Validation Identify Shared Aging-Related Molecular Signatures in Alzheimer's Disease and Osteoporosis.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {622187},
pmid = {43001175},
issn = {1178-7074},
abstract = {BACKGROUND: Aging is a key biological driver implicated in the initiation and progression of both Alzheimer's Disease (AD) and Osteoporosis (OP). However, the shared aging-related molecular alterations underlying these disorders remain incompletely understood.

METHODS: Transcriptomic datasets of AD and OP, together with curated aging-related genes (ARGs), were systematically collected. Differential expression analysis was conducted using the limma algorithm, followed by weighted gene co-expression network analysis (WGCNA) to identify disease-associated gene modules. Multiple machine learning algorithms were subsequently employed to prioritize candidate biomarkers, and model interpretability was assessed using SHapley Additive exPlanations (SHAP). Immune infiltration profiles were characterized via CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). Finally, quantitative real-time PCR (RT-qPCR) was conducted to validate the expression of six core candidate genes.

RESULTS: Integrated analysis identified 228 aging-related genes shared by AD and OP. EGR1, NFKBIA, UQCRC2, RB1, CREBBP, and NDUFV1 were selected based on the comparative performance of 130 machine learning models for disease prediction. Enrichment analyses linked these genes to cellular senescence, inflammatory signaling, mitochondrial oxidative phosphorylation, and cell-cycle regulation, suggesting convergent aging-related alterations in AD and OP. RT-qPCR analysis in the D-galactose-induced senescence models revealed cell-type-specific expression patterns: all six genes were significantly altered in HT22 cells, whereas EGR1, NFKBIA, UQCRC2, and NDUFV1 were significantly altered in MC3T3-E1 cells, with no significant changes observed in RB1 or CREBBP. Moreover, they exhibited robust diagnostic potential, as reflected by nomogram analyses, and showed significant correlations with immune cell infiltration profiles.

CONCLUSION: This study elucidates shared aging-related genes linking AD and OP. The six identified hub ARGs demonstrate significant immunological relevance and diagnostic value. Collectively, these findings offer novel insights into shared pathogenic mechanisms and highlight potential targets for integrated therapeutic strategies.},
}

@article {pmid43001258,
year = {2026},
author = {Tao, Z},
title = {The hypertension-NVU-cognition Axis: Mechanisms and interventions.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100174},
pmid = {43001258},
issn = {2589-9589},
abstract = {Midlife hypertension is a major modifiable risk factor for Alzheimer's disease, but the specific molecular pathways through which it contributes to cognitive decline-pathways that are partially independent of, and interact with, amyloid-β pathology-are not fully elucidated. This review synthesizes and elaborates the "Hypertension-NVU-Cognition" axis, building on the established cerebrovascular biology, neurovascular unit, cerebral small vessel disease (CSVD), and vascular cognitive impairment (VCID) literature, within which this axis is positioned as an integrative, complementary framework rather than a wholly novel or independent pathway. Sustained hypertension damages the neurovascular unit (NVU) through hemodynamic stress, blood-brain barrier (BBB) disruption (via tight junction and pericyte loss), and neuroinflammation (pro-inflammatory microglial activation and reactive astrogliosis). This NVU dysfunction directly impairs cognition via glutamate excitotoxicity, cholinergic axonal ischemia, and reduced Aβ clearance. Critically, midlife blood pressure trajectories are stronger predictors of late-life cognition than late-life levels. NVU injury frequently coexists with amyloid pathology, yet emerging evidence indicates it also contributes to cognitive decline in individuals with low amyloid burden, highlighting its complementary and potentially synergistic role alongside classical AD mechanisms. This axis highlights candidate molecular targets and biomarkers that merit further investigation for early intervention. Promising biomarkers include plasma sPDGFRβ (pericyte injury) and DCE-MRI Ktrans (BBB leakage). Promising future research directions include standardizing NVU biomarkers and conducting targeted trials that combine intensive blood pressure control with investigational NVU-protective agents (e.g., GLP-1 receptor agonists) in at-risk midlife individuals; these approaches are not yet clinically actionable and require validation in adequately powered randomized controlled trials. Understanding this axis is crucial for developing effective preventive therapies against vascular cognitive impairment.},
}

@article {pmid43001342,
year = {2026},
author = {Matton, A and Udeh-Momoh, C and Daniilidou, M and Bereczki, E and Alanko, V and Padilla, P and Baker, LD and Ban, K and Borda, MG and Caramelli, P and Martinez-Lage Alvarez, P and Del Campo, M and Ferrarese, C and Hartmann, T and Huque, H and Karikari, TK and Kaya, D and Kruger, R and Kuan, YC and Lai, MKP and Mather, K and Meyers, E and Okubadejo, N and Onyango, S and Rajab, N and Rocha da Silva Nunes, MV and Rosenberg, A and Sala, G and Salinas Contreras, RM and Sayed, S and Scales, M and Choi, SH and Sohrabi, H and Soininen, H and Sugimoto, T and Surace, E and Wang, Y and Zetterberg, H and Zwan, M and Solomon, A and Mangialasche, F and Kivipelto, M and , },
title = {Developing the World-Wide FINGERS biorepository for dementia risk reduction trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
doi = {10.1002/alz.71949},
pmid = {43001342},
issn = {1552-5279},
support = {101132933//European Union (EU) Innovative Health Initiative Joint Undertaking (IHI JU) AD-RIDDLE/ ; //Alzheimerfonden/ ; //Demensfonden/ ; //Center for Innovative Medicine/ ; //Stiftelsen Stockholms sjukhem/ ; //the Swedish Research Council/ ; //European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for clinical research/ ; R01AG057531//the NIH/ ; //Gun och Bertil Stohnes Stiftelse/ ; //Åhlén-stiftelsen/ ; 101053962//HORIZON EUROPE Framework Programme/ ; #2023-00356//Vetenskapsrådet/ ; #2022-01018//Vetenskapsrådet/ ; #2019-02397//Vetenskapsrådet/ ; //Forte foundation Sweden/ ; //Stockholms Läns Landsting/ ; //European Union Innovative Health Initiative Joint Undertaking/ ; //Gates Ventures/ ; //Alzheimer's disease data initiative (ADDI)/ ; },
mesh = {Humans ; *Dementia/prevention & control ; *Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; *Risk Reduction Behavior ; *Biological Specimen Banks ; Specimen Handling ; },
abstract = {INTRODUCTION: Dementia prevention research increasingly uses multimodal interventions. Harmonized biomarker practices are essential to enable comparable cross-population analysis with initiatives such as the World-Wide FINGERS (WW-FINGERS) network contributing to this effort.

METHODS: To advance globally representative biomarker research in dementia prevention trials, we conducted a cross-sectional, network-wide survey of WW-FINGERS teams assessing biospecimen collection, processing and storage, biomarker measurements, and readiness for harmonized procedures.

RESULTS: Most studies (30/39) had or were developing biorepositories; four planned collection and five had none. Practices were broadly aligned, but remaining variability highlights priority targets for harmonization. Clinical biomarkers (lipids, glucose, liver/kidney function) were obtained even in lower-resourced settings. Many studies measured Alzheimer's disease and related dementias (ADRD) biomarkers (blood-based amyloid/tau and neurodegeneration; cerebrospinal fluid where feasible) and increasingly used multi-omics platforms. Evidence-based preanalytical guidance were provided.

CONCLUSION: The WW-FINGERS biorepository provides a world-first platform for harmonized biomarker discovery across diverse populations in dementia prevention, helping to reduce inequities in research participation, accelerating globally representative strategies.},
}

Humans
*Dementia/prevention & control
*Biomarkers/cerebrospinal fluid
Cross-Sectional Studies
*Risk Reduction Behavior
*Biological Specimen Banks
Specimen Handling

@article {pmid43001353,
year = {2026},
author = {Mu, R and Zhang, Y and Zhou, C and Yuan, L and Liu, T and Lu, M and Zheng, D and Ma, W},
title = {n-3 polyunsaturated fatty acids ameliorate obesity with cognitive impairment by promoting adipose browning and remodeling of brain lipid metabolism.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo04237f},
pmid = {43001353},
issn = {2042-650X},
abstract = {In the context of population aging, the global prevalence of obesity and mild cognitive impairment (MCI) continues to rise, underscoring the need for effective interventions. While n-3 polyunsaturated fatty acids (n-3 PUFAs) benefit weight reduction and cognition, the underlying mechanism remains unclear. This study investigated this mechanism using human data and animal models. Cross-sectional analysis of UK Biobank data showed that plasma n-3 PUFA levels were significantly lower in patients with MCI than in healthy controls, indicating an association between lower n-3 PUFA levels and MCI. In a mouse model of obesity with underlying Alzheimer's disease (AD)-like pathology (high-fat diet-fed 5xFAD mice, a transgenic model of familial AD), dietary fish oil intervention reduced white adipocyte size, upregulated beige fat markers (UCP1 and Prdm16), and improved cognitive performance alongside increased synaptic protein PSD95. Furthermore, n-3 PUFAs decreased plasma pro-inflammatory factors (GROα and Eotaxin) and remodeled the brain lipid profile of obese mice with cognitive impairment. Dietary fish oil intervention significantly increased the brain PUFA content, along with marked elevations in the relative levels of sphingomyelin, diglyceride, triglyceride, fatty acids, phosphatidylcholine, phosphatidic acid, phosphatidylserine, and phosphatidylethanolamine, whereas ceramide levels were significantly reduced. These findings suggest that n-3 PUFAs may ameliorate obesity and cognitive impairment in the context of underlying AD pathology through two parallel mechanisms linked to lipid metabolism: promoting adipose tissue browning and directly reprogramming brain lipid metabolism.},
}

@article {pmid43001365,
year = {2026},
author = {Hoffmann, D and Ahola, V and Haapasalo, A and Hiltunen, M},
title = {Targeting disease pathways in Alzheimer's utilizing lithium compounds.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2762575},
pmid = {43001365},
issn = {1744-7631},
}

@article {pmid43001556,
year = {2026},
author = {de Kleer, MAC and Ditmarsch, M and Kastelein, JJP},
title = {Cholesteryl ester transfer protein inhibition: from LDL lowering to dementia prevention.},
journal = {Current opinion in lipidology},
volume = {37},
number = {6},
pages = {263-272},
doi = {10.1097/MOL.0000000000001068},
pmid = {43001556},
issn = {1473-6535},
mesh = {Humans ; *Cholesterol Ester Transfer Proteins/antagonists & inhibitors/metabolism ; *Dementia/prevention & control/metabolism ; Animals ; *Cholesterol, LDL/metabolism ; *Anticholesteremic Agents/pharmacology/therapeutic use ; },
abstract = {PURPOSE OF REVIEW: Cholesteryl ester transfer protein (CETP) inhibitors most importantly lower apoB-containing lipoproteins, yet genetic and pharmacological intervention data underscore possible benefits extending to new-onset diabetes, kidney function, septicemia and possibly dementia. To understand these sequelae, this review examines in what manner CETP inhibition reshapes lipoprotein composition, with special focus on HDL structure and function, and how these changes may underlie clinical benefits beyond consequences of LDL lowering alone.

RECENT FINDINGS: Because of its central role in lipoprotein metabolism, potent CETP inhibition leads to comprehensive lipid modulation: coordinately reducing LDL-C, apoB, non-HDL-C and Lp(a) while raising HDL-C, apoA-I, preβ1 and preβ2 HDL. Beyond these changes, it remodels HDL towards a more functional cargo-carrying particle, enriched with monomeric lipid-free apoA-I, apoE, apoM-sphingosine-1-phosphate and a host of lipophilic antioxidants. These findings offer a plausible mechanistic basis for the observed reduction in new-onset diabetes, modest attenuation of kidney-function decline, preliminary sepsis-related signals and lowering of early Alzheimer's disease markers.

SUMMARY: By simultaneously lowering apoB-lipoproteins and remodeling HDL to become more functional, CETP inhibition offers a coherent rationale for potential benefit across cardiovascular, metabolic, renal, immune and neurological disease. The currently ongoing obicetrapib cardiovascular outcomes trial will test whether clinical benefit follows this biology.},
}

Humans
*Cholesterol Ester Transfer Proteins/antagonists & inhibitors/metabolism
*Dementia/prevention & control/metabolism
Animals
*Cholesterol, LDL/metabolism
*Anticholesteremic Agents/pharmacology/therapeutic use

@article {pmid43001795,
year = {2026},
author = {Kortmann, E and Steinacker, P and Guthknecht, A and Barba, L and Otto, M},
title = {Limited Passive Diffusion of Apolipoprotein E Across the Human Blood-CSF Barrier: Evidence From Paired CSF/Serum Quotients.},
journal = {Journal of neurochemistry},
volume = {170},
number = {11},
pages = {},
doi = {10.1111/jnc.70585},
pmid = {43001795},
issn = {1471-4159},
support = {101156175//Horizon Europe Health: PredictFTD, SYNAPSING/ ; 101156566//Horizon Europe Health: PredictFTD, SYNAPSING/ ; 01EW2008//ERA-NET NEURON (MOODMARKER)/ ; FTLDc 01GI1007A//German Federal Ministry of Education and Research (BMBF)/ ; },
mesh = {Humans ; *Apolipoproteins E/cerebrospinal fluid/blood ; *Blood-Brain Barrier/metabolism ; Diffusion ; Female ; Male ; Apolipoprotein E4/cerebrospinal fluid/blood ; Aged ; },
abstract = {Apolipoprotein E (ApoE) is a major genetic risk factor for sporadic Alzheimer's disease and a potential therapeutic target, but the relative contribution of peripheral blood-derived and intrathecally synthesized ApoE to the CNS remains unclear. A novel electrophoresis-based capillary Western blot assay was validated to quantify Pan-ApoE and ApoE4 in paired human CSF and serum samples (n = 34), followed by analysis of CSF/serum quotients. Serum ApoE concentrations were ninefold higher than CSF concentrations, with CSF/serum quotients of 0.132 for Pan-ApoE and 0.191 for ApoE4. Compared with theoretical quotients predicted for proteins entering CSF solely by passive diffusion according to their hydrodynamic radius according to Felgenhauer et al., the observed quotients were 66- to 1320-fold higher for Pan-ApoE and 96- to 1910-fold higher for ApoE4. Based on this model, passive diffusion was estimated to account for less than 1.5% of CSF ApoE. These estimates are model-dependent and may vary with ApoE isoform and extent of lipidation, which could potentially be affected by serum fibrin clot formation. The remaining ApoE fraction (> 98.5%) may reflect active transport, intrathecal synthesis or both. Pan-ApoE and ApoE4 CSF/serum quotients lacked statistically significant association with CSF/serum albumin quotient as a marker of blood-CSF barrier function. Both quotients also exceeded the values predicted by a theoretical reference curve relating CSF/serum protein quotients to the albumin quotient, adapted from the Reiber model using immunoglobulin G parameters based on the comparable hydrodynamic radii of IgG and ApoE.},
}

Humans
*Apolipoproteins E/cerebrospinal fluid/blood
*Blood-Brain Barrier/metabolism
Diffusion
Female
Male
Apolipoprotein E4/cerebrospinal fluid/blood
Aged

@article {pmid43001957,
year = {2026},
author = {Drew, SC},
title = {Murine Aβ4-x Peptides Retain High-Affinity Redox-Silent Cu2+ Binding.},
journal = {Inorganic chemistry},
volume = {65},
number = {44},
pages = {26091-26100},
doi = {10.1021/acs.inorgchem.6c04247},
pmid = {43001957},
issn = {1520-510X},
support = {NA//Ministerstwo Edukacji i Nauki/ ; },
mesh = {*Copper/chemistry/metabolism ; Oxidation-Reduction ; Animals ; Mice ; *Amyloid beta-Peptides/chemistry/metabolism ; Humans ; *Coordination Complexes/chemistry ; *Peptide Fragments/chemistry/metabolism ; Protein Binding ; Binding Sites ; },
abstract = {β-Amyloid peptides N-truncated at Phe4 (Aβ4-x) contain an amino-terminal Cu- and Ni-binding (ATCUN) motif that can form high-affinity, redox-silent Cu2+ complexes. Human Aβ4-40/42 is present in the brains of individuals with and without Alzheimer's disease, and soluble Aβ4-9 can be generated by neprilysin proteolysis of Aβ1-40/42 in vitro. These observations led to the proposal that Aβ4-x may be functional Cu2+-binding peptides. Because amyloid precursor protein is constitutively expressed in mammals, this study assessed whether murine Aβ4-x peptides retain the properties of the human analogues. Cu2+ coordination, binding affinity, and redox activity were compared for murine and human Aβ4-9 and Aβ4-16. The murine peptides formed Cu2+ complexes with spectroscopic parameters closely matching those of the human peptides. Competitive binding against glycylglycylhistidine gave conditional Cu2+ dissociation constants at pH 7.4 of 3-4 fM for murine Aβ4-x and 8-10 fM for human Aβ4-x. All Cu(Aβ4-x) complexes were redox-silent in an aminophenyl fluorescein/ascorbate assay. Thus, murine Aβ4-x has the chemical capacity required for a Cu2+-binding role if generated in vivo. However, because endogenous murine Aβ4-x has not been detected in wild-type mice, the present findings challenge the support for a broadly conserved physiological role for Aβ4-x in mammalian Cu2+ handling.},
}

*Copper/chemistry/metabolism
Oxidation-Reduction
Animals
Mice
*Amyloid beta-Peptides/chemistry/metabolism
Humans
*Coordination Complexes/chemistry
*Peptide Fragments/chemistry/metabolism
Protein Binding
Binding Sites

@article {pmid43002148,
year = {2026},
author = {Abdelsalam, OK and Mosad, N and Abouelmagd, ME and Messak, M and Almosilhy, NA and Harb, A and Hassan, MK and Shata, A and Makhlouf, HA},
title = {Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation (rTMS) in Alzheimer's disease: An Updated Meta-analysis of 35 Randomized Sham-controlled Trials.},
journal = {Neuromodulation : journal of the International Neuromodulation Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurom.2026.09.008},
pmid = {43002148},
issn = {1525-1403},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia worldwide, causing progressive cognitive and functional decline that adversely affects patients' independence and increases caregivers' burden. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is being increasingly studied in AD; however, trials differ widely in targeted regions, stimulation parameters, and outcome measures, limiting clinical guidance. However, existing meta-analyses are limited by conflicting outcome findings, inconsistent protocol evaluations (e.g., rTMS vs. Intermittent Theta Burst Stimulation (iTBS), a modified version of rTMS), and a lack of formal Grading of Recommendations Assessment, Development, and Evaluation (GRADE) certainty assessments. This updated meta-analysis integrates subgroup, trial-sequential, and GRADE analyses to address these gaps and provide clear clinical guidance.

MATERIALS AND METHODS: We systematically searched PubMed, Scopus, Web of Science, and the Cochrane Library for randomized controlled trials (RCTs) assessing the efficacy and safety of rTMS versus sham in adults with Alzheimer's disease. The primary outcome was global cognition, measured by the Mini-Mental State Examination (MMSE) or Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog). Secondary outcomes included neuropsychiatric symptoms, functional status, depression, dementia severity, and adverse events. We performed random-effects meta-analysis in R, with additional sensitivity analyses, subgroup analyses (stimulation type: rTMS and iTBS; AD stage; stimulation area; frequency; therapeutic approach; intervention duration; follow-up duration), trial sequential analysis (TSA), publication bias assessment, and GRADE certainty evaluation.

RESULTS: The updated meta-analysis included 35 RCTs (n = 1746 patients) with Alzheimer's disease. Compared with sham, active rTMS was associated with a moderate improvement in global cognition (standardized mean difference (SMD) 0.57, 95% CI: 0.33, 0.81; p < 0.0001; moderate certainty); however, subgroup analysis revealed that iTBS showed no statistically significant improvement. Active rTMS was also associated with clinically meaningful reductions in neuropsychiatric symptoms (mean difference (MD) -3.28, 95% CI: -5.09, -1.46) and dementia severity (MD -0.29, 95% CI: -0.57, -0.01). No significant benefit was observed for functional status or depression. Headache, scalp discomfort, and fatigue did not differ between the groups, but active rTMS carried a higher overall rate of adverse events (RR 1.51, 95% CI: 1.07, 2.14; p = 0.02).

CONCLUSION: Active rTMS appears to provide short-term cognitive benefits in Alzheimer's disease, with additional improvements in neuropsychiatric symptoms and dementia severity. Although adverse events were more frequent overall, they were generally mild and well-tolerated. Protocol heterogeneity and limited long-term follow-up prevent definitive recommendations for routine clinical use; larger, standardized, adequately powered RCTs are needed to define optimal targets, stimulation parameters, durability, and likely responder subgroups.},
}

@article {pmid43002276,
year = {2026},
author = {You, N and Li, J and Li, S and Miao, S and Yang, M and Wang, J and Yu, Y and Ding, K},
title = {Sensitive detection of amyloid-β42 using a graphitic carbon nitride-boosted electrochemical peptide biosensor.},
journal = {Mikrochimica acta},
volume = {193},
number = {12},
pages = {},
pmid = {43002276},
issn = {1436-5073},
support = {42675241//General Program of the National Natural Science Foundation of China/ ; 2024YFC3014900//Project of National Key Research and Development Plan of China/ ; },
mesh = {*Graphite/chemistry ; *Amyloid beta-Peptides/blood/chemistry ; *Biosensing Techniques/methods ; Humans ; *Peptide Fragments/blood/chemistry ; *Electrochemical Techniques/methods ; Limit of Detection ; *Nitrogen Compounds/chemistry ; Gold/chemistry ; Metal Nanoparticles/chemistry ; Dielectric Spectroscopy/methods ; Alzheimer Disease/diagnosis ; Reproducibility of Results ; },
abstract = {Amyloid-beta 42 (Aβ42) is a key biomarker associated with Alzheimer's disease (AD), and its plasma levels serve as a crucial indicator for early detection of AD. In this study, an electrochemical impedimetric biosensor capable of rapid, sensitive, and specific quantitative determination of Aβ42 protein was designed for the early diagnosis of Alzheimer's disease. The composite two-dimensional nanomaterial reduced graphene oxide/protonated graphitic carbon nitride (p-CN/rGO) was used for signal amplification, with gold nanoparticles (AuNPs) providing molecular binding sites. An artificially designed peptide (sequence: CPPPEKEKEKKLVFF) enables specific recognition of Aβ42, and the fabrication and quantitative determination of Aβ42 were monitored by electrochemical impedance spectroscopy (EIS). The fabricated electrochemical biosensing platform exhibits a broad linear detection range (1 fg/mL to 1 ng/mL) and a low limit of detection (1.97 × 10[- 2] fg/mL), enabling sensitive and precise detection of Aβ42 protein. Furthermore, the biosensor was investigated for excellent reproducibility, stability, selectivity, and regeneration, and demonstrates reliability in the practical analysis of Aβ42 in simulated human serum. Thus, this electrochemical biosensing platform offers a novel approach to blood-based detection of Aβ, providing an experimental foundation for early diagnosis and research into the pathological mechanisms of AD.},
}

*Graphite/chemistry
*Amyloid beta-Peptides/blood/chemistry
*Biosensing Techniques/methods
Humans
*Peptide Fragments/blood/chemistry
*Electrochemical Techniques/methods
Limit of Detection
*Nitrogen Compounds/chemistry
Gold/chemistry
Metal Nanoparticles/chemistry
Dielectric Spectroscopy/methods
Alzheimer Disease/diagnosis
Reproducibility of Results

@article {pmid43002489,
year = {2026},
author = {Kim, DY and Yoon, J and Kim, S and Park, J and Kim, JH and Yoo, H and Kim, J and Kim, K and Woo, HG and Woo, S and Yon, DK},
title = {Decoding the Drivers of Alzheimer's Disease and Other Dementias Mortality in Asia, 1990-2023: A Global Burden of Diseases Study 2023.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1159/ned/adwag033},
pmid = {43002489},
issn = {1423-0208},
support = {IITP-2026-RS-2024-00438239//Ministry of Science and ICT/ ; RS-2025-02220492//Ministry of Health & Welfare/ ; },
abstract = {BACKGROUND: Despite the burden of Alzheimer's disease and other dementias (ADOD) in Asia, evidence on patterns of mortality attributable to risk factors remains limited. This study aimed to analyze the spatiotemporal burden of ADOD mortality attributable to modifiable risk factors across Asia from 1990 to 2023.

METHODS: We used data from the Global Burden of Diseases Study (GBD) 2023 to examine mortality from ADOD attributable to GBD-quantified risk factors in Asia from 1990 to 2023. Analyses included 34 countries and territories. These were grouped into five regions according to the GBD classification: Central Asia, East Asia, South Asia, Southeast Asia, and the high-income Asia Pacific. ADOD was defined as dementia characterized by progressive cognitive decline with functional impairment. ADOD mortality attributable to air pollution, tobacco use, high fasting plasma glucose (FPG), and high body mass index was assessed among adults aged ≥70 years using the GBD comparative risk assessment framework. The Das Gupta decomposition method was applied to quantify the contributions of population growth, population aging, and epidemiological change. Uncertainty was reported as 95% uncertainty intervals (UIs) derived from 250 posterior draws.

RESULTS: In 2023, ADOD mortality rates in Asia showed marked variation, with the highest burden in high-income Asia Pacific (661.10 [95% UI, 189.78-1,504.67] per 100,000 population) and the lowest in Central Asia (273.00 [65.15-695.77]). From 1990 to 2023, the burden attributable to high FPG increased across all regions. High-income Asia Pacific remained the highest, increasing from 75.60 (95% UI, 17.97-204.39) per 100,000 population to 139.21 (32.10-323.57). Air pollution remained a major driver, while tobacco-attributable burden in 2023 remained concentrated in East Asia (16.86 [95% UI, 3.38-41.27] per 100,000 population). The burden increased steeply with age and differed by sex, with higher burdens from air pollution and high FPG in females and from tobacco in males. Decomposition analyses showed varying contributions of population growth, population aging, and epidemiological change to changes in attributable mortality. The Maldives showed the largest increases for air pollution, high FPG, and tobacco.

CONCLUSION: The substantial heterogeneity in risk-attributable ADOD mortality across regions, age groups, and sexes supports risk- and region-specific prevention priorities across Asia. Dementia prevention should be aligned with local cardiometabolic, tobacco, and air-pollution risk profiles, while future studies should assess whether reducing these exposures translates into lower ADOD mortality.},
}

@article {pmid43002725,
year = {2026},
author = {López Román, FJ and Sebastián, M and Pérez-Piñero, S and Hernández-Manzano, I and Laosa-Zafra, O and Rodríguez-Mañas, L and Tarazona-Santabalbina, FJ and Borrás, C and Viña, J},
title = {Effects of Supplementation With Genistein on the Progression of Cognitive Decline in Patients With Mild Cognitive Impairment Due to Alzheimer Disease: Protocol for a Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e98087},
doi = {10.2196/98087},
pmid = {43002725},
issn = {1929-0748},
mesh = {Humans ; *Genistein/administration & dosage/therapeutic use/pharmacology ; *Alzheimer Disease/complications/drug therapy ; *Cognitive Dysfunction/drug therapy/etiology ; Double-Blind Method ; Randomized Controlled Trials as Topic ; Disease Progression ; *Dietary Supplements ; Multicenter Studies as Topic ; Female ; Aged ; Male ; Middle Aged ; Biomarkers/blood ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) may represent a prodromal stage of Alzheimer disease, but interventions to delay progression remain limited. Genistein is a phytoestrogenic isoflavone with potential effects on several pathways implicated in Alzheimer disease. We previously showed that genistein reverses cognitive decline and lowers brain amyloid β (Aβ) in the Aβ precursor protein/presenilin 1 double transgenic (AβPP/PS1) model of Alzheimer disease.

OBJECTIVE: The study aimed to evaluate whether oral genistein supplementation affects cognitive decline in patients with MCI due to Alzheimer disease, compared with a placebo, and to assess its effects on brain amyloid burden and plasma biomarkers.

METHODS: This multicenter, randomized, double-blind, placebo-controlled trial will include adults aged 50 years or older with MCI due to Alzheimer disease. Participants will be randomized 1:1 to genistein (200 mg/day) or a maltodextrin-based placebo for 18 months. The primary outcome is change in the Integrated Alzheimer's Disease Rating Scale (iADRS) score. Secondary outcomes include other neuropsychological measures, amyloid burden measured by [18]F-flutemetamol positron emission tomography, plasma Alzheimer disease biomarkers, and safety. Outcomes will be assessed at baseline, midstudy, and study completion. Analyses are planned in the intention-to-treat and per-protocol populations using repeated-measures analysis of variance, with time as the within-participant factor, treatment group as the between-participant factor, and study site as a covariate.

RESULTS: Funding for the study began in January 2024 and was provided by Trugon Investigaciones (AIE) through a grant to the Chair of Geroscience at Universidad Católica de Murcia. Data collection began in July 2026 and is projected to conclude in January 2029, consistent with the estimated 30-month study duration. Enrollment is expected to last approximately 9 months. As of August 5, 2026, a total of 4 participants had been recruited. Data analysis has not begun and will start after the final participant completes follow-up. Results are expected to be published in late 2029.

CONCLUSIONS: This trial will provide evidence on whether genistein supplementation may help slow cognitive decline and reduce amyloid burden in patients with MCI due to Alzheimer disease.},
}

Humans
*Genistein/administration & dosage/therapeutic use/pharmacology
*Alzheimer Disease/complications/drug therapy
*Cognitive Dysfunction/drug therapy/etiology
Double-Blind Method
Randomized Controlled Trials as Topic
Disease Progression
*Dietary Supplements
Multicenter Studies as Topic
Female
Aged
Male
Middle Aged
Biomarkers/blood

@article {pmid43002819,
year = {2026},
author = {Meng, Y and Wang, C and Hu, Y and Zhou, H and Zhou, J and Gao, W and Xing, W and Shu, X and Shang, J},
title = {A ratiometric dual-modal photoacoustic and near-infrared fluorescence probe for in vivo spatiotemporal mapping of butyrylcholinesterase in Alzheimer's disease.},
journal = {Talanta},
volume = {314},
number = {},
pages = {130903},
doi = {10.1016/j.talanta.2026.130903},
pmid = {43002819},
issn = {1873-3573},
abstract = {Butyrylcholinesterase (BChE) is a critical biomarker for the progression of Alzheimer's disease (AD) pathology; however, real-time visualization of its dynamic activity changes in deep biological tissues remains highly challenging. Herein, we report the development of BChE-PA, a novel hemicyanine-based dual-modal probe for the ratiometric detection of BChE through integrated near-infrared (NIR) fluorescence and photoacoustic (PA) imaging. The probe design utilizes a specific cyclopropanecarbonyl recognition moiety that effectively masks the internal charge transfer (ICT) process of the fluorophore. Enzymatic cleavage of the cyclopropanecarbonyl group by BChE restores the ICT effect and extends the molecular π-conjugation, triggering a significant 93 nm bathochromic shift in absorption (from 622 nm to 715 nm) and a dramatic NIR fluorescence "turn-on" response. BChE-PA exhibits an exceptional detection limit of 0.03 U/mL and high selectivity over competing esterases. By leveraging the ratiometric PA signal (PA755/PA680), we successfully performed self-calibrating, deep-tissue mapping of elevated BChE levels in the brains of APP/PS1 transgenic mice. This dual-modal platform provides a robust tool for the spatiotemporal tracking of BChE, bridging the gap between molecular environmental surveillance and clinical neuroimaging.},
}

@article {pmid43002856,
year = {2026},
author = {Wilson, SA and Churilla, JR and Bigliassi, M and Richardson, MR},
title = {The joint association of cognitive function and sedentary time on mortality risk in older adults: National health and nutrition examination survey 2011-2014.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {74},
number = {Pt B},
pages = {104420},
doi = {10.1016/j.gerinurse.2026.104420},
pmid = {43002856},
issn = {1528-3984},
abstract = {BACKGROUND: Examining the joint association of cognitive function and sedentary time may provide insight into the complex mechanisms underlying mortality risk within older adults. This longitudinal observational study examines the joint association of cognitive function and sedentary time on mortality risk in older adults.

METHODS: Sample included older adult participants from the 2011-2014 National Health and Nutrition Examination Survey. The Digit Symbol Substitution Test, Consortium to Establish a Registry for Alzheimer's Disease subtests, and Animal Fluency were used to assess cognitive function. Average daily sitting and television time represented sedentary time. Cognitive function (lowest quartile) and sedentary time (above median) were combined for analysis.

RESULTS: Older adult participants (N = 2,230; ≥ 60 years; 49% male) were shown to have a significant (p < 0.05) increase in mortality within the lowest quartile of cognitive function and above-median sedentary time. A 2.8, 3.9, 2.8, and 2.5-fold increased risk for all-cause mortality for the Digit Symbol Substitution Test, Consortium to Establish a Registry for Alzheimer's Disease Immediate Learning, Delayed Learning, Animal Fluency test, respectively, were observed. Our analysis also revealed a 3.8, 3.2, 3.5, and 2.7-fold increased risk for cardiovascular disease-related mortality for the Digit Symbol Substitution Test, Consortium to Establish a Registry for Alzheimer's Disease Immediate Learning, Delayed Learning, and Animal Fluency test, respectively.

CONCLUSION: The combination of cognitive function scores with sedentary time has been shown to be strongly associated with increased risks of both all-cause and cardiovascular disease-related mortality.},
}

@article {pmid43002898,
year = {2026},
author = {Yu, X and He, J and Liu, M},
title = {Critical advances and translational bottlenecks of gut microbiota-gut-brain axis targeted therapy for neurodegenerative and neurodevelopmental disorders.},
journal = {Journal of neuroimmunology},
volume = {423},
number = {},
pages = {579117},
doi = {10.1016/j.jneuroim.2026.579117},
pmid = {43002898},
issn = {1872-8421},
abstract = {Neurological diseases have become a major global public health burden. Existing central nervous system-targeted therapies can only alleviate clinical symptoms but fail to halt the progression of neurodegenerative diseases, presenting mechanistic limitations and therapeutic bottlenecks. The gut microbiota participates in the regulation of central nervous system (CNS) homeostasis and neuropathological processes via the microbiota-gut-brain axis (MGBA). Notably, dysbiosis may induce damage to the blood-brain barrier, neurotransmitter dysregulation, and immune imbalance, thereby mediating the onset and progression of various neurological diseases, including Parkinson's disease, Alzheimer's disease (AD), autism spectrum disorder (ASD), and multiple sclerosis (MS). This article provides a systematic review of the core mechanisms by which the gut microbiome regulates neurological diseases, including inflammation regulation, oxidative stress responses, and neuroendocrine remodeling mediated by microbial metabolites. It also comprehensively summarizes the research progress, application advantages, and existing limitations of novel gut-targeted interventions, such as probiotics, prebiotics, fecal microbiota transplantation (FMT), dietary interventions, and live biological therapies. At the same time, the article critically examines key bottlenecks prevalent in the field: the causal relationship between the microbiota and disease remains unclear; there is a significant translational gap between animal and human studies; there is a lack of unified standards for multi-omics analysis systems; and interference from confounding factors such as age, diet, and medications is significant. Existing research indicates that gut microbiota interventions complement traditional symptomatic treatments and hold promising prospects for early disease intervention and adjunctive therapy for refractory patients. Future efforts should integrate multi-omics and artificial intelligence technologies to decipher the causal networks governing gut-central nervous system regulation, establish standardized research frameworks, advance the clinical translation of precision gut microbiota therapies, and provide new approaches for the comprehensive prevention, control, and personalized treatment of neurological disorders.},
}

@article {pmid43002947,
year = {2026},
author = {A Rahman, A and Galhom, RA and Makary, S and Nooreldien, NM and Fekry, E},
title = {Possible therapeutic effects of native ADMSCs versus CSF preconditioned ADMSCs against colchicine-induced hippocampal damage in Wistar rats.},
journal = {Tissue & cell},
volume = {105},
number = {},
pages = {104102},
doi = {10.1016/j.tice.2026.104102},
pmid = {43002947},
issn = {1532-3072},
abstract = {BACKGROUND: Colchicine is an anti-inflammatory drug causes significant hippocampal neurotoxicity in animal models mimics Alzheimer's disease (AD) like pathology. Stem cells demonstrated a crucial role in AD treatment. Preconditioning of mesenchymal stem cells (MSCs) using cerebrospinal fluid (CSF) enhancing their therapeutic potential.

AIM OF THE STUDY: This study aims to evaluate the possible therapeutic effects of native adipose derived mesenchymal cells (ADMSCs) versus CSF preconditioned ADMSCs against colchicine-induced hippocampal damage in Wistar rats.

METHODS: 48 adult male Wistar rats were randomized into 4 groups (12/each). Group I: Control, Group II: Colchicine, Group III: Native ADMSCs + Colchicine. Group IV: CSF Preconditioned ADMSCs + Colchicine. Three weeks after stem cells injection, spatial working memory (SWM) assessment was performed, then all animals were sacrificed, and their cerebral hemispheres were prepared for transmission electron microscopic (TEM) and light microscopic (LM) examination of hippocampi using H& E stain, tumor necrosis factor alpha (TNF-α) and doublecortin (DCX) immunostaining.

RESULTS: Rats of group II showed decrease in SWM. Histological results revealed necrotic changes, increased immunostaining reaction of both TNF- α and DCX of the hippocampal neurons in both Cornu ammonis 1 and dentate gyrus compared to control. Groups III and IV revealed improvement in all assessed parameters compared to group II. However, this improvement was more significant in group IV compared to group III.

CONCLUSION: CSF preconditioned ADMSCs revealed more therapeutic effects compared to native ADMSCs against colchicine-induced hippocampal damage in Wistar rats.},
}

@article {pmid43002967,
year = {2026},
author = {Chen, X and Yang, Y and Liao, Y and Chen, L and Cheng, L and Su, C and Shi, X and Chen, J and Lin, Z and Hong, G},
title = {CRISPR-enabled ultrasensitive surface-enhanced Raman scattering sensing platform for background-free detection of phosphorylated tau in Alzheimer's disease.},
journal = {Biosensors & bioelectronics},
volume = {318},
number = {},
pages = {119400},
doi = {10.1016/j.bios.2026.119400},
pmid = {43002967},
issn = {1873-4235},
abstract = {Accurate and ultrasensitive detection of phosphorylated tau at threonine 231 (P-tau231), a pathologically validated early biomarker of Alzheimer's disease (AD), is essential for preclinical diagnosis and longitudinal monitoring. However, blood-based detection remains challenging because of the femtomolar physiological abundance, substantial interference from the serum matrix, and the reliance of conventional clustered regularly interspaced short palindromic repeats (CRISPR) assays on nucleic acid amplification. Herein, we present an amplification-free CRISPR/Cas12a-assisted surface-enhanced Raman scattering (SERS) aptasensor for the background-free quantification of P-tau231. This platform integrates aptamer-mediated target recognition, programmable Cas12a trans-cleavage-based signal transduction, and hierarchical plasmonic enhancement. Au-4-Mercaptobenzonitrile@Au (Au-4-MBN@Au) core-shell nanoprobes coupled with Ag nanocube arrays provide uniform plasmonic enhancement, while the characteristic C ≡ N peak of the 4-MBN reporter at 2230 cm[-1] lies within the biological Raman-silent window (1800-2800 cm[-1]), thereby minimizing inference from endogenous scattering. This biosensor exhibits a linear detection range of 50 fg/mL to 5 ng/mL and an ultralow limit of detection of 2.53 fg/mL. Overall, this work established an effective amplification-free CRISPR/Cas12a-SERS platform for the highly sensitive detection of serum P-tau231 and offers a promising analytical approach for the blood-based early diagnosis of AD.},
}

@article {pmid43003069,
year = {2026},
author = {Witte, MH and Erickson, RP and Bartlett, M},
title = {Lymphangiopathy in Cerebral Amyloid Angiopathy and Alzheimer's Disease?.},
journal = {Lymphology},
volume = {59},
number = {3},
pages = {115-116},
pmid = {43003069},
issn = {2522-7963},
mesh = {Humans ; *Alzheimer Disease/complications/pathology/metabolism ; *Cerebral Amyloid Angiopathy/complications/metabolism/pathology ; *Lymphatic Diseases/etiology/metabolism/pathology ; *Lymphatic Vessels/pathology/metabolism ; Animals ; },
abstract = {Whereas extensive study has been done on amyloid hemangiopathy in blood vessels exiting the brain there have been no studies of amyloid lymphangiopathy which may play an unrecognized role in impaired lymphatic drainage in Alzheimer's Disease.},
}

Humans
*Alzheimer Disease/complications/pathology/metabolism
*Cerebral Amyloid Angiopathy/complications/metabolism/pathology
*Lymphatic Diseases/etiology/metabolism/pathology
*Lymphatic Vessels/pathology/metabolism
Animals

@article {pmid43003088,
year = {2026},
author = {Jiang, L and Tan, ZC and Grabski, IN and Hao, Y and Nakatsuka, N and Sarkar, S and Shenoy, A and Satija, R},
title = {Reconstructing developmental and disease progression with sample-level embeddings.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.10.018},
pmid = {43003088},
issn = {1097-4172},
abstract = {Single-cell genomics is transformative for characterizing cellular heterogeneity, but many biological questions require comparing samples rather than individual cells. Typical analyses compare "case" and "control" groups, ignoring sample-level variation within them. Here, we present scSLIDE (single-cell sample-level inference using density estimation), a framework that transforms each sample's single-cell data into a compact profile describing where its cells are distributed in high-dimensional space. By comparing these density profiles, scSLIDE calculates embeddings to characterize variation across samples. We implement scSLIDE in version 6 of our Seurat package and apply it to COVID-19 infection, Alzheimer's disease, and zebrafish embryogenesis. scSLIDE reveals patient subgroups, reconstructs disease trajectories, and identifies coordinated cellular programs across samples. We discover separable axes of infection and severity, a trajectory of Alzheimer's progression, and embryonic "pseudostages" that vary across and within time points. Our results demonstrate how case-control analyses collapse rich biological variation into binary labels and how sample-level embedding represents a powerful analytical alternative.},
}

@article {pmid42998661,
year = {2026},
author = {Hu, Y and Cheng, Y and Su, Y and Han, Z and Shen, X and Hu, H and Wang, Q and Wan, S and Li, H and Zhang, N},
title = {Efficacy and safety of anti-tau drugs for Alzheimer's disease: A systematic review and network meta-analysis.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100693},
doi = {10.1016/j.tjpad.2026.100693},
pmid = {42998661},
issn = {2426-0266},
abstract = {OBJECTIVE: To evaluate and compare the effects of different anti-tau drugs on clinical and biological outcomes in patients with Alzheimer's disease (AD).

METHODS: PubMed, Cochrane Library, and Embase databases were searched for identifying randomized, controlled clinical trials from inception to December 2025.

RESULTS: Twelve high-quality studies with 11 drugs were evaluated. Systematic meta-analysis did not demonstrate significant efficacy of anti-tau drugs in preventing cognitive and functional declines or clearance of tau deposition on PET. However, effects in reducing levels of p-tau (SMD=-0.48, 95% CI: -0.73 to -0.22, P < 0.01) and t-tau (SMD=-0.69, 95% CI: -0.94 to -0.45, P < 0.01) in the cerebrospinal fluid were observed. Network analysis revealed that MAPTRx and nicotinamide ranked highest for improving cognitive function, and gosuranemab ranked highest for tau biomarker changes.

CONCLUSION: The current findings highlight the disease-modifying potential of anti-tau therapies for AD, although clinical benefit is limited. The observed reductions in CSF tau biomarkers and the favourable safety profile of current anti-tau therapies suggest promising therapeutic potential for the treatment of AD. However, the clinical value of anti-tau therapies should be confirmed in adequately powered phase III trials with biomarker-enriched populations.},
}

@article {pmid42998768,
year = {2026},
author = {Lindsley, PM and Karcher, NR and Kochunov, P and Barch, DM},
title = {Examining the Relationship Between Regional Vulnerability and Psychotic-Like Experiences in Adolescents: The Potential Mediating Role of Cognition.},
journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpsc.2026.10.015},
pmid = {42998768},
issn = {2451-9030},
abstract = {BACKGROUND: Psychotic-like experiences (PLEs) are subclinical hallucinations or unusual thought content that, when distressing or persistent, signal heightened risk for psychosis spectrum disorders and cognitive impairments.

METHODS: We used data from the Adolescent Brain Cognitive Development (ABCD) study (N = ∼11,800) to examine if structural brain deviations toward neuropsychiatric disorders, quantified using disorder-specific Regional Vulnerability Indices (RVIs), were associated with distressing PLEs at age 13-14, and whether cognition mediated these relationships. Cortical and subcortical RVIs were calculated for schizophrenia, bipolar disorder, major depressive disorder, Alzheimer's disease, Parkinson's disease, metabolic disorder, and 22q11.2 deletion syndrome.

RESULTS: Linear mixed-effects models revealed that higher cortical RVIs for schizophrenia, Alzheimer's disease, bipolar disorder, metabolic disorder, and Parkinson's disease-and all subcortical RVIs-were significantly associated with greater distressing PLE severity. Both cortical and subcortical RVIs were negatively associated with fluid and crystallized cognition, with subcortical RVIs showing the largest effects. Mediation analyses indicated that crystallized cognition, and to a lesser extent fluid cognition, mediated many RVI-distressing PLE relationships.

DISCUSSION: These findings suggest that neuroanatomical differences confer risk for psychotic-like experiences partly through their impact on cognitive development. The results highlight RVIs as sensitive markers of distributed brain vulnerability in youth and suggest that cognitive function, particularly crystallized ability, is a potential pathway linking brain structural alterations to emerging psychotic symptoms.},
}

@article {pmid42998805,
year = {2026},
author = {Mondal, S and Sharma, N and Mishra, N},
title = {Single-cell and spatial transcriptomic insights into neural substrates of Behavioural dysfunction in Alzheimer's disease.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104132},
doi = {10.1016/j.mcn.2026.104132},
pmid = {42998805},
issn = {1095-9327},
abstract = {The transition from bulk-tissue profiling to single-cell and spatially resolved transcriptomics has reshaped our understanding of Alzheimer's disease (AD) from a passive proteinopathy to a coordinated multicellular process spanning the neurovascular unit. However, translating these molecular catalogues into disease-modifying therapies requires a framework that links cellular transitions to neural circuit dysfunction and behavioural abnormalities. This review synthesizes the multicellular landscape of AD, tracing how cell-state-specific remodelling drives network collapse and cognitive decline. Neuronally, selective vulnerability targets projection networks and subclass-specific inhibitory interneurons. Their transcriptional silencing compromises projection pathways, including the entorhinal-hippocampal perforant path, disrupts cortical microcircuits, and underlies episodic memory impairment, hyperexcitability, and executive control failure. This neuronal degeneration is dynamically coupled to reactive glial and vascular remodelling across distinct spatial niches. We examine the non-linear transition of homeostatic astrocytes and microglia into specialized, plaque-associated reactive sub-states, as well as paracrine signalling decay at the neurovascular interface. Compromised capillary tight junctions and the shedding of pericytic survival receptors are proposed to promote blood-brain barrier disintegrity, triggering a feed-forward neuroinflammatory cascade of complement-mediated synaptic pruning. Crucially, we establish a three-tiered hierarchy of evidence, rigorously distinguishing cross-sectional, associative human postmortem findings from inferred functional trajectories in human cellular platforms, and causal, perturbation-based validations in transgenic rodent models. We review how contemporary multi-scale integration-combining single-nucleus transcriptomics with functional electrophysiological platforms and biophysical connectomic modelling-bridges the gap between terminal postmortem signatures and living brain dynamics. Finally, we outline a coordinated translational roadmap illustrating how spatially resolved cell-state networks can guide the development of fluid and imaging biomarkers, support biologically informed patient stratification, enrich clinical trials, and accelerate the development of circuit-restoring precision therapies, thereby providing a mechanistic framework that links cell-state transitions to neural circuit dysfunction, behavioural impairment, and precision medicine in Alzheimer's disease.},
}

@article {pmid42998901,
year = {2026},
author = {Smith, W and Signorile, JF and Seixas, AA and Chung, DP and Larsen, B and Flanagan, C},
title = {Blood Pressure Variability in Neurodegenerative Disease: Evidence From a Large-Scale Remote Patient Monitoring Program.},
journal = {Journal of clinical hypertension (Greenwich, Conn.)},
volume = {28},
number = {11},
pages = {},
pmid = {42998901},
issn = {1751-7176},
mesh = {Humans ; Female ; Remote Patient Monitoring/methods ; Aged ; Male ; *Blood Pressure/physiology ; *Neurodegenerative Diseases/physiopathology/complications ; Retrospective Studies ; Blood Pressure Monitoring, Ambulatory/methods ; *Hypertension/physiopathology/diagnosis/epidemiology ; Parkinson Disease/physiopathology/complications ; Middle Aged ; Alzheimer Disease/physiopathology/complications ; Blood Pressure Determination/methods ; Cardiovascular Diseases/epidemiology ; Dementia/physiopathology/complications ; },
abstract = {BACKGROUND: Blood pressure variability (BPV) is an established predictor of cardiovascular risk, yet its physiologic determinants in specific populations remain incompletely defined. Neurodegenerative diseases are associated with autonomic dysfunction that may alter blood pressure regulation.

METHODS: We compared day-to-day systolic blood pressure (SBP) variability between patients with neurodegenerative disease and matched controls in a retrospective analysis of de-identified home blood pressure data from a remote patient monitoring platform. Eligible patients transmitted readings on at least three days per week over a monitoring stretch of at least eight weeks. Patients with Alzheimer's disease, Parkinson's disease, or dementia were propensity-matched 1:3 to controls on age, mean SBP, mean diastolic blood pressure (DBP), stretch duration, and days per week with readings. The primary metric was average real variability (ARV), the mean absolute difference between consecutive values; standard deviation (SD) and variability independent of the mean (VIM) were secondary metrics.

RESULTS: The matched cohort included 49 neurodegenerative patients and 147 controls. SBP ARV was higher in the neurodegenerative group (median 12.92 [IQR 10.74-15.35] vs. 11.19 [9.46-12.99] mmHg; p = 0.003), as was DBP ARV (7.72 [6.34-8.87] vs. 6.76 [5.67-7.75] mmHg; p = 0.002). SD and VIM results were concordant (all p ≤ 0.001). Mean blood pressure, monitoring duration, measurement frequency, and reading timing were comparable between groups.

CONCLUSIONS: Neurodegenerative disease is associated with elevated day-to-day BPV despite similar mean blood pressure and monitoring behavior, suggesting that routine home monitoring may reveal autonomic dysregulation and cardiovascular risk beyond mean blood pressure alone.},
}

Humans
Female
Remote Patient Monitoring/methods
Aged
Male
*Blood Pressure/physiology
*Neurodegenerative Diseases/physiopathology/complications
Retrospective Studies
Blood Pressure Monitoring, Ambulatory/methods
*Hypertension/physiopathology/diagnosis/epidemiology
Parkinson Disease/physiopathology/complications
Middle Aged
Alzheimer Disease/physiopathology/complications
Blood Pressure Determination/methods
Cardiovascular Diseases/epidemiology
Dementia/physiopathology/complications

@article {pmid42999037,
year = {2026},
author = {Madamanchi, K and Gurrala, S and Watson, J and Melkani, G},
title = {Gut microbiome depletion aggravates glial-mediated Alzheimer's disease pathology through inflammatory, metabolic, and proteostatic dysregulation.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2753247},
doi = {10.1080/19490976.2026.2753247},
pmid = {42999037},
issn = {1949-0984},
mesh = {Animals ; *Alzheimer Disease/microbiology/metabolism/pathology/physiopathology ; *Neuroglia/metabolism/pathology ; Humans ; *Gastrointestinal Microbiome/drug effects ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Proteostasis ; Brain/metabolism/pathology ; Drosophila ; Drosophila melanogaster ; Bacteria/classification/isolation & purification/genetics ; Inflammation ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by chronic neuroinflammation, metabolic dysfunction, and impaired proteostasis. Emerging evidence suggests that the gut microbiome influences brain function through the gut-brain axis; however, the mechanisms by which this communication affects AD pathology remain poorly understood. In this study, we used humanized Drosophila AD models expressing human AD-related transgenes in glial cells to investigate how glial AD pathology influences the gut microbiome and how microbiome depletion affects behavior and disease progression. Our findings revealed significant alterations in the abundance of several gut microbial taxa, including Lactobacillus, Acetobacter, Enterococcus, Enterobacter, Pseudomonas, Leuconostoc, Providencia, and Gluconobacter, suggesting a potential interaction between the gut microbiome and AD progression. To further define the role of the gut microbiome in AD progression, we treated Drosophila with antibiotics to achieve substantial microbiome depletion (SMD) and evaluated the resulting behavioral, physiological, and molecular changes. Compared with conventional controls, flies with SMD exhibited enhanced inflammatory signaling and cell death, impaired autophagy, lipid dysregulation, and increased accumulation of amyloid β-42 (aβ42) and phospho-tau (pTau), with the extent of these changes varying among the different humanized AD models. These molecular alterations further exacerbated sleepcircadian disruption, altered locomotor performance, and worsened learning and memory deficits. Furthermore, we demonstrated a link between enhanced neuroinflammation and the accumulation of aβ42, pTau, and amyloid precursor protein (APP) proteins. Collectively, our findings demonstrate that gut microbiome depletion aggravates glial-mediated AD pathology through the coordinated disruption of inflammatory, metabolic, and proteostatic pathways, ultimately leading to behavioral dysfunction. These results identify the gut microbiome as a critical regulator of glial homeostasis and provide new insights into its contribution to the progression of neurodegenerative disorders.},
}

Animals
*Alzheimer Disease/microbiology/metabolism/pathology/physiopathology
*Neuroglia/metabolism/pathology
Humans
*Gastrointestinal Microbiome/drug effects
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Proteostasis
Brain/metabolism/pathology
Drosophila
Drosophila melanogaster
Bacteria/classification/isolation & purification/genetics
Inflammation

@article {pmid42999062,
year = {2026},
author = {Chattopadhyay, T and Shelar, K and Thomopoulos, SI and Thompson, PM},
title = {Understanding Performance Plateaus and Representation Collapse in 3D MRI Transformers Trained to Classify Brain Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.15.759510},
pmid = {42999062},
issn = {2692-8205},
abstract = {In medical imaging AI, we commonly assume that diagnostic classifiers will increase in accuracy if they are trained on more data, but in reality, their performance often plateaus. To understand this behavior, we ran a spectral analysis of 3D vision transformers, a common supervised deep learning model that can be trained to classify disease based on 3D brain MRI. For simpler classification methods such as linear discriminant analysis, the classifier performance AUC(N), when trained on a sample of size N, is known to depend on the encoder's eigenspectrum. Each class-discriminative direction in the latent space contributes only after the sample size N reaches a threshold N i = λ i /α i [2] - so the spectrum influences how performance scales with training data. Building on this theory, we show that supervised transformers compress almost all of their discriminative signal into one principal component (EVR@1 = 0.90-0.96): after this "representation collapse" happens, no further directions cross the threshold as training data increases, and accuracy plateaus. In principle, this plateau in performance could be due to either the encoder's learned feature space or the difficulty of the task. To distinguish these cases, we trained three types of supervised 3D transformers (ViT3D, MINiT, NIT) and, as a non-collapsing alternative, a frozen self-supervised encoder (DINO), to classify people with dementia or mild cognitive impairment (MCI) versus cognitively normal (CN) individuals from 3D brain MRI, using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We froze each encoder and applied it to a new task, so that only the task difficulty varied. An "easy" task encoder (Dementia vs CN), transferred to the harder task (MCI vs CN), did not reproduce the plateau (MINiT threshold 9.2), but full retraining did (2758.5). The plateau is therefore due to the learned encoder, rather than task difficulty. Ranking the feature directions by the proportion of the disease signal they contain, we were able to identify a sign of representation collapse, i.e., a single dominant spike in the latent feature eigenspectrum. This spike was 11-26 times larger than predicted from the rest of the spectrum for the disease-trained (supervised) encoders, but was absent for DINO (0.66). To predict how transformer accuracy scales with the number of training scans, a large spike in the encoder spectrum suggests that the representation has collapsed and additional scans will not help; a small spike means that the signal is spread across many encoder latent space directions, and more training data should boost the classifier performance.},
}

@article {pmid42999108,
year = {2026},
author = {Kong, Y and Zhai, TY and Zhao, HB},
title = {Spatiotemporal transcriptomic dynamic across the auditory pathway from young to old age in 5xFAD Alzheimer disease mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.17.759861},
pmid = {42999108},
issn = {2692-8205},
abstract = {Auditory dysfunction can precede clinical dementia, but the molecular progression of Alzheimer disease (AD) pathology from the sensory periphery to auditory cortex remains poorly resolved. We performed bulk RNA sequencing of auditory cortex (AC), inferior colliculus (IC), cochlear nucleus (CN), and cochlea from 5xFAD and wild-type mice at postnatal day 50 (P50), 8 months, 11 months, and 16 months. Age-specific genotype effects and Genotype×Age interactions were evaluated using DESeq2, followed by Hallmark, KEGG, and Gene Ontology gene-set enrichment analyses and a cross-region synthesis of interaction trajectories. At P50, AC, IC, and cochlea showed coordinated suppression of mitochondrial metabolism, translation, RNA processing, and proteostasis, whereas CN displayed the opposite metabolic and biosynthetic profile together with reduced synaptic and adhesion programs. At 8 months, inflammatory interactions converged across all four regions, including interferon, complement, IL6-JAK-STAT3, and broader immune-response pathways. This coordination fractured at 11 months: AC and IC retained inflammatory and negative synaptic shifts, whereas CN and cochlea frequently changed in the opposite direction, including transient positive shifts in synaptic programs. By 16 months, immune interactions converged again, while metabolic, proteostatic, and synaptic trajectories remained region dependent; CN opposed AC, IC, and cochlea in several major metabolic programs. These findings define a distributed, asynchronous response rather than a monotonic bottom-up or top-down progression. The resulting spatiotemporal map links early metabolic stress, intermediate central-peripheral decoupling, and late inflammatory convergence, providing a molecular framework for evaluating peripheral-to-central auditory gain and temporal-processing measures as candidate indicators of AD progression.},
}

@article {pmid42999164,
year = {2026},
author = {Kaur, B and Abdo, AN and Cho, S and Gabr, MT},
title = {DNA-Encoded Library-Guided Discovery of a First-in-Class Molecular Glue of the NOS1AP-SCRIB Complex in Alzheimer's Disease Patient-Derived Neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.12.758423},
pmid = {42999164},
issn = {2692-8205},
abstract = {NOS1AP is an adaptor for neuronal nitric oxide synthase that engages several partner proteins and is implicated in Alzheimer's disease. Efforts to drug NOS1AP have sought to disrupt these; we instead report pharmacological stabilization of one interaction. Affinity selection of a 1.4-billion-member DNA-encoded library identified a benzimidazole-5-carboxamide chemotype, optimized by fragment-directed SAR to NOSTRA with submicromolar NOS1AP binding affinity. Of six interactions, NOSTRA enhanced only SCRIB binding, with a cooperativity factor of 30, predominantly through a 14-fold slowing of dissociation; native mass spectrometry resolved a NOS1AP:NOSTRA:SCRIB ternary complex. In healthy human iPSC-derived cortical neurons, NOSTRA engaged the endogenous complex and activated Rac1 without cytotoxicity; in Alzheimer's patient-derived neurons, it lowered the Aβ42/Aβ40 ratio and p-tau217, reduced neurofilament light and improved network activity. With an in vitro ADME profile consistent with CNS exposure, NOSTRA is the first molecular glue for a NOS1AP complex, establishing interaction stabilization as a viable NOS1AP pharmacology.},
}

@article {pmid42999190,
year = {2026},
author = {Kumar, A and Zhang, J and Harvey, J and Guenter, R and Chkheidze, R and Sethu, P and Beck, AW and Ren, B},
title = {Endothelial CD36 links arteriolar remodeling to metabolic and immune alterations in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.13.758947},
pmid = {42999190},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is accompanied by profound cerebrovascular dysfunction, yet it remains unclear whether endothelial abnormalities reflect only vascular injury or altered regulatory states connecting vascular remodeling with metabolic and immune function. We integrated human brain transcriptomic and histopathological data with complementary mouse genetic and human iPSC-derived endothelial models to examine a CD36-centered endothelial-state framework in AD. Analysis of the Seattle Alzheimer's Disease Brain Cell Atlas identified three CD36-expressing endothelial populations; intermediate-CD36 Endo 2 predominated in both reference and AD samples, although the relative subset distributions differed. In hippocampal and cortical tissue from six AD patients, endothelial CD36 expression was observed in structurally abnormal arterioles with disrupted mural organization. In complementary mouse studies, endothelial PKD1 deficiency was accompanied by increased vascular CD36 and cerebrovascular abnormalities, whereas endothelial CD36 deletion altered lipid-metabolic and innate-immune-associated transcriptional programs, including AD-relevant genes and pathways, under metabolic-inflammatory stress. To assess whether distinct human endothelial backgrounds remained pharmacologically responsive, we treated control and CRISPR-engineered PSEN1 E276A iPSC-derived ECs with GS4898, a small molecule previously linked to arterial specification. Both maintained endothelial identity but displayed different baseline transcriptional profiles and shared as well as cell-line-dependent responses to GS4898. Together, our study identifies a CD36-associated vascular phenotype in human AD, demonstrates CD36-dependent regulation of brain endothelial metabolic-immune transcriptional programs in vivo, and reveals endothelial transcriptional responsiveness to pharmacologic perturbation. The observed endothelial transcriptional plasticity may provide a basis for developing state-selective therapeutic strategies targeting cerebrovascular dysfunction in AD.},
}

@article {pmid42999232,
year = {2026},
author = {Morello-Megias, A and Dhulipalla, BS and Kahvecioglu, HA and Shin, J and Joseph, S and Aggarwal, D and Luebke, JI and Rosene, DL and Dimovasili, C and Roussarie, JP},
title = {Molecular anatomy of the entorhinal cortex.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.13.758661},
pmid = {42999232},
issn = {2692-8205},
abstract = {The entorhinal cortex (EC) is critical for episodic memory formation and is the epicenter of neurofibrillary tangle formation in Alzheimer's disease. Its cytoarchitectonic and functional heterogeneity has been recognized for decades, but the molecular underpinnings of this heterogeneity are still relatively uncharted. While many features of the region appear to be conserved between rodents and primates, very little is known about the conservation of the molecular identity of EC neurons. Here we perform single-nucleus RNAseq (snRNAseq) of the mouse EC and use in situ hybridization, as well as publicly available transcriptomics data, to enhance the understanding of the heterogeneity of neuron types present in the area. While the well-known dichotomy between lateral and medial EC is evident in superficial layers of EC, we highlight that the medioventral region of EC forms a different population from the caudomedial section. We identify molecular correlates for the previously described parcellation of lateral EC, and show that, at least in layer IIa, subterritories of EC are not separated by abrupt borders but rather form smooth gradients. Lastly, we show that both lateral vs. medial ECIIa markers, and markers that reveal finer grain heterogeneity within ECIIa have conserved patterns of expression in macaque, highlighting the high degree of homology between the two species. Overall this molecular atlas of the mouse EC with some comparative elements is a resource for anatomically-informed molecular studies of the EC and lays the groundwork for mechanistic studies of selective neuronal vulnerability of the region in the context of AD.},
}

@article {pmid42999242,
year = {2026},
author = {Ruiz-Uribe, NE and Alfadhel, M and Wolf, N and Murray, SE and Gross, E and Devine, A and Shaby, DG and Belali, S and Vinogradov, S and Zwang, T and Thunemann, M and Sakadzic, S and Bennett, RE},
title = {Depth-Dependent Alterations in Cerebral Blood and Tissue Oxygenation Associated with Tau in Alzheimer's Disease Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.09.757981},
pmid = {42999242},
issn = {2692-8205},
abstract = {Vascular dysfunction is increasingly recognized as a feature of Alzheimer's disease (AD), and inadequate oxygen delivery may contribute to neuronal death. However, the relationship between cerebral oxygenation and neuronal pathology remains unclear. Here, we used two-photon phosphorescence lifetime microscopy (2PLM) with Oxyphor2P to measure intravascular and tissue partial pressure of oxygen (pO2) at three cortical depths (0, 100 and 200 µm) in awake rTg4510 and THY-Tau22 mice. In 9-month-old rTg4510 mice, capillary and venular pO2 were lower than in WT, mainly in deeper layers, and oxygen extraction fraction was increased, whereas 6-month-old mice showed increases in capillary and venular pO2. Suppressing the tau transgene with doxycycline for three months did not restore vascular pO2. THY-Tau22 mice, despite limited tangle pathology, showed even greater reductions in capillary pO2 at every depth. In 6-month-old rTg4510 mice, tissue pO2 trended lower than in WT mice, and the fraction of low pO2 values (< 18 mmHg) increased with depth, reaching 33% at 200 µm versus 4% in WT. By labeling neurofibrillary tangles (NFTs) with the tau-binding dye HS84, we found that tissue pO2 was significantly lower in tangle-positive areas at 100 and 200 µm. Longitudinal imaging of 2,282 neurons showed that disappearing neurons were not located in relatively hypoxic tissue within an animal. Finally, ex vivo immunostaining revealed neuronal loss and increased astrogliosis in rTg4510 mice, while vascular architecture was unchanged. Altogether, our results indicate that tau disrupts cerebrovascular and tissue oxygenation in a depth- and age-dependent manner, and that neuronal loss is not explained by the oxygen levels of a neuron's immediate microenvironment but may instead reflect a global reduction in cortical oxygenation.},
}

@article {pmid42999245,
year = {2026},
author = {Lee, H and Peppler, GB and Sewell, M and Münch, A and Podleśny-Drabiniok, A and Kim, JJ and Orrick, J and Marcora, E and Goate, AM},
title = {A rapid, genetically-tractable human iPSC-derived model for studying tissue-resident macrophage biology in Alzheimer's and other diseases.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757653},
pmid = {42999245},
issn = {2692-8205},
abstract = {Large-scale genetic and preclinical studies strongly implicate myeloid cells, particularly brain-resident macrophages, in the pathogenesis of Alzheimer's disease (AD). Efferocytic clearance of apoptotic cells and other cholesterol-rich cellular debris is a core macrophage function and represents an active area of AD research. However, human tissue-resident macrophages remain difficult to model in vitro as they acquire their transcriptional and functional identities in response to signals from their host tissue microenvironment. Many existing differentiation protocols mimic human brain macrophage developmental trajectories, but these protocols rely either on multi-step cytokine cocktails and lengthy differentiation or transduction of multiple transcription factors, both of which introduce variability and complicate genetic manipulation. To address these limitations, we developed a simplified protocol that generates high-purity (>90% CD45+CD11b+) human iPSC-derived macrophage-like cells (iMacs) from cryopreservable erythro-myeloid progenitor (EMP)-like intermediates in 19 days, including a final 7-day maturation step driven by macrophage colony-stimulating factor (M-CSF) alone. Transcriptomic profiling reveals that iMacs show enrichment for phagocytic and lysosomal programs, processes integral to efferocytosis. At both the transcriptional and protein level, iMacs have higher expression of scavenger receptors such as CD36 , CD163 and MRC1 , and of AD risk genes such as TREM2 and APOE . Functionally, iMacs show enhanced phagocytic uptake of diverse substrates relative to iPSC-derived microglia, including carboxylated latex beads, zymosan, amyloid-β 1-42, and amyloid-β 1-40, and exhibit expanded lysosomal mass. Robust TREM2 expression and signaling make iMacs a sensitive platform for interrogating TREM2 biology, with markedly higher phosphorylation of SYK and PLCγ2 in response to TREM2 engagement compared to iPSC-derived microglia. iMacs also tolerate lipid-mediated siRNA transfection with high survival and knockdown efficiency, enabling rapid genetic perturbation of AD risk genes. Together, these features make iMacs a practical, scalable, and genetically tractable human macrophage model for studying the regulation and cell biology of core macrophage functions that are known to play critical roles in AD, aging, and other disorders.},
}

@article {pmid42999263,
year = {2026},
author = {Tristão-Pereira, C and Silva, G and Lopez, KA and Ku, V and Gonzalez, A and Martinez, JE and Giudicessi, A and Rowe, M and Garcia, S and Catalan, MG and Saldana, DG and Gatchel, J and Ramirez-Gomez, LA and Quiroz, YT},
title = {Alzheimer's disease blood-based biomarkers in the Boston Latino Aging Study (BLAST): Associations with cognition and depressive symptoms.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.13.26365304},
pmid = {42999263},
abstract = {BACKGROUND: Blood-based biomarkers (BBMs) may facilitate early detection of Alzheimer's disease (AD), yet data in Latino populations remain limited. We examined associations of plasma biomarkers with cognition and depressive symptoms in Spanish-speaking Latino older adults enrolled in the Boston Latino Aging Study (BLAST).

METHODS: Baseline data from 122 adults aged ≥55 years without dementia were analyzed. Plasma Aβ42/40, brain-derived phosphorylated tau (p-tau) 217, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured using NULISA. Cognition was assessed with the Latin American Spanish version of the Preclinical Alzheimer's Cognitive Composite (LAS-PACC5) and depressive symptoms with the Geriatric Depression Scale (GDS). Regression models were adjusted for age, sex, and education.

RESULTS: Cognitively impaired participants had higher p-tau217 and GFAP than cognitively normal participants. Higher p-tau217 and GFAP were associated with poorer LAS-PACC5 performance, while higher NfL was associated with greater depressive symptoms. Aβ42/40 showed no significant associations.

CONCLUSIONS: Distinct biomarker associations with cognitive and emotional functioning support further longitudinal evaluation of BBMs for risk characterization in Latino older adults and potential disease monitoring applications.},
}

@article {pmid42999265,
year = {2026},
author = {Martinez-Molina, N and Aquilue-Llorens, D and Rass, L and Montana-Valverde, G and Patow, G and Escrichs, A and Sanz-Perl, Y and Kringelbach, ML and Palva, S and de Maestu, F and Deco, G},
title = {Turbulent dynamics and in silico perturbation-based measures are disrupted across biological stages of Alzheimers disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.12.26365318},
pmid = {42999265},
abstract = {According to the AT(N) framework, Alzheimers disease (AD) can be biologically characterised by amyloid deposition, tau pathology, and neurodegeneration, yet how these processes relate to whole-brain dynamics remains unclear. Here, we investigated these relationships and the link between whole-brain dynamics and cognitive dysfunction using multimodal neuroimaging from 145 ADNI3 participants. We combined multiscale measures of turbulent dynamics with responses to in silico perturbations obtained from whole-brain models. AD progression was characterised by a scale-dependent reorganisation of turbulent dynamics where information flow showed the strongest contribution to the dynamics-related variance in cognitive performance. Large-scale turbulence was associated with all three AT(N) components. Model-based information capability and susceptibility measures progressively decreased across AD stages and were associated with amyloid burden and regional tau deposition. Model-free features discriminated comparisons involving AD dementia, whereas adding model-based measures produced modest, metric-dependent changes in classification performance. Exploratory analyses showed spatial alignment between large-scale turbulence alterations and AD-risk gene-expression gradients, with APOE among the strongest associations in both disease-stage contrasts examined. Lastly, we found a progressive decoupling between turbulent dynamics and the E:I balance across AD stages. Together, these findings link model-based and model-free measures of whole-brain dynamics to proteinopathy, neurodegeneration, and cognitive impairment, supporting their complementary value for characterising AD progression.},
}

@article {pmid42999266,
year = {2026},
author = {Hoang, DT and Thompson, RC and Lund, AN and Kritzer, E and Buxbaum-Grice, AS and John, D and Nadkarni, GN and Golestani, N and Charney, AW and Beckmann, ND},
title = {Surrogate variables and the risk of overfitting in neuropsychiatric gene expression analyses.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.756826},
pmid = {42999266},
issn = {2692-8205},
abstract = {The reproducibility crisis in biomedical research calls for re-evaluation of how common analytic approaches affect results. One such approach, surrogate variable analysis (SVA), is widely used to adjust for unmeasured drivers of variation in transcriptomic differential expression analyses. We systematically quantified the impact of SVA using synthetic data with known ground truth and fourteen brain RNA-seq and microarray datasets spanning Alzheimer's disease, autism spectrum disorder, bipolar disorder, schizophrenia, and Parkinson's disease. In synthetic data, SVA usage frequently led to high false positive rates. This issue was not revealed by standard diagnostics nor resolved by strategies such as maximizing cross-dataset signal correlation. In real data, using SVA reduced cross-cohort reproducibility of differential expression signatures regardless of the number of surrogate variables included. These findings show that SVA risks inducing overfitting at realistic signal levels, advocating for a cautious, case-by-case application, with a preference for modeling known covariates.},
}

@article {pmid42999309,
year = {2026},
author = {Perovnik, M and Eidelberg, D},
title = {Neurodegenerative disorders: Stereotyped relationships between pathological metabolic topographies and the healthy default mode network.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11320531/v1},
pmid = {42999309},
issn = {2693-5015},
abstract = {Background and Objectives: Neurodegenerative disorders are associated with disease-specific networks on metabolic brain imaging. Depending on the disease, the associated pathological topography overlaps to varying degrees with the healthy default mode network (DMN). In this study, we examined the relationships of these networks in various neurodegenerative disorders and in prodromal syndromes. Methods: We analyzed FDG PET scans from 1,117 patients with neurodegenerative disorders manifest by dementia (Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), and dementia with Lewy bodies (DLB)), parkinsonism (Parkinson's disease (PD) and PD dementia (PDD)), or by mixed/atypical syndromes (progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and X-linked dystonia-parkinsonism (XDP)). We also studied scan data from 120 individuals with prodromal syndromes. Topographic relationships between the disease-specific networks and the healthy DMN were assessed by computing spatial similarity indices and voxel-wise correlations. We also computed the expression of the two networks in each patient and in 499 healthy subjects. In each patient group, the resulting values were correlated with each other and with corresponding MMSE scores. Results: The disorders fell into one of three categories based on the topographic relationship of the disease-specific and healthy networks. Category 1 (bvFTD, PSP, CBD, and XDP) was characterized by substantial spatial overlap of the two metabolic networks, tight correlations between their respective expression levels, and significant DMN reductions. Category 2 (PD, AD, DLB, and their associated prodromal syndromes) was characterized by less pronounced overlap, correspondingly weak correlations, and smaller DMN reductions, particularly at prodromal stages. In this group, correlations with MMSE were greater for the difference between disease network and DMN scores than for the disease network alone. Category 3 (MSA) had no discernible network overlap and no loss of DMN expression. Discussion: Category 1 disorders were associated with close relationships between the pathological and healthy topographies, indicating primary DMN involvement. Category 2 disorders were characterized by weaker network relationships, consistent with secondary DMN involvement. Category 3 disorders showed no evidence of DMN involvement. The degree to which disease-specific networks overlap with DMN provides unique insight into the underlying neurodegenerative process.},
}

@article {pmid42999311,
year = {2026},
author = {Sharma, N and Dai, S and Mallus, FA and Kand, A and Lemnitzer, M and Nguyen, MH and Sulaikha, MMH and Xing, J and Zabihi, M and Lale, G and Vijayakrishnan, GP and Schreiner, E and Punitha, MS and Buttkus, P and Yıldız, Ç and Kumar, P and Grote, T and Leonardsen, E and Sammarco, F and Jangir, VK and Sobotta, S and Bučková, BR and de Boer, AAA and Tsilimparis, K and Gaser, C and Fraza, C and Rutherford, S and Kia, SM and Marquand, AF and Yang, Y and Dinga, R and Wolfers, T},
title = {Transferable conditional brain charts link cortico-subcortical structure to Alzheimer's disease progression.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42999311},
issn = {2331-8422},
abstract = {Normative models chart how brain measures vary across the lifespan, expressing each individual as a deviation from a healthy reference. However, most regional models of cortical thickness disregard dependencies between cortical and subcortical anatomy, and transferring them to a new site typically requires retraining or a recalibration of location and scale alone. We condition lifespan norms of cortical thickness on subcortical volume, such that each deviation indicates whether an individual's cortex lies within the healthy range given their subcortical anatomy, and make them transferable. In 21,351 healthy individuals from 216 sites, conditioning on ten subcortical structures improved out-of-sample prediction on average, most for the amygdala and hippocampus. Refitting only the intercepts of all four distributional parameters on about 20 healthy individuals, as implemented in our open-source package NormGAMLSS, calibrated most of six unseen sites without retraining, for base and conditional models. In the Alzheimer's Disease Neuroimaging Initiative, global deviation and structural dissociation (the reduction in mean absolute deviation under conditioning) predicted conversion to mild cognitive impairment and dementia beyond the Clinical Dementia Rating and dissociation added beyond global deviation for dementia, even at similar clinically recorded impairment. Conditional norms thus provide relevant, individual-level information.},
}

@article {pmid42999317,
year = {2026},
author = {Saadi, F and Cho, Y and Katritch, IV and Lugo, B and Wu, Y and Smyth, LC and Bosch, M and Telfer, KA and Hyrc, K and Parhizkar, S and Bao, X and Nambiar, A and Zinselmeyer, BH and Hu, S and Kipnis, J and Randolph, GJ and Ulrich, JD and Holtzman, DM},
title = {APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.02.756327},
pmid = {42999317},
issn = {2692-8205},
abstract = {UNLABELLED: Cerebral amyloid angiopathy (CAA), characterized by cerebrovascular amyloid deposition, is strongly associated with Alzheimer's disease, ischemic injury, and lobar hemorrhages. APOE4 is the strongest known genetic risk factor for CAA, yet the cellular sources of APOE4 that drive pathogenic vascular amyloid deposition remain poorly defined. Here, we identify vascular-associated fibroblasts (VAFs) as a key source of APOE4 that mediates CAA and cerebrovascular dysfunction. In post-mortem brain tissue from APOE4/E4 patients with confirmed CAA, APOE colocalizes with COL6[+] VAFs around Aβ-laden vessels. Therefore, to study the contribution of APOE4 derived from VAFs in CAA, independently of parenchymal sources, we used 5xFAD mice in which the endogenous mouse Apoe coding exons are replaced with floxed human APOE4 sequences. This enables selective suppression of APOE4 expression in VAFs upon tamoxifen induction of Col1a2-CreERT [+] . APOE4 reduction in VAFs markedly reduced CAA, with the strongest effects observed in leptomeningeal vessels. Additionally, Aβ40, which preferentially associates with vascular amyloid, was significantly reduced in the vascular fraction. VAF APOE4 depletion resulted in fewer small microbleeds and an approximately 50% reduction in parenchymal border macrophages within the leptomeningeal compartment, whereas astrocytic reactivity remained unchanged. Functional assessment using in vivo multi-parametric photoacoustic microscopy revealed improved arterial dilation and blood flow in amyloid-laden leptomeningeal arteries. Together, these findings establish VAF-derived APOE4 as a compartment-specific driver of CAA and cerebrovascular dysfunction.

ONE SENTENCE SUMMARY: Vascular-associated fibroblasts are a major source of pathogenic APOE4 that drives vascular dysfunction in cerebral amyloid angiopathy.},
}

@article {pmid42999337,
year = {2026},
author = {Huang, H and Chen, L and Chen, J and Hyun, J and Loftus, J and Melmed, K and Orringer, D and Frontera, J and Dehkharghani, S and Masurkar, A and Razavian, N},
title = {Neuro-JEPA: Building and Evaluating Health-System Scale Neuroimaging Foundation Models with Mixture of Experts.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11130462/v1},
pmid = {42999337},
issn = {2693-5015},
abstract = {Magnetic resonance imaging (MRI) of the brain routinely combines complementary contrasts-including T1-weighted (T1w), T2-weighted (T2w) and FLAIR sequences-to capture anatomy and pathology. Although foundation models trained on large neuroimaging datasets have shown promise, it remains unclear whether they effectively integrate these complementary contrasts across diverse clinical settings. Here we present Neuro-JEPA, a multimodal foundation model that learns unified representations across structural brain MRIs. Neuro-JEPA combines latent predictive learning with a sparse Mixture-of-Experts architecture to encode multiple MRI contrasts within a single model. The model is pretrained on 1.55 million scans from 428,647 clinical imaging studies spanning T1w, T2w and FLAIR sequences. The model performance is evaluated on 47 downstream tasks across three independent health systems and 12 public datasets, encompassing single-contrast, multimodal and cross-domain applications. Across these evaluations, Neuro-JEPA achieved the strongest overall performance and generalized robustly across heterogeneous cohorts, outperforming existing neuroimaging foundation models and strong conventional baselines in the majority of comparisons despite using less than one-third of the pretraining data of leading models. Performance gains were particularly pronounced in data-scarce settings, reaching up to 15% over prior foundation models for clinically important pathologies including gliosis and multiple sclerosis. Neuro-JEPA showed clinically relevant capabilities across domains, including prediction of amyloid status and progression from mild cognitive impairment to Alzheimer's disease dementia, stroke identification and classification, and prediction of post-stroke functional outcome and length of stay. Together, these results show that data scale, curation and principled model design can act synergistically to produce broadly transferable neuroimaging representations, and establish Neuro-JEPA as a scalable framework toward general-purpose multimodal foundation models for neurological imaging.},
}