@article {pmid41916749,
year = {2026},
author = {Hong, L and Zeng, Q and Luo, X and Li, K and Liu, X and Li, J and Zhang, M and Cui, F and , },
title = {Distinct Patterns of Cortical Atrophy Predict Cognitive Progression in Age-Related Hearing Loss: A Longitudinal MRI Study.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9326},
pmid = {41916749},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Age-related hearing loss (ARHL) and dementia are common chronic conditions among the elderly, significantly impacting the quality of life of older adults. Additionally, ARHL is an important and modifiable risk factor for dementia. This study aimed to investigate distinct patterns of cortical atrophy in patients with ARHL and mild cognitive impairment (MCI), comparing those with stable cognition (sMCI) with those who progressed to dementia (pMCI), using longitudinal MRI data.

MATERIALS AND METHODS: We included a total of 93 participants from the Alzheimer's Disease Neuroimaging Initiative: 51 sMCI with normal hearing (sMCI+healthy control, group 1), 20 with sMCI with ARHL (sMCI+ARHL, group 2), and 22 with pMCI and ARHL (pMCI+ARHL, group 3). All subjects underwent 3 longitudinal T1-weighted MRI scans at approximately 1-year intervals. Cortical thickness was measured using FreeSurfer 6.0 in regions including the entorhinal cortex, parahippocampal gyrus, and temporal gyri. Repeated-measures ANOVA was used to compare atrophy rates, and receiver operating characteristic analysis evaluated the predictive value of significant regions.

RESULTS: Group 3 showed substantial faster annual atrophy rates in the left entorhinal cortex, left middle temporal gyrus, and bilateral superior temporal gyri compared with group 1. Group 2 also exhibited faster atrophy in temporal regions than group 1. Receiver operating characteristic analysis demonstrated that combined use of these regions improved predictive accuracy for cognitive progression.

CONCLUSIONS: Patients with ARHL with progressive cognitive decline exhibit accelerated atrophy in the auditory and early Alzheimer vulnerable regions. Combined cortical thickness measures may serve as a neuroimaging biomarker to predict cognitive progression in populations with ARHL.},
}

@article {pmid42922083,
year = {2026},
author = {Qin, W and Yang, L and Deng, X and Yuan, W and Guo, D and Xiao, S and Zhang, R and Zhang, Q and Chen, XZ and Zhou, C and Tang, J},
title = {Transcriptional control of autophagy: mechanisms, dynamics, and pharmacological modulation.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/15548627.2026.2753996},
pmid = {42922083},
issn = {1554-8635},
abstract = {The network of transcription factors (TFs) is an integral component of executing macroautophagy/autophagy-lysosome gene expression to maintain cellular homeostasis. Across metazoans, conserved TFs, particularly the helix-loop-helix factor TFEB, convert upstream signals into specific genetic programs through mechanisms ranging from DNA recognition and chromatin remodeling to biomolecular condensates. The dysregulation of TF-governed gene programming disrupts the progression of metabolic disease and cancer, highlighting that dissection of transcriptional regulation makes it a promising therapeutic target. Consequently, instead of indirectly modulating the pathways in which they are involved, targeting these essential TFs directly is becoming a new trend for pharmaceutical development. In this review, we systematically elucidate current mechanisms of the TF-driven autophagic transcriptome, and summarize current small molecules targeting these TFs in various disease.Abbreviations: AD: Alzheimer disease; AFF4: ALF transcription elongation factor 4; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; AR: androgen receptor; ATF4: activating transcription factor 4; ATG: autophagy related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BRD4: bromodomain containing 4; CRC: colorectal cancer; CREBBP/CBP: CREB binding lysine acetyltransferase; CTNNB1/β-catenin: catenin beta 1; DBD: DNA-binding domain; DDIT3: DNA damage inducible transcript 3; DRAM1: DNA damage regulated autophagy modulator 1; E2F1: E2F transcription factor 1; EHMT2/G9a: euchromatic histone lysine methyltransferase 2; EO: eltrombopag; EP300/p300: EP300 lysine acetyltransferase; ERBB2: erb-b2 receptor tyrosine kinase 2; FOXO3: forkhead box O3; GSH: glutathione; GSK3B/GSK3β: glycogen synthase kinase 3 beta; HD: Huntington disease; KAT2B/GCN5: lysine acetyltransferase 2B; HMGB1: high mobility group box 1; KDACs: lysine deacetylases; KEAP1: kelch like ECH associated protein 1; KLF4: KLF transcription factor 4; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MITF: melanocyte inducing transcription factor; MTORC1: mechanistic target of rapamycin kinase complex 1; MiT/TFE: microphthalmia-transcription factor E; MYC: proto-oncogene, bHLH transcription factor; NDs: neurodegenerative disorders; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; P-TEFb: positive transcription elongation factor b; PARP1: poly(ADP-ribose) polymerase 1; PD: Parkinson disease; PIC: pre-initiation complex; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PTMs: post-translational modifications; POLR2: RNA polymerase II; SIRT1: sirtuin 1; SNAI2: snail family transcriptional repressor 2; STAT3: signal transducer and activator of transcription 3; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TFs: transcription factors; TNKS: tankyrase; TP53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; YWHA/14-3-3: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein; YY1: YY1 transcription factor; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.},
}

@article {pmid42951564,
year = {2026},
author = {Zou, Y and Shi, W and Jiang, F and Liu, T and Liu, Z and Wang, X and Li, Y and Chen, Z and Ao, JP},
title = {Optoelectronically synergized MoS2 field-effect transistor sensor for the detection of Alzheimer's disease biomarker Aβ42.},
journal = {Analytica chimica acta},
volume = {1425},
number = {},
pages = {346329},
doi = {10.1016/j.aca.2026.346329},
pmid = {42951564},
issn = {1873-4324},
mesh = {*Molybdenum/chemistry ; *Amyloid beta-Peptides/analysis ; *Disulfides/chemistry ; *Biosensing Techniques/instrumentation/methods ; *Alzheimer Disease/diagnosis ; *Transistors, Electronic ; *Peptide Fragments/analysis ; Humans ; Biomarkers/analysis ; Limit of Detection ; },
abstract = {BACKGROUND: Early diagnosis of Alzheimer's disease (AD) relies heavily on the ultra-sensitive detection of its core biomarker, amyloid-beta 42 (Aβ42). To address this critical need, this paper presents a photoelectric synergistically enhanced field-effect transistor (FET) biosensor based on two-dimensional molybdenum disulfide (MoS2) for the highly sensitive and specific detection of Aβ42.

RESULTS: Experimental results demonstrate that light illumination significantly amplifies the sensing current under identical gate voltages and target concentrations. This enhancement enables the device to effectively overcome the subthreshold region and smoothly transition into the linear operating regime at lower voltages, thereby substantially optimizing signal readout efficiency in low-concentration regions. Benefiting from this photoelectric synergy, the sensor exhibits a markedly enhanced signal response and an optimized dynamic range. The limit of detection decreases to 4.15 × 10[-18] g/mL, representing a 26.29% reduction compared to dark conditions. Furthermore, the relative standard deviation (RSD) of the current response under illumination improves to 2.47% (n = 3), outperforming the 4.86% recorded in the dark and indicating simultaneous enhancements in detection repeatability and device stability. Supported by Silvaco TCAD simulations, the core operating mechanism is elucidated: the specific binding of target Aβ42 molecules inherently introduces localized interface charge perturbations at the MoS2 channel. This alteration of the interfacial charge state fundamentally governs the electrical response of the device, which is synergistically amplified under light illumination to achieve ultra-high sensing sensitivity.

SIGNIFICANCE AND NOVELTY: This study demonstrates that the photoelectric synergistic strategy offers a highly effective pathway to overcome the sensitivity and performance bottlenecks of traditional FET biosensors. Concurrently, it establishes a novel and promising paradigm for the design of high-performance, multimodal photoelectric biomedical diagnostic chips.},
}

*Molybdenum/chemistry
*Amyloid beta-Peptides/analysis
*Disulfides/chemistry
*Biosensing Techniques/instrumentation/methods
*Alzheimer Disease/diagnosis
*Transistors, Electronic
*Peptide Fragments/analysis
Humans
Biomarkers/analysis
Limit of Detection

@article {pmid42951923,
year = {2026},
author = {Ferreira, J},
title = {Alzheimer's disease pathology progression in J20 mice.},
journal = {Lab animal},
volume = {55},
number = {11},
pages = {415},
doi = {10.1038/s41684-026-01827-1},
pmid = {42951923},
issn = {1548-4475},
}

@article {pmid42951976,
year = {2026},
author = {Uffelmann, E and Wightman, DP and Bahrami, S and Shadrin, AA and Fominykh, V and Ojima, T and Jiang, C and Benner, C and Moreno, E and Campos, AI and Thomassen, JQ and Minois-Genin, E and Wu, HM and Walters, GB and Sherva, R and Lin, T and Wang, X and Bryois, J and Krebs, K and Schipper, M and Narita, A and Serretti, A and Simonsen, AH and van Seumeren, AL and Corbett, A and Knapskog, AB and Hartmann, AM and den Braber, A and van Harten, AC and Harder, A and Rongve, A and Madsen, BO and Tijms, BM and Aagaard, B and Lichtwarck, B and Kirsebom, BE and Creese, B and Reynolds, CA and Hägg, S and Karlsson, IK and Erikstrup, C and Mikkelsen, C and Ballard, C and Aarsland, D and Shigemizu, D and Rujescu, D and Gudbjartsson, D and Aakhus, E and Sørensen, E and Stordal, E and Duits, FH and Wolters, FJ and Blanc, F and Biessels, GJ and Selbæk, G and Bråthen, G and Tamiya, G and Waldemar, G and Seelaar, H and Eyjolfsdottir, H and Holstege, H and Bundgaard, H and Zetterberg, H and Ullum, H and Giegling, I and Skoog, I and Medbøen, IT and Saltvedt, I and Rektorova, I and Gaziano, JM and Haavik, J and Hjerling-Leffler, J and Luo, J and Snaedal, J and Vijverberg, EGB and Sealock, JM and Blennow, K and Nordengen, K and Persson, K and Scheffler, K and Matsuda, K and Ozaki, K and Pihlstrøm, L and Athanasiu, L and Pålhaugen, L and Hulsman, M and Waern, M and Averina, M and Wettergreen, M and Moksnes, MR and Huisman, M and Yamamoto, M and Toft, M and Panizzon, MS and Topholm Bruun, M and Ghanbari, M and Franc, M and Pedersen, NL and Bell, NY and Tesi, N and Pedersen, OB and Frei, O and Bousiges, O and Svenningsson, P and Visser, PJ and Li, QS and Hauger, R and Zhang, R and Namba, S and Sando, SB and Kern, S and Djurovic, S and Thordardottir, S and Phung, TN and Truelsen, T and Werge, T and Hansen, TF and Kyosaka, T and Engstad, T and Fladby, T and Merritt, V and Bergh, S and van der Flier, WM and Wang, R and Stahl, EA and Hooli, B and , and , and , and , and , and , and , and , and , and , and , and , and Davis, LK and Logue, MW and Lehto, K and Zettergren, A and Brumpton, BM and Zeng, J and Visscher, PM and O'Reilly, PF and Mahajan, A and Ferreira, M and Okada, Y and van der Lee, SJ and Ostrowski, SR and Frikke-Schmidt, R and Stefansson, H and Heilbron, K and Andreassen, OA and Posthuma, D and , },
title = {Alzheimer's disease genetics converges on microglial and neuronal dysregulation.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42951976},
issn = {1476-4687},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050[1]. AD is highly heritable, with twin-based heritability estimates of 60-80%[2]. Although 1,200 causal loci are predicted to exist for AD[3], approximately 80 loci have been associated with AD in two recent studies[4,5]. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found[6]. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.},
}

@article {pmid42952031,
year = {2026},
author = {Lee, SH and Blecha, J and Kim, JM and Nillo, RM and Flavell, RR and Chao, CK and Forsayeth, JR and Gerdes, JM and VanBrocklin, HF and Wilson, DM},
title = {Copper-Mediated Radiofluorination of the Excitatory Amino Acid Transporter 2 (EAAT2)-Targeted PET Tracer [[18]F]RP-115: Alternate Synthetic Method.},
journal = {Journal of labelled compounds & radiopharmaceuticals},
volume = {69},
number = {13-14},
pages = {},
pmid = {42952031},
issn = {1099-1344},
support = {RC-201810-2017455//Alzheimer's Drug Discovery Foundation/ ; 1R01AG072743-01A1/AG/NIA NIH HHS/United States ; },
mesh = {*Fluorine Radioisotopes/chemistry ; *Positron-Emission Tomography ; *Copper/chemistry ; *Radiopharmaceuticals/chemical synthesis/chemistry ; *Excitatory Amino Acid Transporter 2/metabolism ; Chemistry Techniques, Synthetic ; Halogenation ; },
abstract = {Excitatory amino acid transporter 2 (EAAT2) is a key regulator of extracellular glutamate in the central nervous system. Dysregulated EAAT2 is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), highlighting EAAT2 as a potential target for PET imaging. We previously reported a multistep radiosynthesis of [[18]F]RP-115, a CNS-permeable prodrug that undergoes esterase-mediated hydrolysis in the CNS to yield the active EAAT2-binding carboxylate. Motivated by recent advances in copper-mediated radiofluorination (CMRF), we sought to develop a more efficient late-stage radiosynthesis of [[18]F]RP-115. A two-step radiosynthesis of [[18]F]RP-115 using CMRF provided [[18]F]RP-115 in high radiochemical yield (52.8% ± 2.1 %, decay-corrected from starting [[18]F]fluoride ion, n = 4), high molar activity (355 ± 61 GBq/μmol), and high radiochemical purity (> 99%) with a total synthesis time of 70 min. Chiral HPLC analysis demonstrated that the configuration of the aspartic acid residue remained intact without racemization during both the CMRF and trifluoroacetic acid mediated deprotection. We developed an efficient radiosynthesis of [[18]F]RP-115 via CMRF, achieving high radiochemical yield and molar activity. This efficient synthesis may serve as a basis for the future implementation of a CMRF-based automated radiosynthesis of [[18]F]RP-115.},
}

*Fluorine Radioisotopes/chemistry
*Positron-Emission Tomography
*Copper/chemistry
*Radiopharmaceuticals/chemical synthesis/chemistry
*Excitatory Amino Acid Transporter 2/metabolism
Chemistry Techniques, Synthetic
Halogenation

@article {pmid42952059,
year = {2026},
author = {Cellular Longevity, OMA},
title = {RETRACTION: Probiotics Fermentation Technology, a Novel Kefir Product, Ameliorates Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer's Disease in Mice.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {},
pmid = {42952059},
issn = {1942-0994},
}

@article {pmid42952081,
year = {2026},
author = {Velazquez, S and Juber, MC and Brindley, D and Thakur, A and Anasori, B and Lau, E and Ashkarran, AA},
title = {MXene-Protein Corona Interfaces for Molecular Profiling of Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01228},
pmid = {42952081},
issn = {2576-6422},
abstract = {The protein corona (PC) that forms on the surface of nanomaterials upon contact with biological fluids provides a molecular snapshot of the host's physiological and pathological state. Here, we investigate two-dimensional (2D) titanium carbide (Ti3C2Tx) MXene nanosheets as nanobiointerfaces for capturing Alzheimer's disease (AD)-associated plasma protein signatures. Ti3C2Tx MXene flakes were incubated with plasma from clinically diagnosed AD patients and age-matched healthy controls (HC), leading to the formation of Ti3C2Tx MXene-PC complexes. Physicochemical characterization using dynamic light scattering, zeta potential analysis, and transmission electron microscopy revealed disease-dependent changes in hydrodynamic size, surface charge, and PC profile. Proteomic analysis of the isolated PC layers quantified 1,611 proteins without prior fractionation, demonstrating broad plasma proteome coverage. Principal component analysis (PCA) revealed disease-associated separation between AD and HC-derived Ti3C2Tx MXene PC proteomes along specific principal components despite interindividual heterogeneity. Differential abundance analysis identified selective enrichment of heterogeneous nuclear ribonucleoproteins (hnRNPs), annexins, and inflammatory mediators in AD-derived PC, implicating dysregulated RNA metabolism, membrane stress responses, and immune activation, hallmark processes in AD pathology. Our findings demonstrate that Ti3C2Tx MXene-PC interfaces reshape the detectable plasma proteome and enable disease-associated molecular phenotyping, establishing a versatile nanointerface-driven framework for AD-related proteomic fingerprinting and molecular profiling. These results provide a foundation for future studies exploring MXene-based biointerfaces for plasma biomarker discovery and translational diagnostic applications.},
}

@article {pmid42952112,
year = {2026},
author = {Rocha, A and Machado, LS and Soares, C and L Ferreira, PC and Bellaver, B and Carvalho, P and Lazzarotto, G and Vidor, P and Kunach, P and T Venturin, G and Greggio, S and C da Costa, J and Bastos de Mello, F and Milinkeviciute, G and Forner, S and Green, K and Rosa-Neto, P and Pascoal, T and Souza, DO and Zimmer, E},
title = {EXPRESS: Longitudinal FDG-PET reveals early hypermetabolism associated with astrocyte changes in TgF344-AD rats.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261504653},
doi = {10.1177/0271678X261504653},
pmid = {42952112},
issn = {1559-7016},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by alterations in brain glucose metabolism, classically showing [18F]FDG-PET hypometabolism in later stages. However, emerging evidence suggests a transient phase of glucose hypermetabolism early in the disease, for which biological basis remains unclear.

METHODS: We combined longitudinal and cross-sectional approaches in TgF344-AD rats and wild-type controls at 3, 6, 9, and 12 months. Longitudinal assessments included [[1][8]F]FDG-microPET imaging, behavioral testing, and cerebrospinal fluid biomarker analysis. Cross-sectional analyses included amyloid histopathology, western blot and ex vivo glutamate uptake measurements.

RESULTS: TgF344-AD rats exhibited increased cerebral glucose metabolism at 9mo, predominantly in cortical regions. This phase coincided with emerging cognitive impairment and early amyloid deposition. CSF analyses showed increased GFAP at 9-12mo and reduced S100B at 9mo, while microglial/inflammatory markers remained unchanged. WB confirmed region-specific GFAP alterations without changes in neuronal or synaptic markers. Glutamate uptake was increased in the cortex and hippocampus at 9mo.

CONCLUSION: These findings identify a transient phase of increased glucose metabolism early in disease progression, associated with astrocyte-related changes, suggesting that early hypermetabolism may reflect non-neuronal processes. This has implications for the interpretation of [18F]FDG-PET as a biomarker in early AD and for understanding early physiological responses to AD pathology.},
}

@article {pmid42952140,
year = {2026},
author = {Sun, B and Gu, M and Maher, A and DuBois, KN and Kanaan, NM and Bross, J and Koeppe, R and Persad, CC and Murphey, YL and Kavcic, V and Ren, J and Giordani, B and Li, T},
title = {EEG-based brain effective and functional connectivity predict PET-defined amyloid positivity in cognitively normal individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42952140},
issn = {1552-5279},
support = {NSF-2032709//National Science Foundation/ ; NSF-1919154//National Science Foundation/ ; NSF-2535060//National Science Foundation/ ; P30AG072931/NH/NIH HHS/United States ; P30AG024824/NH/NIH HHS/United States ; S10OD034250-01/NH/NIH HHS/United States ; R01AG068338/NH/NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography ; *Brain/diagnostic imaging/physiology/metabolism ; *Electroencephalography/methods ; Female ; *Amyloid beta-Peptides/metabolism ; Male ; Alzheimer Disease/diagnosis ; tau Proteins/blood ; Aged ; Machine Learning ; Cognition/physiology ; Biomarkers ; },
abstract = {INTRODUCTION: Early identification of amyloid-beta (Aβ) pathology is essential for timely intervention in Alzheimer's disease (AD), as Aβ accumulation precedes clinical symptoms by years.

METHODS: We predicted positron emission tomography (PET) -defined Aβ status in cognitively normal individuals using non-invasive resting-state dry electroencephalography (EEG). Brain effective and functional connectivity were quantified to characterize dynamic information transfer between regions. Features derived from dynamic brain connectivity were used to train machine learning models for Aβ classification.

RESULTS: EEG-based models can predict amyloid positivity with accuracy comparable to, or in some cases exceeding, that of plasma p-tau217 and previously reported predictors based on cognitive measures, demographics, and health factors, depending on the model.

DISCUSSION: Beyond near real-time Aβ inference, the framework identifies the most affected brain regions and connections associated with neurodegeneration, offering complementary information to blood-based biomarkers and supporting its potential as an affordable tool for early AD detection in primary care and population screening.},
}

Humans
*Positron-Emission Tomography
*Brain/diagnostic imaging/physiology/metabolism
*Electroencephalography/methods
Female
*Amyloid beta-Peptides/metabolism
Male
Alzheimer Disease/diagnosis
tau Proteins/blood
Aged
Machine Learning
Cognition/physiology
Biomarkers

@article {pmid42952210,
year = {2026},
author = {Hossain, MK and Lee, HY and Kim, HJ and Kim, HR},
title = {The Brain-Tooth Axis as an Early Predictor of Alzheimer's Disease.},
journal = {Biomolecules & therapeutics},
volume = {34},
number = {6},
pages = {1322-1330},
doi = {10.4062/biomolther.2026.165},
pmid = {42952210},
issn = {1976-9148},
abstract = {Alzheimer's disease (AD) is typically diagnosed after irreversible neuronal loss. Recent evidence links oral health deterioration-especially tooth loss, periodontal disease, and reduced masticatory function-to accelerated cognitive decline and dementia risk. Aging also promotes structural and immunological changes in the oral cavity, accelerating periodontal breakdown, microbiome dysbiosis, and functional tooth loss. This emerging "brain-tooth axis" suggests bidirectional interactions between the oral cavity and central nervous system via inflammatory, microbial, and sensory pathways. Periodontal inflammation, oral microbiome dysbiosis, and loss of trigeminal sensory input may promote neuroinflammation, amyloid accumulation, and hippocampal dysfunction. Conversely, early neural degeneration can impair oral maintenance and chewing behavior. This perspective outlines mechanistic hypotheses, clinical implications, and a research roadmap for integrating oral health metrics into multimodal AD risk prediction. Validating this axis could establish oral assessments as accessible biomarkers for early disease detection and prevention strategies.},
}

@article {pmid42952261,
year = {2026},
author = {Lee, S and Purewal, E and Rasgon, N and Kwan, A and Dri, CE and Ho, R and McIntyre, RS},
title = {Sex differences in glucagon-like peptide-1 signalling and the implications for Alzheimer's disease: A narrative review.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e49},
doi = {10.1017/S1092852926101291},
pmid = {42952261},
issn = {2165-6509},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Glucagon-Like Peptide 1/metabolism ; *Sex Characteristics ; Signal Transduction/physiology ; Animals ; Female ; Male ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia. Women are differentially affected by AD, and several sex-specific mechanisms have been explored, including hormonal differences (eg, estrogen). Glucagon-like peptide-1 (GLP-1R) are located in brain regions implicated in the pathogenesis of AD and shows preliminary evidence of modulating sex-specific pathways that may underlie differential disease risk and progression. Herein, we synthesize the extant literature on the mechanisms of GLP-1 in neurobiological systems relevant to AD pathology. Metabolic signalling (eg, GLP-1, insulin) intersects with known sex-specific pathways hypothesized to subserve AD progression in women. The preceding effects may be attributable to the disruption of estrogen signalling during the postmenopausal period, which impairs hippocampal insulin receptor function and exacerbates mitochondrial dysfunction. In addition, these mechanisms provide an explanation for AD comorbidities (eg, type 2 diabetes mellitus [T2DM]). The multidimensional effects demonstrated in GLP-1 paradigms provide a compelling rationale for further investigation of the role of metabolic signalling on sex-specific alterations in AD. Evidence across preclinical and early clinical studies suggests that GLP-1RAs may differentially influence neurobiological pathways implicated in AD pathogenesis, particularly those that interact with hormonal and metabolic systems.},
}

Humans
*Alzheimer Disease/metabolism
*Glucagon-Like Peptide 1/metabolism
*Sex Characteristics
Signal Transduction/physiology
Animals
Female
Male
*Brain/metabolism

@article {pmid42952670,
year = {2026},
author = {He, Y and Zhou, J and Wu, X and Sheng, J and Zhang, Z and Feng, Z and Zhang, S},
title = {Peripheral hematological inflammatory signatures in the amyloid-defined Alzheimer's disease continuum: associations with disease stage, cognitive function, and astroglial activation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1959479},
pmid = {42952670},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/blood/diagnosis/psychology/metabolism ; Female ; Male ; Cross-Sectional Studies ; Biomarkers/blood ; Aged ; *Cognition ; *Astrocytes/metabolism/immunology ; Amyloid beta-Peptides/metabolism ; *Inflammation/blood ; Neutrophils/immunology ; Positron-Emission Tomography ; Cognitive Dysfunction ; Aged, 80 and over ; Lymphocytes/immunology ; Disease Progression ; },
abstract = {BACKGROUND: Peripheral immune-inflammatory dysregulation has been implicated in Alzheimer's disease (AD) and cognitive decline. However, whether routinely available hematological inflammatory indices are associated with biological and clinical stages across the AD continuum and provide incremental information beyond established risk factors remains unclear. We aimed to investigate the associations of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and hemoglobin-to-red blood cell distribution width ratio (HRR) with AD continuum stage, cognition, and AD biomarkers.

METHODS: This cross-sectional study included 267 participants who underwent comprehensive cognitive assessment, peripheral blood testing, and amyloid-β positron emission tomography (Aβ-PET) imaging. Participants were categorized into three groups according to cognitive status and available amyloid biomarker profiles: cognitively unimpaired (CU-Aβ[-]), amyloid-positive mild cognitive impairment (MCI-Aβ[+]), and amyloid-positive Alzheimer's disease dementia (AD-Aβ[+]). Hematological inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and hemoglobin-to-red cell distribution width ratio (HRR), were calculated from routine blood parameters. A composite inflammatory index (Inflam_PC1) was derived using principal component analysis. Ordinal logistic regression models were used to examine the associations between inflammatory indices and AD continuum stage after adjustment for demographic, vascular, metabolic, and genetic factors.

RESULTS: Inflammatory profiles differed across the AD continuum, with increased NLR and SII and decreased HRR levels in more advanced stages. Higher NLR (OR = 1.54, 95% CI: 1.25-1.91, P < 0.001) and SII (OR = 1.29 per 100-unit increase, 95% CI: 1.15-1.45, P < 0.001) were independently associated with advanced AD continuum stages, whereas HRR was not. The composite inflammatory signature showed the strongest association (OR = 1.63 per SD increase, 95% CI: 1.30-2.03, P < 0.001) and provided incremental statistical improvement beyond conventional risk factors. Higher inflammatory burden was associated with poorer cognitive and functional performance and correlated with plasma glial fibrillary acidic protein (GFAP) level.

CONCLUSIONS: Peripheral hematological inflammatory signatures were associated with Alzheimer's disease continuum. Higher NLR and SII levels and a composite inflammatory signature were independently associated with more advanced disease stages, cognitive impairment, and functional decline. The association between inflammatory signatures and plasma GFAP, but not amyloid or tau biomarkers, suggests a relationship between peripheral inflammatory profiles and glial-related biomarker alterations that requires further longitudinal investigation.},
}

Humans
*Alzheimer Disease/immunology/blood/diagnosis/psychology/metabolism
Female
Male
Cross-Sectional Studies
Biomarkers/blood
Aged
*Cognition
*Astrocytes/metabolism/immunology
Amyloid beta-Peptides/metabolism
*Inflammation/blood
Neutrophils/immunology
Positron-Emission Tomography
Cognitive Dysfunction
Aged, 80 and over
Lymphocytes/immunology
Disease Progression

@article {pmid42952769,
year = {2026},
author = {Lan, X and Xia, M and Chen, L and Zheng, S and Jin, L and Wang, Y and Lu, S and Xu, J and Xu, L and Li, C and Yan, P},
title = {Family hardiness and associated factors among Chinese family caregivers of people with Alzheimer's disease: an explanatory sequential mixed-methods study.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1940356},
pmid = {42952769},
issn = {1664-1078},
abstract = {AIM: To examine family hardiness and associated factors among Chinese family caregivers of people with Alzheimer's disease (AD), and to explore caregivers' experiences of family adaptation in daily care.

METHODS: An explanatory sequential mixed-methods design was used. In the quantitative phase, 201 family caregivers recruited from a tertiary hospital in Zhejiang Province completed the Family Hardiness Index (FHI) and measures of potential associated factors. Multivariable linear regression examined associations with total and subscale FHI scores. Twelve caregivers subsequently took part in semi-structured interviews. Directed content analysis was used to interpret the quantitative findings in context and identify additional themes. The two phases were integrated through a following-a-thread approach and a convergence coding matrix.

RESULTS: The mean total FHI score was 56.85 ± 6.27. Commitment/responsibility had the highest mean subscale score (26.09 ± 3.71), and challenge the lowest (13.49 ± 2.04). In the final model for total FHI score (adjusted R[2] = 0.477), family resources (β = 0.390, p < 0.001), female patient sex (β = -0.286, p = 0.005), perceived caregiving burden (β = -0.262, p < 0.001), and family meaning-making (β = 0.190, p = 0.003) were independently associated with family hardiness. The qualitative analysis generated eight themes. Integration yielded two convergent findings, five complementary findings, and one exploratory theme found only in the interviews: companion-animal support.

CONCLUSION: Family resources, perceived caregiving burden, family meaning-making, and patient sex were associated with total FHI scores. Interviews provided context on family obligation, changing roles, and urban-rural differences in access to support. Companion-animal support, mentioned by two participants, is reported as a hypothesis-generating observation. Prospective studies are needed to examine causal relationships and the effects of family-support interventions.},
}

@article {pmid42952777,
year = {2026},
author = {Ren, X and Li, T and Liu, S and Li, L and Li, F},
title = {Sex and stage-defined exploratory inflammatory and amyloid-associated readout patterns in female APP/PS1 mice exposed to TAK-242.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1944097},
pmid = {42952777},
issn = {1663-4365},
abstract = {TLR4-related inflammatory signaling has been implicated in Alzheimer's disease-related immune responses, and TAK-242 has been used as an experimental tool in studies examining this signaling context. This exploratory study characterized inflammatory cytokine and amyloid-associated histological readout patterns associated with TAK-242 exposure in female early-stage APP/PS1 mice. Female APP/PS1 mice were assigned to saline, lipopolysaccharide, or TAK-242 exposure conditions for 6 weeks, with age-matched non-transgenic mice serving as reference controls (n = 8/group). Brain TNF-α, IL-1β, and IL-6 levels were measured by ELISA, and 6E10-positive staining area was quantified by immunohistochemistry. Directional differences in cytokine levels and 6E10-positive staining area were observed between APP/PS1 mice exposed to TAK-242 and untreated APP/PS1 mice. However, because a vehicle-matched APP/PS1 control group was not included, these differences cannot be attributed specifically to TAK-242 and were interpreted as exploratory exposure-associated patterns rather than pharmacological efficacy. This study provides a sex and stage-defined exploratory dataset of inflammatory and amyloid-associated readout patterns in female early-stage APP/PS1 mice to inform future vehicle-controlled investigations.},
}

@article {pmid42952837,
year = {2026},
author = {Zhao, Y and Sun, J and Reheman, B and Bai, X and Zhang, C and Ding, W and Zou, B and Zhang, H and Zhang, Z and Zhang, N},
title = {Grey matter atrophy signatures and their genetic associations: a trans-disease study of Alzheimer's disease and multiple sclerosis.},
journal = {Frontiers in neuroimaging},
volume = {5},
number = {},
pages = {1917609},
pmid = {42952837},
issn = {2813-1193},
abstract = {BACKGROUND: Alzheimer's disease (AD) and multiple sclerosis (MS) share neuroimmune mechanisms that drive neurodegeneration. Current clinical interventions are largely confined to a single-disease approach, owing to the absence of trans-disease diagnostic markers and common therapeutic targets.

OBJECTIVE: To map common and disease-specific grey matter (GM) atrophy patterns in AD and MS and identify their genetic correlations.

METHODS: We performed a trans-disease meta-analysis in large-sample neuroimaging data from 2001 to 2024 (2,070 MS versus 1,625 healthy control, and 1,624 AD versus 1,607 healthy control) to map GM atrophy regions. The cross-sample partial least squares regression was applied to integrate gene expression profiles from the Allen Human Brain Atlas with region-specific GM atrophy patterns, achieving cross-scale analysis of identify neurodegeneration-associated genes.

RESULTS: MS-specific atrophy localized to the bilateral dorsomedial thalamic nucleus and precentral gyrus, whereas AD-specific atrophy centered on bilateral hippocampus-amygdala complex in age-unadjusted comparisons. The common atrophy patterns were found in the bilateral superior temporal gyrus, insulae, posterior cingulate cortex, amygdalae, and striatal components. We identified 834 genes whose spatial expression patterns were associated with the common GM atrophy pattern in AD and MS, including PLS2 + and PLS2- subsets, which encompass biological processes such as immunological homeostasis imbalance, cellular stress response, and neurometabolic/functional regulation.

CONCLUSION: Findings establish shared cortical-limbic-striatal atrophy as pivotal neurodegeneration nexus in AD and MS. The identified gene-imaging signatures provide insights into potential pathway-specific mechanisms and may inform future therapeutic target discovery for dual-disease intervention.},
}

@article {pmid42952982,
year = {2026},
author = {Zhang, Y and Li, L and Ouyang, H and Zhao, Z and Mei, X and Qiu, C},
title = {Peripheral serum copper metabolite levels measured by ultrafiltration aid in the clinical screening of Alzheimer's disease.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1954419},
pmid = {42952982},
issn = {1664-0640},
abstract = {BACKGROUND: The number of patients with Alzheimer's disease (AD) is increasing, yet misdiagnosis remains common and early accurate diagnosis is lacking. Previous studies have suggested abnormalities in peripheral serum copper levels in AD patients. This study sought to explore the diagnostic value of peripheral serum copper-related biomarkers for clinically diagnosed AD.

METHODS: Peripheral serum samples were collected from 115 clinically diagnosed AD patients and 96 healthy controls (HC). A preliminary experiment on five samples determined the use of a 10 kDa ultrafiltration membrane. Four serum copper parameters-serum total copper (tot-Cu), free copper (free-Cu), serum immunological ceruloplasmin concentration (iCp), and ceruloplasmin enzymatic activity (eCp)-were quantitatively measured in all samples using ultrafiltration, atomic absorption spectrometry, and ELISA.

RESULTS: Peripheral tot-Cu and free-Cu levels in clinically diagnosed AD patients were significantly elevated in the early stage of the disease, while iCp, eCp, and the iCp/eCp ratio were significantly decreased. The diagnostic efficacy of tot-Cu and free-Cu for these Alzheimer's disease patients was significantly higher than that of the Mini-Mental State Examination (MMSE) score. Nevertheless, these indicators could not distinguish different severity stages of clinically phenotyped AD.

CONCLUSION: Our results indicate that tot-Cu or free-Cu holds promise as biomarkers for the clinical screening of AD; peripheral copper metabolic dysregulation may be involved in the pathogenesis of clinically phenotyped AD.},
}

@article {pmid42953065,
year = {2026},
author = {Xin, J and Teng, X and Su, H and Wang, X and Li, M},
title = {Luteolin for Alzheimer's disease and related cognitive impairment: a systematic review and meta-analysis of efficacy and molecular mechanisms.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1976119},
pmid = {42953065},
issn = {2296-858X},
abstract = {BACKGROUND: The multifactorial pathogenesis of Alzheimer's disease (AD) renders conventional single-target therapies largely ineffective. Luteolin, a natural flavonoid, has demonstrated promising pleiotropic neuroprotective potential. This study aims to systematically evaluate the preclinical efficacy and multi-target mechanisms of luteolin in rodent models of AD and associated cognitive impairment.

METHODS: Eight major electronic databases were systematically searched from January 1, 2000 to June 1, 2026. In vivo preclinical studies evaluating luteolin monotherapy in AD-specific and general cognitive impairment rodent models were included. Methodological quality was assessed using the SYRCLE risk of bias tool. Standardized mean differences and 95% confidence intervals were calculated using a random-effects model.

RESULTS: Fifteen eligible studies were included. Meta-analysis revealed that luteolin significantly ameliorated cognitive and memory impairments in both AD-specific and non-AD cognitive impairment models. Mechanistically, luteolin significantly restored redox homeostasis and suppressed neuroinflammatory cascades at both transcriptional and translational levels. Subgroup analyses indicated that oral administration and prolonged interventions were associated with significant efficacy; however, these observations are heavily influenced by study-level confounding and cannot conclusively establish pharmacokinetic superiority. Furthermore, the certainty of evidence is limited by predominantly unclear risks of bias, substantial statistical heterogeneity, and potential publication bias.

CONCLUSION: Current preclinical evidence suggests that luteolin is a promising multi-target neuroprotective candidate for AD and related cognitive impairments, highlighted by its anti-inflammatory and antioxidant properties. However, given the substantial methodological limitations and extremely large pooled effect sizes, these findings must be interpreted with caution. Future research must prioritize rigorous preclinical designs, advanced brain-targeted delivery systems, and GLP-compliant toxicological profiling before clinical translation.},
}

@article {pmid42953191,
year = {2026},
author = {Deng, L and Zeng, Y and Ou, P and Zhou, S and Gou, Y and Huang, C},
title = {Advances in artificial intelligence-driven MRI research in Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1943265},
pmid = {42953191},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Artificial Intelligence ; *Neuroimaging/methods ; Machine Learning ; Deep Learning ; },
abstract = {Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, poses substantial challenges for early diagnosis and longitudinal monitoring-two cornerstones of effective clinical management and therapeutic intervention. Magnetic resonance imaging (MRI), owing to its non-invasiveness and high spatial resolution, has emerged as an indispensable tool in AD research. In recent years, artificial intelligence (AI), particularly deep learning (DL) and machine learning (ML) techniques, has demonstrated remarkable potential for automating MRI analysis, extracting subtle imaging features, and supporting objective disease prediction. This review comprehensively summarizes the latest advances in AI-driven MRI applications for AD diagnosis, staging, prognosis, and adjuvant therapeutic monitoring. It highlights key progress in AI model development, multimodal data processing, and clinical translational value. Furthermore, current bottlenecks, including data heterogeneity, model interpretability, and real-world deployment, are systematically discussed, and future directions are outlined to enhance the precision and clinical utility of AI-assisted MRI in AD. Overall, AI-MRI has evolved from laboratory validation toward early clinical adoption, with explainability and multi-center generalizability identified as critical priorities in the next research phase.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Magnetic Resonance Imaging/methods
*Artificial Intelligence
*Neuroimaging/methods
Machine Learning
Deep Learning

@article {pmid42953259,
year = {2026},
author = {Tábuas-Pereira, M and Silva-Spínola, A and Agostinho, C and Alves, L and Araújo, R and Bernardes, C and Branco, M and Borbinha, C and Cabreira, V and Costa, S and Silva, AD and Durães, J and Faustino, P and Félix, C and Fernandes, A and Ferreira, J and Gago, M and Guarda, C and Ionel, C and Jesus-Ribeiro, J and Laranjinha, I and Leitão, A and Letra, L and Lopes das Neves, P and Maia, LF and Machado, Á and Martins, B and Massano, J and Mendonça, A and Mendonça, M and Miguel, R and Miranda, M and Morgado, J and Nóbrega, C and Coutinho, MP and Oliveira, T and Pita, F and Sabença, F and Rocha, S and Ruano, L and Santos, T and Simões do Couto, F and Taipa, R and Cruz, VT and Valverde, AH and Vélon, A and Verdelho, A and Viana Baptista, M and Vieira, D and Lima, M and Oliveira, TG and Santana, I and , },
title = {Current capacity of Portuguese specialized dementia centers in the era of anti-amyloid antibodies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70513},
pmid = {42953259},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major cause of cognitive decline and societal burden. The recent approval of disease-modifying therapies (DMTs) lecanemab and donanemab represents a paradigm shift in AD treatment. We assessed the preparedness of Portuguese centers to implement DMTs.

METHODS: A nationwide survey-based cross-sectional service-capacity study targeted memory clinics, focusing primarily on National Health System (NHS) centers. Data were collected on clinical capacity, diagnostic access, treatment capability, and research activity.

RESULTS: Among 51 responding units, 20 had organized memory clinics (17 in the NHS), covering 60.7% of the population. In 2024, these centers conducted 21,721 consultations, representing expert care for <10% of the total AD patients estimated to exist in Portugal. Bottlenecks included long waiting times and limited biomarker access (26.2% underwent cerebrospinal fluid or amyloid positron emission tomography). Nationwide, from experts' estimates, 701 patients could currently start treatment.

DISCUSSION: Portugal's current NHS capacity appears insufficient for broad DMT implementation, requiring major investment in diagnostics, training, infrastructure, and research to ensure equitable and effective treatment access.},
}

@article {pmid42953343,
year = {2026},
author = {Liu, Z and Qin, M and Zhao, C and Ding, J and Li, Y and Cheng, W},
title = {Mediterranean Diet Adherence and Cognitive Function in Older Adults: Heterogeneity in the Association Across BMI Categories.},
journal = {International journal of endocrinology},
volume = {2026},
number = {},
pages = {7060250},
pmid = {42953343},
issn = {1687-8337},
abstract = {Cognitive decline is a major public health concern among older adults, and both dietary quality and adiposity have been associated with cognitive health. Using data from the 2011-2014 National Health and Nutrition Examination Survey, we conducted a cross-sectional analysis of 2492 U.S. adults aged ≥ 60 years. Adherence to the Mediterranean diet was quantified using the Mediterranean diet index (MEDI) derived from two 24-h dietary recalls, and body mass index (BMI) was classified into four categories: underweight, normal weight, overweight, and obesity. Global cognitive function was computed by standardizing and summing scores from the Consortium to Establish a Registry for Alzheimer's disease immediate and delayed recall tests, the animal fluency test, and the Digit Symbol Substitution test. After multivariable adjustment, higher MEDI scores were associated with better global cognitive function, with positive associations also observed for verbal fluency and processing speed. Restricted cubic spline analysis supported a positive, approximately linear dose-response association between MEDI score and global cognitive function. However, in the linear interaction analysis, this association differed across BMI categories. Among normal-weight participants, higher MEDI scores were associated with better global cognitive function. Underweight status was associated with poorer immediate and delayed recall, whereas overweight status was associated with lower verbal fluency. Overall, greater adherence to a Mediterranean dietary pattern was associated with better cognitive performance, particularly verbal fluency and processing speed, among older U.S. adults. BMI-related heterogeneity in this association supports prospective longitudinal studies and intervention trials incorporating repeated assessments of diet, adiposity, metabolic health, and cognition.},
}

@article {pmid42953353,
year = {2026},
author = {Copeland, MH and Youngstrom, DE and Konrad, KS and Diering, GH and Letsinger, AC and Aksu, LR and Yakel, JL and Cushman, JD},
title = {Diphenhydramine disrupts sleep architecture in 5XFAD Alzheimer's disease model and wild-type mice.},
journal = {Neurobiology of sleep and circadian rhythms},
volume = {21},
number = {},
pages = {100154},
pmid = {42953353},
issn = {2451-9944},
abstract = {Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type female mice. Female 5XFAD (n = 16) and wild-type (WT) littermates (n = 14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG) and electromyography (EMG) continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD female mice had more time in NREM1 than WT female controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, and disrupted the light-dark distribution of sleep. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment resulted in NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model female mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.},
}

@article {pmid42953479,
year = {2026},
author = {Gill, N and Sohi, SK and Bhatti, N and Joseph, G and Abhilasha, P},
title = {Brexpiprazole in India and the United States: A Comparative Review of Regulatory Status, Clinical Evidence, Market Access, and Evidence Gaps.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e117032},
pmid = {42953479},
issn = {2168-8184},
abstract = {Brexpiprazole is a serotonin-dopamine activity modulator first cleared by the United States Food and Drug Administration (FDA) in 2015 for adults with schizophrenia and as an adjunct to antidepressants in major depressive disorder (MDD); later authorizations extended its use to adolescent schizophrenia and to agitation arising in dementia due to Alzheimer's disease. Over the past decade, randomized controlled trials, long-term open-label extensions, and analyses of real-world claims have converged on a consistent efficacy profile and a tolerability profile that has generally been favorable, although direct head-to-head comparisons with other second-generation agents remain limited. The evidence base and access environment differ markedly between the two countries. In the United States, brexpiprazole is an established product with an extensive clinical evidence base supplemented by real-world claims, utilization, safety, and economic analyses. In contrast, India has only recently received regulatory approval for brexpiprazole, and brexpiprazole-specific clinical, real-world utilization, pricing, reimbursement, and pharmacoeconomic data remain limited. This narrative review consolidates the pharmacology, clinical-trial findings, safety record, and health-economic data on brexpiprazole and contrasts the mature evidence environment of the United States with the emerging one in India. The principal Indian evidence gap is therefore no longer regulatory recognition but the generation of local data on availability, affordability, utilization, effectiveness, and pharmacoeconomic value. Framed as a collaboration between Christian Medical College and Hospital, Ludhiana, and New York Medical College at St Clare's and St Mary's, New Jersey, the review aims to support the equitable and evidence-based uptake of newer antipsychotics in emerging settings.},
}

@article {pmid42953588,
year = {2026},
author = {Sayegh, M and Azarfar, K and Reyna, EM and Kennedy, JM and Sabbagh, MN and Decourt, B},
title = {TREM2 Signaling and Alzheimer's Disease: Experimental Modulators, Progress, and Challenges.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {611558},
pmid = {42953588},
issn = {1177-8881},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Receptors, Immunologic/metabolism/genetics ; *Membrane Glycoproteins/metabolism/genetics/antagonists & inhibitors ; *Signal Transduction/drug effects ; Animals ; },
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia worldwide, with a growing global burden and limited disease-modifying therapeutic options. The transmembrane receptor termed triggering receptor expressed on myeloid cells 2 (TREM2), which is mainly expressed by myeloid cells, has emerged as a target of interest in AD due to its role in modulating microglia functions, including cholesterol metabolism, phagocytosis of amyloid-beta (Aβ), inflammatory signaling, and innate immune neuronal protection. Genetic research has also shown that partial loss-of-function mutations in the TREM2 gene, particularly the R47H and R62H variants, substantially increase the risk of late-onset AD, further underscoring the therapeutic rationale for enhancing TREM2 signaling to combat the disease. Therapeutic strategies targeting TREM2 have exponentially increased in recent years, spanning monoclonal antibodies (mAbs) with distinct epitopes and mechanisms of receptor modulation, orally bioavailable small-molecule drugs capable of penetrating the blood-brain barrier (BBB), and upstream mechanisms targeting the shedding of the TREM2 ectodomain. Early clinical trials have revealed that target engagement does not translate directly into clinical benefit in patients, highlighting knowledge gaps in the timing of intervention, patient selection, dose optimization, and the complex dichotomy of TREM2 signaling, in which both insufficient and excessive activation may be detrimental to AD patients. Nonetheless, the continued advancement of therapeutics into clinical trials reflects the confidence in the underlying scientific rationale. This narrative review summarizes the current understanding of wild-type and variant TREM2 signaling in AD pathogenesis, evaluates the preclinical and clinical evidence supporting each class of TREM2-targeted therapeutic strategies, and discusses the challenges, emerging insights, and future directions that could shape the next generation of TREM2-based interventions for AD.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Receptors, Immunologic/metabolism/genetics
*Membrane Glycoproteins/metabolism/genetics/antagonists & inhibitors
*Signal Transduction/drug effects
Animals

@article {pmid42953729,
year = {2026},
author = {Moattar-Husseini, Z and Ahmadi, A and Mohebi, N},
title = {Multi-region transcriptomics and unsupervised clustering reveal recurrent and region-specific gene signatures in Alzheimer's disease.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {1010-1028},
pmid = {42953729},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) exhibits anatomically heterogeneous transcriptomic alterations, complicating the identification of disease-associated genes with consistent external support. We compared four gene-prioritization strategies, absolute log2 fold change, false discovery rate (FDR), CombinedScore, and RankSum, using laser-capture-microdissected neuronal expression profiles from six brain regions in GSE5281. Differential expression was assessed separately within each region using limma, followed by within-region gene prioritization and cross-region comparison to identify recurrent and anatomically specific candidates. Robustness was evaluated through resampling stability, sensitivity to candidate-list size and scoring formulation, and external benchmarking in three anatomically matched regions of GSE48350. STAT4, SST, and NVL emerged as recurrent candidates, whereas ZNRD2, ANKRD12, and NME7 were prominent regionally prioritized signals. External directional agreement across Top-100 lists ranged from 68.3% to 72.0%; RankSum achieved 71.7% agreement and the highest or joint-highest directional agreement at Top-50 and Top-200. A fixed expression score comprising the three recurrent genes showed higher values in AD in the external cohort. Exploratory six-gene clustering revealed diagnosis-associated structure with modest separation. 14 of 18 gene-region comparisons showed concordant AD-control directions, although cross-dataset effect-size correlations were weak. This study establishes a comparative framework linking regional gene prioritization with stability assessment and independent-cohort benchmarking, identifying recurrent AD-associated candidates and quantifying their external support.},
}

@article {pmid42953958,
year = {2026},
author = {Cerini, M and Leuci, R and Paparella, M and Roselli, V and Piemontese, L},
title = {Cholinergic-targeted molecular hybrids: a renewed strategy for Alzheimer's disease?.},
journal = {Expert opinion on drug discovery},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17460441.2026.2749525},
pmid = {42953958},
issn = {1746-045X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by a complex and multifactorial etiology that complicates its diagnosis, prevention, and treatment. Among the most historically and extensively investigated therapeutic targets are cholinesterases (ChEs), which have guided the development of most currently available symptomatic drugs. Consequently, anti-ChE activity is frequently incorporated into the design of potential multi-target anti-AD compounds.

AREAS COVERED: This critical perspective highlights recent advances in multi-target derivatives with a central anti-ChE property. Various structural scaffolds have been explored, bearing additive properties to the final hybrids, designed by combining structural features of anti-AD drugs (namely rivastigmine and donepezil). Many of these compounds have demonstrated promising outcomes, with some exhibiting greater potency than their reference drugs.

EXPERT OPINION: Multi-target small-molecule hybrids may represent a promising perspective for Alzheimer's disease, shifting the focus from cholinesterase-centered design to compounds primarily aimed at interfering with protein misfolding and aggregation, as well as other targets. In this framework, anticholinesterase activity would remain an accessory but still important component for symptomatic control.},
}

@article {pmid42953974,
year = {2026},
author = {Hayes, CA and Dharmapuri, A and Agwu, C and Ramirez, V and Newman, J and Chambers, M and Odden, MC and Younes, K},
title = {Alzheimer's pathology mediates arteriolosclerosis and cerebral amyloid angiopathy associations with cognition.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag380},
pmid = {42953974},
issn = {1460-2156},
abstract = {Vascular and neurodegenerative pathologies frequently co-occur in aging brains, yet the mechanisms linking vascular neuropathologies to cognitive impairment remain incompletely understood. We examined whether Alzheimer's disease neuropathologic change (ADNC) and Lewy body disease (LBD) mediate or modify associations between vascular neuropathologies and domain-specific cognitive performance. The analytic sample included 1,269 decedents (mean age at death, 84.3 ± 9.1 years; 43.3% female; 94.7% White). At the last evaluation prior to death, 22.5% were cognitively normal, 2.4% were impaired but not mild cognitive impairment (MCI), 14.9% had MCI, and 60.2% had dementia. Vascular neuropathologies included arteriolosclerosis, atherosclerosis of the circle of Willis, cerebral amyloid angiopathy (CAA), gross infarcts/lacunes, and microinfarcts. Multivariable linear regression models evaluated associations with harmonized memory, executive function, and language z-scores adjusting for age at death, sex, education, and apolipoprotein E ε4 status. Effect modification by ADNC and LBD was tested. Mediation models estimated indirect and direct effects of vascular neuropathologies on cognition through ADNC or LBD using 5,000 bootstrap samples. Greater arteriolosclerosis severity was associated with worse memory (β=-0.16, 95% CI -0.23 to -0.09), executive function (β=-0.18, 95% CI -0.24 to -0.11), and language (β=-0.18, 95% CI -0.24 to -0.12; all p<0.001). CAA was strongly associated with poorer cognition across domains, including memory (β=-0.26, 95% CI -0.33 to -0.19; p<0.001). Atherosclerosis and infarcts showed more limited associations, while microinfarcts were not significantly associated with cognition. Mediation analyses indicated that ADNC statistically accounted for approximately 13-29% of the associations between arteriolosclerosis and cognition across domains and 64-91% of the associations between CAA and cognition. Direct effects of arteriolosclerosis remained significant, whereas CAA effects were largely explained by ADNC. Effect modification by ADNC and LBD was limited, although LBD attenuated associations of arteriolosclerosis and CAA with executive function. Mediation through LBD was not observed. This novel evidence shows that vascular neuropathologies influence cognition through defined pathways with statistically significant patterns of associations. In this autopsy-confirmed cohort, vascular neuropathologies showed different patterns of association with domain-specific cognitive performance and ADNC. A larger proportion of the association involving CAA was statistically accounted for by ADNC, whereas direct associations remained more apparent for arteriolosclerosis. This study clarifies how vascular and neurodegenerative processes interact to shape cognitive impact and inform mechanistic preventions.},
}

@article {pmid42954140,
year = {2026},
author = {Blotenberg, I and Kim, H and Soberanes, D and Dubbelman, MA and Minto, LR and Udeogu, OJ and Lubbat, V and Buckley, RF and Marshall, GA and Johnson, KA and Rentz, DM and Sperling, RA and Papp, KV and Amariglio, RE},
title = {Detection of Age-Related Cognitive Decline Over Short Time Frames Using Digital Multiday Learning Assessments: Longitudinal Study.},
journal = {JMIR aging},
volume = {9},
number = {},
pages = {e100917},
doi = {10.2196/100917},
pmid = {42954140},
issn = {2561-7605},
mesh = {Humans ; Female ; Longitudinal Studies ; Aged ; Male ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; *Aging/psychology ; Aged, 80 and over ; Time Factors ; },
abstract = {BACKGROUND: High-resolution digital cognitive tools administered at frequent intervals enable the study of age-related cognitive change at a previously unattainable level of granularity. Computational modeling further enables the simultaneous examination of multiple aspects of cognitive performance.

OBJECTIVE: The objective of this study was to examine whether repeated digital multiday learning assessments can detect age-related cognitive decline over short time frames in cognitively unimpaired older adults and to quantify age-related differences in process-based cognitive markers derived from computational modeling.

METHODS: A total of 209 cognitively unimpaired older adults (mean age 73.6, SD 8.2 years; n=136, 65.1% female) from the Harvard Aging Brain Study and affiliated studies were administered the Boston Remote Assessment for Neurocognitive Health, which includes the face-name task, a paired associative learning task. Daily median response times for correct responses were used as the primary outcome. A new version of the face-name task was administered across up to 4 testing intervals over a mean of 2.8 (SD 0.4) years. Using computational modeling, we estimated longitudinal changes in peak performance, a practice-adjusted marker of an individual's best expected response time, as an indicator of age-related cognitive decline. We further examined age-related differences in peak performance, stability (within-person variability), learning within and across testing intervals, and between-interval forgetting, with embedded linear regressions for age, sex, years of education, and device type.

RESULTS: Peak performance slowed by 0.04 seconds per year (95% credible interval 0.02-0.06; approximately 2% per year), indicating age-related cognitive decline. Higher age (+1-SD) was associated with slower peak performance (+0.19 seconds, 95% credible interval 0.12-0.26), steeper annual slowing in peak performance (+0.036 seconds per year), greater within-person variability (+0.043 seconds), reduced learning across testing intervals, and more forgetting.

CONCLUSIONS: Our findings indicate that a digital multiday learning paradigm combined with computational modeling of response times sensitively detects age-related cognitive decline over short timescales (<3 years), which are difficult to capture in conventional study designs relying on infrequent assessments. In addition, this approach identifies specific process-based cognitive markers associated with aging, including slower performance, reduced stability, and diminished learning across testing intervals.},
}

Humans
Female
Longitudinal Studies
Aged
Male
*Cognitive Dysfunction/diagnosis
Neuropsychological Tests
*Aging/psychology
Aged, 80 and over
Time Factors

@article {pmid42954299,
year = {2026},
author = {Kjær, NK and Lykkegaard, J and Ibsen, H and Llor, C and Søndergaard, J},
title = {A general practice-centred model for early diagnosis and management of Alzheimer's disease in Denmark: rationale, evidence and a pragmatic diagnostic approach.},
journal = {Scandinavian journal of primary health care},
volume = {44},
number = {1},
pages = {2752758},
doi = {10.1080/02813432.2026.2752758},
pmid = {42954299},
issn = {1502-7724},
mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; *Early Diagnosis ; *General Practice ; Denmark ; Biomarkers/blood ; *Primary Health Care ; Neuroimaging ; Referral and Consultation ; },
abstract = {PURPOSE: Alzheimer's disease is a leading cause of disability among older adults and poses increasing challenges for healthcare systems. In Denmark, demographic changes and healthcare reform are driving greater involvement of primary care in diagnosis and management.

MATERIALS AND METHODS: This paper examines the rationale for a general practice-centred model and summarises recent diagnostic developments, including blood-based biomarkers.

RESULTS: Although current disease-modifying therapies show only modest benefit, ongoing research and scalable biomarkers enable earlier and more accessible diagnosis. We propose a pragmatic three-step diagnostic approach for primary care, with structured clinical and cognitive assessment, exclusion of secondary causes including structural neuroimaging, and in the near future, the availability of feasible biomarkers to support diagnosis and guide referral. We also outline key organisational, educational and ethical requirements for implementation.

CONCLUSION: A general practice-centred model may improve diagnostic timeliness, accessibility and continuity of care if integrated within a robust clinical and ethical framework.},
}

*Alzheimer Disease/diagnosis/therapy
Humans
*Early Diagnosis
*General Practice
Denmark
Biomarkers/blood
*Primary Health Care
Neuroimaging
Referral and Consultation

@article {pmid42954557,
year = {2026},
author = {Li, WB and Li, J and Ning, XY and Tian, JH and Chen, FY and Zhang, SX and Wang, ZH and Pan, YC and Zhang, W and Guo, DS},
title = {Super-Cross-Reactive Recognition Enables Preclinical Diagnosis of Alzheimer's Disease.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {42},
pages = {45971-45982},
doi = {10.1021/jacs.6c14717},
pmid = {42954557},
issn = {1520-5126},
support = {NA//Fundamental Research Funds for the Central Universities/ ; 2025XJS014//China University Industry-Academia-Research Innovation Fund/ ; 52533006//National Natural Science Foundation of China (NSFC)/ ; 52573168//National Natural Science Foundation of China (NSFC)/ ; NA//Tianchi Talent Plan/ ; },
mesh = {*Alzheimer Disease/diagnosis/cerebrospinal fluid ; Animals ; Humans ; Biomarkers/cerebrospinal fluid ; Rats ; Machine Learning ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) is impeded by the subtle, heterogeneous nature of fluid biomarkers during the disease's initial phases. Current detection tools, which target single biomarkers, often lack the necessary sensitivity and specificity for presymptomatic screening. To address this, we develop a machine learning-informed supramolecular sensor array that leverages a holistic design to overcome the limitations of "lock-and-key" recognition. By engineering macrocyclic receptors with semiselective properties, we generate a competitive signal transduction process characterized by multiple equilibria and nonlinear responses. This design confers high-dimensional cross-reactivity, delineating distinct fluorescent fingerprints for specific AD stages. The array achieves 100% diagnostic accuracy in cerebrospinal fluid from 1-month-old rat models─predating conventional ELISA detection by 3 months and behavioral symptoms by 4 months. Crucially, the array identifies human patients at the subjective cognitive decline stage with >95% accuracy. This work presents a clinically viable tool for early AD diagnosis and establishes a generalizable, modular framework for multiplexed biomarker analysis in neurodegenerative diseases.},
}

*Alzheimer Disease/diagnosis/cerebrospinal fluid
Animals
Humans
Biomarkers/cerebrospinal fluid
Rats
Machine Learning

@article {pmid42955064,
year = {2026},
author = {Gordon, L and Buyuksandalyaci Tunc, E and Vaikutis, L and Grossberg, GT},
title = {Vitamin supplementation and Alzheimer's disease: what the evidence shows.},
journal = {Panminerva medica},
volume = {},
number = {},
pages = {},
doi = {10.23736/S0031-0808.26.05448-0},
pmid = {42955064},
issn = {1827-1898},
abstract = {Alzheimer's disease (AD) is the most common cause of major neurocognitive disorder worldwide, with growing prevalence and limited disease-modifying treatment options. Vitamin supplementation has attracted considerable interest as a potentially modifiable strategy in AD because several vitamins are involved in biological pathways implicated in AD pathogenesis, including oxidative stress, neuroinflammation, and homocysteine metabolism. However, the clinical relevance of these mechanistic associations remains uncertain, and findings from interventional studies have been inconsistent. This narrative review critically evaluates the current evidence regarding vitamin supplementation across the AD spectrum, including associations between vitamin deficiency and AD risk, the potential role of supplementation in AD prevention, and cognitive or functional outcomes among individuals with mild cognitive impairment or established AD. Among the vitamins reviewed, folic acid and vitamin B12 demonstrate the most consistent, although still limited, signal for potential cognitive benefit, particularly when used in combination although whether this benefit is concentrated among individuals with elevated homocysteine levels remains uncertain. Vitamin D deficiency has been relatively consistently associated with increased AD risk in observational studies, supporting consideration of vitamin D assessment and correction of documented deficiency as part of routine clinical care in older adults. Evidence for vitamin E suggests possible attenuation of functional decline at higher doses but does not support routine use for cognitive benefit or AD prevention. For vitamins A, C, thiamine, and niacin, clinical evidence remains sparse, indirect, and insufficient to support supplementation beyond correction of documented deficiencies. Overall, biological plausibility has consistently outpaced demonstrated clinical efficacy in vitamin literature. Vitamin supplementation should not be considered a disease-modifying intervention for AD; however, vitamin assessment, including baseline serum vitamin levels where clinically indicated, and supplementation should be individualized, with correction of documented deficiencies remaining appropriate for general health, particularly in older adults with poor intake, malabsorption risk, or medication-related deficiencies. Ensuring adequate B vitamin intake and correcting vitamin D deficiency when documented may be incorporated into a broader brain-health strategy alongside pharmacologic treatments and lifestyle interventions. Future research should prioritize adequately powered clinical trials with standardized outcomes, longer follow-up periods, and stratification by baseline nutritional status.},
}

@article {pmid42955216,
year = {2026},
author = {Oria, RS and Esomonu, UG and Sunday, KI and Oge, PA},
title = {Microglial perturbation in heavy metal-induced neuroinflammation and neurodegeneration: mechanisms, phenotypic plasticity, and therapeutic prospects.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {42955216},
issn = {1572-8773},
abstract = {Heavy metal exposure has emerged as a significant environmental contributor to neurodegenerative disease, and a substantial body of mechanistic evidence implicates microglia in the pathological cascades that follow. Lead, cadmium, arsenic, manganese, copper, cobalt, mercury, and zinc disrupt central nervous system homeostasis through multiple cellular targets, but the resident innate immune cells of the brain are well placed to translate these insults into sustained neuroinflammation. Evidence for this critical narrative review was assembled through a purposive search of PubMed, MEDLINE, and Google Scholar for mechanistically informative studies reporting glial endpoints, with reference lists searched by hand and no systematic protocol applied. This review synthesizes current understanding of how individual metals engage microglial signaling networks, with particular attention to oxidative stress, NF-κB activation, NLRP3 inflammasome assembly, MAPK cascades, and suppression of the Nrf2 antioxidant axis. We examine the phenotypic spectrum that extends well beyond the classical M1/M2 dichotomy, including disease-associated microglia, lipid-droplet-accumulating microglia, and interferon-responsive states, and consider how metal-specific signatures map onto these transcriptional programs. Manganese-driven inflammasome assembly, cadmium-induced mitochondrial impairment, lead-mediated disruption of calcium homeostasis, and mercury-evoked autophagic dysfunction are discussed as illustrative examples of mechanistic divergence within a common neuroinflammatory framework. Glial responses to metal mixtures, which better represent real exposure than single-element designs, are considered separately, and the evidence for greater-than-additive effects is appraised. Downstream consequences for astrocyte reactivity, blood-brain barrier integrity, synaptic remodeling, and neuronal viability are placed in the context of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic avenues are appraised, including chelation, natural antioxidants, NLRP3 inhibitors, TREM2 modulation, and microglial replacement strategies. Methodological constraints, particularly the overreliance on BV-2 cells and acute high-dose exposure paradigms, are critically considered. The review concludes by identifying priorities for translational research, including longitudinal human cohort studies, single-cell transcriptomic profiling of metal-exposed microglia, and the development of region-specific exposure models that better reflect chronic environmental realities.},
}

@article {pmid42955508,
year = {2026},
author = {Gupta, SK and Aran, KR},
title = {Unraveling the role of CARM1 in Alzheimer's disease: molecular mechanisms and therapeutic potential.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42955508},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a progressive neurological condition that has manifestations of cognitive decline, accumulation of neurofibrillary tau pathology, amyloid-β (Aβ), synaptic dysfunction, neuroinflammation, oxidative stress, and cerebrovascular abnormalities. Evidence is growing that epigenetic dysfunction is involved in the development of AD. The coactivator-associated arginine methyltransferase 1 (CARM1), also known as protein arginine methyltransferase 4 (PRMT4), is an epigenetic enzyme that functions in transcriptional control, chromatin remodeling, maintenance of cellular homeostasis, and neuronal functions. CARM1-mediated histone H3 arginine 17 methylation (H3R17me2a) and NF-κB-dependent transcription provide a link to inflammatory gene regulation; however, a direct role for CARM1 in AD-associated neuroinflammation remains unconfirmed. Findings from cultured hippocampal neurons implicate CARM1 in dendritic maturation and synaptic organization, although these effects have not established therapeutic benefits in AD models. Evidence from female 3xTg-AD mice indicates that pharmacological CARM1 inhibition can improve selected cerebrovascular parameters, including nitric oxide synthase coupling and cerebral blood flow. CARM1 phosphorylation may also influence its enzymatic activity and localization, but its involvement in AD-related neuronal pathology remains hypothetical. The aim of this study is to put together in a comprehensive manner the role of CARM1 in the molecular and cellular mechanisms involved in AD pathology and its potential as a therapeutic target. Future studies should focus on brain penetrants and selective CARM1 modulators, cell-specific functions, long-term safety, target engagement, and clinical translation. In conclusion, CARM1 may be a potential AD therapeutic target that is still in the preclinical phase.},
}

@article {pmid42955542,
year = {2026},
author = {Anderson, SD and Jomsky, J and Chaudhari, NN and Chowdhury, NF and Zheng, XR and Irimia, A and , },
title = {Graph Neural Network Reveals the Cortical Morphology of Local Brain Aging in Normal Cognition and Alzheimer's Disease.},
journal = {Neuroinformatics},
volume = {24},
number = {4},
pages = {},
pmid = {42955542},
issn = {1559-0089},
support = {R01 AG 079957/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/psychology ; *Graph Neural Networks ; *Aging/pathology ; Magnetic Resonance Imaging/methods ; Female ; *Cerebral Cortex/diagnostic imaging/pathology ; *Cognition/physiology ; Aged ; Male ; Aged, 80 and over ; Brain/pathology ; Middle Aged ; },
abstract = {Estimating brain age (BA) from T1-weighted magnetic resonance images (MRIs) provides a powerful framework for quantifying anatomical brain aging. Whereas global BA (GBA) summarizes overall brain health, local BA (LBA) provides cortically specific patterns of aging at the subject level. Although previous studies have examined anatomical contributors to GBA, to our knowledge, no framework has been established to estimate LBA using cortical morphology. To address this gap, we introduce a graph neural network (GNN) that uses morphometric features-cortical thickness, surface area, curvature, gray/white matter intensity ratio (GWR), sulcal depth-to estimate LBA across the cortical surface at high spatial resolution (mean inter-vertex distance = 1.37 mm). Trained on cortical surface meshes extracted from the MRIs of cognitively normal (CN) adults (N = 14,423), our model achieves better test-retest performance than the existing state-of-the-art, while identifying more biologically plausible patterns of aging in Alzheimer's disease (AD) on the ADNI dataset. Association cortices emerge as primary sites of morphometric aging in CNs, whereas mild cognitive impairment is characterized by widespread aging that is pronounced in the parahippocampal gyrus. AD subjects demonstrate significant aging across the entire cortex, particularly within medial temporal regions and associated cortical networks. Feature ablation highlights curvature and GWR as preferentially sensitive to AD pathology. Regional LBA gaps are significantly associated with neuropsychological measures of AD-related cognitive impairment, linking cortical aging patterns to clinical outcomes. These results demonstrate that GNN-based modeling of cortical morphometry enables biologically interpretable mapping of local brain aging with greater fidelity than prior work.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/psychology
*Graph Neural Networks
*Aging/pathology
Magnetic Resonance Imaging/methods
Female
*Cerebral Cortex/diagnostic imaging/pathology
*Cognition/physiology
Aged
Male
Aged, 80 and over
Brain/pathology
Middle Aged

@article {pmid42955716,
year = {2026},
author = {Carney, J},
title = {Quantitatively modelling the phenomenology of Alzheimer's-type dementia using frame-theoretic semantics and psycholinguistic norms.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498421},
doi = {10.1177/13872877261498421},
pmid = {42955716},
issn = {1875-8908},
abstract = {BackgroundThe phenomenology of Alzheimer's disease-the "what is it like?" of the condition-has previously been approached via either quantitative analyses of granular linguistic features or qualitative analyses of lived experience.ObjectiveWhat is lacking is an empirically credible framework that captures high-level qualitative insight by way of cognitive models rather than surface linguistic features.MethodsFrame semantics and a 1.19 million-token psycholinguistic word norm lookup were applied to two topic-matched corpora: the DementiaBank Pitt Cookie Theft recordings and a COVID-era diary corpus combining CoSoWELL controls with Dementia Diaries entries. Gradient-boosted classifiers under participant-level cross-validation were compared against Fraser et al.'s 52-feature benchmark and statistically evaluated.ResultsA combined classifier contributed information statistically independent of the Fraser set on both corpora. On Pitt, four variance-based features defined a variance-collapse signature, with imageability being most significant; the within-document standard deviation of imageability replicated on COVID. Twelve semantic-frame comparisons survived Holm correction; Kinship was under-used on both corpora, giving a second cross-corpus anchor alongside imageability. A four-feature minimal classifier drawing equally from both feature families achieved AUC 0.748 on Pitt and 0.781 on COVID.ConclusionsAlzheimer's-type dementia is characterized not by a shift in the mean of any linguistic dimension but by a flattening of the phenomenological range across which a speaker moves when describing and experiencing the world. Because the diagnostic labels available in both corpora are coarse, the extent to which this flattening reflects a unitary phenomenology of Alzheimer's disease rather than heterogeneity within the diagnostic category remains to be established.},
}

@article {pmid42955763,
year = {2026},
author = {Dan, T and Huang, X and Cao, Y and Ding, J and Yang, Y and Wu, G},
title = {GeoMind: Dancing with Geometric Brain Rhythm on Symmetric Positive Definite Manifolds.},
journal = {IEEE transactions on medical imaging},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TMI.2026.3745506},
pmid = {42955763},
issn = {1558-254X},
abstract = {State space model (SSM) is a powerful tool in neuroscience field to characterize the dynamic nature of brain functions by elucidating the mechanism of how brain system transits between brain states and how underlying states give rise to the observed neural activities. Although tremendous efforts have been made to lend the power of deep learning and mathematical insight of SSM in various functional neuroimaging studies, current state-of-the-art methods lack a holistic view of brain state evolution as a self-organized dynamical system where each part of the brain is functionally inter-connected. Since the topological co-activation of functional fluctuations exhibits an intrinsic geometric pattern (symmetric and positive definite, SPD) on the Riemannian manifold, the call for understanding how a selective set of functional connectivities in the brain supports diverse behavior and cognition emerge a new machine learning scenario of manifold-based SSM for largescale functional neuroimages. To that end, we propose a geometric neural network of SSM, coined GeoMind, designed to uncover evolving brain states by tracking the trajectory of functional dynamics on a high-dimensional Riemannian manifold of SPD matrices. GeoMind demonstrates promising results in identifying specific brain states on task-based functional Magnetic Resonance Imaging (fMRI) data, as well as in diseases early diagnosis for Alzheimer's disease, Parkinson's disease and Autism, by using resting-state fMRI. These results highlight the applicability of GeoMind in neuroscience research. To further evaluate generalizability of GeoMind, we applied GeoMind to electroencephalography (EEG) emotion datasets, outperforming competing methods and demonstrating scalability across neuroimaging modalities.},
}

@article {pmid42956044,
year = {2026},
author = {Lian, SL and Storås, TH and Gløersen, EM and Løvland, G and Hopp, E and Mossige, I and Hovd, M and Uggerud, HT and Kardel, KR and Bye, HA and Buset, AL and Valdmanis, K and Knapskog, AB and Øksengård, AR and Fladby, T and Nilsen, KB and Mardal, KA and Ringstad, G and Eide, PK and Toft, M and Nordengen, K},
title = {Understanding Glymphatic's Role In Proteinopathies (GRIP): A single centre case-control study protocol.},
journal = {PloS one},
volume = {21},
number = {10},
pages = {e0360617},
doi = {10.1371/journal.pone.0360617},
pmid = {42956044},
issn = {1932-6203},
mesh = {Humans ; *Glymphatic System/metabolism/diagnostic imaging ; Case-Control Studies ; Female ; *Parkinson Disease/metabolism/diagnostic imaging/pathology/cerebrospinal fluid ; *Alzheimer Disease/metabolism/diagnostic imaging/cerebrospinal fluid/pathology ; Male ; Aged ; *Lewy Body Disease/metabolism/diagnostic imaging/pathology/cerebrospinal fluid ; tau Proteins/metabolism ; Biomarkers/cerebrospinal fluid/metabolism ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; alpha-Synuclein/metabolism ; Magnetic Resonance Imaging ; },
abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) are proteinopathies characterized by pathological accumulation of amyloid beta, phosphorylated-tau, and alpha-synuclein. Impaired clearance of these proteins is thought to contribute to disease pathogenesis, whereas preserved or enhanced clearance may be compensatory. Beyond intracellular degradation within neurons and glial cells, an extracellular clearance pathway, the glymphatic system, facilitates cerebrospinal fluid flow into perivascular spaces, exchange with interstitial fluid, and subsequent clearance from the brain. Glymphatic transport may therefore be critical for removal of excess proteins and metabolic waste, and its dysfunction could promote protein aggregation and neurodegeneration. The Glymphatic's Role In Proteinopathies (GRIP) study is an observational case-control imaging and biomarker study comparing glymphatic clearance in patients with AD, PD, and DLB versus healthy controls. We aim to recruit 70 participants: PD (n = 20), DLB (n = 10), AD (n = 20), and age- and sex-matched healthy controls (n = 20). The AD group will be stratified by pathology, with half amyloid-positive/tau-negative (A + T-) and half amyloid- and tau-positive (A + T+). The PD group will be stratified by disease duration. Participants will undergo baseline MRI followed by intrathecal injection of gadobutrol (0.25 mmol) and serial MRI at 5, 24, 48, and 72 hours. Influx and efflux of tracer will be modeled from T1 signal changes. Blood will be sampled repeatedly from 1 to 72 hours; cerebrospinal fluid will be collected at baseline. Individual glymphatic clearance will be estimated using population pharmacokinetic methods, where gadobutrol serves as a tracer. Sleep will be monitored with triaxial accelerometry and sleep diaries. The primary outcome is group differences in glymphatic clearance metrics between each disease group and controls; secondary analyses will explore associations with cognition, disease severity and duration, sleep quality, and cerebrospinal fluid protein levels.},
}

Humans
*Glymphatic System/metabolism/diagnostic imaging
Case-Control Studies
Female
*Parkinson Disease/metabolism/diagnostic imaging/pathology/cerebrospinal fluid
*Alzheimer Disease/metabolism/diagnostic imaging/cerebrospinal fluid/pathology
Male
Aged
*Lewy Body Disease/metabolism/diagnostic imaging/pathology/cerebrospinal fluid
tau Proteins/metabolism
Biomarkers/cerebrospinal fluid/metabolism
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
alpha-Synuclein/metabolism
Magnetic Resonance Imaging

@article {pmid42956236,
year = {2026},
author = {Nemecz, Z and Ilyés, A and Kerekes, L and Kis, H and Werkle-Bergner, M and Keresztes, A},
title = {Different object features shape mnemonic discrimination in younger and older adults.},
journal = {Psychology and aging},
volume = {41},
number = {7},
pages = {821-839},
doi = {10.1037/pag0001021},
pmid = {42956236},
issn = {1939-1498},
support = {//Nemzeti Kutatási Fejlesztési és Innovációs Hivatal/ ; //MaxPlanck-Gesellschaft/ ; //Magyar Tudományos Akadémia/ ; //Hungarian Research Network/ ; },
mesh = {Humans ; Aged ; Aged, 80 and over ; Female ; *Discrimination, Psychological/physiology ; Male ; Adult ; Young Adult ; *Aging/physiology/psychology ; *Pattern Recognition, Visual/physiology ; Age Factors ; *Memory/physiology ; *Recognition, Psychology/physiology ; },
abstract = {The ability to discriminate experiences in memory is an important indicator of cognitive health in older age and a sensitive marker of hippocampal integrity. Measures of mnemonic discrimination, such as the mnemonic similarity task, have the potential to become early diagnostic tools of Alzheimer's dementia. It is thus important to understand how hippocampus-dependent memory functions interact with nonmnemonic processes to determine mnemonic discrimination performance. In this study, we investigate which features contribute to mnemonic discrimination in younger and older age. First, we found in a sample of younger (n = 93, 20-30 years) and older adults (n = 103, 65-82 years) that age impacted performance on the mnemonic similarity task above and beyond the effect of perceptual discrimination of novel 2D configurative objects. Next, in two experiments, we acquired similarity and feature difference ratings for the mnemonic similarity task lures from younger (n = 25 and n = 47, 19-37 years) and older (n = 25 and n = 47, 65-79 years) adults. Using random forest regression and representational similarity analysis, we found that the two groups exhibited unique similarity rating patterns. Finally, enriching our memory data with the feature information, we showed, on the trial level, that mnemonic decisions of older and younger adults are affected by distinct object features. Altogether, these results provide evidence that older adults perceive the differences in lure images distinctively and they may rely on different levels of representations for mnemonic discrimination. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

Humans
Aged
Aged, 80 and over
Female
*Discrimination, Psychological/physiology
Male
Adult
Young Adult
*Aging/physiology/psychology
*Pattern Recognition, Visual/physiology
Age Factors
*Memory/physiology
*Recognition, Psychology/physiology

@article {pmid42956264,
year = {2026},
author = {Said, MA and Al-Kaff, NS and Hughes, DL and Sarkar, B},
title = {Towards Greener Pastures in Alzheimer's Therapy: Synthesis and XRD/HSA/DFT Mechanistic Investigation of Novel Trifluoromethylated Compounds.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {11},
pages = {},
doi = {10.1002/ardp.70375},
pmid = {42956264},
issn = {1521-4184},
mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; Acetylcholinesterase/metabolism ; Crystallography, X-Ray ; Molecular Structure ; Density Functional Theory ; Structure-Activity Relationship ; Molecular Docking Simulation ; Schiff Bases/chemical synthesis/chemistry/pharmacology ; },
abstract = {A concise, high-yield one-pot protocol afforded two novel trifluoromethylated Schiff base hybrids, (E)-2,2,2-trifluoro-N-(2-((2-hydroxybenzylidene)amino)-2-methylpropyl)acetamide (1) and its 2-hydroxynaphthyl analogue (2). Both combine a branched diamine core, a phenolic/naphtholic imine, and a trifluoroacetamide fragment, giving fluorinated frameworks distinct from reported donepezil and galantamine analogues, which typically use extended benzyl-piperidine architectures. Both compounds were characterised by multinuclear NMR, IR, MS and elemental analysis; their purity was established by reverse-phase HPLC (98.8% for 1 and > 99% for 2 after recrystallisation), and their structures were determined by single-crystal X-ray diffraction. Crystal structure and Hirshfeld surface analyses reveal a tautomerism-controlled switch in supramolecular assembly: compound 1 adopts an enol-imine form, generating discrete amide-phenol dimers via a robust heterosynthon, while 2 exists as a keto-enamine, forming infinite N-H···O hydrogen-bonded chains reinforced by π-π stacking of naphthalene rings. DFT calculations (B3LYP/6-311 + G(d,p)) support these findings, showing distinct charge distributions and a reduced HOMO-LUMO gap for 2, consistent with enhanced electronic polarizability. Molecular docking against acetylcholinesterase (PDB: 1EVE) predicted that both compounds adopt binding modes within the catalytic gorge, with 2 showing particularly favourable interactions within the catalytic gorge. These predictions were tested experimentally. In a colorimetric AChE inhibitor screening assay both compounds inhibit the enzyme in a concentration-dependent manner, with IC50 values of 22.5 µM (1) and 55.0 µM (2) against 15.0 µM for the galantamine reference measured alongside. Compound 1 is the more potent of the pair, by a factor of 2.4, and comes within 1.5-fold of the reference inhibitor, identifying the compact phenolic scaffold rather than the extended naphthalenic one as the better lead for further development. Computational ADME/Tox profiling tentatively predicts compliance with Lipinski and Veber criteria, oral bioavailability, blood-brain barrier permeation, and acceptable toxicity classes, pending experimental confirmation. Overall, this work establishes a synthetically accessible, structurally tunable family of trifluoromethylated scaffolds whose solid-state behaviour and preliminary computational pharmacology indicate potential as crystallography-guided AChE inhibitor candidates warranting further investigation.},
}

*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry
*Alzheimer Disease/drug therapy
Acetylcholinesterase/metabolism
Crystallography, X-Ray
Molecular Structure
Density Functional Theory
Structure-Activity Relationship
Molecular Docking Simulation
Schiff Bases/chemical synthesis/chemistry/pharmacology

@article {pmid42956415,
year = {2026},
author = {Ahmad, AL and Sánchez-Bornot, JM and Sotero, RC and Coyle, DH and Idris, Z and Faye, I},
title = {Towards improving Alzheimer's intervention: a machine learning approach for biomarker detection through combining MEG and MRI pipelines.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/aebb66},
pmid = {42956415},
issn = {1741-2552},
abstract = {OBJECTIVE: To identify robust biomarkers for early cognitive decline, classification performance was evaluated for healthy controls (HC) versus mild cognitive impairment (MCI) using MEG-derived spectral features at the sensor and source levels, and by testing whether adding MRI anatomical features improves discrimination in the BioFIND cohort.

APPROACH: Data from 324 participants (166 HC and 158 MCI) were analyzed using automated artifact rejection and source reconstruction. Spectral biomarkers, including sensor-space and sourcespace representations, were extracted from the magnetometer and gradiometer signals. Five inverse-solution methods were assessed (including linearly constrained minimum variance [LCMV] and exact low-resolution electromagnetic tomography analysis [eLORETA]) to increase the robustness of source-based biomarker selection. Multiple classifiers, including a support vector machine (SVM) and L1-regularized logistic regression (GLMNET), were compared using nested K-fold cross-validation embedded in Monte Carlo replications to limit overfitting.

MAIN RESULTS: The best performance was obtained by combining MRI features with source-based MEG features using GLMNET, achieving 76.31 ± 1.47% accuracy and 82.44 ± 1.44% AUC. MEG-only models showed strong discrimination and outperformed MRI-only analyses, particularly those based on the LCMV and eLORETA features. Across settings, the SVM and GLMNET were the most consistently effective classifiers.

SIGNIFICANCE: These findings support MEG/EEG spectral biomarkers, particularly source-based representations, as sensitive markers of early AD-related functional changes. Integrating MEG with MRI can further improve HC-versus-MCI classification. The study also demonstrated that rigorous validation (nested cross-validation with Monte Carlo replication) is essential for reliable biomarker assessment and for comparing preprocessing, inverse-solution, and classifier choices in translational neuroimaging pipelines.},
}

@article {pmid42956425,
year = {2026},
author = {Bollack, A and Buckley, C and Battle, M and Smith, R and Stromrud, E and Mattsson-Carlgren, N and Palmqvist, S and Hansson, O and Takemoto, S and March, A and La Joie, R and Schwarz, AJ and Farrar, G},
title = {[[18]F]-flutemetamol across acquisition timeframes: clinical interpretability combining visual read and Centiloids.},
journal = {NeuroImage. Clinical},
volume = {52},
number = {},
pages = {104071},
doi = {10.1016/j.nicl.2026.104071},
pmid = {42956425},
issn = {2213-1582},
abstract = {BACKGROUND: Quantification is now in the prescribing information of amyloid-PET tracers allowing its use to support visual read. As Centiloid (CL) scaling is increasingly used for decision-making, its robustness to scanning parameters is essential. We aim to examine the impact of timing on the interpretability of [[18]F]-flutemetamol PET scans, combining visual read and quantification.

METHODS: We analysed two datasets: (1) real-world static scans from the IDEAS study (N = 499), and (2) 'dynamic' data reconstructed into pseudo-static frames in the same individual at varying start times (N = 89). Visual reads were performed by local and expert readers. Linear models were used to assess the impact of acquisition start time and duration on CL quantification. Measurement variability was compared to test-retest repeatability.

RESULTS: Visual interpretation was robust across start times, with no significant impact on the ability to classify scans as amyloid positive/negative. Some amyloid-negative scans acquired earlier (60-80 min start-time) exhibited lower grey-white matter contrast, which could reduce expert reader confidence. Quantitative analysis showed that CL values increased with later acquisition times, especially for amyloid-positive scans. In the intermediate CL range (10-30), differences between acquisitions starting at 60 vs 90 min were within expected test-retest variability (<6CL). Group-level adjustment factors can partially mitigate timing effects, but substantial individual variability remains.

DISCUSSION: With the presently available data, the individual-level effect of acquisition start time on CL cannot be reliably and accurately estimated from static imaging. Combined visual and quantitative assessment of [[18]F]-flutemetamol PET scans across the recommended timeframe supports reliable clinical interpretation. Consistency in acquisition parameters is recommended for repeat scans.},
}

@article {pmid42956527,
year = {2026},
author = {Alkhalifa, AE and Al-Ghraiybah, NF and Al-Gharaibeh, AF and Kaddoumi, A},
title = {Wnt/β-catenin signaling dysregulation in Alzheimer's disease and therapeutic opportunities.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {204},
number = {},
pages = {120020},
doi = {10.1016/j.biopha.2026.120020},
pmid = {42956527},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal and neurovascular dysfunction. Wnt/β-catenin signaling is a highly conserved pathway that plays essential roles in central nervous system development and homeostasis, including regulation of neurogenesis, synaptic plasticity, neuronal survival, cerebrovascular development, and blood-brain barrier (BBB) maintenance. Growing evidence increasingly implicates disruption of Wnt/β-catenin signaling in multiple neuronal and neurovascular processes relevant to AD. This review summarizes current knowledge of the Wnt/β-catenin pathway and examines evidence linking its dysregulation to AD from human studies, omics datasets, experimental models, and patient-derived cellular systems. It focuses on endothelial Wnt/β-catenin dysfunction as a potential early contributor to BBB breakdown, rather than on neuronal Wnt signaling. We also emphasize its role in BBB development and maintenance, neurovascular dysfunction, and emerging evidence that endothelial Wnt/β-catenin impairment may contribute to BBB dysfunction in AD. Additionally, we discuss cell-type-specific effects of Wnt signaling and therapeutic strategies targeting glycogen synthase kinase (GSK-3β), extracellular Wnt antagonists, and BBB integrity. Although challenges remain regarding cell-type specificity, disease-stage dependence, safety, biomarker development, and the efficacy of preclinical-to-clinical translation for targeting the Wnt/β-catenin pathway, modulating Wnt/β-catenin signaling represents a potential therapeutic approach to preserve neuronal and neurovascular function in AD.},
}

@article {pmid42956622,
year = {2026},
author = {Rodolfo, CC and Vinícius, SR and Francesca, B and Alexandra, Y and Neil, O and James, C and Carlos, SG and , },
title = {Stratifying heterogeneity in mild cognitive impairment: A multimodal subtype and stage inference approach.},
journal = {Neurobiology of aging},
volume = {170},
number = {},
pages = {50-63},
doi = {10.1016/j.neurobiolaging.2026.10.006},
pmid = {42956622},
issn = {1558-1497},
abstract = {This study aims to identify distinct clinical and biological subtypes of Mild Cognitive Impairment (MCI) and their progression stages using a data-driven multimodal approach, aimed at improving the stratification and prediction of conversion to Alzheimer's disease (AD). We applied the Subtype and Stage Inference (SuStaIn) algorithm to a multimodal dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify distinct MCI subtypes and their progression stages on 558 patients classified as MCI amyloid-positive. Our model incorporated T1-weighted structural MRI (measuring cortical, subcortical, and hippocampal volumes), CSF biomarkers (Aβ1-42 and p-TAU), APOE-ε4 status, and a comprehensive set of neuropsychological scores. We delimited four subtypes, which two exhibited higher risk for conversion to AD. The remaining two were characterized by prominent ventricular enlargement and a significant association with geriatric depression, respectively. Predictive performance was driven mainly by the class of input features: a multimodal model using individual biomarkers alone achieved the best discrimination (AUC 0.865; accuracy 0.810), and adding SuStaIn subtype and stage did not improve it. However, subtype and stage in isolation (two variables rather than sixteen) reached an AUC of 0.811 with the highest recall observed (0.867), statistically indistinguishable from the full model. Thus, applying SuStaIn to multidomain data successfully disentangles the phenotypic heterogeneity of MCI. By separating temporal disease progression (staging) from inherent trait differences (subtyping), this framework provides a more refined diagnostic tool for patient stratification and early intervention in the AD continuum.},
}

@article {pmid42956664,
year = {2026},
author = {Wang, A and Lahogue, C and Curel, T and Lanthier, C and Groo, AC and Davis, A and Corvaisier, S and Fayolle, D and Modeste, F and Brazzolotto, X and Nachon, F and Lecoutey, C and Claeysen, S and Malzert-Fréon, A and Freret, T and Boulouard, M and Since, M and Rochais, C and Dallemagne, P},
title = {Design, synthesis and biological evaluation of pleiotropic prodrugs activated by cholinesterases and releasing a 5-HT4R agonist, with in vivo antiamnesic activity.},
journal = {European journal of medicinal chemistry},
volume = {321},
number = {Pt 3},
pages = {119383},
doi = {10.1016/j.ejmech.2026.119383},
pmid = {42956664},
issn = {1768-3254},
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are hydrolases that specialize in the cleavage of esters such as acetylcholine. However, they can also cleave the carbamate group of certain drugs, such as rivastigmine. This leads to inhibition of these ChEs and preservation of acetylcholine (ACh), their physiological substrate, providing symptomatic benefits in Alzheimer's disease (AD). The present work aims to exploit ChE's capacity to cleave synthetic carbamates, not only to inhibit these enzymes but also to release a potent 5-HT4 receptor partial agonist upon interaction, thereby exerting an additional disease-modifying effect in AD. Such carbamates would behave as pleiotropic prodrugs. This work relates to the synthesis of the latter compounds and the kinetic study of their enzymatic inhibition to select one of the best candidates from the synthesized compounds for a preliminary in vivo study in an AD model. The latter has been achieved by administering the drug intranasally to bypass the blood-brain barrier (BBB) and avoid peripheral side effects. This has required a special formulation, which was created using liposomes embedded in a thermosensitive mucoadhesive gel. When administered intranasally, the pleiotropic prodrug demonstrated a clear antiamnesic effect in vivo in mice, providing proof of concept for further investigations.},
}

@article {pmid42956716,
year = {2026},
author = {Alexopoulou, L and Rua, R},
title = {Guardians at the gate: cMAF keeps the brain's vasculature in check.},
journal = {Cell},
volume = {189},
number = {22},
pages = {6904-6906},
doi = {10.1016/j.cell.2026.09.056},
pmid = {42956716},
issn = {1097-4172},
mesh = {Humans ; Animals ; *Brain/blood supply/metabolism ; Insulin-Like Growth Factor I/metabolism ; *Alzheimer Disease/metabolism ; Macrophages/metabolism ; Mice ; },
abstract = {In this issue of Cell, Brioschi et al. identify cellular musculoaponeurotic fibrosarcoma (cMAF) as a key regulator of brain perivascular macrophages that supports cerebrovascular function through insulin-like growth factor 1 (IGF1) production. This cMAF-IGF1 program is enhanced in Alzheimer's disease (AD), potentially reflecting a protective response that is lost in APOE4 carriers.},
}

Humans
Animals
*Brain/blood supply/metabolism
Insulin-Like Growth Factor I/metabolism
*Alzheimer Disease/metabolism
Macrophages/metabolism
Mice

@article {pmid42956845,
year = {2026},
author = {Tian-Yang, X and Er-Deng, E and Ting, Z and Xiao-Qin, Z},
title = {Selective neuronal vulnerability in Alzheimer's disease: mechanisms, biomarkers, and therapeutic implications.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103430},
doi = {10.1016/j.arr.2026.103430},
pmid = {42956845},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is characterized by marked heterogeneity in the timing and extent of neuronal dysfunction and degeneration. Specific neuronal populations, including entorhinal cortex layer II stellate cells, hippocampal CA1 pyramidal neurons, basal forebrain cholinergic neurons, locus coeruleus noradrenergic neurons, and prefrontal parvalbumin interneurons, show different combinations of functional, pathological, and degenerative vulnerability during disease progression. The strength and nature of this evidence, however, vary across neuronal populations and between human studies and experimental models. Selective vulnerability is therefore unlikely to reflect a single cell-type-specific mechanism. Instead, pathological stress in AD interacts with intrinsic cellular properties, circuit organization, and the local microenvironment. Metabolic stress, axonal transport impairment, excitotoxicity and Ca[2+] dysregulation, neuroinflammation, lipid dysregulation and ferroptotic stress, and proteostasis failure may consequently produce distinct functional and degenerative outcomes across neuronal populations. Advances in transcriptomics, neuropathology, multimodal imaging, and circuit-level analyses are also identifying molecular, regional, and functional measures associated with early involvement of vulnerable neuronal systems, although validated cell-type-specific biomarkers remain limited. In this Review, we integrate these findings to examine the evidence for selective neuronal vulnerability, the mechanisms that may modify neuronal susceptibility, and their implications for biomarker development and therapy. We further consider how vulnerability-informed strategies could complement pathology-directed therapies by aligning therapeutic mechanisms with prominent cellular or circuit dysfunction and disease stage. This perspective may help explain the spatial and temporal heterogeneity of AD and guide more biologically informed approaches to early detection and intervention.},
}

@article {pmid42956863,
year = {2026},
author = {Xiao, Y and Li, XY and Ding, H and Wen, JX and Dai, YX and Zhang, YJ and Li, SP and Wang, YX and Zhou, HJ and Zhang, BM and Huang, ZY and Lou, HK and Wang, YJ and Cui, XJ and Wang, HS and Yao, M},
title = {Scutellarin as a multi-target neuroprotective agent: analytical evidence, pharmacokinetic insights and translational strategies across neurodegenerative disorders.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109714},
doi = {10.1016/j.phrs.2026.109714},
pmid = {42956863},
issn = {1096-1186},
abstract = {Neurodegenerative disorders are a leading cause of disability and mortality globally, but effective disease-modifying therapeutic strategies are still largely unavailable. Scutellarin is a flavonoid glycoside extracted from Erigeron breviscapus (Vant.) Hand-Mazz. It has been widely studied in preclinical models of neurodegenerative disorders. In this study, we performed a systematic review of preclinical animal studies. We combined comprehensive database retrieval with quantitative synthesis of eligible outcomes. The pooled results demonstrated that scutellarin significantly reduced cerebral infarct volume and improved neurological deficit scores in cerebral ischemia-reperfusion models. It also ameliorated learning and memory impairments in experimental Alzheimer's disease (AD) models. Consistent neuroprotective effects were also found in models of depression, anxiety, Parkinson's disease, etc. Mechanistic analysis indicated that scutellarin produces multi-level neuroprotective effects. It acts by reducing oxidative stress, inhibiting neuroinflammation, suppressing apoptosis, stabilizing the neurovascular unit and other neurobiological processes. This review first evaluated the preclinical efficacy of scutellarin through systematic review and meta-analysis. It then integrated cross-disease mechanisms with network pharmacology, reverse virtual screening and molecular docking to identify computationally predicted targets. Although scutellarin shows promising preclinical effects, its clinical translation faces major limitations. These limitations include low oral bioavailability, poor blood-brain barrier (BBB) penetration and insufficient data on brain exposure. Overall, scutellarin is a multi-target neuroprotective candidate. Future studies should focus on target validation, exposure-response modeling, delivery optimization and clinically relevant translational evaluation.},
}

@article {pmid42957097,
year = {2026},
author = {Caon, B and Corti, M and Bonizzoni, F and Antonietti, PF},
title = {High-fidelity and network-based spatio-temporal mathematical models of Alzheimer's disease progression and their comparison with PET-SUVR imaging data.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112182},
doi = {10.1016/j.brainresbull.2026.112182},
pmid = {42957097},
issn = {1873-2747},
abstract = {Alzheimer's disease is the most common neurodegenerative disorder. Its pathological development is connected with the misfolding and accumulation of two toxic proteins: amyloid-β and tau proteins. Mathematical models provide a valuable quantitative tool for monitoring disease progression. In this work, we proposed and compare a novel framework where the spatio-temporal dynamics of amyloid-β and tau proteins is modeled based on employing either three-dimensional patient-specific geometries or through reduced network-based models defined on the brain connectome. More specifically, a high-fidelity biophysical model is proposed on three-dimensional brain geometries reconstructed from magnetic resonance imaging, whereas a network-based reduced formulation is defined on the brain connectome. For both approaches, a suitable numerical discretisation is proposed. A sensitivity analysis is presented to quantify the influence of model parameters on protein concentration patterns as well as compare the quality of the predictions. For both approaches, the results are compared with group-level PET-SUVR clinical data using [[18]F]AZD4694 for amyloid-β and [[18]F]MK6240 for tau protein. The results indicate that the three-dimensional model provides the most accurate and biologically consistent description of the disease progression, but remains computationally demanding. On the other hand, the reduced graph-based model is cheaper, but it is not always able to achieve reliable results.},
}

@article {pmid42957107,
year = {2026},
author = {Hu, D and Li, D and He, L and Mao, S and Zhu, YA and Chen, X and Zhang, J and Zhou, C and Zhou, X},
title = {Integrative network pharmacology, machine learning, and experimental validation identify the TLR4/NF-κB/NLRP3 axis as a potential mechanism underlying the therapeutic effects of Lingguizhugan decoction in Alzheimer's disease.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122517},
doi = {10.1016/j.jep.2026.122517},
pmid = {42957107},
issn = {1872-7573},
abstract = {Lingguizhugan decoction, a traditional formula originating from Zhang Zhongjing's Treatise on Cold Damage and Miscellaneous Diseases, has shown cognitive benefits in APP/PS1 mice in our earlier study, partly through restoration of meningeal lymphatic drainage and enhancement of amyloid-β (Aβ) removal. Whether other molecular events contribute to its therapeutic action in Alzheimer's disease (AD) remains to be clarified.

AIM OF THE STUDY: This work was designed to clarify additional potential mechanisms by which LGZG may act against AD.

METHODS AND MATERIALS: The chemical constituents of LGZG were profiled by UPLC-Q-TOF-MS. Candidate targets and pathways were screened by integrating public databases, transcriptomic analysis, network pharmacology, and enrichment analysis. Eight machine learning models and SHAP analysis were subsequently used to prioritize candidate regulators. Molecular docking and molecular dynamics simulations were performed to evaluate the potential interactions between representative LGZG constituents and TLR4. APP/PS1 mice and BV2 microglial cells were used for experimental validation. Spatial learning and memory, hippocampal pathological alterations, Aβ deposition, inflammatory cytokines, microglial inflammatory phenotype-associated markers, and TLR4/NF-κB/NLRP3 signaling were evaluated using behavioral testing, histological staining, ELISA, immunofluorescence, qRT-PCR, and Western blotting. TAK-242 inhibition and TLR4 overexpression were further used to assess the involvement of TLR4 signaling.

RESULTS: Twenty-three candidate constituents were retained following chemical profiling and in silico screening of LGZG. Integrated analysis of network pharmacology, AD-related genes, and transcriptomic data identified 46 candidate LGZG-AD-DEG targets. Machine learning and SHAP analyses further prioritized several inflammation-related regulators, including RELA and NFKBIA, supporting inflammation-related signaling as a major direction for subsequent validation. Molecular docking and molecular dynamics simulations suggested potential interactions between representative LGZG constituents and the TLR4 receptor. In APP/PS1 mice, LGZG improved spatial learning and memory, attenuated hippocampal neuronal injury, reduced Aβ deposition, and decreased IL-1β, IL-6, and TNF-α levels. LGZG also reduced hippocampal TLR4, P-IκBα, P-NF-κB, and NLRP3 expression and decreased TLR4/NF-κB/NLRP3-related signals in Iba1-positive microglia. In LPS-stimulated BV2 cells, LGZG shifted inflammatory phenotype-associated markers toward a less pro-inflammatory profile and suppressed TLR4/NF-κB/NLRP3 signaling. TAK-242 treatment and TLR4 overexpression experiments further supported the involvement of TLR4 signaling in these effects.

CONCLUSION: LGZG alleviated cognitive impairment, hippocampal pathological alterations, Aβ deposition, and neuroinflammatory responses in APP/PS1 mice. Integrated bioinformatic analyses and experimental validation suggest that regulation of TLR4/NF-κB/NLRP3 signaling contributes to the anti-neuroinflammatory effects of LGZG in AD.},
}

@article {pmid42957174,
year = {2026},
author = {Chen, D and Wang, H and Su, C and Lv, S and He, M and Li, N},
title = {The Effects of Virtual Reality Group Reminiscence Therapy on Agitation, Cognition, Depression and Social Function in Patients With Alzheimer's Disease.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {},
doi = {10.1111/psyg.70196},
pmid = {42957174},
issn = {1479-8301},
support = {SKY2023164//Science and Technology Development Plan Project of Suzhou/ ; BXLC2024017//Boxi Clinical Research Project of The First Affiliated Hospital of Soochow University/ ; 2023001312060001//Project for Strengthening Health through Science and Education of Suzhou/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/therapy/psychology ; Male ; Aged ; *Cognition ; *Psychotherapy, Group/methods ; *Depression/therapy/psychology ; Aged, 80 and over ; *Virtual Reality ; Treatment Outcome ; *Psychomotor Agitation/therapy/psychology ; Neuropsychological Tests ; Surveys and Questionnaires ; *Virtual Reality Exposure Therapy/methods ; },
abstract = {OBJECTIVE: This study examined the impact of multisensory virtual reality (VR) group reminiscence therapy on behavioural, cognitive and psychosocial outcomes in Alzheimer's disease (AD) patients, while evaluating intervention feasibility and safety.

METHODS: An assessor-blinded randomised controlled trial was employed. Sixty participants with AD were randomly allocated to either the intervention group (n = 30) or the control group (n = 30). The intervention group underwent VR-based reminiscence sessions twice weekly, each lasting 40 min, for 8 weeks. The control group received routine care. Outcomes were measured before and after the intervention using the NPI-agitation subscale, Mini-Mental State Examination (MMSE), the 15-item Geriatric Depression Scale (GDS-15) and Short Form-36 (SF-36). Questionnaires including Presence Questionnaire (PQ), Motivation Inventory (IMI) and Virtual Reality Sickness Questionnaire (VRSQ) were used to assess intervention acceptance and side effects. The Autobiographical Memory Test (AMT) was used to evaluate memory specificity.

RESULTS: Post-intervention, VR participants showed markedly lower agitation scores (NPI) (4.2 ± 1.9 vs. 1.7 ± 1.2, p < 0.001), MMSE scores (23.5 ± 2.1 vs. 27.1 ± 1.4, p < 0.01), GDS-15 scores (9.8 ± 1.3 vs. 3.1 ± 1.2, p < 0.001) and SF-36 subscales of social function and mental health (both p < 0.05), compared with the control group. PQ and IMI scores indicated high acceptance of the intervention. VRSQ scores showed minor side effects (e.g., eye fatigue < 1.3). AMT results also improved significantly (event specificity: 3.2 vs. 6.2, p < 0.01).

CONCLUSION: VR group reminiscence therapy significantly improved agitation, cognition and mood in AD patients and enhanced their quality of life. The method is safe, feasible and provides a novel non-pharmacological option with an interactive and immersive experience.},
}

Humans
Female
*Alzheimer Disease/therapy/psychology
Male
Aged
*Cognition
*Psychotherapy, Group/methods
*Depression/therapy/psychology
Aged, 80 and over
*Virtual Reality
Treatment Outcome
*Psychomotor Agitation/therapy/psychology
Neuropsychological Tests
Surveys and Questionnaires
*Virtual Reality Exposure Therapy/methods

@article {pmid42957281,
year = {2026},
author = {Zhang, K and Liang, L and Jiang, H and Wang, J and Cai, X},
title = {Deep learning for identifying Alzheimer's disease and mild cognitive impairment with optical coherence tomography angiography.},
journal = {The British journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1136/bjo-2025-328423},
pmid = {42957281},
issn = {1468-2079},
}

@article {pmid42680483,
year = {2026},
author = {Kim, SH and Lee, SK},
title = {Lithium: the protective cation singled out by Alzheimer's disease.},
journal = {BMB reports},
volume = {59},
number = {10},
pages = {456-465},
pmid = {42680483},
issn = {1976-670X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Lithium/pharmacology/therapeutic use/metabolism ; Animals ; Glycogen Synthase Kinase 3 beta/metabolism ; Lithium Compounds/pharmacology/therapeutic use ; Phosphoric Monoester Hydrolases/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Lithium is a mood stabilizer that is most prescribed in psychiatry for managing mental disorders. Many findings indicate that lithium is also neuroprotective in various neurodegenerative diseases. In particular, lithium has been of great interest as an affordable but still effective treatment for Alzheimer's disease (AD), due to its diverse neuroprotective actions and mechanistic overlap with key AD pathways, such as A(?) production and tau modification. While the multifaceted activities may result from lithium's inhibitory action on two key enzymes, glycogen synthase kinase-3 beta (GSK-3(?)) and inositol monophosphatase (IMPase), recent findings suggest that selective lithium depletion in neurons mediated by amyloid deposits may be a key pathological trigger in AD and supplementation with lithium orotate, a lithium salt with reduced amyloid binding, may even reverse brain damage and prevent cognitive decline. In this study, we review the neuroprotective properties of lithium, its known mechanisms of action, and discuss its therapeutic potential in AD, a topic that has been debated for decades. [BMB Reports 2026; 59(10): 456-465].},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Lithium/pharmacology/therapeutic use/metabolism
Animals
Glycogen Synthase Kinase 3 beta/metabolism
Lithium Compounds/pharmacology/therapeutic use
Phosphoric Monoester Hydrolases/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42946777,
year = {2026},
author = {Fan, X and Truong, JB and Okada, K and Lin, H and Ori-McKenney, KM and McKenney, RJ},
title = {A pathological phosphorylation pattern enhances tau cooperativity on microtubules and facilitates tau filament assembly.},
journal = {Communications biology},
volume = {9},
number = {1},
pages = {},
pmid = {42946777},
issn = {2399-3642},
support = {25PRE1362890//American Heart Association (American Heart Association, Inc.)/ ; P30AG072972//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {*tau Proteins/metabolism ; Phosphorylation ; *Microtubules/metabolism ; *Neurofibrillary Tangles/metabolism ; Animals ; Humans ; Protein Binding ; },
abstract = {Phosphorylation of the microtubule-associated protein tau plays important roles in both normal physiology and disease. While tau phosphorylation levels are similarly elevated in processes such as fetal development and hibernation and in pathological states like Alzheimer's disease, the pattern of phosphorylation differs between these contexts. Whether distinct phosphorylation patterns differentially impact tau's function on microtubules and its propensity to form neurofibrillary tangles (NFTs) has remained unclear. Here we investigated how differential phosphorylation affects microtubule binding, cooperative tau envelope formation, and NFT-relevant filament assembly. Consistent with prior work, phosphorylation decreases tau's overall microtubule affinity. However, we find that phosphorylation more dramatically impacts cooperativity between tau molecules during envelope formation. Strikingly, the specific pattern of phosphorylation, rather than overall level, strongly promotes tau filament assembly in vitro. These findings provide insights into how tau phosphorylation modulates its physiological microtubule interactions and its pathoconversion into NFTs.},
}

*tau Proteins/metabolism
Phosphorylation
*Microtubules/metabolism
*Neurofibrillary Tangles/metabolism
Animals
Humans
Protein Binding

@article {pmid42946784,
year = {2026},
author = {Tong, J and Li, L and Zhang, D and O'Brien, KS and Lu, Y and Wu, Q and Zhou, T and Zhang, B and Lei, Y and Tang, H and Jing, N and Li, H and Xu, Z and Huang, Y and Hu, Y and Zhou, Y and Lin, F and Jiang, Y and Chu, H and Chen, Y and Wang, F and Bian, J and Xu, H and Wolk, DA and Chen, Y},
title = {FLAT-WHITE: from target trial emulation to federated high-throughput causal machine learning using decentralized real-world data.},
journal = {npj health systems},
volume = {3},
number = {1},
pages = {},
pmid = {42946784},
issn = {3005-1959},
support = {U01TR003709, U24MH136069, U24AG098157, RF1AG077820, R01AG073435, R01LM013519, 1R01LM014344, R01DK128237, R21AI167418, R21EY034179/NH/NIH HHS/United States ; },
abstract = {Randomized clinical trials remain the gold standard for evaluating treatment effects but are often infeasible for rapidly assessing drug repurposing opportunities, particularly in complex conditions such as Alzheimer's disease. Target trial emulation (TTE) provides a principled framework for causal inference with electronic health records and, when coupled with modern machine learning, enables scalable analyses across distributed health systems. We present FLAT-WHITE (Federated Lossless Algorithm for Target Trial Emulation with Overlap Weighting for Healthcare Data Integration via Trusted and Efficient Communication), a novel federated causal machine learning pipeline for high-throughput treatment effect estimation without sharing patient-level data. FLAT-WHITE is a one-shot, lossless algorithm, requiring a single communication round while achieving results equivalent to centralized pooled analyses. With overlap weighting on the propensity score, it robustly addresses heterogeneity in treatment assignment and ensures valid causal inference in decentralized settings. We demonstrate FLAT-WHITE in a Alzheimer's drug repurposing study, scanning 181 candidate drugs using data from four health learning systems encompassing approximately 150,000 patients with mild cognitive impairment. Findings were validated externally in 339,180 patients from the TriNetX global research network. FLAT-WHITE enables rapid, large-scale, and secure evaluation of treatment effects and establishes a foundation for collaborative clinical research across diverse healthcare systems.},
}

@article {pmid42946892,
year = {2026},
author = {Creecy, A and Waning, DL and Khurram, I and Warsame, A and Blosser, RJ and Karnik, SJ and Xu, J and Yamada, C and Smith, DK and Oblak, AL and Fehrenbacher, JC and Movila, A and Kacena, MA and Huot, JR},
title = {Characterization of sex-dependent skeletal muscle alterations in the 3xTg Alzheimer's disease mouse model.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42946892},
issn = {2509-2723},
support = {R01AG064003/AG/NIA NIH HHS/United States ; K022AG068595/AG/NIA NIH HHS/United States ; R37CA299888//Basic Research Laboratory/ ; RSG-24-1258280-01-CDP//American Cancer Society/ ; HF-GRO-23-1199172-46//Hevolution/ ; RX004809//U.S. Department of Veterans Affairs/ ; 1I21BX006307//U.S. Department of Veterans Affairs/ ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic condition with effects beyond the central nervous system. Skeletal muscle dysfunction, including sarcopenia and reduced physical performance, is prevalent in AD patients, yet the underlying mechanisms remain poorly understood. In this study, we characterized skeletal muscle alterations in male and female 3xTg-AD mice at 3, 6, and 12 months of age and compared them to age- and sex-matched B6129 controls. We measured body composition, muscle function, and skeletal muscle parameters including fiber type distribution, cross-sectional area (CSA), and neural cell adhesion molecule (NCAM) expression. Our findings revealed early-onset and progressive impairments of skeletal muscle mass, morphology, and function in 3xTg-AD mice, with sex-specific differences. Male mice exhibited reduced lean mass, muscle weight, and torque generation as early as 3 months and decreased CSA of type IIB and IIX fibers and increased NCAM expression by 12 months, indicating a potential neuromuscular junction deficiency. Female mice in this study generally exhibited a milder phenotype. Together, these results identify skeletal muscle dysfunction as an early and sex-dependent feature of AD pathology in 3xTg-AD mice. Our study underscores the importance of considering systemic effects in AD and highlights skeletal muscle as a potential target for therapeutic intervention aimed at preserving mobility and quality of life in affected individuals.},
}

@article {pmid42946915,
year = {2026},
author = {Challapalli, SSA and Bhattarai, KM and Kamangar, FA and , },
title = {UNICAL: Uncertainty-Aware Multimodal Learning with MRI-Derived Synthetic Amyloid PET for Alzheimer's Disease Classification.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02442-9},
pmid = {42946915},
issn = {2948-2933},
abstract = {Limited availability of amyloid positron emission tomography (PET) motivates imaging-informatics methods that derive complementary molecular-imaging representations from routinely acquired magnetic resonance imaging (MRI). We developed UNICAL, an uncertainty-aware multimodal framework for Alzheimer's disease-spectrum versus cognitively normal classification that combines a self-supervised three-dimensional MRI encoder, Contourlet Wavelet Stationary Radiomics (CoWS-Rad) engineered MRI features, and MRI-derived synthetic 18F-florbetapir (AV45) PET. CoCoLIT generated four stochastic PET realizations per MRI; their mean and voxelwise variance were used for uncertainty gating before probability-anchored transformer fusion. Synthetic PET was validated in 228 paired OASIS-3 MRI-AV45 examinations, achieving a mean per-examination voxelwise Pearson correlation of r = 0.864 and strong cortical-composite SUVR agreement with acquired PET (Pearson r = 0.954). In the OASIS-3 development cohort (813 sessions from 811 participants), participant-grouped five-fold cross-validation repeated across 20 seeds yielded AUROC 0.868 and expected calibration error (ECE) 0.061. The OASIS-3 development endpoint used the manuscript's AD-spectrum reference standard, whereas ADNI3 used AD-versus-CN research-group labels, providing cross-dataset evaluation on a related but non-identical prediction endpoint. Without retraining, feature refitting, threshold optimization, or recalibration, the frozen framework was evaluated in an independent matched ADNI3 cohort of 261 participants (87 AD, 174 CN), achieving AUROC 0.836 (95% CI 0.791-0.876). ECE increased to 0.089 under external transfer, indicating that calibration was more sensitive to domain shift than rank discrimination. Ablation analysis and K-sample sensitivity supported the contributions of uncertainty gating, adaptive weighting, modality dropout, residual correction, and the K = 4 synthesis configuration. UNICAL therefore provides an uncertainty-aware MRI-derived multimodal representation for AD-spectrum classification that retains substantial cross-dataset discrimination while remaining distinct from acquired molecular imaging and not replacing amyloid PET as a clinical biomarker.},
}

@article {pmid42947097,
year = {2026},
author = {Wang, JY and Ansorge, O},
title = {Menopause and Alzheimer's disease: can hormone replacement therapy modify the risk? A narrative review.},
journal = {BMC women's health},
volume = {26},
number = {1},
pages = {},
pmid = {42947097},
issn = {1472-6874},
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; Female ; *Menopause ; Risk Factors ; *Hormone Replacement Therapy/adverse effects ; *Estrogen Replacement Therapy ; Women's Health ; },
abstract = {Alzheimer's Disease (AD) prevalence and lifetime risk are higher in women than men. This led to the hypothesis that menopause, with its associated changes in female hormone homoeostasis, may be an AD risk factor modifiable by hormone replacement therapy (HRT). However, HRT is not without its risks to women's health, and any recommendations must rest on sound evidence. Here, we critically review data concerning sex-specific epidemiological and biological parameters that may influence AD development. Recent epidemiological studies suggest that the age-adjusted incidence of AD is not higher in women than men. Whilst there is mechanistic experimental evidence that female sex hormones modulate the metabolism of β-amyloid and tau, the neuropathological hallmarks of AD, no clear conclusions can be drawn from studies conducted in humans. Exposure to HRT may modify the development of AD; however, data are weak and the influence of timing, duration, type of HRT, and ethnic, socioeconomic, educational and genomic factors such as APOE genotype, requires further clarification. Large prospective biobank studies in diverse populations, with long follow-up periods and application of biological consensus criteria for the diagnosis of AD provide opportunities to conclusively clarify the relationship between menopause, HRT therapy and risk for the development of AD. Based on current evidence, HRT cannot be recommended as a generic intervention for the reduction of AD risk in women. Any decision to take HRT must consider the individual circumstances and overall health of a woman.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control
Female
*Menopause
Risk Factors
*Hormone Replacement Therapy/adverse effects
*Estrogen Replacement Therapy
Women's Health

@article {pmid42947146,
year = {2026},
author = {Zhang, S and Wang, Q},
title = {Astrocytes and memory: emerging evidence and a paradigm shift.},
journal = {Cell communication and signaling : CCS},
volume = {24},
number = {1},
pages = {},
pmid = {42947146},
issn = {1478-811X},
mesh = {*Astrocytes/metabolism/cytology ; Humans ; Animals ; *Memory/physiology ; },
abstract = {In recent years, with the discovery of astrocytes as components of the tripartite synapse and the development of tools for manipulating astrocyte calcium events, learning and memory are no longer considered the exclusive domain of neurons; activation of astrocytes alone can also trigger memory recall. The mnemonic functions of astrocytes have now been demonstrated in the hippocampus, nucleus accumbens, and amygdala, and are mainly manifested during the memory retrieval phase. On the other hand, cooperation between astrocyte-derived gliotransmitters and memory engram neurons is crucial for the formation and consolidation of both short-term and long-term memory. For example, activation of astrocytic calcium signaling and stimulation by endocannabinoids can induce the release of D-serine, ATP/adenosine, and glutamate, which act on GPCR and thereby influence LTD or LTP. Among these molecules, lactate can also function as a signaling molecule to activate downstream memory processes, potentially involving D-serine- and NMDAR-mediated synaptic plasticity. Similarly, α1, α2, and β-adrenergic receptors, which are predominantly expressed in astrocytes, participate in memory in distinct ways across different brain regions. In addition, this review discusses the mechanisms by which astrocytes, as a medium for memory storage, participate in Alzheimer's disease, addictive behaviors, sleep disorders, depression, and post-traumatic stress disorder, as well as their therapeutic potential. Finally, this review systematically details the challenges and future directions in elucidating the mechanisms by which astrocytes store and process memory at the current stage, which may facilitate the development of novel astrocyte-targeted therapies for cognition-related disorders.},
}

*Astrocytes/metabolism/cytology
Humans
Animals
*Memory/physiology

@article {pmid42947225,
year = {2026},
author = {Beament, M and Wiltshire, K and Belder, CRS and Abel, E and Hart, M and Heslegrave, AJ and Lunn, MP and Rosa-Grilo, M and Swann, O and Schott, JM and Zetterberg, H and Fox, NC and Keshavan, A},
title = {Short-interval variability and test-retest reliability of Alzheimer's disease plasma biomarkers in a clinically heterogenous cohort.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42947225},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Female ; Reproducibility of Results ; Male ; tau Proteins/blood ; Aged ; Amyloid beta-Peptides/blood ; Cohort Studies ; Aged, 80 and over ; Peptide Fragments/blood ; Glial Fibrillary Acidic Protein/blood ; },
abstract = {BACKGROUND: Assessment of short-term within-subject variability and test-retest reliability of Alzheimer's disease (AD)-related plasma biomarkers is important for real-world clinical implementation and interpretation in research studies. In this study we aimed to assess short-term variability and reliability of core AD plasma biomarkers, proposed ratios, and evaluate a broader proteomic panel.

METHODS: Two serial plasma samples were collected from each of the 92 participants enrolled in observational research studies over intervals ranging from 30 minutes to three months. Test-retest reliability and within-subject variability were assessed for 131 biomarkers measured on three immunoassays (Lumipulse G plasma p-tau217; Fujirebio, NULISAseq CNS Disease Panel and NULISAqpcr AD 5-Plex; Alamar Biosciences). We subsequently evaluated the stability of a dual cut-point approach for AD probability diagnostic categorisation and examined whether within-subject variability was associated with inter-sample interval (time between serial blood sampling).

RESULTS: All core AD plasma biomarkers assessed in this study (Aβ42, BD-p-tau181, BD-p-tau217, BD-p-tau231, p-tau181, p-tau217, p-tau231, GFAP and NfL) demonstrated strong correlations (r ≥ 0.79) and high reliability (ICC ≥ 0.84). Within-subject variability was moderate to low for core AD plasma biomarkers. Using a validated dual cut-point approach for plasma p-tau217, most individuals (92%) remained within the same diagnostic category (high/indeterminate/low) across both timepoints, and no individual moved across two boundaries (i.e. from high to low AD probability categorisation or vice versa). For the majority of analytes, within-subject variability was not associated with inter-sample interval after adjustment for age and sex, however, the core AD plasma biomarker, NfL did have a significant association.

CONCLUSIONS: While core AD plasma biomarkers had limited variability and high reliability over short-intervals, other central nervous system (CNS)-relevant biomarkers showed greater variability, which may be relevant for interpretation in association studies and clinical applications.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Female
Reproducibility of Results
Male
tau Proteins/blood
Aged
Amyloid beta-Peptides/blood
Cohort Studies
Aged, 80 and over
Peptide Fragments/blood
Glial Fibrillary Acidic Protein/blood

@article {pmid42947251,
year = {2026},
author = {Peter, DC and McLachlan, M and DiFilippo, AH and Yang, KL and Pasquesi, ME and Barnhart, TE and Engle, JW and Betthauser, TJ and Asthana, S and Johnson, SC and Christian, BT and Bendlin, BB and Otto, M and Oeckl, P},
title = {Plasma β-synuclein associates with hippocampal synaptic density measured with [[11]C]UCB-J PET and plasma tau markers in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71900},
pmid = {42947251},
issn = {1552-5279},
support = {R01 AG062285/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; R01 AG021155/AG/NIA NIH HHS/United States ; F31 AG087651/AG/NIA NIH HHS/United States ; 24-SGP-691 23-PPG-674-2//ALS Association/ALS Finding A Cure/ ; //EU Horizon Europe/ ; //Horizon Europe (EU)/ ; //DZNE Innovation-to-Application/ ; //Cure Alzheimer's Fund/ ; D.7090//Fondation Charcot/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; Positron-Emission Tomography ; Female ; Male ; *tau Proteins/blood ; Aged ; Biomarkers/blood ; *Hippocampus/diagnostic imaging/pathology/metabolism ; *Synapses/pathology/metabolism ; Middle Aged ; *beta-Synuclein/blood ; Glial Fibrillary Acidic Protein/blood ; Neuropsychological Tests ; Cognitive Dysfunction/blood/diagnostic imaging ; Carbon Radioisotopes ; Pyridines ; },
abstract = {INTRODUCTION: Plasma β-synuclein is a promising blood-based synaptic biomarker, but relationships with synaptic density as indicated by [[11]C]UCB-J positron emission tomography (PET), and blood biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and astrocyte activation need further characterization.

METHODS: Middle-aged and older adults with and without cognitive impairment (N = 83 total, 68.7% cognitively unimpaired) underwent blood draw, PET imaging, and neuropsychological testing. Primary analyses focused on relationships between plasma β-synuclein and synaptic density, and associations with related plasma biomarkers (tau phosphorylated at threonine 217 [p-tau217], brain-derived tau [BD-tau], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]).

RESULTS: Plasma β-synuclein levels were higher in cognitively unimpaired and impaired participants with positive amyloid PET. Synaptic density was lower in cognitively impaired participants only. In the full sample, higher plasma β-synuclein levels associated with lower synaptic density in the hippocampus, higher concentrations of plasma tau markers, and higher plasma GFAP.

DISCUSSION: This work further supports utilization of plasma β-synuclein to track synaptic degeneration in AD.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/pathology
Positron-Emission Tomography
Female
Male
*tau Proteins/blood
Aged
Biomarkers/blood
*Hippocampus/diagnostic imaging/pathology/metabolism
*Synapses/pathology/metabolism
Middle Aged
*beta-Synuclein/blood
Glial Fibrillary Acidic Protein/blood
Neuropsychological Tests
Cognitive Dysfunction/blood/diagnostic imaging
Carbon Radioisotopes
Pyridines

@article {pmid42947268,
year = {2026},
author = {Zhao, X and Xu, M and Chen, H and Lei, Z and Yu, Q and Liu, J and Liao, W},
title = {Cost-effectiveness of lecanemab for early Alzheimer's disease in China.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71941},
pmid = {42947268},
issn = {1552-5279},
support = {82371186//National Natural Science Foundation of China/ ; //National Key Clinical Specialty (Neurology)/ ; //Key Medical Discipline of Guangzhou (2025-2027)/ ; //Clinical Key Specialties (Clinical Medical Research) of Guangzhou/ ; 2024312093//University Scientific Research Project of Guangzhou Municipal Education Bureau/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; *Cost-Benefit Analysis ; China ; *Cost-Effectiveness Analysis ; Markov Chains ; Female ; Quality-Adjusted Life Years ; Male ; Aged ; },
abstract = {BACKGROUND: Although lecanemab has demonstrated clinical efficacy in early Alzheimer's disease (AD), its cost-effectiveness in China remains uncertain. This study evaluated the long-term cost-effectiveness of lecanemab in Chinese patients from a societal perspective and estimated its value-based price (VBP).

METHODS: A Markov state transition model based on Chinese real-world data was developed to compare the long-term health progression and economic outcomes of lecanemab combined with standard of care (SoC) versus SoC alone.

RESULTS: Compared to SoC alone, the lecanemab combination therapy gained an additional 1.2432 Quality-adjusted life years (QALYs) at an incremental cost of 463,228 Chinese yuan (CNY), resulting in an incremental cost-effectiveness ratio (ICER) of 372,609 CNY/QALY (≈ 52,783 USD/QALY). To achieve cost-effectiveness within the willingness-to-pay threshold, the price of a single vial of lecanemab must be reduced by at least 18.0%.

DISCUSSION: Lecanemab can provide health benefits to Chinese patients with early AD, but it is not cost-effective under the current pricing system.},
}

Humans
*Alzheimer Disease/drug therapy/economics
*Cost-Benefit Analysis
China
*Cost-Effectiveness Analysis
Markov Chains
Female
Quality-Adjusted Life Years
Male
Aged

@article {pmid42947278,
year = {2026},
author = {Wu, W and Liu, H and Liang, Y and Li, H and Zhang, J and Sun, Z and Song, Y and Fei, M and Wu, H and Jiang, M and Fan, S and Zhou, C and Cao, Y and Chen, H and Liu, S},
title = {Caregiver positivity as a psychosocial modifier of lecanemab-related outcomes in Alzheimer's disease: A multicenter longitudinal study in China.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71894},
pmid = {42947278},
issn = {1552-5279},
support = {2025017//Tianjin Scientific Research Projects in Key Areas of Traditional Chinese Medicine/ ; TJYXZDXK-3-014B//Tianjin Key Medical Discipline Construction Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; *Caregivers/psychology ; Female ; Male ; Longitudinal Studies ; Aged ; China ; Aged, 80 and over ; Activities of Daily Living ; Middle Aged ; },
abstract = {INTRODUCTION: Real-world modifiers of lecanemab benefit in Alzheimer's disease (AD) remain elusive. We examined associations between caregiver positivity and longitudinal outcomes in AD.

METHODS: This seven-center longitudinal study followed 127 biomarker-supported AD patient-caregiver dyads over 18 months. Mixed-effects, spline, and propensity-score analyses evaluated continuous Positive Aspects of Caregiving (PAC) scores.

RESULTS: Higher baseline PAC scale scores were associated with more favorable 18-month outcomes in cognition (Mini-Mental State Examination (MMSE): β = 0.42, 95% confidence interval [CI]: 0.24-0.59; p < 0.001), daily function (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]: β = 0.68, 95% CI: 0.42-0.93; p < 0.001), disease severity (Clinical Dementia Rating-Sum of Boxes [CDR-SB]: β = -0.26, 95% CI: -0.37 to -0.14; P < 0.001), patient quality of life (Quality of Life in Alzheimer's Disease [QOL-AD]: β = 0.53, 95% CI: 0.34-0.71; p < 0.001), and lower apathy (β = -0.09, 95% CI: -0.16 to -0.03; p = 0.003); these associations remained significant after multiplicity correction (all q's ≤ 0.004). Patient QOL-AD showed the most consistent sensitivity-analysis association. Apathy was associated with caregiver burden and caregiver quality of life, but mediation was not established.

DISCUSSION: Caregiver positivity may stratify lecanemab efficacy in AD, supporting psychosocial assessment in personalized, caregiver-inclusive management pathways.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
*Caregivers/psychology
Female
Male
Longitudinal Studies
Aged
China
Aged, 80 and over
Activities of Daily Living
Middle Aged

@article {pmid42947286,
year = {2026},
author = {Kanekiyo, T and White, LJ and Ye, H and Ren, Y and Ulrich, JD and Raulin, AC and Alnobani, A and Xiong, C and Asmann, YW and Vassilaki, M and Algeciras-Schimnich, A and Peng, J and Amtashar, FS and Schindler, SE and Holtzman, DM and Bu, G and Petersen, RC and Heckman, MG and Han, X},
title = {CSF and plasma lipid profiling predicts risk of cognitive impairment in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71924},
pmid = {42947286},
issn = {1552-5279},
support = {U19 AG069701/NH/NIH HHS/United States ; R01 AG061729/NH/NIH HHS/United States ; R01 AG071226/NH/NIH HHS/United States ; R01 AG057181/NH/NIH HHS/United States ; R01 AG068034/NH/NIH HHS/United States ; R01 AG081203/NH/NIH HHS/United States ; U01 AG006786/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; U19 AG102336/NH/NIH HHS/United States ; U19 AG102336/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/blood/cerebrospinal fluid/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Aged ; Male ; Female ; *Lipids/blood/cerebrospinal fluid ; Lipidomics ; Longitudinal Studies ; tau Proteins/cerebrospinal fluid ; Aged, 80 and over ; Lipid Metabolism ; },
abstract = {INTRODUCTION: Age-related cognitive decline and Alzheimer's disease (AD) are strongly influenced by lipid metabolism, yet how central and peripheral lipid profiles relate to disease risk before symptom onset remains unclear.

METHODS: We performed comprehensive shotgun lipidomics in cerebrospinal fluid (CSF) and plasma from cognitively unimpaired older adults, with longitudinal follow-up for Clinical Dementia Rating (CDR) conversion.

RESULTS: CSF lipidomes were primarily associated with age and established CSF AD biomarkers, whereas plasma lipid profiles were strongly influenced by sex. Specific CSF phosphatidylethanolamine subspecies showed robust positive associations with CSF total tau, phosphorylated tau 181, neurogranin, and chitinase-3 like-1. CSF triacylglycerol TAG(C49:6), phosphatidylglycerol PG(18:0-18:1), cholesteryl ester CE(20:3), and phosphatidylethanolamine PE(D16:0-18:1) independently predicted CDR conversion, improving risk prediction. Plasma sphingomyelin subspecies were modestly associated with cognitive decline risk.

DISCUSSION: These findings identify distinct CSF and plasma lipid signatures linked to preclinical cognitive decline and highlight brain lipid metabolism as a promising source of predictive biomarkers and therapeutic targets.},
}

Humans
*Cognitive Dysfunction/blood/cerebrospinal fluid/diagnosis
Biomarkers/cerebrospinal fluid/blood
Aged
Male
Female
*Lipids/blood/cerebrospinal fluid
Lipidomics
Longitudinal Studies
tau Proteins/cerebrospinal fluid
Aged, 80 and over
Lipid Metabolism

@article {pmid42947582,
year = {2026},
author = {Fernandez-Bonet, A and Temprano-Sagrera, G and Genius, P and Rodriguez-Fernandez, B and Domingo-Guell, E and Huguet, J and Buongiorno, M and Sánchez-Benavides, G and Cirach, M and Nieuwenhuijsen, M and de Bruijne, M and Evans, TE and Vilor-Tejedor, N},
title = {EXPRESS: Multidomain determinants of perivascular spaces indicate early cerebrovascular vulnerability in individuals at risk of Alzheimer's disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261503069},
doi = {10.1177/0271678X261503069},
pmid = {42947582},
issn = {1559-7016},
abstract = {BACKGROUND: Perivascular spaces (PVS) are MRI-visible markers of cerebrovascular and glymphatic function, but their regional determinants in preclinical Alzheimer's disease (AD), regarding sex and AD biomarkers, remain poorly understood.

METHODS: We studied 1,199 cognitively unimpaired ALFA study participants (aged 54-65 years), genetically enriched for AD risk, with CSF biomarker phenotyping in 296 participants. PVS were automatically quantified in basal ganglia, centrum semiovale, hippocampus, and midbrain on 3T MRI. Counts were modelled using Poisson or negative binomial regression, adjusting for demographics, cardiometabolic, lifestyle, and genetic factors, with effect modification by sex and amyloid/tau (AT) status.

RESULTS: PVS showed marked regional specificity. Centrum semiovale PVS were associated with age, male sex, and cardiometabolic factors, whereas hippocampal and midbrain PVS were more closely related to AD biomarker status and sleep or psychological measures. Men exhibited higher centrum semiovale burden while women showed higher counts in hippocampus, midbrain, and basal ganglia. Associations were stronger in amyloid-positive individuals with concurrent tau pathology. Polygenic scores for lipid and metabolic traits contributed modestly to regional PVS variation.

CONCLUSIONS: PVS burden is associated with multidomain determinants in preclinical AD with regional, sex-specific, and biomarker-dependent patterns, supporting PVS as accessible MRI markers for risk stratification and precision prevention.},
}

@article {pmid42947687,
year = {2026},
author = {Viola, KL and Chromy, BA and Nowar, R and Lambert, MP and Klein, WL},
title = {Safe and efficient intracellular delivery of functional antibodies into cultured neural cells shows a role for Alzheimer's-relevant tau phosphorylation in cell integrity.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1737082},
pmid = {42947687},
issn = {2813-3919},
abstract = {INTRODUCTION: Protein proteoforms generated by post-translational modification are increasingly recognized as important regulators of neuronal function and neurodegenerative disease. However, methods for acutely interrogating specific intracellular proteoforms in living neuronal populations remain limited. We evaluated cationic liposomal delivery (CLD) as a strategy for introducing full-length functional antibodies into living neurons and used this approach to investigate the role of a phosphorylated tau proteoform recognized by the monoclonal antibody PHF-1.

METHODS: Cationic liposomes composed of DOPC+ were complexed with antibodies or molecular probes and applied to cultured neuronal cell lines and primary mouse cortical neurons. Intracellular delivery, cellular localization, viability, and biological activity were assessed using fluorescence microscopy and live-cell imaging.

RESULTS: CLD efficiently delivered full-length antibodies and molecular probes into living neuronal cells and primary neurons without detectable toxicity. Internalized antibodies retained target specificity, producing intracellular staining patterns consistent with the known localization of tau, vinculin, paxillin, and Fyn. Delivery was observed across essentially all cells in treated cultures and remained effective under standard culture conditions. Intracellular delivery of PHF-1 produced a rapid and striking morphological response characterized by neurite retraction and cell-body rounding within hours of treatment. These effects were not observed with heat-inactivated PHF-1, vehicle controls, or other intracellular antibodies, supporting a specific effect of intracellular engagement of PHF-1-reactive tau species.

DISCUSSION: These findings establish CLD as a practical platform for the intracellular delivery of functional full-length antibodies into living neuronal populations. Beyond validating a delivery technology, the study demonstrates that acute intracellular engagement of PHF-1-reactive phosphorylated tau rapidly alters neuronal morphology, suggesting that this tau proteoform contributes to the maintenance of neurite integrity. CLD provides a versatile approach for probing the function of intracellular proteoforms that are difficult to study using conventional genetic or biochemical methods.},
}

@article {pmid42947719,
year = {2026},
author = {H F, T and Jacob, JE},
title = {Computational approaches to deep learning-driven EEG analysis for neurological disease diagnosis: a systematic review.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1778980},
pmid = {42947719},
issn = {1662-5196},
abstract = {Electroencephalography (EEG) is a widely used non-invasive neurophysiological technique for analyzing brain dynamics and diagnosing neurological diseases. However, the non-stationary nature, low signal-to-noise ratio, and inter-subject variability of EEG signals cause significant challenges to traditional analytical approaches. In recent years, deep learning has emerged as a powerful computational tool for EEG analysis, which enables automated feature learning and improved diagnostic accuracy with minimal human-driven feature extraction. This review systematically explains computational approaches in deep learning-driven EEG analysis for the diagnosis of neurological diseases. It includes recent advances in deep learning architectures, such as convolutional neural networks (CNN), recurrent neural networks (RNN), hybrid configurations, Generative Adversarial Networks (GAN), Large Language Models (LLM), autoencoders, and transformer-based models, with a focus on their capacity to model spatial, temporal, and spatiotemporal dynamics in EEG signals. This is applicable in diagnosing major neurological disorders such as Epilepsy, Alzheimer's disease (AD), Encephalopathy, Parkinson's disease (PD), Mild Cognitive Impairment (MCI), sleep disorders, and developmental brain disorders. Furthermore, we discuss essential preprocessing strategies and denoising techniques, showing how removing biological artifacts prevents diagnostic models from confusing noise with actual signs of disease. Key challenges such as limited data availability, lack of model interpretability, inter-subject variability, and difficulty in clinical translation are identified and critically discussed. Finally, key emerging trends and future research directions are identified to support the development of clinical applications of EEG-based disease diagnostic systems.},
}

@article {pmid42947816,
year = {2026},
author = {Dawson, WD and Canty, AJ and Migeot, J and O'Philbin, L and Gelmon, SB},
title = {Editorial: Innovations in dementia policies and services.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {2006454},
pmid = {42947816},
issn = {2813-3919},
}

@article {pmid42947905,
year = {2026},
author = {Majeed, Z and Majeed, J and Ponce, FA and Mahanti, H and Decourt, B and Burke, AD and Sabbagh, MN},
title = {Deep brain stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261441166},
pmid = {42947905},
issn = {2542-4823},
abstract = {Deep brain stimulation (DBS) is a well-established treatment for neurological disorders, but its efficacy and safety in Alzheimer's disease (AD) remain uncertain. This narrative review synthesizes nine clinical trials in patients with mild to severe AD, focusing on stimulation of the fornix, nucleus basalis of Meynert (NBM), and ventral capsule/ventral striatum. Literature was identified through PubMed using the terms "deep brain stimulation" and "Alzheimer's disease," and the results were restricted to clinical trials and case reports in English, with additional references identified through Google Scholar. Across studies, DBS was safe and well tolerated, with few adverse events. Stimulation produced short-term cognitive improvements, most commonly measured by Alzheimer's Disease Assessment Scale cognitive subscale, along with transient reversal of glucose hypometabolism and activation of memory-related networks. One study reported slowed hippocampal atrophy, suggesting neuroplastic effects. In severe AD, DBS targeting both the fornix and NBM yielded transient cognitive gains, with NBM-DBS showing greater benefit for neuropsychiatric symptoms and caregiver burden. Patients with higher baseline cognition and glucose metabolism responded more favorably to DBS. Age-related differences emerged: younger patients (<65 years old), with earlier onset and more aggressive progression, showed less favorable responses to DBS targeting the fornix, whereas older patients (≥65 years old) had comparatively better outcomes. Despite these benefits, DBS does not halt disease progression or reverse AD pathology. Larger, biomarker-stratified, sham-controlled trials with extended follow-up are needed to clarify durability, identify optimal patient subgroups, and determine the most effective stimulation targets.},
}

@article {pmid42947965,
year = {2026},
author = {Han, S and Wang, S and Liu, J and Liu, X and Wang, Q and Meng, C},
title = {Dynamic remodeling of microglial responses in Alzheimer's disease: heterogeneous states, spatiotemporal progression, and immunometabolic dysregulation.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1929282},
pmid = {42947965},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) is characterized by progressive neuroinflammation involving microglia whose functional responses extend far beyond the classical M1/M2 framework and form a dynamically heterogeneous continuum. Here, we review recurrent disease-associated microglia (DAM) states and transcriptional programs, including DAM-associated, interferon-responsive, cytokine-responsive, proliferative, antigen-presentation-associated, and lipid-associated features, emphasizing that these labels do not necessarily represent fixed or mutually exclusive cellular subtypes. Across AD progression, the relative engagement and functional consequences of these programs vary according to Aβ and tau burden, local microenvironment, genetic background, metabolic status, and disease stage. DAM-associated programs may support phagocytosis and plaque containment in some contexts, whereas persistent inflammatory and metabolic stress can increase lipid dysregulation, mitochondrial dysfunction, impaired phagocytic competence, and inflammatory signaling in subsets of microglia. Microglia also exert bidirectional effects on tau pathology. Core AD risk pathways, including TREM2 and APOE, together with immunometabolic remodeling, shape microglial plasticity in a context-dependent manner. We discuss the implications of this dynamic framework for stage- and state-aware therapeutic strategies and highlight the need to integrate single-cell, spatial, and multi-omic approaches to resolve microglial trajectories and functional states in human AD.},
}

@article {pmid42947971,
year = {2026},
author = {Chigriai, M and Kraskovskaya, N and Bolshakova, A and Porozova, NO and Porozov, YB and Pešić, M},
title = {PP2A targeting: balancing anticancer potential and neurological risk.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1945801},
pmid = {42947971},
issn = {2296-634X},
abstract = {Protein phosphatase 2A (PP2A) is a multifunctional serine/threonine phosphatase that regulates cell-cycle progression, oncogenic signaling, neuronal development, synaptic homeostasis, and protein proteostasis. Its dysregulation contributes to cancer, whereas impaired PP2A activity in the nervous system is linked to neurodevelopmental disorders and neurodegenerative proteinopathies, including tau and α-synuclein pathology. These divergent roles create both opportunities and safety challenges for PP2A-directed therapies. This review examines PP2A as a modular holoenzyme system whose subunit composition determines substrate specificity and context-dependent biological effects. We discuss PP2A dysfunction in cancer, including genetic and regulatory alterations affecting PP2A subunits, assembly, and endogenous inhibitors, and compare therapeutic PP2A activation with transient inhibition. The latter approach is exemplified by LB100, which sensitizes treatment-stressed tumor cells to chemotherapy, radiotherapy, or immunotherapy by disrupting checkpoint adaptation and stress recovery. We further evaluate the neurological implications of systemic phosphatase inhibition, LB100 conversion to the active metabolite endothall, clinical safety and pharmacokinetic data, and the limited brain-tumor penetration of intact LB100. We propose that the clinical utility of PP2A inhibition depends on defining a therapeutic corridor that integrates dosing schedule, parent-drug and metabolite exposure, tumor target engagement, biomarker-informed patient selection, and preservation of PP2A-dependent homeostasis in normal tissues, particularly the nervous system.},
}

@article {pmid42947982,
year = {2026},
author = {Lozano, R and Lin, X and Hagerman, R and Martínez-Cerdeño, V and Pinto, D},
title = {DNA methylation and proteomic profiling of postmortem brain tissue reveals epigenetic dysregulation and inflammatory signaling in fragile X-associated tremor/ataxia syndrome.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1932396},
pmid = {42947982},
issn = {1662-5099},
abstract = {BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a CGG repeat expansion in the premutation range of FMR1. The epigenetic landscape of the FXTAS brain remains largely uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex and targeted proteomic profiling to investigate molecular alterations associated with FXTAS and evaluate convergence on inflammatory signaling.

METHODS: DNA methylation was profiled in postmortem prefrontal cortex from 27 male FXTAS cases and 29 male controls using Illumina MethylationEPIC arrays. Surrogate variable analysis was used to account for latent sources of variation. Differentially methylated positions (DMPs) were defined as well as differentially methylated regions (DMRs). Exploratory functional analyses and comparison with published FXTAS transcriptomic and neurodegenerative-disease methylation datasets. Targeted proteomic profiling using the Olink Inflammation panel was performed in 9 male FXTAS cases and 12 male controls.

RESULTS: We identified 98 DMPs which mapped to 70 genes. Notable DMP-associated genes included CYP2E1, related to oxidative stress; TRAF3, BATF, RCOR1, and MSI2, with roles in immune and NF-κB-related signaling; and genes associated with myelination (LINGO1), synaptic function (SYT3), and zinc homeostasis (SLC39A4). TRAF3, a negative regulator of NF-κB and type I interferon signaling, contained one of the most significant DMPs. Exploratory Reactome analysis highlighted biological themes related to inflammatory resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism, although no pathway remained significant after multiple-testing correction. Transcription-factor motif enrichment and protein-protein interaction analyses identified no significant higher-order regulatory or interaction modules. Seven DMP-associated genes overlapped with differentially expressed genes from an independent FXTAS mouse transcriptomic study, whereas no gene-level overlap was detected with the Alzheimer's, Parkinson's, or Huntington's disease methylation signatures examined. Olink profiling identified 60 significantly altered inflammation-related proteins, 59 of which showed lower abundance in FXTAS, including TLR3, IRAK1, IRAK4, IKBKG/NEMO, and C1QA.

CONCLUSION: These findings identify previously unrecognized DNA methylation alterations in FXTAS prefrontal cortex involving genes related to oxidative stress, myelination, zinc homeostasis, and innate immune/NF-κB signaling. Convergence between methylation changes in immune-regulatory genes, including TRAF3, and a predominantly reduced inflammatory protein signature provides complementary evidence for altered inflammatory signaling in FXTAS.},
}

@article {pmid42947994,
year = {2026},
author = {Islam, K and Hossen, B and Manjar, MTA and Sultana, S},
title = {ConvNeXt-KAN: a Kolmogorov-Arnold Network head for robust multi-class staging of Alzheimer's disease from brain MRI.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1903281},
pmid = {42947994},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which accurate, stage-wise classification from structural magnetic resonance imaging (MRI) can support earlier intervention. Convolutional neural networks (CNNs) dominate this task, but their classifier heads rely on fixed activation functions and linear weights, which constrain the modelling of the subtle, highly non-linear atrophy and texture patterns that separate dementia stages. In addition, the widely used Open Access Series of Imaging Studies (OASIS) collection is severely imbalanced, and two common practices-undersampling every class to the smallest one, and splitting at the image (slice) level-respectively discard most of the data and inflate reported accuracy.

METHODS: We propose ConvNeXt-KAN, a hybrid model that couples a transfer-learned ConvNeXt-Tiny feature extractor with a Kolmogorov-Arnold Network (KAN) classification head whose edges are learnable spline activations implemented efficiently with Gaussian radial basis functions. The model is trained with a robustness-oriented recipe (MixUp and CutMix, label smoothing, decoupled weight decay, a cosine learning-rate schedule with warm-up, and test-time augmentation) and a data strategy that caps abundant classes and oversamples only the training partition, while evaluating on a fixed, balanced, leakage-controlled test set.

RESULTS: On the held-out test set the model attains 94.5% accuracy, a macro-averaged F1 of 0.944, and a mean one-vs.-rest ROC-AUC of 0.991, with an ablation confirming that pre-trained features and expanded data are the main drivers of performance. A head-to-head comparison under a matched protocol shows that the KAN and MLP heads are statistically indistinguishable (McNemar p = 0.52), while the proposed image-space resampling strategy outperforms focal loss, class-balanced cross-entropy and feature-space SMOTE. Evaluated without any fine-tuning on an independent four-class Alzheimer's MRI collection distributed on Kaggle, test-time-augmented accuracy is 61.6% with a macro-averaged F1 of 0.565.

DISCUSSION: The learnable-activation head improves the discrimination of the difficult non-demented vs. very-mild-demented boundary at negligible runtime cost, and the efficient formulation keeps the approach practical in standard deep-learning frameworks. A class-wise analysis of the external evaluation shows that moderate dementia continues to be recognized perfectly while the two clinically intermediate stages absorb most of the domain-shift error. We further quantify the impact of the evaluation protocol and argue that subject-level validation and multi-site external testing are essential before clinical claims.},
}

@article {pmid42948010,
year = {2026},
author = {Gao, Z and Ren, M and Yang, R and Yu, J},
title = {Bipolar disorder and risk of all-cause and specific dementia: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1980508},
pmid = {42948010},
issn = {1663-4365},
abstract = {BACKGROUND: Bipolar disorder (BD) is associated with cognitive impairment and an increased risk of dementia; however, the magnitude of this association and subtype-specific risk patterns remain unclear. This systematic review and meta-analysis quantified the associations between BD and the risks of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD), and explored potential sources of between-study heterogeneity.

METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to September 15, 2026. Eligible cohort and case-control studies reported adjusted effect estimates for the association between BD and dementia. Hazard ratios and odds ratios were converted to risk ratios (RRs) prior to quantitative synthesis. Random- or fixed-effects models were applied according to heterogeneity. Leave-one-out sensitivity analyses, Egger's test for publication bias, and subgroup analyses stratified by follow-up duration, sex, age at BD onset, and study design were conducted.

RESULTS: Eleven studies involving 1,536,508 participants and 90,864 all-cause dementia cases were included. BD was associated with an increased risk of all-cause dementia (RR = 3.55, 95% CI 2.48-5.07; I[2] = 98.7%), AD (RR = 5.08, 95% CI 1.87-13.84; I[2] = 97.2%), and VaD (RR = 4.33, 95% CI 3.06-6.13; I[2] = 71.7%). Estimates for all-cause dementia and VaD were robust in sensitivity analyses, whereas the AD estimate was sensitive to the exclusion of individual studies and should therefore be interpreted cautiously. The association between BD and increased dementia risk was observed across the examined subgroups. Formal tests for subgroup differences showed no statistically significant differences according to sex or age at BD onset.

CONCLUSION: BD is associated with an increased risk of all-cause dementia, AD, and VaD. However, substantial between-study heterogeneity and the limited evidence available for specific dementia subtypes warrant cautious interpretation of the pooled estimates. Further high-quality longitudinal studies are needed to clarify the factors underlying heterogeneity and subtype-specific associations.

https://www.crd.york.ac.uk/prospero/, identifier [CRD420261395626].},
}

@article {pmid42948024,
year = {2026},
author = {Kim, J and Jeong, SY and Lee, SW and Yoon, U and Kang, K},
title = {Altered hippocampal morphology and its association with gait impairment in idiopathic normal-pressure hydrocephalus.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1914240},
pmid = {42948024},
issn = {1664-2295},
mesh = {Humans ; *Hydrocephalus, Normal Pressure/diagnostic imaging/complications/pathology/physiopathology ; *Hippocampus/diagnostic imaging/pathology ; Female ; Male ; Magnetic Resonance Imaging ; Aged ; *Gait Disorders, Neurologic/etiology/diagnostic imaging/pathology/physiopathology ; Positron-Emission Tomography ; Aged, 80 and over ; },
abstract = {UNLABELLED: Background and purpose: This study aimed to characterize structural alterations of the hippocampus associated with idiopathic normal-pressure hydrocephalus (INPH), and to explore their relationship with gait disturbances in affected patients.

METHODS: A total of 48 patients with INPH and 25 β-amyloid-negative healthy controls underwent MRI-based, vertex-wise three-dimensional hippocampal shape analysis. Additionally, all participants received 18F-florbetaben positron emission tomography to assess amyloid status.

RESULTS: Hippocampal shape analysis revealed marked bilateral deformation in the INPH group compared to controls. Both hippocampi exhibited elongation and narrowing, with the middle and posterior regions showing upward curvature, indicating vertical displacement from the hippocampal body to the tail. The normalized hippocampal volume was significantly smaller in INPH patients. No substantial volumetric or morphological differences were observed between amyloid-positive and amyloid-negative individuals within the INPH group. Notably, localized shape deformities correlated with performance on the Timed Up and Go and 10-meter walk tests, more prominently in the right hippocampus. Bilateral inward deformations at the superomedial tail and inferior body of the hippocampus were consistently linked to worse gait performance. Furthermore, smaller right normalized hippocampal volumes were negatively associated with gait test outcomes.

CONCLUSION: These findings indicate that INPH is associated with characteristic hippocampal shape abnormalities. The observed associations between hippocampal morphology and gait disturbances suggest that the hippocampus may contribute to gait and postural control in INPH.},
}

Humans
*Hydrocephalus, Normal Pressure/diagnostic imaging/complications/pathology/physiopathology
*Hippocampus/diagnostic imaging/pathology
Female
Male
Magnetic Resonance Imaging
Aged
*Gait Disorders, Neurologic/etiology/diagnostic imaging/pathology/physiopathology
Positron-Emission Tomography
Aged, 80 and over

@article {pmid42948155,
year = {2026},
author = {Koukoura, A and Antonopoulou, K and Tsolakis, AC and Solomon, A and Tsolaki, M and Froelich, L and Tsolaki, A and Papadaki, E and Vassiliadis, E and Holst, GJ},
title = {Perspectives on plasma biomarkers for point-of-care diagnostics in Alzheimer's disease: Insights into 2D-BioPAD.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261437790},
pmid = {42948155},
issn = {2542-4823},
abstract = {We investigated the potential of plasma biomarkers for point-of-care in vitro diagnostics in Alzheimer's disease by collecting insights from 99 stakeholders primarily from Greece, including patients, caregivers, healthcare professionals, and researchers. Data from an online survey was analyzed using descriptive statistics and thematic analysis. Key biomarkers reported by participants included Aβ40, Aβ42, pTau181, pTau217, and neurofilament light chain. While biomarkers were recognized for their value in prognosis, diagnosis, and monitoring, most participants were unfamiliar with point-of-care in vitro diagnostics. Major concerns regarding implementation included cost, reimbursement, and accessibility, underscoring the need for more feasible and context-appropriate diagnostic solutions.},
}

@article {pmid42948157,
year = {2026},
author = {Teng, Z and Hu, M and Zhang, Z and Zhou, M and Yin, P and , },
title = {Heterogeneous progression of AT(N) biomarkers in data-driven subtypes of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1902282},
pmid = {42948157},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) exhibits substantial heterogeneity in brain atrophy patterns and progression rates. Data-driven subtyping based on the Subtype and Stage Inference (SuStaIn) model has identified distinct MRI-derived subtypes, but the longitudinal dynamics of these subtypes within the AT(N) framework remain unknown.

METHODS: This study included 1,576 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with at least two visits. SuStaIn was applied to volumetric measurements of 11 brain regions to identify imaging-based subtypes. Within each subtype, we fitted a Bayesian latent time longitudinal joint mixed-effects model incorporating six biomarkers: amyloid PET (A), CSF p-tau (T), hippocampal volume, cingulate volume, thalamic volume (N), and ADAS-Cog13 (X), with APOE ε4 as a covariate.

RESULTS: The three subtypes exhibited distinctly different longitudinal patterns. Subtype 1 showed early elevation of amyloid, followed by a sharp decline in hippocampal volume, which was tightly coupled with cognitive deterioration. Subtype 2 featured early involvement of cortical regions such as the cingulate cortex, with hippocampal changes occurring at a similar timing to Subtype 1 but accompanied by earlier cortical and thalamic involvement. Subtype 3 exhibited early rapid hippocampal atrophy that later plateaued, and demonstrated the strongest hippocampus-cognition coupling. The association of APOE ε4 with biomarker trajectories was subtype-dependent: its effect estimates were largest for amyloid and p-tau in Subtype 1, whereas in Subtype 3 the effect estimates were significant for nearly all biomarkers, with the largest estimate for cognition.

CONCLUSION: This study demonstrates that AD subtypes defined by spatial atrophy patterns also differ fundamentally in temporal biomarker dynamics and APOE ε4 association, supporting subtype-stratified modeling of disease progression.},
}

@article {pmid42948203,
year = {2026},
author = {Iwasa, K and Omori, N and Ishida, M and Tanaka, T and Nagai, A},
title = {Digital completion time relates more strongly to Alzheimer's disease-type atrophy than to vascular burden in a community cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70526},
pmid = {42948203},
issn = {2352-8729},
abstract = {INTRODUCTION: Slowing on digital cognitive testing may reflect Alzheimer's disease (AD)-type atrophy, small-vessel disease, or both. Single-outcome studies cannot determine whether slowing preferentially reflects one type of brain change or general brain health. We tested whether response-time features from the tablet-based Cognitive Assessment for Dementia, iPad version 2 (CADi2) were more strongly associated with AD-type atrophy than with vascular burden.

METHODS: In 1163 community-dwelling adults undergoing brain-health screening (Izumo cohort, 2019-2025), CADi2 response-time features predicted two primary MRI markers from one framework under repeated nested cross-validation: Alzheimer's disease likelihood score (ADLS; similarity to an AD-type atrophy pattern) and normalized white matter lesion (WML) volume. The primary metric was the incremental observed-predicted correlation (ΔR) over age and sex. Silent brain infarcts, microbleeds, and a composite small vessel disease score were additional vascular outcomes.

RESULTS: CADi2 features improved prediction of ADLS (ΔR = +0.054, 95% confidence interval [CI] +0.010 to +0.095) but not WML (ΔR = -0.006). The improvement reflected completion time, not accuracy. Because predictive headroom differed, we repeated the comparison in residual space. There, the increment correlated about twice as strongly with ADLS as with WML (r = 0.160 vs. 0.080; p = 0.044), although both remained significant. A parallel contrast against the composite vascular score gave Δr = 0.100 (p = 0.008).

DISCUSSION: Digital completion time was preferentially, but not exclusively, associated with AD-type atrophy (neurodegeneration axis) relative to vascular burden. Because ADLS indexes an atrophy pattern rather than amyloid or tau pathology, these cross-sectional findings characterize a structural phenotype.},
}

@article {pmid42948208,
year = {2026},
author = {Li, L and Yu, Y and Fan, J and Zhang, N and Yang, J and Li, H and Zheng, J},
title = {Multifaceted neuroprotection of ginsenosides: Mechanisms, nano-delivery advances, and therapeutic potential in central nervous system disorders.},
journal = {Journal of ginseng research},
volume = {50},
number = {6},
pages = {101149},
pmid = {42948208},
issn = {1226-8453},
abstract = {BACKGROUND: Central nervous system (CNS) diseases remain therapeutic challenges due to complex pathology and poor drug penetration across the blood-brain barrier (BBB). Ginsenosides, the active components of Panax ginseng, possess multi-target neuroprotective properties but exhibit low bioavailability.

PURPOSE: This review synthesizes current evidence on ginsenoside mechanisms and evaluates the role of nanotechnology in enhancing their delivery and efficacy for CNS disorders.

STUDY DESIGN: A systematic search was conducted following PRISMA guidelines across PubMed, Web of Science, CNKI, and Google Scholar (2015-present). Included studies investigated ginsenosides in neurological disease models and nano-formulation strategies.

RESULTS: Ginsenosides modulate neuroinflammation, oxidative stress, apoptosis, and calcium homeostasis through pathways involving NF-κB, Nrf2, and Bcl-2/Bax. Nano-delivery systems-such as liposomes, polymeric nanoparticles, and biomimetic vesicles-significantly improve ginsenoside stability, BBB traversal, and brain-targeted accumulation. Functionalization with ligands (e.g., Angiopep-2) or cell membranes further enhances specificity and therapeutic outcomes in ischemic stroke, glioma, Alzheimer's disease, and spinal cord injury models.

CONCLUSION: Nanotechnology-based delivery systems potently augment the neuroprotective potential of ginsenosides, offering a promising strategy for multi-target CNS therapy. Future efforts should focus on translational safety, scalable production, and clinical validation.},
}

@article {pmid42948220,
year = {2026},
author = {Choe, YM and Kim, JH and Choi, HJ and Suh, GH and Lee, BC and Kim, HS and Kim, JW and Kim, SG and Hwang, J and Yi, D and Kim, JW},
title = {Association of ginseng intake and serum zinc with Alzheimer's disease-related cognition.},
journal = {Journal of ginseng research},
volume = {50},
number = {6},
pages = {101119},
pmid = {42948220},
issn = {1226-8453},
abstract = {OBJECTIVE: Ginseng intake and zinc homeostasis are potential protective factors against Alzheimer's disease (AD), but their interrelationship in cognition remains unclear. This study examined the association of ginseng intake and serum zinc with AD-related cognitive function in older adults.

METHODS: We conducted a cross-sectional study of 160 community-dwelling older adults. Ginseng intake was assessed through structured interviews, and serum zinc levels were measured by inductively coupled plasma-mass spectrometry. Cognitive function, focusing on delayed episodic memory (an early AD-related marker) and non-memory cognition, was assessed using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K) neuropsychological battery. Multiple linear regression analyses were conducted to evaluate independent predictors.

RESULTS: Ginseng intake was significantly associated with higher serum zinc levels (P = 0.002) and better delayed episodic memory (P = 0.005). Higher serum zinc levels were also significantly associated with better delayed episodic memory (P = 0.023) in separate regression models. However, in a simultaneous model including both ginseng and serum zinc, ginseng intake remained a significant independent predictor of delayed episodic memory (P = 0.017), whereas the association between zinc and memory was attenuated.

CONCLUSION: Ginseng intake was associated with better AD-related memory in older adults and may be related to the zinc pathway as an upstream factor. These findings suggest that ginseng may be associated with higher zinc bioavailability while also showing associations with memory that appear independent of zinc homeostasis, supporting its potential value as a nutritional strategy for maintaining cognitive function in early AD.},
}

@article {pmid42948355,
year = {2026},
author = {Li, M and Zhang, Y and Lü, P and Li, J and Zhang, Y and Wang, S and Bai, Y and Wang, Y},
title = {Emerging roles of apolipoprotein E4 in cerebral small vessel disease-related cognitive impairment: mechanistic insights and therapeutic perspectives.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1957032},
pmid = {42948355},
issn = {1662-5161},
abstract = {Cerebral small vessel disease (CSVD) is a major contributor to cognitive decline and vascular cognitive impairment in the elderly. However, the extent to which apolipoprotein E4 (ApoE4) contributes to sporadic, non-amyloid CSVD remains unclear. Previous literature has often inferred CSVD mechanisms from Alzheimer's disease (AD) research, carrying the risk of overstating disease-specific causal relationships. Therefore, this narrative review re-evaluates the relationship between ApoE4 and CSVD using a CSVD-centric hierarchy of evidence. Population-based imaging and epidemiological data suggest that "APOE" ε4 may alter susceptibility to white matter injury and cognitive impairment; however, the effect sizes are generally small or context-dependent, and associations are influenced by factors such as age, hypertension, diabetes, total vascular risk burden, AD pathology, ancestry, sex, and "APOE" gene dosage. Evidence is stronger for cerebral amyloid angiopathy (CAA)-which involves mechanisms distinct from sporadic arteriolosclerotic CSVD-and thus warrants separate discussion. At the mechanistic level, direct evidence regarding CSVD supports endothelial dysfunction, BBB leakage, neurovascular unit (NVU) instability, and white matter injury as core pathological processes. Among the evidence specific to ApoE4, models involving impaired neurovascular regulation and chronic hypoperfusion are the most compelling; conversely, mechanisms such as the cyclophilin A-MMP-9 pathway, TREM2-ApoE signaling, insulin receptor trafficking, reelin-related synaptic effects, endoplasmic reticulum stress, and autophagy currently rely primarily on AD research or preclinical evidence. Two recently proposed specific hypotheses-the brain-heart-kidney axis hypothesis and the microglial lipid droplet model-offer valuable conceptual frameworks but should be viewed as testable theories rather than established mechanisms. To date, no ApoE4-targeted therapies have been proven effective for CSVD-related cognitive impairment future research should prioritize genotype-stratified longitudinal CSVD cohorts, standardized imaging studies, adjustment for Alzheimer's disease (AD) biomarkers, analysis of interactions between vascular risk factors, studies on human white matter tissue, and the development of ApoE4 disease models that integrate chronic hypoperfusion and vascular comorbidities.},
}

@article {pmid42948602,
year = {2026},
author = {Choi, HJ and Choe, YM and Kim, JH and Suh, GH and Lee, BC and Hwang, J and Kim, SG and Kim, HS and Yi, D and Kim, JW},
title = {Panax ginseng in psychiatric disorders: Mechanisms and therapeutic potentials.},
journal = {Journal of ginseng research},
volume = {50},
number = {6},
pages = {101151},
pmid = {42948602},
issn = {1226-8453},
abstract = {Panax ginseng C.A. Meyer is a traditional medicinal herb with a long-standing history as a tonic and adaptogen. Accumulating evidence suggests its therapeutic potential for enhancing mood and cognition, as well as mitigating stress-related psychiatric conditions. This comprehensive review assesses the neuropharmacological mechanisms and potential therapeutic effects of Panax ginseng in psychiatric disorders, based on preclinical and clinical data. Ginseng and its active constituents, particularly ginsenosides, modulate key neurotransmitter systems-including serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid-while exerting neuroprotective, anti-inflammatory, and antioxidant effects. Furthermore, it plays a crucial role in regulating the hypothalamic-pituitary-adrenal axis and stress responses. Preclinical models have shown antidepressant and anxiolytic properties comparable to conventional pharmacotherapies, alongside pro-cognitive and neuroprotective actions. Although clinical evidence remains emerging, existing studies indicate potential benefits for depression, anxiety, and cognitive impairment, specifically improving symptoms in patients with Alzheimer's disease and schizophrenia. Consequently, Panax ginseng may hold promise as an adjunctive therapy for various psychiatric disorders. Its multimodal mechanisms-encompassing monoamine modulation, neurotrophic support, and adaptogenic stress reduction-provide a rationale for its clinical application. Nonetheless, rigorous large-scale clinical trials are essential to confirm efficacy, determine optimal dosing, and ensure safety.},
}

@article {pmid42948702,
year = {2026},
author = {Yin, J and Lv, W and Zhao, W and Ding, Z and Zhu, F and Liu, H and Li, S and Cao, X and Liu, L and Song, K and Gong, Y and Xu, J and Chen, Y and Zhang, Z and Fang, X and Xin, H},
title = {Lysosomal membrane damage repair and acidification impairment restoration triggered by smart lipid nanoparticles for Alzheimer's disease treatment.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {10},
pages = {7037-7053},
pmid = {42948702},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), characterized by amyloid (Aβ) deposition in neurons, is the most serious neurodegenerative disorder, but lacks effective therapeutic drugs in the clinic. Impaired neuronal lysosomal function drives the pathological accumulation of intracellular Aβ. Targeted rehabilitation of lysosomal dysfunction may offer a potential strategy to restore neuronal homeostasis and mitigate AD progression. In this study, we developed a brain-targeted smart lipid nanoparticle (A-PSL@7BIO) to repair lysosomal membrane damage and restore impaired acidification in the brain for AD therapy. The system was composed of Angiopep-2 peptide-conjugated lipid nanoparticles, which were loaded with a Glycogen synthase kinase-3β (GSK-3β) inhibitor 7-bromoindirubin-3'-oxime (7BIO) and incorporated with dipalmitoyl-phosphatidylserine (DPPS) and a reactive oxygen species (ROS) responsive phospholipid. Through Angiopep-2-mediated blood-brain barrier (BBB) transcytosis, the smart lipid nanoparticles could enhance brain biodistribution with subsequent neuronal internalization. Pathologically elevated intracellular ROS levels in AD could induce stimulus-responsive payload release, wherein 7BIO selectively inhibited aberrant GSK-3β hyperphosphorylation to restore the physiological acidic lysosomal environment and DPPS structurally repaired compromised lysosomal membranes, synergistically addressing dual aspects of lysosomal pathology. This smart lipid nanoparticles synergistically restored physiological lysosomal homeostasis, reversed neuronal dysfunction, and ameliorated cognitive deficits in AD models, indicating that A-PSL@7BIO could be used as a potential nanomedicine for AD therapy.},
}

@article {pmid42948713,
year = {2026},
author = {Zhang, Q and Gong, X and Liu, H and Yao, X},
title = {Application of computational methods in the drug discovery and development of Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {10},
pages = {6526-6552},
pmid = {42948713},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder marked by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive decline. As the most common dementia, AD affects over 50 million individuals worldwide, with 10 million new cases each year. Despite many significant progresses in AD research fields, there is still no effective treatment. Advances in molecular modelling and artificial intelligence (AI) algorithm have facilitated the application of computational methods in AD drug development, offering advantages in terms of efficiency, cost-effectiveness, and resource conservation. These strategies, including molecular docking, molecular dynamics simulation, protein structure prediction, virtual screening, and de novo drug design, have been widely employed in the past decades. Additionally, AI pharmaceutical companies have revolutionized the traditional drug development pipeline such as AD biomarker discovery, accurate diagnosis and precision medicine, etc. This review offers a thorough summary of recent progresses in computational-based methodologies in the study of AD drug development, including the elucidation the pathological mechanism at the molecular level, target identification, target 3D structure prediction, lead compound discovery, de novo molecular generation, multi-target directed ligands, drug repurposing, biomarker discovery, etc., showing promising applications of molecular modelling and AI in the development of AD therapy.},
}

@article {pmid42948724,
year = {2026},
author = {Yao, W and Su, L and Lu, Z and Chen, J and Duan, L and Meng, X and Wan, H and Chen, S and Mi, Y and Ji, A},
title = {Genomic characterization of AP2/ERF transcription factors related to cannabinoids biosynthesis in Cannabis sativa.},
journal = {Chinese herbal medicines},
volume = {18},
number = {4},
pages = {1056-1066},
pmid = {42948724},
issn = {2589-3610},
abstract = {OBJECTIVE: Cannabinoids, secondary metabolites produced by Cannabis sativa (cannabis), have various pharmacological effects, such as anti-inflammatory and analgesic effects, and they can be used in the treatment of Alzheimer's disease. Although the biosynthetic pathway of cannabinoids has been elucidated, relatively few reports about the transcription factors involved in this pathway exist. APETALA2 (AP2)/ethylene-responsive factor (ERF) transcription factor (TF) families play an important role in plant growth and secondary metabolism.

METHODS: APETALA2 (AP2)/ethylene-responsive factor (ERF) transcription factor (TF) family was identified in cannabis plants via phylogenetic analysis, chromosomal distribution, gene structure, conserved motif identification, synteny analysis, alternative splicing event identification, response element prediction, and gene expression analysis.

RESULTS: A total of 111 AP2/ERF members belonging to the APETALA2 subfamily (17 genes), dehydration-responsive element-binding proteins subfamily (39 genes), and ethylene-responsive factor subfamily (53 genes), related to the ABI3/VP1 subfamily (two genes), exist in cannabis. Based on the expression profiles of AP2/ERFs in the genome, quantitative real-time PCR (qRT-PCR) detection and coexpression analysis results, the functional genes of six TFs were clustered with those of other species, and two gene clusters are speculated to be related to cannabinoid biosynthesis. A total of six CsERF proteins were found to be located in the cell nucleus by subcellular localization detection. CsERF02 and CsERF19 exhibited transcriptional activation activity through the AH109 yeast system.

CONCLUSION: CsERF02, CsERF05, CsERF18, CsERF19, CsERF21, CsERF46 and two gene clusters may function in cannabinoid biosynthesis. These results contribute to the characterization of functional AP2/ERF family members in cannabis and lay a foundation for regulating cannabinoid content through metabolic pathways.},
}

@article {pmid42948807,
year = {2026},
author = {Rice, JA and Bouteiller, JC and Khachaturian, AS},
title = {Integrating cure and care in Alzheimer's disease: a systems perspective for precision medicine.},
journal = {Frontiers in molecular medicine},
volume = {6},
number = {},
pages = {1960763},
pmid = {42948807},
issn = {2674-0095},
abstract = {Alzheimer's disease remains a major global health challenge, with limited disease-modifying therapies and a rapidly growing societal burden. Although amyloid and tau remain central to the field, current evidence also implicates neuroinflammation, immune dysregulation, vascular dysfunction, and host-microbe interactions in disease pathogenesis. These developments support a broader systems framework, but simply combining additional disciplines or data modalities does not by itself preserve the dynamic biology or lived experience of disease. Artificial intelligence multi-omics, and digital biomarkers can help identify clinically meaningful patterns only when data and models preserve relevant structure across time, scale, context, and uncertainty. Realizing this potential will require responsible international data sharing, interoperable infrastructure, explicit evidence provenance, and ethical governance grounded in FAIR principles, context-appropriate explainability, and privacy-preserving approaches such as federated learning. Scientific progress should therefore be measured not only by disease modification, but also by patterns of cognition, behavior, function, quality of life, and caregiver burden. This Perspective argues that cure and care are not competing or merely parallel priorities; they are linked outputs of the same continuously learning research and care ecosystem.},
}

@article {pmid42948835,
year = {2026},
author = {Li, S and Huang, L and Guo, Q},
title = {Blood-Based Biomarkers in Alzheimer's Disease: Advances in Detection Technologies and Clinical Applications.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {},
number = {},
pages = {},
pmid = {42948835},
issn = {2475-0360},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder. Irreversible pathological alterations are already present when clinical symptoms emerge. Therefore, early diagnosis and intervention are crucial for improving patient outcomes and reducing the social and healthcare burden. With its advantages of minimal invasiveness, convenience, affordability, and high accessibility, blood-based testing has overcome the limitations of conventional methods, becoming a major focus of research in early AD diagnosis in recent years. Based on the key domestic and international research findings in recent years, this paper systematically reviews the types, mechanisms of action, and relevant detection technologies of blood-based biomarkers for AD.},
}

@article {pmid42948999,
year = {2026},
author = {Mankoo, OK and Priyadarshi, N and Singh, PP and Goyal, B and Singhal, NK and Goyal, D},
title = {Unraveling the synergistic potential of naringenin as an Aβ fibrillation inhibitor with metal chelating and antioxidant properties.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp01611a},
pmid = {42948999},
issn = {1463-9084},
abstract = {Alzheimer's disease (AD) is a fatal, multifaceted degenerative brain disorder characterized by amyloid-β (Aβ) fibrillation leading to the formation of neurotoxic oligomers and fibrils, metal ion dysregulation, and oxidative stress, all of which contribute to its pathophysiology. Naringenin (NAR), a flavonoid isolated from citrus fruits, has been identified as a potential therapeutic agent for AD, due to its ability to cross the blood-brain barrier (BBB) and modulate key pathogenic processes. In this work, the synergistic potential of NAR to modulate Aβ42 fibrillation, disaggregate preformed Aβ42 fibrils, metal-induced Aβ42 fibrillation, and oxidative stress was examined using various biophysical techniques. Notably, NAR effectively inhibits Aβ42 fibrillation (96.6 ± 0.2% inhibition at a 1 : 4 ratio of Aβ42 : NAR), with an IC50 value of 9.62 ± 0.14 µM, and disrupts preformed Aβ42 fibrils by 85.1 ± 1.0%. NAR shows antioxidant properties and thus halts the formation of reactive oxygen species (ROS). Notably, NAR restored 94.1 ± 4.7% of the tyrosine fluorescence at 20 µM concentration, suggesting its potential to extract metal from the Aβ42-Cu[2+] complex and thus mitigate Cu[2+]-induced Aβ42 toxicity. Importantly, at doses up to 100 µM, NAR shows nearly 90% cell viability in PC12 cells, highlighting its safety profile and alleviating the cytotoxicity induced by Aβ42 aggregates. Furthermore, molecular dynamics (MD) simulations highlighted favourable binding of NAR to Aβ42 protofibrils (ΔGfit = -12.85 ± 1.21 kcal mol[-1]), resulting in overall structural deformation of the anti-parallel β-sheet-rich Aβ42 protofibrils. Importantly, NAR-induced lowering in the β-sheet content with an associated rise in the coil content was noted in the Aβ42 protofibrils, consistent with ThT, CD, and TEM assays depicting NAR-mediated disassembly of pre-existing Aβ42 fibrils. The study highlights the potential of NAR as a multifunctional ligand, targeting Aβ42 fibrillation, metal-induced Aβ42 fibrillation, and oxidative stress. Furthermore, MD simulations in this work illuminated the molecular mechanism by which NAR disrupts the Aβ42 protofibril structure, which will provide key insights into the rational design and development of potent therapeutics against the disruption of neurotoxic β-sheet-rich Aβ42 aggregates in AD.},
}

@article {pmid42949022,
year = {2026},
author = {Shah, RC and Borson, S and Luchsinger, JA},
title = {Using the 4Cs of Primary Care to Ensure Timely Diagnosis of Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000759},
pmid = {42949022},
issn = {1546-4156},
support = {//Novo Nordisk, Inc./ ; },
abstract = {BACKGROUND: Disease-modifying treatment is available for patients diagnosed with early symptomatic Alzheimer disease [AD, mild cognitive impairment (MCI), and mild dementia]. Recognition and diagnosis of MCI and dementia occur every day in the primary care setting, but diagnostic challenges and delays are common. Over 90% of MCI cases are missed, and more than half of AD diagnoses occur when the disease is in the moderate or advanced stage, when crises and emergencies are more likely to occur.

DISCUSSION: Diagnostic delays limit opportunities to organize and implement proactive, comprehensive patient care and treatment and to prepare individuals and caregivers for the long-term implications of progressive dementia. With the advent of new diagnostic methods, including blood-based biomarkers, AD can now be diagnosed with greater precision and ease at a lower cost. Given the expected increase in prevalence of AD in the next 2 decades and the growing shortage of geriatricians and memory disorders specialists, the role of the PCP in diagnosing AD will be of even greater importance. However, many PCPs do not feel confident or equipped to recognize and diagnose patients with early symptomatic AD. To empower PCPs as key participants in diagnosis, we propose an approach aligned with the fundamental strengths of primary care, codified in the 4Cs (first contact, comprehensiveness, coordination, and continuity of care).

CONCLUSION: Using the 4Cs framework, PCPs can increase the rate of timely diagnosis of symptomatic AD and be afforded more time to provide comprehensive care, using proactive rather than reactive management strategies throughout the diagnostic process.},
}

@article {pmid42949217,
year = {2026},
author = {Shafiyan, S and Gosselin, N and Léonard, C and Zumbansen, A},
title = {Multimodal Assessment of Emotion in Aging and Dementia: A Laboratory-Based Protocol.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73521},
pmid = {42949217},
issn = {1940-087X},
mesh = {Humans ; *Aging/psychology/physiology ; Aged ; *Dementia/psychology/physiopathology ; *Emotions/physiology ; Female ; Male ; Facial Expression ; },
abstract = {Dementia affects millions worldwide and challenges emotional and social functioning. However, emotional experiences in dementia remain poorly understood. To help better understand this complex phenomenon, the component process model (CPM) was used, which views emotion as a changing process involving appraisal, expression, physiology, motivation, and feeling. It demands a multimodal approach to measure its components. A protocol was developed that combines physiological, facial, vocal, linguistic, and self-report measures, and its feasibility was assessed. The protocol was piloted using iMotions on two older adults with caregiving experience and one with expertise in neuropsychology. Adjustments to instructions, mock tests to familiarize participants with the tasks, and session duration were implemented for a subsequent sample of healthy participants (3 young and 4 older adults) and for 1 older adult diagnosed with dementia due to probable Alzheimer's disease. Participants were screened for impairments in hearing, vision, cognition, and language, as well as psychological distress. The final tasks required watching validated film clips to elicit joy, anger, and sadness. Recorded data according to the CPM included facial movements and voice (expression), electrodermal activity and heart rate (physiology), discourse content, and CoreGRID questionnaire (appraisal; feeling; motivation). Protocol feasibility was assessed by documenting the number of completed tasks, collecting participant feedback via the Post-Study System Usability Questionnaire with comments, and extracting data quality metrics from iMotions for facial expressions and galvanic skin response (percentage of usable data; signal-to-noise ratio). All participants completed the tasks and reported positive feedback on the usability questionnaire. Automated facial expression data were analyzable for all participants, and galvanic skin response recordings were obtained for all participants, with 10 of 11 recordings meeting the predefined signal-to-noise criterion. This protocol was feasible to administer in the tested sample. Further evaluation in larger and more diverse dementia samples is needed.},
}

Humans
*Aging/psychology/physiology
Aged
*Dementia/psychology/physiopathology
*Emotions/physiology
Female
Male
Facial Expression

@article {pmid42949226,
year = {2026},
author = {Yang, S and Grilli, MD and Wootton, RE and van de Weijer, MP and Treur, JL and Klimentidis, YC and Sbarra, DA},
title = {Loneliness as a pathway linking hearing decline to cognitive aging: Longitudinal and genetic evidence.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71950},
pmid = {42949226},
issn = {1552-5279},
support = {R01AG078361-01/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Loneliness/psychology ; *Cognitive Aging/psychology/physiology ; *Hearing Loss/genetics/psychology ; Genome-Wide Association Study ; Longitudinal Studies ; Female ; Male ; Aged ; Europe ; *Cognitive Dysfunction/genetics ; Aging ; },
abstract = {INTRODUCTION: Hearing loss and loneliness are potentially modifiable risk factors for cognitive decline and dementia, but it remains unclear whether loneliness represents a causal pathway linking hearing loss to cognitive aging or whether these associations reflect shared vulnerability.

METHODS: We combined up to 18 years of data from the Survey of Health, Ageing and Retirement in Europe (SHARE; N = 10,375) with summary statistics from eight primary genome-wide association study sources and an independent neuroticism dataset used in sensitivity analyses. Parallel-process latent growth curve models examined level and change associations; additional analyses evaluated hearing-aid moderation, Mendelian randomization, multivariable Mendelian randomization, and colocalization.

RESULTS: At Wave 7, poorer hearing, greater loneliness, and poorer word-recall performance were associated, with a significant indirect association through loneliness. Evidence for coordinated longitudinal mediation was limited, and the primary change-to-change indirect effect was not significant. Current, but not cumulative, hearing-aid use was associated with a weaker concurrent hearing-loneliness association. Genetic analyses provided little evidence for direct or loneliness-mediated causal effects of hearing phenotypes on Alzheimer's disease or all-cause dementia. Results were more consistent with shared liability, including overlap with neuroticism.

DISCUSSION: The findings support late-life associations among hearing difficulty, loneliness, and cognitive performance but provide limited evidence that loneliness is a primary causal pathway linking hearing loss to cognitive aging. Integrating longitudinal and genetic evidence suggests a more complex etiology involving shared liability and supports direct evaluation of hearing care and social connection in intervention studies.},
}

Humans
*Loneliness/psychology
*Cognitive Aging/psychology/physiology
*Hearing Loss/genetics/psychology
Genome-Wide Association Study
Longitudinal Studies
Female
Male
Aged
Europe
*Cognitive Dysfunction/genetics
Aging

@article {pmid42949229,
year = {2026},
author = {Hok-A-Hin, YS and Vermunt, L and de Jong, N and Del Campo Milan, M and Vijverberg, E and Lemstra, AW and Pijnenburg, Y and van Harten, AC and Teunissen, CE},
title = {The Target48 Neurodegeneration panel: A novel tool for profiling protein signatures in neurodegenerative disorders.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71866},
pmid = {42949229},
issn = {1552-5279},
support = {//Stichting Alzheimer Nederland/ ; //Stichting Steun Alzheimercentrum Amsterdam/ ; //Health∼Holland/ ; RYC2023-043831-I//Ramon y Cajal fellowship/ ; MCIN/AEI/10.13039/501100011033//Ramon y Cajal fellowship/ ; FSE+//Ramon y Cajal fellowship/ ; MCIN/AEI/10.13039/501100011033/FEDER//Ramon y Cajal fellowship/ ; EU//Ramon y Cajal fellowship/ ; PID2023-153312OB-I00//Ramon y Cajal fellowship/ ; //CaixaResearch Institute/ ; 860197//European Commission (Marie Curie International Training Network/ ; 101119596//European Commission (Marie Curie International Training Network/ ; 831434//European Commission (Marie Curie International Training Network/ ; 101034344//European Commission (Marie Curie International Training Network/ ; 22HLT07//European Union's Horizon Europe Research and Innovation Programme/ ; 101156175//European Union's Horizon Europe Research and Innovation Programme/ ; 73305095007//Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands/ ; LSHM20106//Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands/ ; 10510032120003//Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands/ ; //Dutch National Dementia Strategy/ ; },
mesh = {Humans ; Biomarkers/cerebrospinal fluid/blood ; Female ; *Neurodegenerative Diseases/cerebrospinal fluid/blood/diagnosis ; Male ; Aged ; *Alzheimer Disease/cerebrospinal fluid/blood/diagnosis ; Lewy Body Disease/cerebrospinal fluid/blood/diagnosis ; Frontotemporal Dementia/cerebrospinal fluid/blood/diagnosis ; },
abstract = {INTRODUCTION: Novel tools for absolute quantification of established and emerging fluid neuro-biomarkers are required to advance diagnostic studies and improve biological insights.

METHODS: We conducted an extensive analytical and clinical validation of the Olink™ Target 48 Neurodegeneration panel (T48 Neuropanel) in 352 paired cerebrospinal fluid (CSF) and plasma samples from cognitively unimpaired controls (CU), Alzheimer's dementia (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB), n = 44 per group. Comparisons with benchmark assays were performed.

RESULTS: Good detectability (CSF: 31 out of 42 assays; plasma: 38 out of 42 assays) and technical performance was observed. Benchmark assays showed good correlations, supporting transformation formula's. Next to emerging biomarkers (MMP10, ITGB2), discriminative performance was excellent in AD: CSF pTau217: area under the curve (AUC) = 1; FTD: plasma neurofilament light chain (NfL): AUC = 0.952; and DLB: CSF dopa decarboxylase (DDC): AUC = 0.901.

DISCUSSION: This analytical and clinical validation of the T48 Neuropanel highlights initial cutoffs and emerging biomarkers to aid clinical studies for the diagnosis, prognosis, and monitoring of neurodegenerative diseases.},
}

Humans
Biomarkers/cerebrospinal fluid/blood
Female
*Neurodegenerative Diseases/cerebrospinal fluid/blood/diagnosis
Male
Aged
*Alzheimer Disease/cerebrospinal fluid/blood/diagnosis
Lewy Body Disease/cerebrospinal fluid/blood/diagnosis
Frontotemporal Dementia/cerebrospinal fluid/blood/diagnosis

@article {pmid42949266,
year = {2026},
author = {Qi, YA and Goldberg, TE and Kim, H and Devanand, DP and Lee, S},
title = {Neuropathological Correlates of Apathy Progression in Alzheimer Disease and Related Dementias: A Longitudinal NACC Cohort Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000754},
pmid = {42949266},
issn = {1546-4156},
abstract = {OBJECTIVE: Apathy is disabling in Alzheimer disease (AD) and related dementias, but its progression across neuropathologies remains unclear. This cohort study examined longitudinal apathy-neuropathology associations.

METHODS: We analyzed 1488 participants from the National Alzheimer's Coordinating Center with autopsy-confirmed neuropathology and at least 2 caregiver-reported Neuropsychiatric Inventory Questionnaire assessments. Generalized linear mixed models tested associations between apathy and AD, Lewy body disease, frontotemporal lobar degeneration (FTLD), hippocampal sclerosis (HS), cerebrovascular disease, and cerebral amyloid angiopathy. Time was modeled as years to death, including pathology-by-time interactions. Models were adjusted for age at death, sex, and Neuropsychiatric Inventory Questionnaire total score excluding apathy. Sex-stratified analyses were conducted.

RESULTS: Apathy prevalence increased over time across all pathology groups. FTLD [odds ratio (OR) = 2.11, 95% CI: 1.32-3.39] and HS (OR = 2.23, 95% CI: 1.38-3.60) were consistently associated with higher odds of apathy. No pathology-by-time interaction was significant. Among males, FTLD (OR = 2.58, 95% CI 1.40-4.77), HS (OR = 2.48, 95% CI 1.29-4.77), and Lewy body disease (OR = 1.64, 95% CI 1.03-2.61) were significantly associated with apathy, while only HS (OR = 2.18, 95% CI 1.06-4.47) remained significant in females.

CONCLUSION: Apathy severity varied by neuropathologies but progressed similarly over time. The elevated burden in FTLD and HS, particularly among males, underscores the importance of stratified approaches to early detection and intervention targeting apathy in AD and related dementias.},
}

@article {pmid42949371,
year = {2026},
author = {Watanabe-Nakayama, T and Noguchi-Shinohara, M and Umeda, K and Muramatsu, D and Konno, H and Kodera, N and Ando, T and Ono, K},
title = {Real-Time Single Molecule Imaging Reveals Pathway-Selective Action of Aducanumab on Amyloid-β Aggregation.},
journal = {Nano letters},
volume = {26},
number = {42},
pages = {14560-14568},
doi = {10.1021/acs.nanolett.6c02842},
pmid = {42949371},
issn = {1530-6992},
support = {NA//Kanazawa University/ ; JP19K07965//Japan Society for the Promotion of Science/ ; JP22K07514//Japan Society for the Promotion of Science/ ; NA//Ministry of Education, Culture, Sports, Science and Technology/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Antibodies, Monoclonal, Humanized/pharmacology/chemistry ; Microscopy, Atomic Force/methods ; *Single Molecule Imaging/methods ; Humans ; Protein Aggregates/drug effects ; *Peptide Fragments/chemistry ; *Alzheimer Disease/drug therapy ; Protein Binding ; },
abstract = {Aducanumab is an anti-amyloid-β (Aβ) antibody that binds aggregated Aβ species and has been reported to inhibit secondary nucleation on fibril surfaces. However, how antibody binding influences aggregate dynamics at the molecular level remains incompletely understood. Here, we used high-speed atomic force microscopy (HS-AFM) to directly visualize the interactions between aducanumab and Aβ42 aggregates in real time at single-molecule resolution. Aducanumab extensively decorated oligomers, protofibrils, and fibrils, with fibril binding depending on local surface structure. Consistent with its reported inhibition of secondary nucleation, bulk thioflavin T assays showed slowed aggregation. Nevertheless, in the continued presence of the antibody, protofibril formation proceeded─a pathway distinct from secondary nucleation. These observations reveal a pathway-selective mode of action: extensive surface binding and the suppression of secondary nucleation do not extend to protofibril formation, which proceeds in the continued presence of the antibody.},
}

*Amyloid beta-Peptides/chemistry/metabolism
*Antibodies, Monoclonal, Humanized/pharmacology/chemistry
Microscopy, Atomic Force/methods
*Single Molecule Imaging/methods
Humans
Protein Aggregates/drug effects
*Peptide Fragments/chemistry
*Alzheimer Disease/drug therapy
Protein Binding

@article {pmid42949499,
year = {2026},
author = {Poddar, K and Wahi, C},
title = {Deep learning models to detect neurodegenerative diseases across different modalities, datasets, and stages: A systematic review.},
journal = {Technology and health care : official journal of the European Society for Engineering and Medicine},
volume = {},
number = {},
pages = {9287329261502060},
doi = {10.1177/09287329261502060},
pmid = {42949499},
issn = {1878-7401},
abstract = {BackgroundNeurodegenerative diseases like Alzheimer's and Parkinson's pose significant diagnostic challenges because they are incurable. Their symptoms often overlap with those of normal ageing and involve progressive neuronal loss. This makes early prediction, proper diagnosis, and ongoing monitoring crucial at every stage of the disease. Deep learning has become a useful tool for handling different types of data. However, the performance of these models relies heavily on the availability and variety of data, making it important to characterize datasets.ObjectiveThis PRISMA-based systematic review looks at 111 studies from 2019 to April 2026, organized into three clinical stages of neurodegenerative diseases: early prediction, diagnosis, and progression.MethodsEach study is assessed across four dimensions: data type (neuroimaging or non-neuroimaging), datasets (open-access, self-created, or hybrid), deep learning model architecture, and the use of explainable AI.ResultsMRI is the only imaging modality that spans all three stages. Speech is the most common non-neuroimaging method for diagnosis, while gait is used only for diagnosis and progression. The ADNI and PPMI datasets are the most commonly used. Self-created datasets introduce new modalities such as ECG and iPSCs, which are not found in open-access datasets. CNNs are the leading models for neuroimaging tasks, while LSTMs and RNNs capture temporal patterns in longitudinal datasets. Survival models are exclusively used for ALS and LATE. Fewer than 6% of the studies used confirmed XAI. Only 2 of the 111 studies validated their results on an independent external cohort.ConclusionThis review is the only one that covers all three disease stages across multiple neurodegenerative diseases.},
}

@article {pmid42949549,
year = {2026},
author = {Xie, T and Xie, X and Chen, X and Jiang, J and Cheng, H and Li, H and Zhang, X and Liu, M and Wang, X and Wu, B and Zhang, JE},
title = {Resistance-to-care behaviors and associated factors among people with dementia in nursing homes based on latent profile analysis and user personas.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498244},
doi = {10.1177/13872877261498244},
pmid = {42949549},
issn = {1875-8908},
abstract = {BackgroundResistance-to-care behaviors are prevalent among people with Alzheimer's disease and related dementia (ADRD), significantly impeding care delivery and causing distress for residents and care workers. However, knowledge regarding scenario-specific resistance-to-care patterns in Chinese nursing homes remains limited.ObjectiveTo identify latent profiles and personas of resistance-to-care behaviors among people with ADRD in Chinese nursing homes and examine associations with background and interpersonal factors based on the need-driven dementia-compromised behavior model.MethodsThis cross-sectional study recruited 574 people with ADRD from six Chinese nursing homes between March 2023 and March 2024. Data on sociodemographics, care worker-initiated communication, resistance-to-care behaviors, cognitive function, functional independence, depression, and pain were collected. Zero-inflated Poisson mixture models identified latent profiles. Personas were developed as group-level summaries integrating profile-defining resistance-to-care patterns with associated descriptive characteristics. Multivariate logistic regression examined factors associated with profile membership.ResultsFour profiles and personas emerged: stable collaborators (low-resistance profile, 77.0%), mealtime resisters (eating-resistance-dominant profile, 6.6%), bathing defenders (bathing-resistance-dominant profile, 13.8%), and high-resistance care responders (high-resistance profile, 2.6%). Eating- and bathing-resistance-dominant profiles were associated with lower cognitive function and absence of care worker-initiated communication during corresponding activities. The high-resistance profile was associated with greater depression and pain.ConclusionsThis study identified latent resistance-to-care profiles and personas, elucidating relationships between background factors, interpersonal factors, and resistance-to-care behaviors. Findings support a culturally informed, scenario-specific framework for dementia care and highlight the potential relevance of regular cognitive monitoring, culturally adapted communication strategies, and systematic depression and pain management for addressing resistance-to-care behaviors.},
}

@article {pmid42949673,
year = {2026},
author = {Vallejo, MS and Paradas, A and Neira, H},
title = {Beyond reproduction: the emerging role of FSH in postmenopausal aging.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {42},
number = {1},
pages = {2752665},
doi = {10.1080/09513590.2026.2752665},
pmid = {42949673},
issn = {1473-0766},
mesh = {Humans ; Female ; *Follicle Stimulating Hormone/blood/physiology ; *Aging/physiology ; *Postmenopause/physiology/blood ; Animals ; },
abstract = {Follicle-stimulating hormone (FSH) is traditionally regarded as a biochemical marker of menopause and declining ovarian function. However, emerging evidence suggests that its role may extend beyond reproductive physiology. During the menopause transition, FSH concentrations rise progressively, initially due to declining inhibin B and later to loss of ovarian estradiol and inhibin production. Evidence of FSH effects in bone, adipose tissue, the cardiovascular system and brain has raised the possibility of broader physiological actions. Higher FSH levels have been associated with bone loss and hip fracture risk, adverse cardiometabolic and vascular changes, and cognitive decline and Alzheimer's disease. Although these associations do not establish causality, they suggest that FSH may contribute to some consequences of reproductive aging rather than simply reflect ovarian failure. Experimental studies indicate that reducing FSH may benefit bone and adiposity, while preliminary clinical evidence regarding cognition remains inconclusive. Thus, FSH may represent not only a marker of menopause, but also a potential marker of risk and, ultimately, a therapeutic target.},
}

Humans
Female
*Follicle Stimulating Hormone/blood/physiology
*Aging/physiology
*Postmenopause/physiology/blood
Animals

@article {pmid42949878,
year = {2026},
author = {Lewis, TS and Wagner, J and Neher, JJ},
title = {Alzheimer's disease research must connect vascular molecular phenotypes with physiology.},
journal = {PLoS biology},
volume = {24},
number = {10},
pages = {e3004051},
doi = {10.1371/journal.pbio.3004051},
pmid = {42949878},
issn = {1545-7885},
mesh = {*Alzheimer Disease/physiopathology/pathology/metabolism/genetics ; Humans ; Phenotype ; Animals ; Hemodynamics ; },
abstract = {Molecular profiling studies have mapped vascular alterations in Alzheimer's disease, but have not proven a role for them in pathology. Longitudinal studies are needed to link molecular and structural changes to vascular mechanics, hemodynamics, and tissue perfusion.},
}

*Alzheimer Disease/physiopathology/pathology/metabolism/genetics
Humans
Phenotype
Animals
Hemodynamics

@article {pmid42950073,
year = {2026},
author = {Jing, Z and Liu, S and Song, Q and Tian, S and Zhou, Q},
title = {The Epidemiological Transition of Neurodegenerative Diseases in China: A Multi-Layered Deconstruction Using Global Burden of Disease Study 2023.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag059},
pmid = {42950073},
issn = {1423-0208},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease and other dementias (ADOD), Parkinson's disease (PD), and motor neuron disease (MND), represent a mounting public health challenge in China amid rapid population aging. A systematic deconstruction of their epidemiological transition using the most recent data remains lacking.

METHODS: Data from the Global Burden of Disease Study 2023 were utilized to examine temporal trends (1990-2023) for ADOD, PD, and MND in China. Age-standardized rates of incidence (ASIR), prevalence (ASPR), mortality (ASMR), and disability-adjusted life-years (ASDR) were analyzed. Joinpoint regression was used to identify significant inflection points. Decomposition analysis quantified the contributions of population aging, population growth, and epidemiological change. And bayesian age-period-cohort models projected trends to 2035.

RESULTS: From 1990 to 2023, the ASIR for ADOD (EAPC 0.41; 95% CI 0.33 to 0.49) and PD (EAPC 0.84; 95% CI 0.76 to 0.92) rose significantly. Between 2019 and 2023, multiple indicators across the three diseases demonstrated a consistently synchronous upward trend. This acceleration coincided with the COVID-19 pandemic. Decomposition demonstrated that population aging was the dominant driver. Sex-specific disparities were pronounced. Females bore a higher ADOD burden, whereas males predominated in PD. ASIR and ASPR are expected to rise, while ASMR and ASDR are projected to decline for ADOD and PD. For MND, only the ASPR indicated a brief, peaked rise in the predicted trends.

CONCLUSIONS: In the field of neurodegenerative diseases, China is projected to undergo an epidemiological transition characterized by chronicization. This trend calls for systematic adjustments in healthcare services, long-term care systems, and social support structures. Sex and gender differences further underscore the need for gender-sensitive prevention, clinical management, and care strategies to prevent the further widening of inequalities. Population aging remains a critical factor that cannot be overlooked. Therefore, there is an urgent need to establish a proactive, gender-sensitive framework for system-wide restructuring that incorporates long-term monitoring and oversight.},
}

@article {pmid42950080,
year = {2026},
author = {Gonzales, PNG and Baroña, EGH and Villaraza, SG and Dela Rosa, JC and Joson, MLC and Ampil, ER},
title = {Characterization of Risk Factors Using Lifestyle for Brain Health (LIBRA) Index Scores Among Filipino Patients with Mild Cognitive Impairment and Dementia.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag056},
pmid = {42950080},
issn = {1423-0208},
abstract = {INTRODUCTION: Dementia prevention focuses on modifiable lifestyle risks which can be summarized by the Lifestyle for Brain Health (LIBRA) index. This index has limited evaluation in Southeast Asian clinical samples. This study aims to characterize LIBRA scores in a Filipino clinical population with mild cognitive impairment (MCI) and all cause dementia and assess associations with dementia etiologies and cognitive severity.

METHODS: Cross sectional analysis of patients from the Philippine Neurological Association One Database - Dementia registry. LIBRA was operationalized from nine available modifiable factors. Group comparisons used nonparametric tests and binary logistic regression to estimate odds ratios with 95% confidence intervals.

RESULTS: The study included 552 individuals, including 97 (17.6%) with MCI and 455 (82.4%) with dementia. The mean age was 73.9 ± 11.47 years, and 62.7% were female. Total LIBRA scores did not differ between MCI and dementia (p = 0.855). In unadjusted logistic regression models, physical inactivity showed an association with higher odds of dementia (OR 3.85, 95% CI 1.81-8.18, p < 0.001), while obesity showed an inverse association with dementia (OR 0.61, 95% CI 0.38-0.98, p = 0.040). Compared with Alzheimer's disease (AD), vascular dementia (VaD) (OR 1.28, 95% CI 1.13-1.46, p < 0.001) and mixed AD+VaD (OR 1.33, 95% CI 1.17-1.50, p < 0.001) had significantly higher LIBRA scores. Total LIBRA scores were not associated with cognitive impairment severity in dementia. These associations should be interpreted cautiously given the descriptive cross-sectional design.

CONCLUSION: LIBRA captures modifiable vascular and lifestyle burden which can be associated with vascular-related dementias. The index is more useful for risk stratification and prevention counseling than for cross sectional diagnosis or severity assessment.},
}

@article {pmid42950713,
year = {2026},
author = {Bodke, S and Shelke, P and Bhatt, LK},
title = {The orexinergic-endocannabinoid interface: mechanistic and therapeutic perspectives in Alzheimer's disease, anxiety, and visceral pain.},
journal = {Neuropeptides},
volume = {120},
number = {},
pages = {102665},
doi = {10.1016/j.npep.2026.102665},
pmid = {42950713},
issn = {1532-2785},
abstract = {Orexinergic system is involved in conditions like narcolepsy, eating disorders, central and neuropathic pain where it is directly or indirectly contributing towards the development of symptoms of these conditions. Endocannabinoid system is present throughout the body and acts via cannabinoid (CB) receptors which have their own role in pain modulation, memory processing, movement and balance control. Evidence is growing that the two systems interact, both through receptor-level mechanisms and through orexin-driven synthesis of 2-arachidonoylglycerol (2-AG). CB1-OX1 heteromer formation has been demonstrated in heterologous cell systems, and OX1 antagonism has been reported to potentiate CB2 signalling in microglial models of Alzheimer's disease (AD), although the therapeutic value of orexin antagonism in AD remains unresolved. In rodent fear-extinction paradigms, orexin-A impairs extinction through a 2-AG-dependent mechanism involving microglial CB2 receptors in the basolateral amygdala. In rodent models of visceral pain, CB1 and CB2 antagonists block the visceral hyposensitivity induced by centrally administered orexin, indicating that endocannabinoid signalling is required for this effect. This review summarises the evidence for orexin-endocannabinoid interaction in AD, anxiety and visceral pain, and discusses translational implications, including the absence of approved drugs acting on both systems.},
}