@article {pmid41787486,
year = {2026},
author = {Yang, T and Ay, Y and Kaur, S and Butler, RR and Tran, KC and Liu, H and Langness, VF and Massa, SM and Longo, FM},
title = {Small molecule modulation of the p75 neurotrophin receptor promotes dendritic spine resilience to pathogenic tau species and reduces their accumulation.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {41787486},
issn = {2051-5960},
abstract = {UNLABELLED: In tauopathies, such as Alzheimer’s disease (AD), oligomeric tau (oTau) can induce tau hyperphosphorylation and further oligomerization, contributing to dendrite and dendritic spine degeneration. The p75 neurotrophin receptor (p75[NTR]), which regulates signaling that overlaps with tauopathy-related degenerative pathways, is a promising therapeutic target. LM11A-31, a small-molecule p75[NTR] modulator, downregulates p75[NTR’]s degenerative signaling and upregulates signaling that promotes dendritic and synaptic integrity. In a tauopathy mouse model, LM11A-31 reversed spine loss in hippocampal pyramidal neurons and improved performance on behavioral tests of hippocampal function. In a Phase 2a randomized, placebo-controlled AD clinical trial, LM11A-31 slowed the progression of synaptic degeneration biomarkers. In the present study, we tested the hypothesis that LM11A-31 enhances resilience of spines and dendrites to pathological forms of tau and/or inhibits the formation and accumulation of pathological tau species. We found that LM11A-31 prevented degeneration of spines and dendrites in cultured hippocampal neurons exposed to recombinant oTau or oTau-containing hippocampal extract fractions from PS19 tauopathy mice. Treating PS19 mice with LM11A-31 reduced the degeneration-promoting activity in oTau-containing hippocampal extract fractions. In cultured hippocampal neurons, LM11A-31 inhibited excess tau phosphorylation and aggregation induced by oTau and counteracted oTau-induced abnormalities in RhoA, PKC, LIMK1, and cofilin signaling, a signaling module known to regulate spine integrity. The ability of LM11A-31 to confer resilience to dendritic spines was partially dependent on LIMK1 activity. These findings demonstrate that small-molecule modulation of p75[NTR] by LM11A-31 both reduces the accumulation of pathological tau species and promotes resilience against oTau-induced dendritic spine degeneration, exemplifying a “dual-mechanism” therapeutic approach for tauopathies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-026-02263-5.},
}

@article {pmid41981367,
year = {2026},
author = {Marawi, T and Rai, H and Kumar, R and Vandeloo, KL and Yep, R and Alexander, MW and Boshmaf, SZ and Chen, SM and Gopinath, G and Malhotra, S and Zhang, A and Nyman, AJ and Perri, LX and Sit, V and Splinter, TFL and Munoz, DP and Swardfager, W and Ryan, JD and Black, SE and Goubran, M and Rabin, JS},
title = {The Canadian multi-ethnic research on aging (CAMERA) study: Design, participant characteristics, and preliminary findings.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71344},
doi = {10.1002/alz.71344},
pmid = {41981367},
issn = {1552-5279},
support = {AARG-23-1144933//the Alzheimer's Association/ ; 173253//the Canadian Institutes of Health Research/ ; },
mesh = {Humans ; Aged ; Male ; Female ; *Aging/ethnology ; Canada ; Longitudinal Studies ; Magnetic Resonance Imaging ; Aged, 80 and over ; Middle Aged ; *Ethnicity ; Brain/diagnostic imaging ; Asian People ; White People ; Neuropsychological Tests ; Mental Status and Dementia Tests ; Dementia ; },
abstract = {INTRODUCTION: South Asian and Chinese individuals are the largest and fastest-growing ethnoracial groups in Canada, yet they remain underrepresented in dementia research. To address this gap, we established the CAnadian Multi-Ethnic Research on Aging (CAMERA) study.

METHODS: CAMERA is a longitudinal observational study conducted in Toronto, Canada, enrolling 300 adults aged 55-85 who self-identify as South Asian, Chinese, or non-Hispanic White (NHW). Participants complete in-person visits at baseline, Year 3, and Year 5, which include clinical and cognitive assessments, brain magnetic resonance imaging (MRI), and blood-based biomarkers. Annual remote questionnaires track health and lifestyle factors.

RESULTS: Among the first 200 participants, vascular and metabolic profiles differed across groups. In addition, South Asian and Chinese participants reported greater cognitive concerns than NHW participants and had lower Montreal Cognitive Assessment (MoCA) scores. The latter was driven primarily by language-heavy and culturally dependent items. Eye-tracking measures did not differ across groups.

DISCUSSION: CAMERA provides a deep phenotyping framework to investigate dementia risk and resilience factors in Asian Canadians.},
}

Humans
Aged
Male
Female
*Aging/ethnology
Canada
Longitudinal Studies
Magnetic Resonance Imaging
Aged, 80 and over
Middle Aged
*Ethnicity
Brain/diagnostic imaging
Asian People
White People
Neuropsychological Tests
Mental Status and Dementia Tests
Dementia

@article {pmid41981379,
year = {2026},
author = {Arslan, B and Gobom, J and Andreasson, U and Montoliu-Gaya, L and Benedet, AL and Dittrich, A and Kern, S and Skoog, I and Ashton, NJ and Chan, T and Rahmouni, N and Rosa-Neto, P and Blennow, K and Zetterberg, H and Kvartsberg, H},
title = {Analytical and clinical validation of the Lumipulse G plasma p-tau217 assay for clinical implementation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71374},
doi = {10.1002/alz.71374},
pmid = {41981379},
issn = {1552-5279},
support = {//University of Gothenburg/ ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; #ADSF-21-831376-C//AD Strategic Fund/ ; #ADSF-21-831381-C//AD Strategic Fund/ ; #ADSF-21-831377-C//AD Strategic Fund/ ; and#ADSF-24-1284328-C//AD Strategic Fund/ ; ADSF-21-831376-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831381-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; 101053962//European Union's Horizon Europe Research and Innovation Programme/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; FO2022-0270//Erling-Persson Family Foundation/ ; //European Union's Horizon research and innovation programme/ ; 860197//Marie Skłodowska-Curie/ ; //National Institute for Health and Care Research University/ ; //Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute/ ; AF-930351//Swedish Alzheimer Foundation/ ; AF-939721//Swedish Alzheimer Foundation/ ; AF-968270//Swedish Alzheimer Foundation/ ; FO2017-0243//Hjärnfonden, Sweden/ ; ALZ2022-0006//Hjärnfonden, Sweden/ ; ALFGBG-715986//County Councils/ ; ALFGBG-965240//County Councils/ ; JPND2019-466-236//European Union Joint Program/ ; ALFGBG-1005471//Swedish state/ ; ALFGBG-965923//Swedish state/ ; ALFGBG-81392//Swedish state/ ; ALF GBG-771071//Swedish state/ ; AF-842471//Swedish state/ ; AF-737641//Swedish state/ ; AF-929959//Swedish state/ ; AF-939825//Swedish state/ ; FO2024-0097//Swedish Brain Foundation/ ; ALFGBG-984092//Swedish Brain Foundation/ ; ALFGBG-984092//Swedish Brain Foundation/ ; MOP-11-51-31//Weston Brain Institute, Canadian Institutes of Health Research/ ; RFN152985//Weston Brain Institute, Canadian Institutes of Health Research/ ; 159815//Weston Brain Institute, Canadian Institutes of Health Research/ ; 162303//Weston Brain Institute, Canadian Institutes of Health Research/ ; 34874//Brain Canada Foundation/ ; 33397//Brain Canada Foundation/ ; 2020-VICO-279314//Fonds de Recherche du Québec - Santé/ ; 2024 VICO-356138//Fonds de Recherche du Québec - Santé/ ; },
mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; Reproducibility of Results ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Alzheimer Disease/blood/cerebrospinal fluid/diagnosis ; Male ; Female ; Immunoassay/methods ; Phosphorylation ; Aged ; Biomarkers/blood/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Although several plasma tau phosphorylated at threonine 217 (p-tau217) immunoassays are now available, comprehensive analytical validation remains limited. We therefore evaluated the Lumipulse G plasma p-tau217 assay and verified established cutoffs for clinical implementation.

METHODS: This study was conducted in two phases: (1) analytical validation of the Lumipulse G plasma p-tau217 assay, assessing precision, lower limit of quantification (LLoQ), selectivity, stability, and interference; and (2) verification of previously established cutoffs using a two-threshold approach in 37 samples with confirmed cerebrospinal fluid (CSF) Aβ42/Aβ40 status.

RESULTS: The assay demonstrated strong analytical performance, with repeatability and intermediate precision (%CV < 7%) and an LLoQ of 0.12 pg/mL. The p-tau217 was stable across freeze-thaw cycles but less so at 4°C, and hemolysis > 2% introduced variability. Cutoff verification showed 97% reproducibility with excellent agreement (ρ = 0.99, p < 0.0001).

DISCUSSION: The Lumipulse assay showed robust analytical performance and reproducibility, supporting clinical use, though certified reference materials are still needed for standardization.},
}

Humans
*tau Proteins/blood/cerebrospinal fluid
Reproducibility of Results
Amyloid beta-Peptides/cerebrospinal fluid/blood
*Alzheimer Disease/blood/cerebrospinal fluid/diagnosis
Male
Female
Immunoassay/methods
Phosphorylation
Aged
Biomarkers/blood/cerebrospinal fluid

@article {pmid41981473,
year = {2026},
author = {Kim, YS and Lee, YJ and Lee, EH and Park, S and Kang, D and Sung, W and Kim, HJ},
title = {Association between dental implantation and dementia: a nationwide population-based study.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07461-3},
pmid = {41981473},
issn = {1471-2318},
support = {HY-202000000003329//The research fund of Hanyang University/ ; },
}

@article {pmid41981607,
year = {2026},
author = {Van Houtven, CH and Ford, CB and Couch, E and Shepherd-Banigan, M and Zhang, W and Bélanger, E and Plassman, BL and Burke, JR and Sorenson, C and DePasquale, N and O'Brien, E and Jutkowitz, E and Wetle, T and Smith, VA},
title = {Amyloid-β PET scans, economic strain and financial decision-making among persons with cognitive impairment and care partners: a mixed-methods analysis of the CARE-IDEAS study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02010-x},
pmid = {41981607},
issn = {1758-9193},
support = {K01AG070284//National Institutes of Health, United States/ ; R01AG053934//National Institutes of Health, United States/ ; P30AG028716/NH/NIH HHS/United States ; 5T32 HS000011-37/HS/AHRQ HHS/United States ; },
}

@article {pmid41981770,
year = {2026},
author = {Bini, M and Tozzini, V and Bellucci, L},
title = {Transient Aggregation-Prone States in Disordered Proteins as Therapeutic Targets: The Amyloid-β Case.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.6c00270},
pmid = {41981770},
issn = {1549-960X},
abstract = {The amyloid-β (Aβ) peptide is an intrinsically disordered protein whose self-association into toxic oligomers underlies Alzheimer's disease. Because of its dynamic and heterogeneous nature, identifying the conformational states that nucleate aggregation remains a central challenge. In this work, we introduce a chemically interpretable descriptor of amyloidogenic propensity derived from self-docking analyses of conformational ensembles generated through temperature-replica exchange molecular dynamics (T-REMD) using different and complementary force fields. This descriptor classifies individual conformers within the generated ensembles according to their intrinsic aggregation tendency, enabling the identification of metastable, aggregation-prone states. The resulting ensembles reproduce experimental observables, and their classification based on amyloidogenic propensity provides a consistent structural basis for the rationalization and study of these metastable conformers. As a test, we demonstrate that the molecular chaperone DNAJB6, experimentally known to bind amyloidogenic conformations, preferentially interacts with aggregation-prone conformers, thus supporting both the proposed protocol and the consistency of the classification scheme. More broadly, this framework outlines a potentially generalizable strategy to identify metastable states in intrinsically disordered proteins as prospective pharmacological targets to help develop drugs or biomolecules capable of inhibiting the early stages of their aggregation.},
}

@article {pmid41981826,
year = {2026},
author = {Li, Y and Li, J and Liu, X and Wang, T and Ma, L and She, R and Chang, Y},
title = {The Role of the Glymphatic System in Alzheimer's Disease: Mechanisms, Evidence, and Therapeutic Implications.},
journal = {Rejuvenation research},
volume = {},
number = {},
pages = {15491684261442832},
doi = {10.1177/15491684261442832},
pmid = {41981826},
issn = {1557-8577},
abstract = {Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation and progressive cognitive decline. Increasing evidence implicates the glymphatic system, a brain-wide perivascular pathway involved in cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, in the removal of Aβ, tau, and other solutes relevant to AD pathogenesis. Aging-related alterations in aquaporin-4 polarization, arterial pulsatility, sleep architecture, and cerebrovascular integrity may impair glymphatic transport and thereby promote protein retention and neurodegeneration. In this review, we summarize current knowledge of glymphatic anatomy and function and discuss its implications for AD, with particular emphasis on modifiable factors such as sleep, exercise, vascular health, and aging-associated decline. We further highlight emerging therapeutic and potential intervention strategies aimed at restoring glymphatic function, and critically evaluate current methods for assessing this system in humans together with the evidence obtained to date. Although human studies increasingly support the relevance of perivascular fluid transport to AD-related pathology and cognitive outcomes, mechanistic insights remain largely derived from animal models, and human assessment is still constrained by methodological and imaging limitations. Overall, the glymphatic system provides a useful framework for linking brain aging to impaired clearance in AD. Further refinement of human biomarkers and longitudinal translational studies will be essential for clarifying their clinical relevance and therapeutic potential.},
}

@article {pmid41981905,
year = {2026},
author = {Zare, F and Shakhmurova, G and Rizaev, J and Smerat, A and Abbood, RS and Patil, V and Kumar-Mishra, M},
title = {Sleep-Dependent Clearance of Brain Metabolites via the Glymphatic System: Implications for Alzheimer's Pathophysiology.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71374},
doi = {10.1002/brb3.71374},
pmid = {41981905},
issn = {2162-3279},
mesh = {Humans ; *Glymphatic System/metabolism/physiopathology ; *Alzheimer Disease/metabolism/physiopathology ; *Brain/metabolism/physiopathology ; *Sleep/physiology ; Animals ; Amyloid beta-Peptides/metabolism ; Aquaporin 4/metabolism ; tau Proteins/metabolism ; },
abstract = {PURPOSE: This review aims to examine how sleep-dependent glymphatic function contributes to the clearance of brain metabolites involved in Alzheimer's disease (AD), with particular emphasis on amyloid-beta (Aβ), tau, astrocytic aquaporin-4 (AQP4), and emerging biomarkers of clearance-related dysfunction.

METHOD: A narrative review of recent mechanistic, preclinical, and human studies was conducted to synthesize current evidence linking sleep, glymphatic transport, and AD pathophysiology. Findings from animal experiments, diffusion MRI proxies such as diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), biomarker studies, and translational intervention research were integrated, with attention to sleep physiology, vascular dynamics, and neuromodulatory regulation.

FINDINGS: Available evidence indicates that sleep is an active physiological state that facilitates cerebrospinal fluid (CSF) exchange with interstitial fluid and promotes the removal of neurotoxic solutes from the brain. Glymphatic transport appears to be most active during non-rapid eye movement sleep, particularly during slow-wave activity, when interstitial space expands and CSF-interstitial fluid exchange increases. Experimental studies show that sleep enhances the clearance of Aβ, tau, and related metabolites, whereas sleep disruption, aging, vascular dysfunction, and AQP4 abnormalities impair this process and may accelerate AD-related pathology. Human evidence has also advanced, including DTI-ALPS studies and a 2026 randomized crossover study reporting higher morning plasma amyloid and tau levels after normal sleep than after sleep deprivation, consistent with greater overnight brain-to-blood clearance during sleep.

CONCLUSION: Sleep-dependent glymphatic clearance is increasingly recognized as an important component of brain homeostasis and a plausible contributor to AD pathophysiology, with promising implications for biomarker development, prevention, and future therapeutic translation.},
}

Humans
*Glymphatic System/metabolism/physiopathology
*Alzheimer Disease/metabolism/physiopathology
*Brain/metabolism/physiopathology
*Sleep/physiology
Animals
Amyloid beta-Peptides/metabolism
Aquaporin 4/metabolism
tau Proteins/metabolism

@article {pmid41981954,
year = {2026},
author = {He, L and He, X and Li, X and Wang, S and Ji, C and Yin, F and Yang, X and He, Y and Zuo, P and Gao, J},
title = {Fusion of Multi-Paradigm EEG Microstate Features to Enhance the Recognition of Mild Cognitive Impairment.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71398},
doi = {10.1002/brb3.71398},
pmid = {41981954},
issn = {2162-3279},
support = {2023AB048//Xinjiang Production and Construction Corps' Science and Technology Project/ ; 2023ZD033//Xinjiang Production and Construction Corps' Science and Technology Project/ ; CZZ24015//Fundamental Research Funds for the Central Universities/ ; CZZ25009//Fundamental Research Funds for the Central Universities/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/physiopathology ; Male ; Female ; *Electroencephalography/methods ; Aged ; Middle Aged ; Support Vector Machine ; Neuropsychological Tests ; Brain/physiopathology ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents a transitional stage between normal aging and Alzheimer's disease. Although neuropsychological screening tools such as the Montreal Cognitive Assessment (MoCA) are widely used, they do not directly capture underlying neural dynamics. EEG microstate analysis provides a fast and noninvasive approach to characterize large-scale brain network activity. However, most previous studies have relied on single-paradigm recordings. This study proposes a unified framework integrating resting-state and task-based EEG microstate features to enhance MCI recognition.

METHODS: EEG data were acquired from 63 age- and sex-matched participants, comprising 32 patients with MCI and 31 healthy controls, during both resting-state and Stroop task paradigms. Data augmentation was applied to generate 10 samples per subject, improving model robustness. We extracted 26 microstate features, including global explained variance (GEV), duration, coverage, transition probability, and Lempel-Ziv complexity. Subsequently, statistically informed minimum redundancy maximum relevance (mRMR) selection was used to determine the optimal feature subset (OFS; ≤ 5 features), followed by classification via a support vector machine (SVM) with stratified fivefold cross-validation.

RESULTS: Based on the OFS, resting-state and task-based models achieved accuracies of 81.8% and 88.0%, respectively. Multi-paradigm EEG fusion improved accuracy to 90.3%. MoCA alone achieved 87.6% accuracy. When MoCA was integrated with multi-paradigm EEG features under the same selection framework, accuracy further increased to 93.8%, with improved balance between sensitivity and specificity.

CONCLUSION: Integrating resting-state and task-evoked microstate dynamics enhances MCI classification beyond single-paradigm EEG. Importantly, EEG features provide complementary diagnostic information beyond conventional cognitive screening, supporting a hybrid electrophysiological-neuropsychological framework for early detection of MCI.},
}

Humans
*Cognitive Dysfunction/diagnosis/physiopathology
Male
Female
*Electroencephalography/methods
Aged
Middle Aged
Support Vector Machine
Neuropsychological Tests
Brain/physiopathology

@article {pmid41981990,
year = {2026},
author = {Vavers, E and Kopanchuk, S and Veiksina, S and Jonane, J and Mathur, C and Nasirova, N and Midekessa, G and Rinken, A},
title = {Simultaneous Expression of Sigma-1 Receptor and Tetraspanins Highlights Pathways of Receptor Sorting Into Extracellular Vesicles.},
journal = {Journal of neurochemistry},
volume = {170},
number = {4},
pages = {e70426},
doi = {10.1111/jnc.70426},
pmid = {41981990},
issn = {1471-4159},
support = {SJD34//Estonian Research Council/ ; },
mesh = {*Receptors, sigma/metabolism/biosynthesis/genetics ; Sigma-1 Receptor ; *Extracellular Vesicles/metabolism ; Humans ; *Tetraspanins/metabolism/biosynthesis/genetics ; Tetraspanin 29 ; Protein Transport/physiology ; Tetraspanin 28 ; },
abstract = {Sigma-1 receptor (Sig1R) is an endoplasmic reticulum (ER) chaperone protein involved in regulating ER function, cellular stress responses, and autophagy, and disturbed Sig1R function has been associated with neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Although Sig1R has been implicated in secretory pathways and detected extracellularly, its direct presence in isolated extracellular vesicles (EVs) has not been clearly established. In this study, we aimed to confirm Sig1R in isolated EVs by co-expressing it alongside tetraspanin EV markers. Expression of fluorescently tagged Sig1R together with fluorescent protein-labeled tetraspanins CD9, CD63, and CD81 in both cells and isolated EVs was verified using live-cell imaging, emission spectrum measurements, and Western blotting. Efficient expression of these proteins in cells was achieved by using the MultiBacMam expression system and their presence in EVs was detected through advanced TIRF-based multi-well single-particle EV analysis. We observed significantly higher levels of Sig1R in CD63- and CD9-labeled EVs in comparison with CD81-labeled EVs. The obtained data suggest that Sig1R may be released into the extracellular space via exocytotic pathways linked to exosome secretion. The presence of Sig1R in exosomes underscores its potential as a biomarker in neurological disorders, emphasizing the need for further exploration of its diagnostic and other applications.},
}

*Receptors, sigma/metabolism/biosynthesis/genetics
Sigma-1 Receptor
*Extracellular Vesicles/metabolism
Humans
*Tetraspanins/metabolism/biosynthesis/genetics
Tetraspanin 29
Protein Transport/physiology
Tetraspanin 28

@article {pmid41981995,
year = {2026},
author = {Wang, Y and Zhu, J and Lizarazo, S and Lee, KY and Wong, O and Azim, S and Yook, Y and Kumar, V and Tsai, NP},
title = {E3 Ubiquitin Ligase Nedd4-2 Exacerbates Seizure-Induced Mitochondrial Defects in an Alzheimer's Disease Mouse Model.},
journal = {Journal of neurochemistry},
volume = {170},
number = {4},
pages = {e70440},
doi = {10.1111/jnc.70440},
pmid = {41981995},
issn = {1471-4159},
support = {AARG-23-1149282/ALZ/Alzheimer's Association/United States ; R21AG071278/AG/NIA NIH HHS/United States ; R21AG089491/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Mitochondria/metabolism/pathology ; *Alzheimer Disease/metabolism/genetics/pathology ; *Seizures/chemically induced/metabolism/genetics/pathology ; Mice ; *Nedd4 Ubiquitin Protein Ligases/metabolism/genetics ; Disease Models, Animal ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Mice, Inbred C57BL ; Male ; Reactive Oxygen Species/metabolism ; Kainic Acid/toxicity ; },
abstract = {Seizure is one of the common comorbidities in Alzheimer's disease (AD). Seizures in AD have been shown to occur more often with early-onset disease, particularly when there is a familial presenilin I (PS1) mutation or abnormal expression of amyloid precursor protein (APP). AD patients with seizures have been associated with a faster decline in cognitive functions. However, it remains unclear how seizures exacerbate neurodegeneration in AD. Here, we showed that, using a kainic acid-induced acute seizure model, mitochondrial function is enhanced and the reactive oxygen species (ROS) are reduced in the brain of wild-type (WT) mice but not in an AD mouse model, APP/PS1 mice. These data suggest a lack of protective mechanism following seizures in APP/PS1 mice. Mechanistically, we found that an E3 ubiquitin ligase, the neural precursor cell-expressed developmentally downregulated protein 4-like (Nedd4-2), is elevated but stays dephosphorylated in APP/PS1 mice upon seizure inductions. Immunocytochemistry and sub-cellular fractionation experiments demonstrate an interaction between Nedd4-2 and mitochondria. Unbiased proteomics analysis suggests that Nedd4-2 regulates the expression of multiple mitochondrial proteins including one of the key mitochondrial outer membrane proteins, Mitofusin 2 (MFN2). Upon seizure induction, Nedd4-2 exhibits elevated interaction with mitochondria and downregulates MFN2 in APP/PS1 mice but not in WT mice. These data suggest that seizures aggravate mitochondrial dysfunction in AD, and Nedd4-2, which acts as a negative mitochondrial regulator, contributes to this effect. Altogether, our findings illustrate a potential mechanism by which seizures exacerbate neurodegeneration in AD and suggest Nedd4-2 as a novel therapeutic target for AD patients with comorbid seizures.},
}

Animals
*Mitochondria/metabolism/pathology
*Alzheimer Disease/metabolism/genetics/pathology
*Seizures/chemically induced/metabolism/genetics/pathology
Mice
*Nedd4 Ubiquitin Protein Ligases/metabolism/genetics
Disease Models, Animal
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics
Mice, Inbred C57BL
Male
Reactive Oxygen Species/metabolism
Kainic Acid/toxicity

@article {pmid41982209,
year = {2026},
author = {Ubuka, T and Yuyama, K and Genjima, A and Nagakura, M and Kato, K and Hayashi, S and Makino, N and Yamane, T and Hirose, T and Yamane, Y},
title = {Mitigating cognitive decline in Alzheimer's disease dementia by enhancing cognitive reserve through neuroplasticity in addition to amyloid-β reduction.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1769431},
pmid = {41982209},
issn = {1663-4365},
}

@article {pmid41982251,
year = {2026},
author = {Liu, X and Zhang, L and Li, Y},
title = {Enhancing Alzheimer's Disease and Related Dementia Burden Projections and Policy Targeting in China-Reply.},
journal = {Health data science},
volume = {6},
number = {},
pages = {0435},
pmid = {41982251},
issn = {2765-8783},
}

@article {pmid41982252,
year = {2026},
author = {Liu, C},
title = {Enhancing Alzheimer's Disease and Related Dementia Burden Projections and Policy Targeting in China.},
journal = {Health data science},
volume = {6},
number = {},
pages = {0436},
pmid = {41982252},
issn = {2765-8783},
}

@article {pmid41982423,
year = {2026},
author = {Ryan, B and Marriott, L and Murray, H and Faull, RLM and Turner, CP and Curtis, MA},
title = {Clinicopathological features of primary tauopathies: a brain bank series.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1768959},
pmid = {41982423},
issn = {1664-2295},
abstract = {INTRODUCTION: This study presents the first comprehensive clinicopathological analysis of primary tauopathies from the Neurological Foundation Human Brain Bank (NFHuBB). Primary tauopathies are a heterogeneous group of neurodegenerative disorders, defined by abnormal tau protein deposition as the core pathological feature. They are further defined by the absence of an additional pathological driver. Historically, they were often accepted into brain banks as Alzheimer's, Parkinson's, or dementia cases.

METHODS: Here, we retrospectively examined all brain donations to the NFHuBB from 1994 to 2022 to identify cases of primary tauopathy, excluding those with known secondary causes such as repetitive head trauma. This is a national-level, single brain bank series. Detailed clinical records, demographic data, and post-mortem pathological investigations, including immunohistochemistry, were analysed to establish clinical and pathological diagnoses according to current criteria.

RESULTS: Fifteen cases were identified, spanning argyrophilic grain disease, primary age-related tauopathy, corticobasal degeneration, genetic frontotemporal dementia, and progressive supranuclear palsy. The mean age of onset was 69 years, with average survival of 6 years. Notably, only 47% of cases showed concordance between clinical and pathological diagnosis, underscoring diagnostic challenges. Neuropathological review revealed marked diversity in tau pathology and regional vulnerability, with most cases demonstrating both neuronal and glial tau pathology.

DISCUSSION: This case series highlights the complexity and heterogeneity of primary tauopathies and the critical role of post-mortem neuropathological examination for diagnosis. By making fixed and frozen tissue, and clinical data available for national and international dissemination, this study provides a valuable resource to advance global research into the pathogenesis and classification of tauopathies. Furthermore, this work highlights the important role of brain banking in the study of rare diseases.},
}

@article {pmid41982483,
year = {2026},
author = {Stokkel, ME and Vermunt, L and Knol, JC and Chiasserini, D and Parnetti, L and Piersma, SR and Pham, TV and de Goeij-de Haas, RR and Lemstra, AW and Pijnenburg, YAL and Visser, PJ and Tijms, BM and Teunissen, CE and Jimenez, CR},
title = {Discovery of cerebrospinal fluid biomarkers for different dementias using mass spectrometry-based proteomics.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70278},
pmid = {41982483},
issn = {2352-8729},
abstract = {INTRODUCTION: Common forms of dementia include Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Disease specific biomarkers are needed for differential disease diagnosis.

METHODS: We performed cerebrospinal fluid (CSF) mass spectrometry proteomics on three cohorts (n = 110, n = 112, n = 78) including AD, DLB, FTD, mild cognitive impairment (MCI) with or without abnormal cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ1-42) levels (MCI Aβ+ and MCI Aβ-, respectively) and controls.

RESULTS: We identified and validated 11, 3, and 5 differentially expressed proteins in AD, DLB, and FTD, respectively. Potential disease specific proteins included fructose-bisphosphate aldolase A (ALDOA), L-lactate dehydrogenase A chain (LDHA), malate dehydrogenase, cytoplasmic (MDH1), and phosphoglycerate mutase 1 (PGAM1), which were upregulated in AD and MCI Aβ+ across multiple cohorts and did not display altered levels in DLB and FTD. Validated DLB and FTD proteins were altered in similar directions in other dementia types in at least one other cohort.

DISCUSSION: Proteomics identified potential disease specific biomarkers in AD which were already altered in the prodromal stage.

HIGHLIGHTS: We studied cerebrospinal fluid (CSF) proteomic alterations in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).Proteins with altered CSF levels were associated with immune related processes in AD, DLB, and FTD, glycolytic processes in AD and amyloid-beta positive mild cognitive impairment (MCI Aβ+), and synaptic processes in FTD.MCI Aβ+ and MCI Aβ- displayed divergent proteomic changes, with MCI Aβ+ being more similar to AD, while alterations in MCI Aβ- were difficult to relate to any of the dementias studied.Glycolytic protein levels were specifically upregulated in AD and MCI Aβ+ in our cohorts and in previously published cohorts, while these were unaltered in DLB and FTD.},
}

@article {pmid41982624,
year = {2026},
author = {Denève, A and Mahut Dubos, A and Tran, TM and Renard, A and Carpentier, C and Forestier, N and Kuchcinski, G and Lopes, R and Amad, A and Lebouvier, T and Bertoux, M},
title = {Multi-level language deficits in behavioural frontotemporal degeneration and related disorders.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag116},
pmid = {41982624},
issn = {2632-1297},
abstract = {Language is essential to social communication. Its complexity and hierarchical organization, from low-level operations to high-order integrative processes, may provide valuable diagnostic insights in neurodegeneration beyond classical aphasia syndromes. However, systematic investigations in these conditions, particularly in behavioural variant frontotemporal degeneration (bvFTD), remain scarce. To refine differential diagnosis, an exhaustive characterization of language functions is required. We systematically compared multi-level language functioning across bvFTD, Alzheimer's disease (AD) and primary psychiatric disorders (PPD), within an integrative neurolinguistic framework distinguishing lexical, syntactic and discursive levels, together with a cross-modal transposition/transcoding dimension. A total of 85 patients (including 34 with bvFTD, 30 with AD, 21 with PPD) and 40 matched healthy controls underwent an extensive language assessment using the GREMOTs battery. Composite, quantitative as well as qualitative indices were computed for each linguistic level. Structural MRI data were analysed using voxel-based morphometry (P < 0.05 corrected for multiple comparisons). All clinical groups exhibited lexical impairments relative to controls, with bvFTD presenting the most severe and widespread deficits across fluency, naming and comprehension (partial eta-squared, ηp [2], ranging from 0.18 to 0.49). AD and PPD showed milder lexical inefficiencies (ηp [2] = 0.11-0.39 and ηp [2] = 0.07-0.29, respectively). Syntactic processing was also more impaired in bvFTD (ηp [2] = 0.03-0.27) than in AD and PPD (ηp [2] = 0.02-0.07 and ηp [2] = 0.00-0.15, respectively). At the discourse-level, bvFTD displayed key deficits (ηp [2] = 0.05-0.29), with pervasive pragmatic breakdowns whereas AD and PPD showed milder integrative deficits with preserved global coherence (ηp [2] = 0.00-0.17 and ηp [2] = 0.02-0.13). Transcoding and transposing tasks revealed minor deficits, mainly in bvFTD (ηp [2] = 0.01-0.25). A logistic regression identified that a subset of 12/23 tasks accurately classified 85.9% of bvFTD cases (sensitivity: 57.6%; specificity: 95.6%). The analysis of the types of responses (including errors) allowed to provide a more comprehensive group profiling. In bvFTD, the decrease of language performance related to widespread frontotemporal and posterior (including cerebellar) atrophy, whereas AD showed more restricted frontal and temporal involvement. PPD displayed smaller fronto-temporal, insular and precuneal associations. In conclusion, these findings delineate a graded, multi-level linguistic profile across neurodegenerative and psychiatric conditions. bvFTD is mainly characterized by pervasive lexical and discursive-pragmatic impairments, alongside syntactic difficulties, while AD and PPD primarily show lexical inefficiencies with preserved syntax. Convergent neural evidence supports a distributed network model of language integrating frontal-insular control and temporal semantic systems. Embedding such multi-level assessments into clinical practice could enhance diagnostic precision and provide valid cognitive endpoints for future trials.},
}

@article {pmid41982714,
year = {2026},
author = {González-Gutiérrez, JP and Castillo-Ríos, DA and González-Gutiérrez, IA and Palma-Ruíz, DR and Vidal-Beltrán, IA and Carvacho, IV and Hinostroza, FA},
title = {Functional Evaluation of Tetrahydroisoquinoline-Derived Ligands Reveals Distinct Modulatory Profiles at the Muscarinic M1 Receptor.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {4},
pages = {813-824},
pmid = {41982714},
issn = {1948-5875},
abstract = {The muscarinic acetylcholine M1 receptor (M1-mAChR) is a key regulator of cognitive processes and remains an attractive target for the modulation of central cholinergic signaling. In this study, tetrahydroisoquinoline-derived ligands (THQ140, THQ790) and a structurally related compound (QPB) were evaluated for their ability to modulate M1-mAChR activity. Intracellular Ca[2+] imaging in HEK-293 cells expressing human M1-mAChR revealed distinct functional profiles, including partial agonist activity and limited or noncooperative modulation of ACh-induced signaling. In contrast to the prototypical M1 positive allosteric modulator benzyl quinolone carboxylic acid (BQCA), which displays minimal intrinsic agonism and strong positive cooperativity with ACh, the compounds reported here exhibited direct receptor activation with weaker or absent potentiation. Molecular docking and molecular dynamics simulations supported preferential interaction at a nonorthosteric region of the receptor. In addition, analysis of single-nucleus RNA sequencing data sets confirmed robust CHRM1 expression in neuronal populations of healthy and Alzheimer's disease brains, supporting the continued relevance of M1-mAChR as a pharmacological target.},
}

@article {pmid41982821,
year = {2026},
author = {Kenny, RPW and Twentyman, K and Craig, D and Meader, N and Norman, G},
title = {The Impact on Systematic Reviews of Risk of Bias Assessment Changes From Conference Abstracts to Full Text.},
journal = {Cochrane evidence synthesis and methods},
volume = {4},
number = {3},
pages = {e70078},
pmid = {41982821},
issn = {2832-9023},
abstract = {Conference abstracts are commonly included in systematic reviews of evidence. Due to limitations in word count, conference abstracts often lack data or information. This causes issues for the assessment of risk of bias (RoB). We therefore aimed to compare the RoB rating, using the Cochrane RoB tool, for abstracts and full texts. This was accomplished using previously published Cochrane reviews and comparing RoB ratings for included studies originally included as an abstract and later as full text. To accomplish this, we searched the Cochrane Database of Systematic Reviews for reviews with updates across numerous disciplines (depression, anxiety, surgical, Parkinson's disease, Alzheimer's disease, multiple sclerosis, motor neuron disease, cancer, cardiovascular disease, and musculoskeletal disease). We identified 29 reviews, with 52 randomized controlled trials included, which had an abstract and subsequent full text available. If abstracts and full texts were not assessed using the Cochrane RoB tool, we obtained the texts and performed the assessment (n = 32). To assess the likelihood of changing the domain assessment rating (low, unclear, or high) from conference abstract to full text, we performed a Bayesian categorical multinomial model for each domain (i.e., signaling question) of the Cochrane tool. At the abstract assessment stage, the most common decision was unclear. Using unclear as the reference level in the model led to increased odds of being rated high at full text, compared to abstract assessment, for domains 2 (allocation concealment: odds ratio [OR] = 3.09, 95% credible intervals (CrI) 1.01 to 9.84) and 3 (blinding: OR = 5.09, 95% CrI 1.67 to 16.20). Domain 2 also had odds of being rated low (OR: 2.93, 95% CrI: 1.13 to 7.87). This suggests an impact of changing conference abstract to full text assessments on RoB. The numerous unclear ratings observed at the abstract assessment were usually due to a lack of reporting. While the findings of this study should be interpreted within the context of small numbers, the evidence still suggests that, in some instances, such as allocation concealment and blinding, it is likely that the decision could change based on full-text assessment. This also has implications for the certainty of the evidence, which is impacted by the RoB assessments, with having abstracts only or full texts available potentially changing the overall certainty. Current RoB tools may not be suitable for assessing conference abstracts.},
}

@article {pmid41983050,
year = {2026},
author = {Fang, Y and Hao, X and Fang, B},
title = {Extracellular vesicle therapeutics in Alzheimer's disease: mechanisms, progress, and prospects.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {1},
pages = {394-424},
pmid = {41983050},
issn = {2767-6641},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, characterized by progressive cognitive decline and a current lack of effective curative treatments. In recent years, extracellular vesicle (EV) therapies have emerged as a cutting-edge approach in AD research due to their unique biological properties. This review systematically examines the role of EVs in the pathogenesis of AD, including their cellular origins and functional attributes. We detail the molecular mechanisms mediated by EVs that influence AD progression and summarize the latest advancements in EV-based therapeutic strategies. Additionally, the review addresses the challenges faced in translating these therapies from bench to bedside, such as standardization, delivery optimization, and safety concerns. Future research directions are discussed to foster the development of innovative and effective treatments for AD. By providing a comprehensive overview, this article aims to lay a theoretical foundation and offer valuable insights for the advancement of novel therapeutic interventions targeting AD.},
}

@article {pmid41983141,
year = {2026},
author = {Janžič, L and Kouter, K},
title = {Complement and inflammasome crosstalk in chronic inflammation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1778759},
pmid = {41983141},
issn = {1664-3224},
mesh = {Humans ; *Inflammasomes/immunology/metabolism ; *Inflammation/immunology/metabolism ; *Complement System Proteins/immunology/metabolism ; Animals ; Chronic Disease ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/immunology ; Signal Transduction/immunology ; *Complement Activation/immunology ; },
abstract = {Chronic inflammation underlies a broad range of human diseases, including autoimmune disorders, neurodegeneration, and metabolic syndromes. While acute inflammation is essential for pathogen clearance and tissue repair, persistent activation leads to tissue damage and disease progression. Two key innate immune pathways, the complement system and inflammasomes, are crucial mediators of inflammation and are increasingly recognized as interdependent effectors that sustain chronic inflammatory states. This review examines the mechanistic crosstalk between complement activation and inflammasome signaling, with an emphasis on the NLRP3 inflammasome. We first outline how complement pathways drive inflammation through cell recruitment, cytokine induction, and failure of regulatory checkpoints. Next, we review the triggers, regulation, and persistence of inflammasome activation, highlighting the central role of NLRP3 and its engagement by diverse danger signals in chronic disease. In the main section, we detail multiple mechanistic intersections between the two systems, including shared activation triggers such as reactive oxygen species and mitochondrial damage, direct priming and activation of inflammasomes by complement components (e.g., C3a, C5a, MAC), and feedback loops driven by inflammasome-derived cytokines (IL-1β, IL-18) that enhance complement activity and immune cell recruitment. We further illustrate these interactions across disease contexts, including gout, atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, and Alzheimer's disease. In each case, complement and inflammasomes form a self-amplifying loop that exacerbates inflammation and tissue damage. We also examine the dual role of C1q as both an enhancer and suppressor of inflammasome activation, depending on the cellular and molecular environment. Finally, we discuss therapeutic strategies targeting these pathways. Complement inhibitors (e.g., eculizumab, avacopan), inflammasome inhibitors (e.g., MCC950), and IL-1β blockers (anakinra) show clinical promise, and dual-targeting approaches may offer synergistic benefit. Understanding the interplay between complement and inflammasomes provides critical insight into the persistence of inflammation and opens new avenues for precise immunomodulation in chronic diseases.},
}

Humans
*Inflammasomes/immunology/metabolism
*Inflammation/immunology/metabolism
*Complement System Proteins/immunology/metabolism
Animals
Chronic Disease
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/immunology
Signal Transduction/immunology
*Complement Activation/immunology

@article {pmid41983237,
year = {2026},
author = {Jahanbin, K},
title = {The Neurogenic Niche: Interactions Among Vessels, Glia, and Neural Stem Cells.},
journal = {Stem cells international},
volume = {2026},
number = {},
pages = {8440764},
pmid = {41983237},
issn = {1687-966X},
abstract = {Adult neurogenesis, the generation of new neurons in the adult brain, acts as a fundamental driver of neural plasticity within specialized microenvironments. The integrity of the hippocampal subgranular zone, essential for pattern separation and mood regulation, relies on a functional syncytium formed by the vasculature, glial cells, and neural stem cells (NSCs). This review delineates the architecture of this system, detailing how the vascular pillar provides angiocrine support via vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), while the glial pillar-comprising astrocytes and microglia-orchestrates metabolic homeostasis and immune surveillance. The dynamic regulation of this local ecosystem by systemic factors, including physical exercise and the gut-brain axis, is also explored. Furthermore, the breakdown of this alliance is examined as a pathological hub in aging, Alzheimer's disease (AD), and chronic stress. Crucially, the text addresses the significant translational gap between rodent models and human physiology. The ongoing controversy regarding the persistence of adult human neurogenesis is critically evaluated, attributing conflicting data to methodological variables such as postmortem interval (PMI) and fixation kinetics. Additionally, the risks of maladaptive plasticity, where aberrant neurogenesis contributes to conditions like epilepsy, are discussed. Finally, future directions involving high-resolution omics and imaging are highlighted, emphasizing that therapeutic strategies must navigate the complex biological risks of neural repair.},
}

@article {pmid41983348,
year = {2026},
author = {Laskar, RU and Meena, BS and Roy, A and Borah, A},
title = {Prediction of acetylcholinesterase inhibition associated with Alzheimer's disease using hybrid descriptor and graph-based machine learning models.},
journal = {SAR and QSAR in environmental research},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1062936X.2026.2647201},
pmid = {41983348},
issn = {1029-046X},
abstract = {Accurate prediction of acetylcholinesterase (AChE) inhibitory activity is important in drug discovery and environmental toxicology because AChE inhibition represents a key mechanism underlying neurotoxicity associated with pharmaceuticals and environmental contaminants. In this study, machine learning approaches were used to develop predictive models for AChE inhibitory activity using experimentally measured bioactivity data for small molecules targeting human AChE. A curated dataset containing 5795 molecules was compiled from BindingDB to support reliable model development. Fifteen predictive models were evaluated, including twelve individual machine learning and deep learning models and three hybrid fusion models, using multiple molecular representations such as physicochemical descriptors derived from RDKit and PaDEL and graph-based molecular structures. Among the individual models, tree-based ensemble methods demonstrated strong baseline performance, indicating that physicochemical descriptors capture important chemical features associated with AChE inhibition. Graph neural networks, particularly Graph Isomorphism Network effectively learn structural patterns related to inhibitory activity. To integrate complementary molecular information, a late-fusion hybrid framework combining descriptor-based predictions and graph-based representations was implemented using leakage-safe stacking with a Ridge regression meta-learner. Across ten independent train-test splits, the best-performing hybrid model integrating PaDEL-based XGBoost and GIN achieved r[2] = 0.7400 ± 0.0138, demonstrating improved and stable predictive performance over individual models.},
}

@article {pmid41983466,
year = {2026},
author = {Russell, A and Vogeley, A and Lovett, R and O'Conor, R and Batio, S and Hurtado, J and Bonham, M and Benavente, JY and Brickman, AM and Williamson, JD and Udeh-Momoh, C and Mielke, MM and Wolf, M},
title = {Patient views on blood-based biomarker tests for Alzheimer's disease in primary care.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71247},
doi = {10.1002/alz.71247},
pmid = {41983466},
issn = {1552-5279},
support = {P30AG059988/AG/NIA NIH HHS/United States ; R01AG030611/AG/NIA NIH HHS/United States ; R01AG070212/AG/NIA NIH HHS/United States ; R01AG075043/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/psychology ; *Biomarkers/blood ; Female ; Male ; Primary Health Care ; Aged ; Middle Aged ; Cross-Sectional Studies ; Aged, 80 and over ; Adult ; },
abstract = {INTRODUCTION: Blood-based biomarkers could offer accessible, cost-effective detection of Alzheimer's disease (AD) in primary care. This study examined patient attitudes toward AD biomarker testing.

METHODS: Crosssectional surveys were conducted with 572 adults from Chicago-area clinics. Participants received brief education on biomarker tests before completing the survey.

RESULTS: Most participants (83.8%) were unfamiliar with biomarker tests; 1.8% previously completed testing. After brief education, most (94.5%) supported offering tests to patients with memory complaints, and 85% were willing to complete testing if recommended by their clinician. Facilitators included tests informing clinical care, coverage by insurance, and education in advance. Barriers included cost and reliability concerns. Participants commonly expected they would experience emotional distress and motivation to improve brain health after a positive test.

DISCUSSION: Primary care patients educated about biomarker testing were generally willing to undergo testing and support its use. After a positive result, informational and psychological support may be needed.},
}

Humans
*Alzheimer Disease/blood/diagnosis/psychology
*Biomarkers/blood
Female
Male
Primary Health Care
Aged
Middle Aged
Cross-Sectional Studies
Aged, 80 and over
Adult

@article {pmid41983942,
year = {2026},
author = {Ghahari, AA and Safaeihavadaragh, L and Nourizadeh, M and Davari, S and Safaei, S and Zare, F and Alkayyat, S and Kamali Far, E},
title = {Neuroprotective roles of klotho: Molecular pathways and therapeutic implications for cognitive health in neurological and psychiatric diseases.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP093571},
pmid = {41983942},
issn = {1469-445X},
abstract = {Klotho, a pleiotropic protein initially identified for its role in kidney function, has garnered significant attention for its neuroprotective properties in various neurodegenerative diseases. It regulates key processes, such as oxidative stress, neuroinflammation, synaptic plasticity and myelination, all crucial for maintaining neuronal integrity and cognitive function. Preclinical studies demonstrate that klotho enhances amyloid-β and tau clearance, stabilizes synaptic function, supports oligodendrocyte maturation and mitigates excitotoxicity. Clinical findings show that higher α-klotho levels are associated with slower cognitive decline in Alzheimer's and Parkinson's diseases, improved outcomes in multiple sclerosis and better recovery after stroke. Notably, the protective effects of klotho appear most pronounced in individuals with high genetic or pathological risks, such as apolipoprotein E ε4 carriers in Alzheimer's disease. Despite these promising insights, the clinical application of klotho-based therapies is hindered by variability in biomarker assays, challenges in crossing the blood-brain barrier, and the need for precision-based interventions tailored to individual genetic profiles. Current strategies to enhance klotho activity include lifestyle changes, pharmacological agents, recombinant protein delivery and gene therapy. Although challenges remain, klotho stands as a potential therapeutic target for mitigating cognitive decline and promoting brain health across a range of neurodegenerative and cerebrovascular conditions.},
}

@article {pmid41983991,
year = {2026},
author = {Truin, LS and Heger, IS and Deckers, K and Knops, R and Palsma, T and de Heus, RAA and Claassen, JAHR and de Vugt, ME and Köhler, S},
title = {Management of dementia risk factors by memory clinic patients and professionals: Pilot study of the BreinZorg (BrainCare) online platform.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261440966},
doi = {10.1177/13872877261440966},
pmid = {41983991},
issn = {1875-8908},
abstract = {BackgroundBrain-healthy lifestyle changes could help reduce dementia risk in individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI), but patients and clinicians in memory clinics often lack practical tools to support this.ObjectiveTo explore the acceptability and usability of BreinZorg (English: BrainCare) in a memory clinic setting. BreinZorg is a co-created prototype consisting of a self-management website and hardcopy conversation aid providing dementia risk reduction information.MethodsThe website includes a lifestyle assessment, personalized module recommendations, practical information on 16 modifiable dementia risk and protective factors (e.g., smoking, sleep) and a goal-setting feature. The hardcopy conversation aid briefly outlines these factors to support clinical risk reduction discussions. This study used semi-structured interviews based on the Program Participation Questionnaire and think-aloud sessions, which were analyzed through thematic content analysis. Participants were individuals with self-reported SCD or MCI (n = 19) and memory clinic professionals (n = 9), i.e., nurses/nurse practitioners, physicians/medical specialists and neuropsychologists.ResultsBreinZorg was generally considered useful, trustworthy, easy to use, and applicable in clinical contexts. The platform's accessible design, nonjudgmental tone, and personalization features were appreciated. Some participants with SCD or MCI, particularly those already interested in brain health, desired more in-depth information. A lack of follow-up on personal goals and misaligned module recommendations after the lifestyle assessment were identified as barriers to sustained engagement.ConclusionsMemory clinic patients and professionals evaluated BreinZorg as practical, useful, and acceptable for supporting dementia risk reduction in clinical care. Offering more detailed information, integrating tailored follow-up support, and enhancing personalization may strengthen long-term user engagement.},
}

@article {pmid41983994,
year = {2026},
author = {Yang, D and Zhang, B and Wang, S and Chen, J and Zhu, J and Wei, R and Cai, H and Teng, B and Xie, X and Li, B and Yu, X and Huang, S and Chen, G and Weng, Y},
title = {Sex-dependent role of inflammatory biomarkers in Alzheimer's disease-related cognitive performance.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261440932},
doi = {10.1177/13872877261440932},
pmid = {41983994},
issn = {1875-8908},
abstract = {BackgroundInflammatory factors are widely recognized as contributors to Alzheimer's disease (AD), along with pathological changes in amyloid-β (Aβ) and tau proteins.ObjectiveWe aimed to determine whether sex influences the inflammation-related cognitive performance.MethodsThis cross-sectional study included 317 patients (260 cognitively impaired and 57 cognitively normal) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) between September 7, 2005, and August 7, 2024. Interaction analysis was used to examine sex-specific effects of interleukins, while logistic regression examined associations between interleukins and clinically relevant worsening on non-memory Mini-Mental State Examination (MMSE) items (BCNMMMS). Linear regression assessed associations with hyperphosphorylated tau proteins (P-tau181). Finally, mediation analysis was conducted to investigate the role of sex hormone-binding globulin (SHBG) in interleukins, BCNMMMS, and P-tau181.ResultsIn BCNMMMS, sex interactions were observed for IL-1β (p = 0.048), IL-21 (p = 0.020), and complement component 3 (C3) (p = 0.041). After adjustment for confounding factors, IL-18 was associated with BCNMMMS in males (OR = 0.520 [0.274, 0.983]), while C3 was associated with BCNMMMS in females (OR = 0.452 [0.215, 0.950]). IL-21 and C3 levels were significantly associated with P-tau181 in females (IL-21: p = 0.002, C3: p = 0.047) but not in males. Besides, SHBG mediated the effect of IL-21 on cognitive performance in females (proportion of mediation = 19.72%; p = 0.032), suggesting a role for SHBG in sex-dependent inflammatory pathways related to cognitive performance.ConclusionsPeripheral inflammatory biomarkers, particularly IL-21, showed sex-specific links to plasma P-tau181 and non-memory impairment in ADNI, supporting sex-stratified analyses.},
}

@article {pmid41984026,
year = {2026},
author = {Peláez Torres, M and Varela Suárez, A},
title = {The expression of emotions in Alzheimer's disease and other dementias: An analysis of the deterioration patterns and compensatory strategies.},
journal = {Clinical linguistics & phonetics},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/02699206.2026.2651133},
pmid = {41984026},
issn = {1464-5076},
abstract = {For populations with language disorders, communicating their affective needs can be frustrating. Research has helped understand how people with dementia express their emotions and how they perceive them. This study aims to: (i) find out whether the capacity to use language to express emotions deteriorates as the cognitive impairment progresses in dementia; (ii) observe whether specific impairment patterns exist for each stage of the disease; (iii) verify whether compensatory strategies are used to express emotions when language begins to deteriorate. Twenty-seven participants at different stages of impairment were videorecorded while talking about their routines. The results show that the number of emotions expressed decreased as the disease progressed. Psychological verbs were the main explicit form used to express emotions. Prosody, figurative language, and gestures were observed as the main implicit devices to express emotions.},
}

@article {pmid41984340,
year = {2026},
author = {Justin, A and Manisha, C and Banerjee, S and Venu, G and Pandi, AV},
title = {Navigating the maze of Alzheimer's: nimodipine and pioglitazone combination in the spotlight through inhibition of P2X7 dependent NLRP3 inflammasome activation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41984340},
issn = {1568-5608},
}

@article {pmid41984490,
year = {2026},
author = {Zhang, Z and Chowdhury, N and Dong, J and Wu, L and Cheng, C},
title = {Systematic identification of cell-cell interactions associated with the severity of patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441603},
doi = {10.1177/13872877261441603},
pmid = {41984490},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder involving dysfunction across multiple brain regions. While accumulating evidence has implicated the roles of diverse cell types, including neurons, glia, and vascular cells in AD pathogenesis, it is still poorly understood how cell type interactions drive or respond to the disease progression and severity.ObjectiveThis study aimed to systematically characterize cell-type-specific alterations and intercellular communication changes associated with AD progression.MethodsWe leveraged the transcriptome profiling and a previously established statistical framework to present a comprehensive mapping of the cellular interaction landscape in the human brain of AD.ResultsWe identified a wide array of AD-associated cell-cell interactions (CCIs), including not only between the non-neuronal and neuron cells, but also among different neuron subtypes. These patterns were further supported by cell-type signature scoring. Moreover, due to the flexibility of the framework, we further examined CCIs associated with clinical dementia rating across multiple cortical regions. Our findings revealed that the temporal and frontal cortices showed a stronger correlation with dementia severity. However, the subregions of the temporal area show specific dementia-associated CCIs, especially between the inferior and middle temporal gyrus.ConclusionsOur work advances our understanding of the cellular microenvironment in AD, offering novel insights into how intercellular interactions shape disease trajectory and cognitive outcomes.},
}

@article {pmid41984491,
year = {2026},
author = {Summers, WK},
title = {Even schizophrenics fear Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441567},
doi = {10.1177/13872877261441567},
pmid = {41984491},
issn = {1875-8908},
abstract = {The term dementia dates back to 50 BC, when Lucretius used it to mean "being out of one's mind." Over time, dementia has become synonymous with Alzheimer's disease (AD), characterized by impaired memory. In the late nineteenth century, Emil Kraepelin's description of dementia praecox-later reclassified as schizophrenia-often included end-stage confusion and memory loss, suggesting a clinical overlap with what is now recognized as AD. Kraepelin's contemporary, Alois Alzheimer, described "presenile dementia" in Auguste Deter, whose history of paranoia and progressive cognitive decline may represent a schizophrenia-to-AD trajectory. The author reports a rare single modern case of a woman with lifelong untreated schizophrenia who developed AD-like dementia in her late 50 s, supporting the speculative hypothesis that AD was once a frequent terminal stage in the natural history of schizophrenia prior to the advent of antipsychotic therapy in the 1950s. Epidemiologic data show substantially elevated dementia prevalence in elderly schizophrenics. Emerging evidence links schizophrenia and AD through shared neurobiological mechanisms, including neuroinflammation and structural brain changes. The author proposes and speculates that long-term antipsychotic use may prevent AD progression via enhanced adult neurogenesis, as dopamine blockade alleviates the neurogenesis-suppressing effects of hyperdopaminergia. This hypothesis, that neurogenesis stimulated by chronic antipsychotic therapy mitigates neurodegeneration, offers a unifying model for the decline in dementia incidence among treated schizophrenics and reframes adherence motivation: treating schizophrenia may not only control psychosis but also protect against AD, a condition even schizophrenic patients fear.},
}

@article {pmid41984492,
year = {2026},
author = {Chiu, PY and Chiu, HJ and Wei, CY and Tzeng, RC and Chang, HT and Chen, HM},
title = {Dementia with Lewy bodies clinical syndrome (DLBCS) questionnaire: A simple tool for the clinical screening of DLB.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441187},
doi = {10.1177/13872877261441187},
pmid = {41984492},
issn = {1875-8908},
abstract = {BackgroundDementia with Lewy bodies (DLB) remains underdiagnosed due to overlapping clinical features with Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Early recognition is crucial, as DLB has distinct prognostic and therapeutic implications.ObjectiveThis study aimed to develop and validate a brief, clinically applicable screening instrument to improve bedside recognition of DLB and to compare its performance with established diagnostic approaches.MethodsWe designed the Dementia with Lewy Bodies Clinical Screening Questionnaire (DLBCSQ) and an extended version (DLBCSQ11) incorporating additional items to differentiate DLB from VCI. Clinical data were collected from a dementia registry in Taiwan, including patients with AD, VCI, and DLB. The diagnostic accuracy of DLBCSQ versions was evaluated using receiver operating characteristic (ROC) analyses across subgroups, including mild cognitive impairment with Lewy bodies (LB-MCI).ResultsBoth DLBCSQ and DLBCSQ11 demonstrated strong discriminatory ability, with area under the curve (AUC) values exceeding 0.84 for differentiating DLB from non-DLB syndromes. DLBCSQ11 showed greater specificity for distinguishing DLB from VCI, though about 20% of VCI patients still exhibited DLB-like features. Supplementary questions on visual hallucinations and tremors further improved detection of prodromal or mixed DLB cases.ConclusionsThe DLBCSQ9 and DLBCSQ11 represent practical and effective tools for clinical and bedside identification of DLB. By improving early recognition and differentiation from AD and VCI, these instruments may facilitate timely diagnosis, guide treatment decisions, and support future research on mixed dementia syndromes.},
}

@article {pmid41984497,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Ginkgo biloba and longitudinal changes in amyloid PET and plasma amyloid-β oligomerization in amyloid-positive mild cognitive impairment: A retrospective analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441816},
doi = {10.1177/13872877261441816},
pmid = {41984497},
issn = {1875-8908},
abstract = {BackgroundAmyloid PET-positive mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD), but its longitudinal clinical and biomarker trajectories vary considerably. Evidence linking oral interventions to amyloid-related biomarkers in this population remains limited.ObjectiveTo compare 18-month clinical outcomes and longitudinal changes in plasma amyloid-β (Aβ) oligomerization tendency and amyloid PET burden according to Ginkgo biloba use in amyloid PET-positive MCI.MethodsThis retrospective cohort study included 35 amyloid PET-positive MCI patients who underwent baseline and 18-month clinical evaluations, serial plasma Aβ oligomerization measurements using the Multimer Detection System-Oligomerized Aβ (MDS-OAβ) assay, and paired baseline and 18-month [18]F-FC119S amyloid PET. Patients received Ginkgo biloba extract 240 mg/day (n = 21) or Non-Ginkgo cognitive enhancers (n = 14). Clinical stability, conversion to AD dementia (Korean Instrumental Activities of Daily Living ≥0.40), changes in MDS-OAβ, and changes in global cortical standardized uptake value ratio (SUVR) were assessed.ResultsBaseline characteristics were comparable between groups. At 18 months, all Ginkgo-treated patients remained clinically stable, whereas 57.1% of Non-Ginkgo patients showed cognitive decline. Conversion to AD dementia occurred in none of the Ginkgo group and in 28.6% of the Non-Ginkgo group. Plasma MDS-OAβ decreased with Ginkgo but increased without Ginkgo. Global amyloid PET SUVR remained stable in the Ginkgo group and increased in the Non-Ginkgo group.ConclusionsIn amyloid PET-positive MCI, Ginkgo biloba use was associated with sustained clinical stability, reduced plasma Aβ oligomerization tendency, and attenuation of amyloid PET progression over 18 months.},
}

@article {pmid41984500,
year = {2026},
author = {Shah, S and Tran, T and Wadhwa, SS and Huerta, GI and Ovalle-Eliseo, S and Martinez, A and Vossel, K and Campos, B and Bholat, M and Moreno, G and Diaz-Santos, M and Chang, TS},
title = {Increased dementia diagnosis and workup in primary care with a bilingual screening tool integrated in the electronic health record.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441776},
doi = {10.1177/13872877261441776},
pmid = {41984500},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) affects over 10% of adults aged 65 and older. Black and Hispanic/Latino individuals experience 1.5-2.0 times higher prevalence than White individuals, yet AD remains underdiagnosed, particularly in non-White populations. Common screening tools such as the Mini-Mental State Examination and Montreal Cognitive Assessment are limited by time burden and cultural sensitivity.ObjectiveTo evaluate the impact of integrating a brief dementia screening tool (DST) into the electronic health record (EHR) on diagnosis, evaluation, and treatment in primary care.MethodsThe DST, developed by the University of California Alzheimer's Disease Centers and the California Department of Public Health, takes under five minutes and includes a three-question patient form, optional informant questionnaire, and Mini-Cog. It was translated and culturally adapted for Spanish-speaking patients and embedded in the EHR. Patients aged ≥60 in a diverse Los Angeles County family medicine clinic completed the DST before annual wellness visits. We conducted a pre-post study comparing patients without prior dementia diagnoses during pre-intervention (February 2021-August 2022) and post-intervention (January 2023-June 2024) periods. Primary outcome was new dementia diagnosis; secondary outcomes included medications, referrals, labs, and imaging.ResultsAmong 1515 eligible patients post-intervention, 1249 completed screening. New dementia diagnoses increased from 0.75% pre-DST to 2.45% among those screening positive (adjusted OR 2.99; p = 0.01). Dementia medications, laboratory orders, and specialty referrals significantly increased; imaging did not.ConclusionsA brief, culturally adapted DST integrated into primary care improved dementia diagnosis, evaluation, and treatment.},
}

@article {pmid41984504,
year = {2026},
author = {Bandaru, M and Rainier, A and Islam, MA and Reddy, PH},
title = {Behavioral consequences of serotonin deficiency in TPH2 knock-in mice: Implications for depression, anxiety, and cognitive dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442229},
doi = {10.1177/13872877261442229},
pmid = {41984504},
issn = {1875-8908},
abstract = {BackgroundSerotonin (5-hydroxytryptamine, 5-HT) is essential to mood regulation, and its dysfunction has been strongly connected to depression and anxiety disorders. The key enzyme for serotonin production is tryptophan hydroxylase 2 (TPH2); genetic abnormalities influencing TPH2 activity have been connected to mood disorders.ObjectiveOur study aims to understand the consequences of human TPH2 mutation-TPH2 R439H in mice, especially depression and anxiety-like behaviors.MethodsCompared to wild-type, we employed 6-month-old knock-in mice, heterozygotes (one allele) and homozygotes (two alleles) expressing TPH2 R439H analogous to the human R441H TPH2 mutation. We examined behavioral differences between TPH2-KI and WT mice, heterozygotes and homozygotes, and males and females. Tail suspension and forced swim assessed depression-like behavior; open field and light-dark tests assessed anxiety and exploration; the Morris water maze tested memory and spatial learning; rotarod assessed balance and motor coordination; and the novel object test assessed recognition memory.ResultsOur findings demonstrate that TPH2 KI mice exhibited increased depression-like behavior in the forced swim and tail suspension tests; increased avoidance in the light-dark and open field tests revealed anxiety-like phenotypes. Furthermore, serotonin deficit decreased locomotion and coordination in the rotarod. In the novel object, recognition memory was impaired, but spatial learning and memory in the Morris water were unaffected. Homozygotes displayed more severe phenotypes than heterozygotes, indicating a gene dosage-dependent effect.ConclusionsOur findings extend prior behavioral characterizations of TPH2 KI mice by providing an integrated profile at 6-month age point, revealing domain-specific effects across mood, anxiety, locomotion, and recognition memory.},
}

@article {pmid41984506,
year = {2026},
author = {Sakurai, K and Kaneda, D and Uchida, Y and Shibata, H and Inui, S and Tanaka, K and Morimoto, S and Hashizume, Y},
title = {Intermediate structural covariance network abnormalities in argyrophilic grain disease between Alzheimer's disease and healthy controls.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261440972},
doi = {10.1177/13872877261440972},
pmid = {41984506},
issn = {1875-8908},
abstract = {BackgroundArgyrophilic grain disease (AGD) is a common tauopathy in the elderly, but its neuroimaging features remain less well characterized compared with Alzheimer's disease (AD). Notably, structural covariance network (SCN) analysis has not previously been applied to AGD.ObjectiveThis study aimed to investigate SCN alterations in pathologically confirmed AGD and AD and to characterize disease-specific patterns of network disruption.MethodsWe examined 12 AGD, 13 AD, and 18 healthy controls (HC). Individualized structural covariance matrices were constructed from regional gray matter volumes, and global and nodal graph-theoretical metrics were computed for each participant. Group differences were assessed using analysis of covariance adjusting for age and sex, and partial correlations were performed to examine associations between global metrics and Mini-Mental State Examination (MMSE) scores.ResultsGlobal SCN metrics showed a graded pattern, with strength, clustering coefficient, and efficiency lowest in AD, highest in HC, and intermediate in AGD. All global metrics except modularity were significantly correlated with MMSE. Nodal analyses revealed widespread reductions in closeness centrality in AD, with more limited decreases in AGD. Betweenness centrality showed an AD > AGD > HC pattern, whereas closeness centrality showed the opposite trend. Eigenvector centrality also suggested a graded trend (AD < AGD < HC), despite regional variability.ConclusionsSCN-derived metrics were consistent with disease-related volume patterns and revealed that AGD exhibits an intermediate network profile between AD and healthy aging. These findings suggest that SCN-based measures offer complementary insights into disease-related patterns of network disruption.},
}

@article {pmid41984510,
year = {2026},
author = {Shouman, M and Jaffa, AA and Sibai, AM and Hunt, K and Jaffa, MA},
title = {Subjective cognitive decline among older adults and its link to diabetes, cardiovascular diseases, and other comorbidities: A US population-based study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441275},
doi = {10.1177/13872877261441275},
pmid = {41984510},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is the self-reported occurrence of increasing confusion or memory loss. Accumulating evidence suggests that SCD may be a prodromal phase of progressed cognitive decline stages, particularly Alzheimer's disease. The risk factors, mainly comorbidities, associated with SCD are not well known.ObjectiveThis study aims to examine whether diabetes, cardiovascular disease (CVD), with a focus on stroke and coronary heart disease (CHD), and other comorbidities are associated with SCD.MethodsWe conducted a quantitative analysis employing weighted analyses on cross-sectional data adopted from the 2022 Behavioral Risk Factor Surveillance System.ResultsOur results showed that out of 60,492 adults aged 45 years and older, 6423 individuals (10.45%) reported experiencing SCD, 19.49% diabetes, 11.78% CHD, and 5.67% stroke. Among diabetics, 33.41% reported insulin use. Comorbidities that were significantly associated with SCD included stroke (OR: 1.61; 95%CI: 1.24-2.08), CHD (OR:1.56; 95% CI: 1.27,1.92), and diabetes (OR: 1.25; 95%CI: 1.02-1.55). Other significant comorbidities included depressive disorder (OR: 2.56; 95% CI: 2.18-3.02), kidney disease (OR: 1.89; 95% CI: 1.24-2.87), arthritis (OR: 1.31; 95%CI: 1.07-1.61), and asthma (OR: 1.27; 95%CI: 1.06-1.52). Age of diagnosis with diabetes was younger among participants with SCD. Insulin use was significantly associated with SCD, particularly among type 2 diabetes, accounting for duration of diabetes. (OR: 1.39; 95% CI:1.02- 1.92).ConclusionsGiven the importance of SCD as a precursor to progressed cognitive impairment, these findings highlight the need for awareness and proactive screening for cognitive dysfunction among high-risk individuals with CVDs, diabetes, depression, and other comorbidities.},
}

@article {pmid41984511,
year = {2026},
author = {Liu, K and Sun, W and Ma, G and Chen, F and Liu, T},
title = {Global burden, trends, and projections of Alzheimer's disease and other dementias attributable to high body mass index from 1990 to 2040: A comprehensive analysis of the Global Burden of Disease Study 2021.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261439948},
doi = {10.1177/13872877261439948},
pmid = {41984511},
issn = {1875-8908},
abstract = {BackgroundHigh body mass index (BMI) is a modifiable risk factor for Alzheimer's disease and other dementias (ADODs), but a global assessment of BMI-attributable ADOD burden and its future trends is limited.ObjectiveTo quantify the spatiotemporal patterns, inequalities, and projections of BMI-attributable ADOD burden across 204 countries and territories from 1990 to 2021, with forecasts to 2040.MethodsUsing Global Burden of Disease (GBD) 2021 risk estimates, we analyzed high BMI-attributable ADOD deaths, disability-adjusted life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR) by age, sex, region, and Socio-demographic Index (SDI). Trends were assessed with estimated annual percentage change (EAPC). Drivers were examined using decomposition analyses, and future trends were projected with autoregressive integrated moving average (ARIMA) models. Population attributable fractions (PAFs) were calculated for selected countries.ResultsHigh BMI-attributable ADOD deaths increased from 31,577 in 1990 to 139,439 in 2021, with ASMR rising from 1.22 to 1.79 per 100,000 people (EAPC=1.17%). DALYs grew from 644,750 to 2,665,746, with ASDR increasing from 21.39 to 32.86 per 100,000 (EAPC=1.32%). Females faced a higher absolute burden, while males showed faster increases in standardized rates. Growth was concentrated in low- and middle-SDI regions, particularly East/Southeast Asia and parts of sub-Saharan Africa.ConclusionsBMI-attributable ADOD burden has risen significantly since 1990, with notable socioeconomic disparities, and is expected to increase through 2040. Urgent action is needed for obesity prevention and integrated risk management.},
}

@article {pmid41984552,
year = {2026},
author = {Garanin, AA and Aydumova, OY and Rubanenko, AO and Khumorova, AR and Kolsanov, AV},
title = {[Speech signal acoustic analysis in the diagnosis of neurological and mental diseases: a systematic review and meta-analysis].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {3},
pages = {38-44},
doi = {10.17116/jnevro202612603138},
pmid = {41984552},
issn = {1997-7298},
mesh = {Humans ; *Parkinson Disease/diagnosis/physiopathology ; *Alzheimer Disease/diagnosis/physiopathology ; *Speech Acoustics ; *Mental Disorders/diagnosis ; *Nervous System Diseases/diagnosis ; },
abstract = {OBJECTIVE: To assess speech signal acoustic parameters for the diagnosis of neurological and mental diseases.

MATERIAL AND METHODS: The data were searched in accordance with the PRISMA requirements and guidelines across the PubMed, Google Scholar, ClinicalTrials.gov, CyberLenink, and eLibrary databases. Seven publications were selected for the final analysis of full-text articles. These papers evaluated the parameters of the speech signal in patients with Parkinson's disease, Alzheimer's disease, and primary depression. The meta-analysis examined Jitter and Shimmer in patients' speech signals compared with those of healthy volunteers.

RESULTS: Six studies were included in the meta-analysis in assessing the diagnostic capabilities of changes in fundamental tone frequency (Jitter) for neurological and mental diseases. The meta-analysis included 180 patients and 193 healthy volunteers. According to the results, Jitter was significantly more pronounced in patients with Alzheimer's disease, depression, and Parkinson's disease than in healthy volunteers (mean difference 0.786 (0.481-1.091), I[2]=45.83%, p<0.001). The meta-analysis of speech-signal acoustic analysis results for diagnosing neurological and mental diseases, based on changes in signal amplitude (Shimmer), included 7 studies involving 222 patients and 295 healthy volunteers. There was no statistically significant difference in Shimmer in patients with Alzheimer's disease, depression, and Parkinson's disease, compared to patients without diseases (mean difference 0.392 (-0.179-0.962), I[2]=88.86%, p=0.178).

CONCLUSION: This systematic review and meta-analysis of studies have shown the potential of acoustic analysis of the speech signal for diagnosing neurological and mental diseases. Jitter is a reliable diagnostic criterion for the presence and progression of neurological and mental diseases.},
}

Humans
*Parkinson Disease/diagnosis/physiopathology
*Alzheimer Disease/diagnosis/physiopathology
*Speech Acoustics
*Mental Disorders/diagnosis
*Nervous System Diseases/diagnosis

@article {pmid41984553,
year = {2026},
author = {Shamakina, IY and Kokhan, VS and Venkova, VA and Baronets, VY and Popov, SS and Anokhin, PK},
title = {[BIN1 (amphiphysin 2) in the pathogenesis of cognitive impairment].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {3},
pages = {45-52},
doi = {10.17116/jnevro202612603145},
pmid = {41984553},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/genetics/metabolism ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Tumor Suppressor Proteins/genetics/metabolism ; *Nerve Tissue Proteins/genetics/metabolism ; Genome-Wide Association Study ; Nuclear Proteins ; },
abstract = {As shown by a genome-wide association study (GWAS), the Bridging Integrator 1 (BIN1) gene is the second most important genetic locus associated with Alzheimer's disease risk, after apolipoprotein E (APOE). Amphiphysin 2 (Bin1), encoded by this gene, is an adaptor protein involved in the regulation of synaptic vesicular transport and neurotransmission. In Alzheimer's disease patients, Bin1 protein expression was found to be altered in several regions of the brain, including the hippocampus, which may affect Tau-dependent neurologic conditions and disease progression. This review presents current data on the structure, functions, and potential role of Bin1 in the pathogenesis of cognitive impairment of varying severity, as well as the potential use of allelic polymorphisms of the BIN1 gene for diagnosing cognitive impairment and assessing AD risk.},
}

Humans
*Cognitive Dysfunction/genetics/metabolism
*Adaptor Proteins, Signal Transducing/genetics/metabolism
*Alzheimer Disease/genetics/metabolism
*Tumor Suppressor Proteins/genetics/metabolism
*Nerve Tissue Proteins/genetics/metabolism
Genome-Wide Association Study
Nuclear Proteins

@article {pmid41984564,
year = {2026},
author = {Shavlovskaya, OA},
title = {[The effectiveness of citicoline in the treatment of cognitive disorders].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {3},
pages = {136-140},
doi = {10.17116/jnevro2026126031136},
pmid = {41984564},
issn = {1997-7298},
mesh = {Humans ; *Cytidine Diphosphate Choline/therapeutic use ; *Nootropic Agents/therapeutic use ; Parkinson Disease/drug therapy/complications ; *Cognitive Dysfunction/drug therapy ; Alzheimer Disease/drug therapy ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Stroke/complications ; },
abstract = {Randomized controlled trials, systematic reviews, and meta-analyses have shown that citicoline is highly effective in the treatment of vascular cognitive impairments (CI) of various origins (post-stroke, chronic cerebral ischemia (CCI)), post-traumatic CI, mild CI in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), and in patients with age-related memory impairments. Citicoline administration regimens: 1) post-stroke CI at a dose of 1000 mg/day. for a course of 4-12 months; 2) mild CI of vascular origin at a dose of 500 mg/day for a course of 3-9 months; 3) CI against the background of CCI at a dose of 500-2000 mg, the duration of the course depends on the severity of the symptoms; 4) non-demented CI at a dose of 1000 mg/day course of 9 months; 5) mild CI against Parkinson's disease at a dose of 1000 mg/day 12-18 months.},
}

Humans
*Cytidine Diphosphate Choline/therapeutic use
*Nootropic Agents/therapeutic use
Parkinson Disease/drug therapy/complications
*Cognitive Dysfunction/drug therapy
Alzheimer Disease/drug therapy
Randomized Controlled Trials as Topic
Treatment Outcome
Stroke/complications

@article {pmid41984821,
year = {2026},
author = {Shao, D and Liang, S and Xiong, Y and Liang, G},
title = {MAISNet: A Multi-Species Integrated Graph Neural Network for Acetylcholinesterase Inhibitor Screening.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag153},
pmid = {41984821},
issn = {1367-4811},
abstract = {MOTIVATION: Global population aging has led to a rapid increase in neurodegenerative disorders such as alzheimer's disease (AD). Although existing drugs can temporarily alleviate symptoms, none have been proven to delay or prevent disease progression. Acetylcholinesterase inhibitors (AChEIs) have been shown to mitigate AD symptoms, yet traditional AChEI screening approaches remain time-consuming and inefficient.

RESULTS: To address this limitation, we developed MAISNet, an AChEI screening framework based on acetylcholinesterase (AChE) data from six species. In MAISNet, inhibitor molecules were represented as SMILES-derived molecular graphs, whereas AChE protein structures were encoded as residue contact maps. Multi-scale molecular and protein features were extracted using the sample and aggregate (GraphSAGE) network and the graph attention network (GAT), respectively, and were subsequently fused through a bidirectional cross-attention mechanism. The integrated representations were then processed by a multilayer perceptron (MLP) to inhibitor classification. On both internal and external validation sets, MAISNet consistently outperformed five baseline models. Furthermore, we applied MAISNet to screen existing small molecules, and Methyl 2-[(3S)-3-(1, 2, 3, 4, 5, 6, 7, 8-octahydro-2-naphthyl)-2-(methoxycarbonyl)-1H-pyrrol-1-yl]acetate subsequently emerged as the top-ranked candidate. Overall, MAISNet significantly improves the accuracy and generalization capability of AChEI screening, providing an efficient and reliable computational tool for accelerating therapeutic discovery for AD.

AVAILABILITY: Code that supports the reported results can be found at: https://github.com/liangshengjie111/MAISNet. The archival version of the code is preserved on Zenodo at https://doi.org/10.5281/zenodo.18721665.},
}

@article {pmid41985059,
year = {2026},
author = {Du, JH and Shen, M and Mathys, H and Roeder, K},
title = {Uncovering causal relationships in single-cell omic studies with causarray.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {2},
pages = {},
doi = {10.1093/bib/bbag175},
pmid = {41985059},
issn = {1477-4054},
mesh = {*Single-Cell Analysis/methods ; Humans ; Animals ; Mice ; Alzheimer Disease/genetics ; *Genomics/methods ; Brain/metabolism ; Autistic Disorder/genetics ; Machine Learning ; Transcriptome ; Case-Control Studies ; },
abstract = {Advances in single-cell sequencing and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technologies have enabled detailed case-control comparisons and experimental perturbations at single-cell resolution. However, uncovering causal relationships in observational genomic data remains challenging due to selection bias and inadequate adjustment for unmeasured confounders, particularly in heterogeneous datasets. To address these challenges, we introduce causarray, a robust causal inference framework for analyzing array-based genomic data at both pseudo-bulk and single-cell levels under unmeasured confounding. causarray integrates a generalized confounder adjustment method to account for unmeasured confounders and employs semiparametric inference with flexible machine learning techniques to ensure robust statistical estimation of treatment effects. Benchmarking results show that causarray robustly separates treatment effects from confounders while preserving biological signals across diverse settings. We also apply causarray to two single-cell genomic studies: (i) an in vivo Perturb-seq study of autism risk genes in developing mouse brains and (ii) a case-control study of Alzheimer's disease (AD) using three human brain transcriptomic datasets. In these applications, causarray identifies clustered causal effects of multiple autism risk genes and consistent causally affected genes across AD datasets, uncovering biologically relevant pathways directly linked to neuronal development and synaptic functions that are critical for understanding disease pathology.},
}

*Single-Cell Analysis/methods
Humans
Animals
Mice
Alzheimer Disease/genetics
*Genomics/methods
Brain/metabolism
Autistic Disorder/genetics
Machine Learning
Transcriptome
Case-Control Studies

@article {pmid41985110,
year = {2026},
author = {Mahajan, A and Dwivedi, AK and Galvin, JE and Maixner, SM and Paulson, HL and Manning, CA and Fields, JA and Boeve, BF and Mills, KA and Morrow, C and Pontone, GM and Armstrong, MJ},
title = {Cognitive Fluctuations, Neuropsychiatric Burden, and Quality of Life in Moderate-Advanced Dementia With Lewy Bodies: The Role of Dysautonomia.},
journal = {Neurology},
volume = {106},
number = {9},
pages = {e214934},
doi = {10.1212/WNL.0000000000214934},
pmid = {41985110},
issn = {1526-632X},
mesh = {Humans ; *Quality of Life/psychology ; Female ; Male ; *Lewy Body Disease/psychology/complications/physiopathology ; Aged ; *Primary Dysautonomias/psychology/complications/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Prospective Studies ; Neuropsychological Tests ; },
abstract = {BACKGROUND AND OBJECTIVES: Cognitive fluctuations are reported in 90% of individuals with dementia with Lewy bodies (DLB) and along with dysautonomia, are a key source of disability. Through this effort, we sought to investigate the relationship between autonomic burden and cognitive fluctuations, neuropsychiatric burden and quality of life in moderate-advanced DLB.

METHODS: This multicenter, prospective, observational, longitudinal cohort study, Predicting ACcurately End-of-Life in Dementia With Lewy Bodies and Promoting Quality End-of-Life Experiences (PACE-DLB), was conducted in the United States to study individuals with moderate-advanced DLB. The primary exposure for the current analysis was time-varying total autonomic burden, as measured by the autonomic symptom checklist (ASC) at baseline and follow-up visits. The primary outcomes were cognitive fluctuations measured by Clinician Assessment of Fluctuations (CAF) scores and neuropsychiatric burden as measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) scores. Secondary outcomes included quality of life (QoL) captured through the Quality of Life-Alzheimer's Disease scale. Mixed-effects regression analyses were conducted to assess the effect of autonomic burden on each primary outcome, with age, sex, education, Charlson Comorbidity Index, anticholinergic burden, levodopa equivalent daily dosage, and EPWORTH sleepiness scale scores adjusted as potential confounders. We additionally conducted modified graphical network model analyses.

RESULTS: A total of 189 patients with 745 longitudinal observations were included in the analysis. Mean age of the cohort was 74.92 years (SD 7.77 years) with 22% female participants. At baseline, ASC was directly associated with CAF (RC = 0.16; 95% CI 0.01-0.31; p = 0.032) and NPI-Q (RC = 3.27; 95% CI 2.37-4.18; p < 0.001). In longitudinal analysis, ASC remained directly associated with CAF (RC = 0.18; 95% CI 0.11-0.24; p < 0.001) and NPI-Q (RC = 2.10; 95% CI 1.49-2.71; p < 0.001). ASC scores were inversely associated with QoL of the caregiver (RC = -0.04; 95% CI -0.06 to -0.02) in longitudinal adjusted analysis. Graphical network modeling incorporating possible relationships across characteristics showed that autonomic burden was directly and stably associated with cognitive fluctuations (weight = 0.15) and neuropsychiatric burden (weight = 0.47).

DISCUSSION: Autonomic burden correlates with severity of cognitive fluctuations and neuropsychiatric burden in moderate-advanced DLB. It also correlates with the QoL of the caregiver over time. These results encourage investigation into novel potential therapeutic avenues in moderate-advanced DLB.},
}

Humans
*Quality of Life/psychology
Female
Male
*Lewy Body Disease/psychology/complications/physiopathology
Aged
*Primary Dysautonomias/psychology/complications/physiopathology
Longitudinal Studies
Aged, 80 and over
Prospective Studies
Neuropsychological Tests

@article {pmid41985127,
year = {2026},
author = {Zhao, B and Sang, L and Zhang, Z and Chen, X and Li, M and Li, Y and Xue, Y and Yan, T and Wang, B and Jian, A},
title = {Genetic Algorithm-Optimized Hyperbolic Metamaterial SPR Sensors for Ultrasensitive Biosensing Applications.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c07195},
pmid = {41985127},
issn = {1520-6882},
abstract = {Enhancing the sensitivity of surface plasmon resonance (SPR) sensors is critical for detecting lower analyte concentrations and smaller biomolecular interactions. In this study, we designed and developed a surface plasmon resonance (SPR) sensor platform based on hyperbolic metamaterials (HMMs). The sensor is composed of Ag/Al2O3 multilayer composites, and a genetic algorithm (GA) was employed to systematically determine the optimal parameter configuration for the HMMs-based SPR sensor. Furthermore, theoretical analysis was conducted using the finite element analysis method, revealing that the electric field intensity within the hyperbolic metamaterial exhibits a layer-by-layer increasing trend, with significant field enhancement predominantly occurring within the dielectric layers. Compared with conventional SPR sensors, where electric field enhancement is confined to a single interface, the HMMs structure demonstrates a clear advantage in field enhancement, thereby substantially improving the sensitivity of the SPR sensor. Experimental results further validated the performance of the sensor, achieving a refractive index (RI) sensitivity of 43.62 μm/RIU, which represents an improvement of approximately 1 order of magnitude compared with traditional SPR sensors. This platform was used to test for the Alzheimer's disease biomarker β-amyloid 1-42 (Aβ1-42), achieving an ultralow limit of detection (LOD) of 0.18 pg/mL. GA design provides a generalized approach to improving device performance and is expected to have a significant impact on the design and application of sensors.},
}

@article {pmid41985272,
year = {2026},
author = {Zhang, Y and Ren, R and Feng, X and Wang, M and Huang, J and Shi, J and Lu, L and Sanford, LD and Vitiello, MV and Tang, X},
title = {Sleep abnormalities across different clinical stages of Alzheimer's disease: A systematic review and network meta-analysis.},
journal = {Sleep medicine reviews},
volume = {88},
number = {},
pages = {102289},
doi = {10.1016/j.smrv.2026.102289},
pmid = {41985272},
issn = {1532-2955},
abstract = {Sleep disturbances play an important role in Alzheimer's disease (AD) pathology. However, it is unclear exactly how sleep changes across the AD continuum. To address this gap, we conducted a network meta-analysis to explore how sleep changes (self-reported sleep quality, daytime sleepiness, polysomnography (PSG) and actigraphy measured sleep) across the clinical stages of AD. We searched MEDLINE, EMBASE, and all EBM databases via OVID and Web of Science. Meta-analyses revealed that although sleep changes are more marked in AD dementia, there are sleep signatures in mild cognitive impairment (MCI) which may exist persistently in more advanced stage. For instance, the decreased sleep efficiency and rapid eye movement (REM) sleep percentage observed in MCI were more obvious in AD dementia, while the decreased slow wave sleep (SWS) was only observed in AD dementia but not in MCI. The increasing abnormalities in objective sleep may be considered as important indicators associated with active pathology across the AD continuum. Interventions to improve PSG measured total sleep time, SWS and REM would likely have potential for slowing AD progression, particularly if employed early in the disease process, e.g., in individuals with mild cognitive impairment due to AD or those with genetic risk for developing AD.},
}

@article {pmid41985299,
year = {2026},
author = {Raka, RN and Zhang, Z and Xiao, J and Wu, H},
title = {Integrative network pharmacology delineates dual GPCR and non-GPCR mechanisms of blended and individual Taikong Blue lavender and Pingyin rose essential oils in neurodegenerative and psychiatric disorders.},
journal = {Computers in biology and medicine},
volume = {208},
number = {},
pages = {111681},
doi = {10.1016/j.compbiomed.2026.111681},
pmid = {41985299},
issn = {1879-0534},
abstract = {Neurodegenerative and psychiatric disorders share overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and neurotransmitter dysregulation. Essential oils from Lavandula angustifolia (TLEO) and Rosa rugosa (PREO) contain neuroactive compounds with therapeutic potential, but their mechanisms remain poorly defined. This study aimed to elucidate the shared and distinct molecular targets and pathways of TLEO and PREO using a multi-scale computational strategy. Compounds identified by GC-MS were evaluated through ADMET profiling, target prediction, and disease-target intersection analysis. Enrichment, network, docking, and dynamics analyses were performed on shared protein-coding targets between essential oils and twelve brain disorders, including seven neurodegenerative conditions (Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy) and five psychiatric disorders (autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia). A total of 110 compounds yielded 252 common targets, with CHRM2 (GPCR) and NR1H3 (non-GPCR) identified as key hubs. Docking suggested strong binding affinities for caryophyllene oxide at CHRM2 (-7.3 kcal/mol) and α-himachalene at NR1H3 (-8.5 kcal/mol). Molecular dynamics simulations confirmed stable, compact complexes with low RMSD and SASA values. MM/PBSA free energy calculations quantitatively validated these interactions, revealing favorable binding energetics driven predominantly by van der Waals and hydrophobic contributions, consistent with the terpenoid chemical profiles. Functional enrichment highlighted involvement in cholinergic signaling, lipid metabolism, and inflammatory regulation. This study demonstrates that PREO and TLEO can modulate multiple targets relevant to brain disorders through both GPCR and non-GPCR mechanisms. These findings provide a computationally inferred mechanistic framework for the potential neuroprotective synergy of these oils and highlight essential oil-derived compounds as promising leads for further experimental investigation.},
}

@article {pmid41985457,
year = {2026},
author = {Kim, J and Hwang, Y and Kim, S and Kwon, D and Park, J and Cho, B and An, S and Kang, S and Kim, Y and Kim, S and Lengner, CJ and Kim, S and Kwon, Y and Sung, JS and Kim, J},
title = {Electromagnetic field-inducible in vivo gene switch for remote spatiotemporal control of gene expression.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.03.029},
pmid = {41985457},
issn = {1097-4172},
abstract = {Gaining precise control of gene expression is crucial in biomedical applications. However, spatiotemporal precision remains challenging. Here, we present a remotely controlled in vivo gene switch responsive to electromagnetic fields (EMFs) that enables precise spatiotemporal activation of target genes. We uncovered the EMF-inducible gene switch activation mechanism via a CRISPR-Cas9 screen, identifying cytochrome b5 type B (Cyb5b) as an essential mediator likely acting as an EMF sensor. The EMF-inducible gene switch was activated by rhythmic oscillatory calcium dynamics rather than generic calcium influx, defining a precisely tuned and bio-orthogonal induction mechanism. Functionally, EMF activation of the Oct4-Sox2-Klf4 (OSK) cassette induced in vivo partial reprogramming in aged mice, conditional expression of human mutant amyloid precursor protein (APP) for Alzheimer's disease (AD) modeling recapitulated pathological features, and EMF-mediated Tph2 expression restored serotonergic activity and ameliorated depressive-like behaviors in Tph2-mutant depression mice. Overall, a remotely controlled EMF-inducible gene switch represents a versatile and effective biomedical platform.},
}

@article {pmid41985514,
year = {2026},
author = {Porcaro, C and Bertoldo, A},
title = {Quantifying Fractal and Oscillatory Components in Neural Signals for Biomarker Development.},
journal = {Progress in biomedical engineering (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/2516-1091/ae6003},
pmid = {41985514},
issn = {2516-1091},
abstract = {Neural activity encompasses both rhythmic oscillations and aperiodic background dynamics, reflecting complex brain function beyond traditional rhythm-centric views. The aperiodic component, once considered noise, is now recognised as a meaningful signal indicative of excitation-inhibition balance and intrinsic neural timescales. Here, we review advanced signal processing frameworks, including spectral parameterisation and burst detection algorithms, that disentangle these periodic and aperiodic components. We critically evaluate evidence suggesting that aperiodic parameters track neurodevelopment and serve as candidate biomarkers for Alzheimer's Disease and Parkinsonism. Furthermore, we highlight how neuroengineering interventions, such as Deep Brain Stimulation and acupuncture, actively modulate these features. Crucially, we address the current methodological heterogeneity in the field, proposing a standardized roadmap for estimation to resolve conflicting interpretations. These findings underscore the complementary roles of oscillatory and aperiodic dynamics, offering novel avenues for closed-loop brain-computer interfaces (BCIs) and personalized neurotherapeutics.},
}

@article {pmid41985741,
year = {2026},
author = {Luo, Q and Huang, N and Li, D and Chen, X and Liu, Z and Sha, L and Liu, C and Yang, Y and Wu, S and Wojtecki, L and Chen, L and Huang, C},
title = {Reclassifying Transcranial Pulse Stimulation as TNUS: Nonlinear Mechanics Necessitate Departure from the ITRUSST Framework.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103099},
doi = {10.1016/j.brs.2026.103099},
pmid = {41985741},
issn = {1876-4754},
abstract = {BACKGROUND: Transcranial ultrasound has emerged as a promising non-invasive neuromodulation modality for Alzheimer's disease (AD). However, its clinical translation is hindered by inconsistent biophysical classification between quasi-linear low-intensity focused ultrasound (LIFU) and nonlinear pulse-based approaches.

OBJECTIVE: To propose a Transcranial Nonlinear Ultrasound Stimulation (TNUS) framework for the formal reclassification of Transcranial Pulse Stimulation (TPS), enabling clear differentiation of nonlinear wave mechanics from quasi-linear acoustics.

METHODS: This perspective review integrates biophysical modeling within the nonlinear Westervelt regime, critically appraises recent clinical trial data, and conducts a comparative analysis of acoustic dosimetry by contrasting the periodic waves characteristic of linear LIFU with the shock-front dynamics of TPS.

RESULTS: TPS is characterized by an extreme pressure gradient (), representing a five-order-of-magnitude divergence from LIFU. This regime facilitates a Volume Force model and Ballistic Gating of ion channels via displacement currents, a mechanism distinct from the steady-state pathways of intramembrane cavitation. In the atrophied AD brain, pathological expansion of the cerebrospinal fluid (CSF) compartment induces focal displacements and compromises wavefront integrity through refractive aberrations at the CSF-parenchyma interface. While the Glassy Regime of tissue provides a biomechanical safety buffer, the compromised compliance in Cerebral Amyloid Angiography (CAA) requires TPS protocols to remain below the vascular ultimate tensile strength (UTS).

CONCLUSIONS: Future clinical optimization of TPS necessitates a transition toward structure-aware dosimetry. The implementation of adaptive beamforming (e.g., TUSNet) and individualized impulse titration is essential to mitigate refractive aberrations and vascular failure risks in the pathologically heterogeneous aging brain.},
}

@article {pmid41985900,
year = {2026},
author = {Nonino, F and Minozzi, S and Sambati, L and Del Giovane, C and Baldin, E and Bassi, MC and De Santis, C and Gonzalez-Lorenzo, M and Vignatelli, L and Filippini, G and Richard, E},
title = {Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease.},
journal = {The Cochrane database of systematic reviews},
volume = {4},
number = {},
pages = {CD016297},
doi = {10.1002/14651858.CD016297},
pmid = {41985900},
issn = {1469-493X},
mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Cognitive Dysfunction/drug therapy/etiology ; *Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Aged ; },
abstract = {RATIONALE: Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid-beta protein deposits are implicated in its pathogenesis. Amyloid-beta-targeting monoclonal antibodies (sometimes represented as Aβ-mAbs) are potentially disease-modifying for Alzheimer's disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline.

OBJECTIVES: To assess the clinical benefits and harms of amyloid-beta-targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer's disease.

SEARCH METHODS: We searched CENTRAL, MEDLINE (PubMed), Embase, and two clinical trials registries (Clinicaltrials.gov and WHO International Clinical Trials Registry Platform), and we undertook reference checking and citation research. The most recent search date was 7 August 2025.

ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared amyloid-beta-targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. We included both parallel-group and cluster designs.

OUTCOMES: Our outcomes of critical importance were: cognitive function; dementia severity; functional ability; any amyloid-related imaging abnormality (ARIA), which includes oedema (E) and haemorrhage (H); any symptomatic ARIA E and H; symptomatic brain haemorrhage; serious adverse events; and any-cause mortality. We analysed data at 12, 18, 24, and over 24 months of treatment.

RISK OF BIAS: We used the Cochrane risk of bias tool RoB 2 to assess the risk of bias in outcomes of critical importance.

SYNTHESIS METHODS: We meta-analysed results for each outcome within each comparison using the inverse variance method and the random-effects model. We used GRADE to assess the certainty of evidence for each outcome as very low, low, moderate, or high.

INCLUDED STUDIES: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants' cognitive impairment ranged from 17 to 52 months. The 17 studies assessed seven different amyloid-beta-targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months. All studies were funded by the pharmaceutical industry.

SYNTHESIS OF RESULTS: Below, we report the results of the studies at 18 months. Cognitive function Compared to placebo, amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive) scale (standardised mean difference (SMD) -0.11, 95% confidence interval (CI) -0.16 to -0.06; 13 studies, 9895 participants; moderate certainty). Dementia severity Amyloid-beta-targeting monoclonal antibodies may result in little to no difference in dementia severity as measured by the CDR-SB (Clincal Dementia Rating Sum of Boxes) scale (SMD -0.12, 95% CI -0.24 to -0.00; 9 studies, 8053 participants; low certainty). Functional ability Amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS-ADL-MCI (Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty). Adverse events Amyloid-beta-targeting monoclonal antibodies probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty) and probably little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty). Three studies assessing any ARIA H showed heterogeneous results (I[2] = 81%), which prevented pooled analysis. At 18 months, amyloid-beta-targeting monoclonal antibodies do not increase serious adverse events (ARD 6 more events per 1000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) or overall mortality (ARD 2 more events per 1000, 95% CI 3 fewer to 11 more; 7 studies, 9733 participants; high certainty). We judged the overall risk of bias as low for the outcomes of serious adverse events and mortality. We had some concerns about the overall risk of bias for efficacy outcomes, mainly due to the risk of functional unblinding (i.e. participants and investigators correctly guessing whether a participant is receiving the active drug or placebo because of noticeable side effects).

AUTHORS' CONCLUSIONS: The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action.

FUNDING: This Cochrane review was funded in part by the Drug and Medical Devices Governance Area, Regione Emilia-Romagna, Bologna, Italy. The publication of this article was supported by "Ricerca Corrente" funding from the Italian Ministry of Health.

REGISTRATION: Protocol (2025): PROSPERO registration number CRD420251114325.},
}

Humans
*Alzheimer Disease/complications/drug therapy
*Cognitive Dysfunction/drug therapy/etiology
*Amyloid beta-Peptides/antagonists & inhibitors/immunology
Randomized Controlled Trials as Topic
*Antibodies, Monoclonal/therapeutic use/adverse effects
Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
Aged

@article {pmid41986146,
year = {2026},
author = {Ebani, EJ and Yadav, D and Knight-Greenfield, A and Gardella, J and Moirano, J and Intorcia, B and RoyChoudhury, A and Keil, SA and Nordvig, AS and Blum, S and Lin, M and Osborne, JR and Chiang, GC and Ivanidze, J},
title = {Cross-Platform Concordance of Quantitative Amyloid PET Z-Scores in a Real-World Clinical Cohort of Patients with Cognitive Impairment and Suspected Alzheimer Disease.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9354},
pmid = {41986146},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Normative modeling tools are FDA-approved clinical software applications that enable quantitative amyloid PET analysis in routine clinical practice, however implementation differences may yield non-interchangeable Z-scores, with implications for diagnosis and treatment eligibility for patients with cognitive impairment and/or suspected Alzheimer disease. This study evaluated the agreement of Z-scores derived from two widely used clinical software packages in a real-world cohort of patients with cognitive impairment/Alzheimer disease.

MATERIALS AND METHODS: Amyloid PET from 100 consecutive patients with cognitive impairment/Alzheimer disease obtained as part of standard-of-care evaluation at a single institution were retrospectively reviewed. Amyloid PET were post-processed using syngo.via MI Neurology (Siemens Healthineers) and MIMneuro (MIM Software/GE Healthcare). Regional Z-scores were obtained for the temporal, precuneus, posterior cingulate, parietal, frontal, and anterior cingulate cortices. Z-scores were compared per patient and stratified by Centiloid burden (low/intermediate/high: < 20/20-30/>30). Agreement was evaluated using Bland-Altman analysis and Deming regression.

RESULTS: Agreement between Syngo.via and MIMneuro varied by region. When regional Z-scores were averaged into a per-patient composite measure, overall bias was near-zero, with tight limits of agreement (slope = 0.97 [95% CI 0.93-1.02], intercept = 0.11 [95% CI -0.05-0.26]), indicating minimal proportional and constant bias between platforms. Bland-Altman analysis showed small bias and narrow limits of agreement (LoA) in the low-centiloid group (mean bias -0.19, 95% LoA -0.93 to +0.55) and the greatest divergence in the intermediate group (mean bias -0.44, LoA -2.02 to +1.14). In the high-centiloid group, bias remained small (+0.16) with wider LoA (-1.92 to +2.24). Temporal cortex Deming regression demonstrated proportional and constant bias (slope = 0.70 [95% CI 0.66-0.74], intercept = 0.34 [95% CI 0.07-0.61]), indicating systematic underestimation of high Z-scores by MIM relative to Syngo.via.

CONCLUSIONS: There was overall concordance between Syngo.Via and MIMneuro quantitative amyloid PET analysis software packages, however with significant region- and amyloid burden-dependent variability that increased in the intermediate-centiloid group. These differences may influence interpretation and determination of treatment eligibility in borderline cases, emphasizing that Z-scores from different commercial platforms should not be used interchangeably without cross-validation.},
}

@article {pmid41986178,
year = {2026},
author = {Watts, JC and Sigurdson, CJ and Yobs, D and Soto, C},
title = {Creutzfeldt-Jakob disease is an Alzheimer's disease-related dementia.},
journal = {Trends in molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molmed.2026.03.009},
pmid = {41986178},
issn = {1471-499X},
abstract = {Neurodegenerative dementias are debilitating diseases that include Alzheimer's disease (AD) and AD-related dementias (ADRDs). Creutzfeldt-Jakob disease (CJD) is a rapidly progressive dementia caused by the accumulation of prions in the brain. Despite the many similarities between CJD and the ADRDs, CJD is currently not included in the ADRD group. In this opinion article, we discuss the significant impact of prion research on our understanding of the molecular pathogenesis of ADRDs as well as on the development of diagnostic tests and therapeutic strategies. We argue that CJD should be included in the group of ADRDs to enhance research cooperation and accelerate understanding of underlying disease mechanisms toward the goal of developing effective therapies to slow neurodegeneration.},
}

@article {pmid41986478,
year = {2026},
author = {Shin, S and Zhu, X and Amartumur, S and Lee, T and Yu, WJ and Park, S and Etemadi, N and Jamsranjav, A and Kang, R and Bak, G and Lee, D and Kim, J and Han, JW and Heo, C and Cho, H and Chang, S and Mook-Jung, I and Lee, SE and Park, JC},
title = {Human brain and organoid transcriptomes reveal key receptor tyrosine kinase pathways and genetic signatures in Alzheimer's disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41986478},
issn = {2092-6413},
support = {RS-2024-00339665//Ministry of Health and Welfare (Ministry of Health and Welfare, Taiwan)/ ; NRF-2022R1C1C2012736 and RS-2023-00266110//National Research Foundation of Korea (NRF)/ ; RS-2025-23323854//National Research Foundation of Korea (NRF)/ ; },
abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disorder marked by transcriptomic alterations affecting multiple genes. Many researchers have tried to predict major hallmarks of AD pathogenesis for diagnosis but the association between receptor tyrosine kinase (RTK) pathways and AD diagnosis is still unclear. This study aims to identify RTK-associated gene signatures crucial to AD pathogenesis and assess their potential as diagnostic biomarkers for AD. The study investigated changes in RTK pathway gene expression related to AD by analyzing brain transcriptome data from two independent public data sets (GSE84422 and GSE109887). Differentially expressed genes (DEGs) were analyzed from the GSE84422 and GSE109887 data sets and overlapping genes (oDEGs) were identified. RTK-related genes (ooDEGs) were subsequently selected through functional enrichment analysis. These were further refined into AD-related genes (disease-associated genes (DAGs)) through protein-protein interaction network analysis. Logistic regression and receiver operating characteristic analyses were conducted on the selected DAGs to evaluate their diagnostic potential, with additional gene expression validation performed in brain organoids and primary neurons. A total of 145 genes were identified as oDEGs in the above two data sets, and 18 genes were selected as ooDEGs. Six DAGs (ITGB1, AXL, GFAP, NRG1, CAV1, and RHOA) were selected. The diagnostic powers of the six DAGs for AD were 0.825 (GSE84422) and 0.884 (GSE109887). Human brain organoids and primary neuronal models were used to validate the biological relevance of these findings. AXL and ITGB1 were finally selected as key genes for RTK pathway in AD and were significantly increased in AD.},
}

@article {pmid41986496,
year = {2026},
author = {Liu, QR and Zhu, M and Perez, K and Yao, Q and Horowitz, MS and Chen, Q and Fantoni, G and An, Y and Resnick, SM and Sedlock, A and Maric, D and Serrano, GE and Egan, JM and Ramsden, CE},
title = {Ser423-phosphorylated MECP2 (MECP2-pS423) accumulates in human brain, cerebrospinal fluid and serum in sporadic Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {41986496},
issn = {1432-0533},
support = {AG000214//Josephine M. Egan/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/cerebrospinal fluid/blood ; Humans ; *Methyl-CpG-Binding Protein 2/metabolism/blood/cerebrospinal fluid ; Phosphorylation ; Male ; Aged ; Female ; *Brain/metabolism/pathology ; Aged, 80 and over ; Animals ; tau Proteins/metabolism ; Middle Aged ; Serine/metabolism ; },
abstract = {Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that serves as a global epigenetic repressor. Activity-dependent Ser421-phosphorylation is permissive to translocation of mouse Mecp2 to the cytoplasm, thereby reducing the repressor functions and activating neurotrophins. Mecp2-pS421 levels increase in neuron soma of AD (APP/PS1) mouse model and ablating Mecp2 increases activity of glycogen synthase kinase 3 beta, implying a link between MECP2 phosphorylation and Tau pathology in Alzheimer's disease (AD). It is currently unknown whether phosphorylation at the corresponding site of human MECP2-pS423 plays a role in AD. We developed an MECP2-pS423-specific antibody, and a quantitative selective reaction monitoring (SRM) assay based on LC-MS/MS analysis, and we used immunohistochemistry and proteomics to study MECP2-pS423 in human brain, cerebrospinal fluid (CSF), and serum specimens. In postmortem cortex and hippocampus, MECP2-pS423 expression increased across the clinicopathological spectrum of AD and correlated with histological progression and cognitive deficits. At the cellular level, MECP2-pS423 and pTau colocalized in granulovacuolar degeneration (GVD) bodies and neuritic plaques. Phosphoprotein levels of MECP2-pS423 increased in CSF and serum samples from patients clinically diagnosed as having AD premortem. Moreover, we found that a primate-specific and N-terminus truncated MECP2-E3 isoform mRNA was increased in postmortem middle temporal gyrus (MTG) of patients with AD. The results suggest that MECP2-pS423 is a promising mechanism-based biomarker and potential therapeutic target because its accumulations correlate with pathological and cognitive deficit in brain, CSF, and serum of human sporadic AD.},
}

*Alzheimer Disease/metabolism/pathology/cerebrospinal fluid/blood
Humans
*Methyl-CpG-Binding Protein 2/metabolism/blood/cerebrospinal fluid
Phosphorylation
Male
Aged
Female
*Brain/metabolism/pathology
Aged, 80 and over
Animals
tau Proteins/metabolism
Middle Aged
Serine/metabolism

@article {pmid41986732,
year = {2026},
author = {Zhang, Z and Li, S and Xu, L and Xiao, S and Li, Y and Huang, J and Huang, J and Zuo, Y and Wen, W and Dai, Q and Xiao, C and Zhang, X and Chen, J and Deng, F and Li, J and Xu, Y and Hu, X and Deng, Z and Luo, Y and Xie, X and Ye, X and Lin, WJ and Tang, Y},
title = {Amyloid-β-driven glymphatic dysfunction in Alzheimer's disease model mice is driven by Ca[2+]-mediated increases in astrocytic cholesterol.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41986732},
issn = {1546-1726},
support = {81925031//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82330099//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82501687//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82372607//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32271068//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81972967//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Disruptions in the glymphatic system and its downstream meningeal lymphatic drainage pathway, crucial for brain waste clearance, are linked to the pathogenesis of Alzheimer's disease (AD), yet the underlying mechanisms remain unclear. Abnormal calcium dynamics in astrocytes represents an early event in the mouse models of AD. Here we show functional association between amyloid-β-induced elevation of Ca[2+] dynamics in medial prefrontal cortex astrocytes and glymphatic dysfunction in cognitively impaired 5xFAD mice, which can be alleviated by the attenuation of Gq GPCR-evoked Ca[2+] activity. Mechanistically, Ca[2+] hyperactivity increases cholesterol synthesis in astrocytes, leading to increased aquaporin-4 (AQP4) endocytosis and relocalization to lysosomes, thereby disrupting AQP4 polarity and glymphatic function. Suppressing cholesterol synthesis by either specifically knocking down squalene epoxidase in astrocytes or atorvastatin administration improves glymphatic perfusion, meningeal lymphatic drainage and cognition performance in 5xFAD mice. Our data reveal potential therapeutic benefits of lowering astrocyte calcium activity and cholesterol synthesis for enhancing glymphatic-lymphatic coupling integrity in the early stages of AD pathogenesis.},
}

@article {pmid41974986,
year = {2026},
author = {Castroflorio, E and Cabot, J and Miralles, M and Suau-Fullana, M and Peter, M and Balogh, G and Torok, Z and Rodríguez, E and Sanchez-Juan, P and Férnandez-García, P and Llado, V and Escribá, PV and Torres, M},
title = {Lipidomic Analysis of Human Plasma and Hippocampus Across Alzheimer's Progression and Preclinical 5xFAD Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41974986},
issn = {1559-1182},
mesh = {*Alzheimer Disease/blood/metabolism/pathology ; Animals ; *Hippocampus/metabolism/pathology ; *Lipidomics/methods ; Mice, Transgenic ; Disease Models, Animal ; Humans ; *Disease Progression ; Male ; Female ; Aged ; *Lipids/blood ; Mice ; Cognitive Dysfunction/blood/metabolism/pathology ; Biomarkers/blood ; },
abstract = {Alzheimer's disease (AD) poses a significant global health burden, underscoring the need for early and accessible biomarkers to enable timely diagnosis and intervention. Lipids, which constitute over half of the brain's mass, play essential roles in numerous cellular processes, and their dysregulation has been increasingly implicated in AD pathophysiology. In this study, we performed lipidomic profiling of hippocampal samples derived from individuals at different Braak stages and plasma samples from patients with mild cognitive impairment (MCI), AD, and healthy controls. Parallel analyses were conducted in 5xFAD transgenic mice and wild-type littermates. Our results revealed lipid alterations across central and peripheral compartments in both human subjects and the 5xFAD mouse model. Notably, specific lipid changes identified in particular lipid species at early/mild Braak stages or in MCI persisted into advanced stages of the disease, highlighting the systemic nature of lipid dysregulation in AD and supporting the potential of these lipid signatures as diagnostic and prognostic biomarkers.},
}

*Alzheimer Disease/blood/metabolism/pathology
Animals
*Hippocampus/metabolism/pathology
*Lipidomics/methods
Mice, Transgenic
Disease Models, Animal
Humans
*Disease Progression
Male
Female
Aged
*Lipids/blood
Mice
Cognitive Dysfunction/blood/metabolism/pathology
Biomarkers/blood

@article {pmid41975027,
year = {2026},
author = {Zhang, W and Lukacsovich, D and Young, JI and Gomez, L and Schmidt, MA and Kunkle, BW and Chen, X and Martin, ER and Wang, L and , },
title = {The aging epigenome: integrative analyses reveal intersection with Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41975027},
issn = {2509-2723},
support = {R01NS128145/NS/NINDS NIH HHS/United States ; R61NS135587/NS/NINDS NIH HHS/United States ; R01AG062634/AG/NIA NIH HHS/United States ; },
abstract = {Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. We performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We adjusted for sex and immune cell-type proportions and corrected batch effects and genomic inflation. Integrative analyses included pathway enrichment, mQTL analysis, colocalization with Alzheimer's disease and related dementia (ADRD) GWAS summary statistics, brain-blood DNAm correlations, and comparison to independent AD methylation studies. We identified 3758 CpGs and 556 differentially methylated regions (DMRs) consistently associated with chronological age in both cohorts at a 5% false discovery rate. Our pathway enrichment analyses highlighted metabolic regulation and synaptic signaling, processes previously implicated in Alzheimer's disease. Colocalization with ADRD GWAS summary statistics identified 32 genomic regions consistent with shared genetic signals for DNAm and ADRD risk. Roughly one-third of aging-associated CpGs overlapped CpGs associated with AD or AD neuropathology in external studies. Finally, we prioritized nine promoter CpGs (including those located in PDE1B, ELOVL2, and PODXL2) showing strong positive blood-to-brain methylation concordance and external AD associations, nominating them as candidate blood-based biomarkers. Our study demonstrated that late-life aging signatures in blood DNAm converge on processes implicated in AD and intersect with dementia genetics. A small set of CpGs with blood-brain concordance and external AD support offers promising candidate blood-based biomarkers for future validation.},
}

@article {pmid41975102,
year = {2026},
author = {Cavalcante, DP and Carvalho, GA and Nunes, AÍS and Quintanilha, AR and Nascimento, LRC and Caixeta, L and Ulrich, H and Gomez, RS and Pinto, MCX},
title = {GlyT1 (SLC6A9) inhibition in neurological and psychiatric disorders.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41975102},
issn = {1432-1912},
support = {APQ-04596-25//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 406765/2021-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 407075/2018-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; AUX2024361000034//Fundação de Amparo à Pesquisa do Estado de Goiás/ ; },
abstract = {Glycine is a fundamental neuroactive amino acid that serves dual roles in the central nervous system: acting as a primary inhibitory neurotransmitter via strychnine-sensitive glycine receptors and as an essential co-agonist at the N-methyl-D-aspartate (NMDA) receptor. This dual functionality is important for maintaining the excitation-inhibition balance, synaptic plasticity, and network stability. The spatial and temporal availability of glycine is strictly regulated by two high-affinity, Na[+]/Cl[-]-dependent transporters: GlyT1 (SLC6A9) and GlyT2 (SLC6A5). These transporters exhibit distinct cellular distributions and functional specializations. GlyT1 is predominantly expressed in astrocytes and specific neuronal populations, where it buffers ambient glycine levels to modulate NMDA receptor activity. In contrast, GlyT2 is primarily localized to presynaptic terminals of glycinergic neurons, where it facilitates vesicular refilling essential for inhibitory signaling. This review provides a comprehensive overview of glycine metabolism, the structural biology and transport cycles of SLC6 glycine transporters, and the neuroanatomical framework of GlyT1 function. We further synthesize pharmacological advances in GlyT1 inhibition, evaluating both sarcosine-derived and non-sarcosine inhibitors, such as NFPS (ALX-5407), bitopertin, and iclepertin. The clinical and preclinical evidence for GlyT1 as a therapeutic target in psychiatric, neurological, and neurodegenerative disorders is critically assessed. Finally, we address key translational challenges, including dosing constraints, compensatory mechanisms, and SLC6 family selectivity, while highlighting the potential of structure-guided design to refine GlyT1-targeted therapies.},
}

@article {pmid41975292,
year = {2026},
author = {Esmaeili, H and Mahdavi-Fikjvar, E and Poureshaghi, F and Moridi Farimani, M and Sonboli, A and Dastres, E and Behboudi, H and Mirjalili, MH},
title = {Variation in phytochemical profiles and anti-cholinesterase activity across wild Iranian populations of Leucojum aestivum L.: a conservation perspective.},
journal = {BMC plant biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12870-026-08717-1},
pmid = {41975292},
issn = {1471-2229},
}

@article {pmid41975524,
year = {2026},
author = {More, SA and Mundke, RN and Agrawal, YO and Awathale, SN and Goyal, SN and Nakhate, KT and Rathod, SS},
title = {Intracerebroventricular streptozotocin-induced animal model of Alzheimer's disease: revealing dose optimization, administration regimen, and molecular pathways.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41975524},
issn = {1738-6055},
}

@article {pmid41975535,
year = {2026},
author = {Life, BE and Navarro-Delgado, EI and Fornes, O and Friedman, JM and Wasserman, WW and Korthauer, K and Leavitt, BR},
title = {Progranulin genetic variant rs5848 displays ancestry-specific associations with Alzheimer's disease.},
journal = {Human genomics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40246-026-00958-3},
pmid = {41975535},
issn = {1479-7364},
}

@article {pmid41975550,
year = {2026},
author = {Falzarano, FB and Greenfield, A and Saviano, SC and Kolla, S and Korian, S and Osso, F and Miller, J and Maciejewski, PK and Whitson, HE and Prigerson, HG},
title = {Living Memory Home for Dementia Care Pairs (LMH-4-DCP): study protocol for a pilot randomized trial of a web-based reminiscence intervention for family caregivers and persons with dementia.},
journal = {Pilot and feasibility studies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40814-026-01781-2},
pmid = {41975550},
issn = {2055-5784},
support = {R21AG077144/AG/NIA NIH HHS/United States ; R00AG073509/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; CA197730/CA/NCI NIH HHS/United States ; UL1TR002384/TR/NCATS NIH HHS/United States ; },
abstract = {BACKGROUND: Family caregivers provide most of the emotional, physical, and logistical support for people living with Alzheimer's disease and related dementias (ADRD). As the caregiving role intensifies with advancing illness, family caregivers navigate the cognitive and functional decline of the care recipient. They also must reconcile the shift from a mutual relationship to one of a primary caregiving role. The unique nature of ADRD makes pre-death grief highly prevalent among family caregivers. Reminiscence therapy, which uses memory prompts to evoke meaningful past experiences, has shown promise in improving psychosocial outcomes for individuals with dementia. Its potential to benefit caregivers through strengthened emotional connections, shared meaning, and mutual engagement among the dyad, however, has been largely underexplored. Guided by the Interdependence Model of Communal Coping and the Micro-Sociological Theory of Adjustment to Loss, the current study aims to assess the feasibility and acceptability of Living Memory Home for Dementia Care Pairs (LMH-4-DCP), a reminiscence-based online intervention for family caregivers and their care-recipients.

METHODS: This multisite pilot randomized controlled trial (RCT) will evaluate the feasibility, acceptability, and preliminary efficacy of LMH-4-DCP. Seventy ADRD family caregivers will be targeted for randomization to a 1:1 ratio to the intervention (n = 35) or attention control (n = 35) conditions and will participate for 2 weeks. Recruitment will be facilitated by the project's two study sites located in urban metropolitan areas of the USA. Primary feasibility outcomes include recruitment, retention, and completion rates, website usability (e.g., perceived usefulness and ease of use), and intervention satisfaction. Exploratory analyses will be conducted to assess the preliminary efficacy of LMH-4-DCP in reducing pre-death grief and improving relationship quality. Outcomes will be measured using validated questionnaires at baseline and 2-week follow-up, along with semi-structured interviews with LMH-4-DCP participants.

DISCUSSION: This pilot trial will offer foundational evidence regarding the feasibility and acceptability of the LMH-4-DCP intervention. Study findings will guide intervention refinements and inform the design of a larger-scale, fully powered RCT to evaluate its efficacy in reducing pre-death grief and enhancing relationship quality among ADRD family caregivers.

TRIAL REGISTRATION: Clinicaltrials.gov: NCT06225986, Registered: January 9, 2024, ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT06225986?term=living%20memory%20home&rank=1.},
}

@article {pmid41975594,
year = {2026},
author = {Xu, L and Cheng, G and Hu, F and Duan, T and Han, M and Meng, H and Sun, Y and Zeng, D and Zheng, W and Yang, X and Wang, X and Tan, W and Zeng, Y},
title = {Molecular subtypes of the Alzheimer's disease spectrum: Multimodal biomarker integration, mechanistic validation, and adaptive clinical translation.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00911},
pmid = {41975594},
issn = {1673-5374},
abstract = {Alzheimer's disease exhibits considerable heterogeneity in its clinical progression, neuropathological features, and underlying etiological mechanisms. However, current clinical diagnosis and treatment primarily rely on positron emission tomography and evidence-based cerebrospinal fluid biomarkers, with less emphasis on molecular subtypes, thereby limiting meaningful subtype stratification and personalized therapeutic interventions. Given advances in large-scale multi-omics technologies, single-cell genomics, and molecular imaging, research on the molecular subtypes of Alzheimer's disease is gradually increasing. In this review, we evaluate the growing body of studies on molecular subtypes of Alzheimer's disease through a comparative analysis of multimodal biomarkers, including cerebrospinal fluid proteomic profiles, single-nucleus transcriptomic architectures, neuroimaging endophenotypes, and adaptive clinical translation. We also analyze phenotypic variations across the Alzheimer's disease continuum to bridge molecular discoveries with clinical manifestations. Findings include proteomics-driven investigations that have identified five distinct cerebrospinal fluid proteomic subtypes. These subtypes are associated with divergent genetic backgrounds, survival rates, and cortical atrophy patterns, and are mechanistically linked to aberrant neuronal hyperproliferation, dysregulated innate immune activation, abnormalities in RNA splicing and processing, choroid plexus dysfunction, and blood-brain barrier impairment. Parallel progress in single-cell technologies, such as single-nucleus RNA sequencing, single-cell ATAC sequencing, and single-cell RNA sequencing applied to postmortem brain tissues, has enabled precise mapping of pathological cellular states across various brain regions. These approaches have revealed that molecular alterations in Alzheimer's disease exhibit high cell-type specificity and have uncovered novel disease-associated vascular-glial-neuronal co-expression modules, as well as vasculature-specific mechanisms correlated with APOE4 genetic risk. Tau- positron emission tomography neuroimaging studies have delineated four distinct spatiotemporal trajectories of tau accumulation, including temporo-lateral, occipital, hippocampal-sparing, and limbic subtypes, each associated with unique clinical phenotypes. From a genetic perspective, large-scale genome-wide association studies have identified approximately 75 risk loci implicated in Alzheimer's disease pathogenesis, including 42 previously unreported genomic regions, highlighting biological processes such as microglial activation, lipid metabolism, and synaptic function. Multi-omics analyses have further defined three hierarchical subtypes of Alzheimer's disease, which are primarily distinguished by dysregulation in either metabolic pathways, astroglial activation, or vascular and leptomeningeal function. Despite these advances in delineating heterogeneity, the field continues to face significant challenges. Key among these are the lack of cross-cohort reproducibility, standardized subtyping criteria, and evidence-based clinical validation.},
}

@article {pmid41975595,
year = {2026},
author = {Tedeschi, V and Ciancio, R and Piccirillo, S and Preziuso, A and Serfilippi, T and Terenzi, V and Magi, S and Lariccia, V and Castaldo, P and Vinciguerra, A and Piccialli, I and Canzoniero, LMT and Pannaccione, A and Secondo, A},
title = {Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01754},
pmid = {41975595},
issn = {1673-5374},
abstract = {Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.},
}

@article {pmid41975601,
year = {2026},
author = {Wei, L and Ren, H and Lin, Y and Sun, J and Nie, S and Gao, X and Huang, Y},
title = {Cultivation and transplantation of engineered stem cells: A new strategy for promoting repair of central nervous system injury.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01121},
pmid = {41975601},
issn = {1673-5374},
abstract = {Due to the complex pathological microenvironment of nerve injury, the ability for self-repair is extremely limited, posing a major challenge for clinical treatment. Stem cell therapy has brought hope for nerve regeneration; however, natural stem cells have limitations such as low survival rates, poor directional differentiation efficiency, and insufficient secretion of neurotrophic factors. In recent years, the development of engineered stem cells through gene editing, biomaterial co-culture, or pretreatment has emerged as a promising new strategy. This review systematically describes the current application status of engineered stem cells in the repair of nerve injury. It summarizes the pathological mechanisms of nerve injury and the biological processes of endogenous neurogenesis and regeneration, providing a theoretical basis for engineering interventions. It details the engineering strategies used, including engineering methods, cell sources, cell processing technologies, cell delivery vehicles, and cell function regulation. Additionally, it discusses the multiple mechanisms of engineered stem cells, highlighting that their therapeutic effect is not solely dependent on differentiation into neurons or glial cells for replacement. Instead, their therapeutic effects primarily arise from the strong paracrine effects of engineered stem cells: they secrete neurotrophic factors to support the survival of host neurons, regulate the immune microenvironment, release exosomes to deliver repair-related miRNA or proteins, and promote angiogenesis and axon myelination, thereby facilitating the reconstruction of neural circuits. This review provides insights into the application of engineered stem cells in preclinical research, highlighting significant functional improvements in various neurological disease models such as spinal cord injury, stroke, Alzheimer's disease, and Parkinson's disease. Finally, this paper discusses the key challenges facing the clinical translation of this technology, including the risks of tumorigenicity, the long-term survival and safety of transplanted cells, the need for standardized preparation processes, and ethical and regulatory considerations. In summary, engineered stem cells demonstrate therapeutic potential beyond that of natural stem cells through synergistic multi-mechanism effects, providing more precise and efficient strategies for nerve injury repair. This review not only outlines the technological systems and theoretical advancements in this field but also establishes an important academic foundation for promoting the transition from basic research to clinical application. It systematically summarizes the mechanisms and applications of engineered stem cells in neural repair, emphasizing their potential and existing bottlenecks in translational medicine, thus providing a theoretical basis and directional guidance for future research.},
}

@article {pmid41975605,
year = {2026},
author = {Luo, L and Yan, T and Liu, W and Gao, Y and Tang, X and Yang, L and Zhao, M},
title = {Homoplantaginin regulates various pharmacological pathways: Candidate drugs for multi-target relief of cognitive decline and pathological changes in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00660},
pmid = {41975605},
issn = {1673-5374},
abstract = {Alzheimer's disease is an age-associated neurodegenerative disorder with a complex pathogenesis. As a result, multi-target drug strategies have emerged in the development of anti- Alzheimer's disease medications. Natural compounds exhibit various pharmacological effects and low toxicity, making them beneficial for multifaceted intervention. Considering that NOD-like receptor protein 3 inflammasome-mediated inflammation is crucial for the treatment of Alzheimer's disease, we identified natural NOD-like receptor protein 3 inhibitors using molecular docking and a lipopolysaccharide/adenosine triphosphate-induced J774A.1 cell inflammation model. We found that homoplantaginin stably bound to NOD-like receptor protein 3, and surface plasmon resonance experiments further demonstrated that its binding affinity was 86.30 μM. Moreover, homoplantaginin effectively inhibited inflammation mediated by NOD-like receptor protein 3 inflammasome activation in J774A.1 cells by reducing the levels of interleukin-1β, interleukin-18, mature interleukin-1β (p17), and active caspase-1 (p20). Additionally, homoplantaginin treatment inhibited apoptosis and oxidative damage in L-glutamate-induced PC12 cells, as well as in aluminum chloride and D-galactose-induced Alzheimer's disease mice. The effects of homoplantaginin on Alzheimer's disease-like behavioral impairments were evaluated using the open field test, Y-maze, and Morris water maze. Results showed that there was no effect on control mice after administration of homoplantaginin once daily for 30 consecutive days, while locomotor and cognitive impairments in Alzheimer's disease mice were significantly alleviated, exhibiting superior efficacy compared with the positive drug donepezil. Importantly, consistent with the observations in J774A.1 cells, homoplantaginin inhibited the activation of the NOD-like receptor protein 3 inflammasome in the serum and brain tissues of Alzheimer's disease mice. NOD-like receptor protein 3 knockout hindered the improvement effect of homoplantaginin on cognitive deficits in Alzheimer's disease zebrafish induced by AlCl3 and D-gal, indicating that homoplantaginin enhances cognitive function by inhibiting activation of NOD-like receptor protein 3. Furthermore, homoplantaginin treatment reduced amyloid-beta deposition, oxidative stress, and apoptosis in Alzheimer's disease mice. Notably, aging is a major risk factor for Alzheimer's disease, and homoplantaginin prevented cellular senescence by regulating related biomarker levels in Alzheimer's disease mice. These results demonstrate that homoplantaginin may serve as a promising multifunctional candidate for the treatment of Alzheimer's disease.},
}

@article {pmid41975609,
year = {2026},
author = {Cao, K and Xie, J and Liang, X and Li, Y and Gong, H and Luo, H},
title = {Dendritic mesoporous silica nanoparticle-based nasal delivery carriers for passive immunotherapy of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00917},
pmid = {41975609},
issn = {1673-5374},
abstract = {Hyperphosphorylation of tau is a key pathological hallmark of Alzheimer's disease and is closely associated with cognitive impairment. Passive immunotherapy targeting hyperphosphorylated tau is a promising approach to inhibit tau pathology. However, the blood-brain barrier restricts antibodies from reaching the central nervous system and exerting their therapeutic effects. Here, we developed an intranasal biomacromolecule delivery strategy for the treatment of Alzheimer's disease using dendritic mesoporous silica nanoparticles modified with hyaluronic acid as a drug carrier. Ten-month-old C57BL/6J mice, htau mice, and 5×FAD mice were intranasally administered 100 μg of hyaluronic acid-dendritic mesoporous silica nanoparticles@4B1 (antibody dose), and brain tissues were collected to evaluate antibody delivery efficiency. Using this delivery system, the anti-p-tau396,404 antibody 4B1 was efficiently delivered to the brains of 5×FAD mice, with an enrichment of 7.31% ± 0.18% ID/g. Entry of the 4B1 antibody into the brain ameliorated tauopathy in Alzheimer's disease model mice, reduced neuronal loss and neuroinflammation caused by tau pathology, and reversed cognitive dysfunction. These findings suggest that the nasal delivery strategy based on hyaluronic acid-responsive release is an effective method for delivering antibody biomacromolecules to the central nervous system, showing high efficiency of antibody entry into brain tissue and intracellular delivery. Our findings also demonstrate the role of p-tau396,404 in passive immunotherapy for Alzheimer's disease, suggesting that immunotherapy targeting p-tau396,404 is a promising strategy for ameliorating Alzheimer's disease pathology, inhibiting the aggregation of hyperphosphorylated tau, and alleviating neurological damage and cognitive dysfunction.},
}

@article {pmid41975618,
year = {2026},
author = {Chen, S and Li, J and Zhou, J and Xie, W and Li, H and Yang, L and Chen, G and Long, C},
title = {NeuroD1 gene therapy converts reactive astrocytes to functional new neurons in a mouse model of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00721},
pmid = {41975618},
issn = {1673-5374},
abstract = {Alzheimer's disease is characterized by the presence of amyloid-beta plaques, neurofibrillary tangles, and chronic neuroinflammation. Effective therapies capable of restoring neuronal loss, a key pathological feature of Alzheimer's disease are lacking. Our previous studies have demonstrated that overexpression of neuronal differentiation 1 (NeuroD1) in astrocytes can convert astrocytes into neurons in Alzheimer's disease models and this astrocyte-to-neuron conversion technology can rescue pathological features in models of stroke and epilepsy. This study investigated whether NeuroD1-mediated in vivo reprogramming of reactive astrocytes into functional neurons could rescue neurodegeneration and cognitive decline in amyloid precursor protein/presenilin 1 transgenic Alzheimer's disease model mice. Using retro-orbital delivery of AAV-PHP.eB-GFAP-NeuroD1-GFP, we achieved broad astrocyte-to-neuron conversion throughout the brain of 7-month-old Alzheimer's disease mice. Three months post-treatment, immunostaining revealed significant neuronal regeneration in the cortex and hippocampus, accompanied by a marked reduction in neuroinflammatory markers. The converted neurons exhibited mature electrophysiological properties, including action potentials and synaptic activity, which correlated with increased neuronal density in the hippocampus. Morris water maze test demonstrated that NeuroD1-treated mice exhibited restored spatial learning and memory compared with control animals. These findings demonstrate that NeuroD1-driven neuroregeneration via gene therapy not only replenishes neuronal populations but also reduces key pathological features related to Alzheimer's disease, including neuroinflammation and amyloid plaque burden, ultimately reducing cognitive impairment. Our findings highlight in vivo astrocyte-to-neuron reprogramming through systemic astrocyte-to-neuron delivery as a promising and transformative strategy for treating Alzheimer's disease and related neurodegenerative disorders.},
}

@article {pmid41975621,
year = {2026},
author = {Li Puma, DD and Boni, G and Puliatti, G and Bandiera, B and Rinaudo, M and Lerose, F and De Chiara, G and Palamara, AT and Piacentini, R and Grassi, C},
title = {Neuroinflammatory responses and synaptic impairment in a Herpes simplex virus type 1 model of sporadic Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01175},
pmid = {41975621},
issn = {1673-5374},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder in which neuroinflammation has emerged as a key contributor to early synaptic and cognitive dysfunction. In previous studies, we demonstrated that the spread of herpes simplex virus type 1 infection to the central nervous system and its reactivation induced by thermal stress, triggers the accumulation of Alzheimer's disease molecular hallmarks and the development of an Alzheimer's disease-like phenotype in wild-type C57BL/6 mice. In particular, two cycles of thermal stress-induced reactivation in wild-type mice induced a marked upregulation of the proinflammatory cytokine interleukin-1β, along with hippocampal synaptic and memory deficits, features reminiscent of an early stage of neurodegeneration. Notably, blocking interleukin-1β signaling with anakinra, a pharmacological interleukin-1 receptor antagonist, fully rescued all structural and functional indices of neurodegeneration, highlighting the central role of neuroinflammation in early phases of the disease. Here, we documented that, in addition to increased interleukin-1β levels, two cycles of thermal stress promoted the activation of glycogen synthase kinase 3β through phosphorylation of the tyrosine residue at position 216 (Tyr216), along with elevated phosphorylation of its direct substrates, amyloid precursor protein (APP) at threonine 668 and tau at Serine 199. To dissect the contribution of APP and tau to herpes simplex virus type 1-induced synaptic dysfunction, we employed APP-/- and Tau-/- mice. After two cycles of thermal stress, these knock-out mouse models exhibited lower increases in interleukin-1β levels and smaller synaptic deficits than infected wild-type mice, along with a distinct profile of microglial activation. To determine whether neuroinflammation remains the predominant pathological driver at later stages, we extended our analyses to herpes simplex virus type 1-infected wild-type mice subjected to six cycles of thermal stress (6TS), which recapitulate an advanced disease stage with features reminiscent of an Alzheimer's disease-like phenotype. Although interleukin- 1β levels remained persistently elevated in mice subjected to six cycles of thermal stress, anti-inflammatory treatments with either anakinra or dexamethasone failed to rescue synaptic and memory deficits, suggesting that neuroinflammation was no longer the primary pathological driver. Instead, synaptic failure correlated with a pronounced increase in glycogen synthase kinase 3β-induced APP cleavage products (e.g., amyloid-β) and hyperphosphorylated tau, indicating a stage-dependent shift in pathogenic mechanisms, whereby early neuroinflammatory responses are progressively replaced by other processes primarily mediated by glycogen synthase kinase 3β. These findings underscore the stage-specific contribution of interleukin-1β and glycogen synthase kinase 3β to herpes simplex virus type 1-induced Alzheimer's disease-like synaptic failure, highlighting the importance of a phase-specific therapeutic strategy.},
}

@article {pmid41975625,
year = {2026},
author = {Singh, S and Kumar, U},
title = {Somatostatinergic and dopaminergic systems in Alzheimer's disease: Mechanistic insights and therapeutic opportunities beyond plaques and tangles.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01038},
pmid = {41975625},
issn = {1673-5374},
abstract = {Alzheimer's disease therapeutic development has largely focused on amyloid-β and tau pathologies, with limited clinical success. This review extends beyond the canonical amyloid/tau paradigm by examining the roles of somatostatin and dopamine neuromodulatory systems, which undergo early degeneration in Alzheimer's disease and contribute mechanistically to disease progression. Somatostatin deficiency impairs amyloid-β clearance by downregulating neprilysin activity and disrupts inhibitory network homeostasis. Somatostatin binds amyloid-β oligomers and attenuates tau hyperphosphorylation via kinase modulation and cytoskeletal stabilization. Dopaminergic deficits, particularly in ventral tegmental and cortical projections, disrupt synaptic plasticity, memory encoding, network oscillations, and neurogenesis. Dopamine receptor activation promotes amyloid-β clearance, enhances autophagy, and modulates tau phosphorylation. The intersection of somatostatin and dopamine pathways through receptor heteromerization and intersecting intracellular cascades delineates a promising therapeutic axis. Preclinical evidence demonstrates that somatostatin and dopamine receptor agonists mitigate amyloid and tau pathologies and preserve cognitive function, attesting the need for integrative therapeutic strategies targeting neural network dysfunction in Alzheimer's disease.},
}

@article {pmid41975761,
year = {2026},
author = {Prawiroharjo, P and Vidyanti, AN and Syafrita, Y and Yunus, RE and Fakhri, A and Martalia, V and Gabrielle, A and Rahmayani, SA and Marcel, G and Wijaya, VG and Tazkia, AA},
title = {Artificial Intelligence-Assisted Volumetric Brain Analysis Correlated with CSF Biomarkers in Alzheimer's Disease: A Pilot Study.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
pmid = {41975761},
issn = {2075-4418},
support = {//Riset Kolaborasi Indonesia (RKI) or Indonesian Research Collaboration Program/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a leading cause of dementia globally, yet standard diagnostic markers like cerebrospinal fluid (CSF) analysis and molecular imaging are invasive and resource-intensive. While artificial intelligence (AI)-based volumetric magnetic resonance imaging (MRI) offers a scalable and non-invasive alternative, data correlating these structural metrics with fluid biomarkers and cognitive status in Southeast Asian populations are scarce. This study addresses this critical gap by examining the within-cohort relationship between CSF biomarkers and regional brain volumes derived from AI-assisted MRI in Indonesian patients with clinically diagnosed AD, providing novel data for an underrepresented population. Methods: Twenty-one AD patients from three national referral hospitals in Indonesia underwent lumbar puncture for CSF biomarker analysis and 3 Tesla structural brain MRI. Brain volumes were analyzed using United Imaging Intelligence software, focusing on AD-relevant regions (hippocampus, entorhinal cortex, parahippocampus, precuneus, and posterior cingulate cortex [PCC]). Results: Spearman's correlation revealed significant positive associations between CSF Aβ42 levels and several brain regions. Strong correlations were found with the right entorhinal volume indexed to intracranial volume (VICV) (r = 0.601, p = 0.004), right PCC VICV (r = 0.603, p = 0.004), right entorhinal volume (r = 0.533, p = 0.013), and right hippocampus VICV (r = 0.503, p = 0.020). Furthermore, MoCA-InA scores demonstrated highly significant positive correlations with CSF Aβ42 concentrations (r = 0.720, p < 0.001), right Hippocampus VICV (r = 0.703, p < 0.001), and right PCC VICV (r = 0.695, p < 0.001). No significant correlations were found between CSF pTau or the pTau/Aβ42 ratio and regional volumes. Conclusions: These results highlight the entorhinal cortex and PCC as early affected regions where CSF Aβ42 correlates with preserved volume, supporting their role as structural markers in early AD. The absence of pTau associations may reflect early-stage pathology or limitations of cross-sectional volumetry. In resource-limited settings, AI-assisted volumetric MRI demonstrates potential utility as a non-invasive tool for stratifying amyloid-associated brain atrophy and staging disease severity.},
}

@article {pmid41975824,
year = {2026},
author = {Al-Bakri, FH and Bejuri, WMYW and Al-Andoli, MN and Ikram, RRR and Khor, HM and Mispan, MS and Yunos, NM and Yusof, NFA and Fauadi, MHFM and Jaya, ASM and Moketar, NA and Yusop, N and Burhanudin, K and Marindah, TP and Bustamin, A and Zainuddin, Z and Wahyuni, D and Ariffin, UK},
title = {Correction: Al-bakri et al. A Hybrid Explainable AI Framework (HXAI) for Accurate and Interpretable Diagnosis of Alzheimer's Disease. Diagnostics 2025, 15, 3118.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
pmid = {41975824},
issn = {2075-4418},
abstract = {Removal of an Author [...].},
}

@article {pmid41975901,
year = {2026},
author = {Risquez-Salgado, N and García-Bravo, S and Huertas-Hoyas, E and Pérez-Corrales, J and Salcedo-Perez-Juana, M and Donovan, M and Palacios-Ceña, D and Bullón-Benito, E and García-Bravo, C},
title = {Understanding the Lived Experience and Bereavement of Caregivers of People with Alzheimer's Disease: A Mixed-Methods Study Protocol.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {7},
pages = {},
pmid = {41975901},
issn = {2227-9032},
abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely affects cognitive, behavioral, and functional abilities, creating a substantial burden for family members who provide continuous care. Caregivers often experience role changes, occupational imbalance, emotional distress, and reduced quality of life, although some report personal growth. These experiences extend beyond active caregiving and include anticipatory grief during disease progression and grief after the relative's death. Despite this continuum, few studies have examined caregiving, loss, and bereavement from an integrative perspective. This protocol describes a mixed-methods study aimed at exploring the lived experiences of family caregivers of individuals with AD, focusing on how evolving relational, occupational, and identity-related losses influence their well-being and adaptation. Methods: A parallel convergent mixed-methods design will be used. The quantitative component consists of a cross-sectional observational study including 66 caregivers recruited through purposive sampling across kinship categories (spouse/partner, adult child, grandchild) and care settings (home care with day-center attendance vs. institutionalized care). Data will be collected using the Zarit Burden Interview, Role Checklist, Short Form-36 Health Survey, and Occupational Balance Questionnaire. Descriptive and subgroup analyses will be conducted using SPSS (version 27). The qualitative component comprises a multiple-case study with approximately 36 participants across three groups: caregivers living with individuals with AD, caregivers of institutionalized relatives, and bereaved family members. Semi-structured interviews (45-80 min) will be conducted online or in person, transcribed verbatim, and analyzed thematically using MAXQDA (version 26). Integration will follow a concurrent approach, combining quantitative and qualitative results through joint narratives and displays to produce a comprehensive interpretation. Discussion: This study aims to deepen understanding of the caregiving-grief continuum in families affected by AD by integrating quantitative indicators of burden, health status, and occupational balance with qualitative accounts of adaptation and meaning-making. Findings are expected to support the development of holistic, evidence-based interventions that promote caregiver well-being throughout the care trajectory and during bereavement. Ethics and Dissemination: Ethical approval was granted by the Research Ethics Committee of Universidad Rey Juan Carlos (Code: 041220246522024; 15 October 2025). ClinicalTrials.gov Identifier: NCT07251738. Registered November 2025. Protocol version: Version 2.},
}

@article {pmid41976093,
year = {2026},
author = {Dondi, M and Bianchi, E and Borghetti, P and Buffagni, V and Di Lecce, R and Gnudi, G and Guarnieri, C and Ravanetti, F and Saleri, R and Corradi, A},
title = {Evidence-Based Clinical Management of Canine Cognitive Dysfunction Syndrome: Diagnostic Algorithms, Practical Guidelines, Critical Appraisal of Biomarkers and Translational Limitations.},
journal = {Animals : an open access journal from MDPI},
volume = {16},
number = {7},
pages = {},
pmid = {41976093},
issn = {2076-2615},
abstract = {Canine Cognitive Dysfunction Syndrome (CCDS) is a progressive neurodegenerative disease affecting older dogs that shares many pathological mechanisms with human Alzheimer's disease (AD). Although it is common in geriatric dogs, CCDS is often underdiagnosed in veterinary medicine. Both CCDS and AD involve a gradual decline in cognitive functions such as memory, learning and executive abilities. From a pathological perspective, dogs with CCDS show brain changes similar to those seen in AD, including cerebral atrophy, loss of neurons and accumulation of amyloid-beta plaques. CCDS is diagnosed by exclusion, meaning that other medical or neurological conditions that could cause similar behavioural signs must first be ruled out. Clinical evaluation mainly relies on structured questionnaires completed by owners. Magnetic resonance imaging is used to confirm cerebral atrophy and, at the same time, to exclude other brain disorders, such as cerebrovascular accidents and neoplasia. Current research focuses on identifying fluid biomarkers, such as amyloid-beta, neurofilament light chain and glial fibrillary acidic protein, to support an early and objective diagnosis. The most effective management combines pharmacological therapy, targeted nutrition and non-pharmacological strategies, including environmental enrichment and behavioural support. Early intervention, ideally during mild cognitive impairment, is crucial to slow disease progression and maintain quality of life.},
}

@article {pmid41976156,
year = {2026},
author = {Phan, TQ and Huang, HT and Wang, SL and Nguyen, DS and Doan, MD and Pham, THT and Phan, TKT and Truong, BP and Nguyen, VB},
title = {Isolation, Identification and In Silico Evaluation of Novel Cholinesterase Inhibitors from Terminalia triptera Stapf.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {7},
pages = {},
pmid = {41976156},
issn = {1420-3049},
support = {T2025-46CBTĐ//Tay Nguyen University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; Molecular Docking Simulation ; Butyrylcholinesterase/chemistry/metabolism ; *Terminalia/chemistry ; Acetylcholinesterase/chemistry/metabolism ; Humans ; *Plant Extracts/chemistry/pharmacology ; Molecular Structure ; Computer Simulation ; Alzheimer Disease/drug therapy ; },
abstract = {Alzheimer's disease (AD) remains a significant global health challenge, highlighting the need for novel dual inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). This study investigated the trunk bark of Terminalia triptera Stapf. as a potential source of bioactive secondary metabolites for AD management. Bioassay-guided isolation led to the identification of two flavan-3-ol derivatives, epicatechin-(4β→8)-ent-catechin (1) and (-)-catechin (2), reported here for the first time from this species. In vitro assays demonstrated that the dimeric compound 1 exhibited stronger dual inhibitory activity against AChE and BChE, with IC50 values of 4.41 × 10[-4] and 4.75 × 10[-4] mol/L, respectively, surpassing the reference compound berberine chloride. Molecular docking analysis revealed that compound 1 formed extensive interactions within both catalytic and peripheral anionic sites of the enzymes. Density Functional Theory (DFT) calculations indicated high kinetic stability, reflected by large HOMO-LUMO energy gaps (6.66-6.97 eV), while global reactivity descriptors suggested lower electrophilicity (ω = 2.19-2.34 eV), supporting a potentially favorable safety profile. Furthermore, 100 ns molecular dynamics simulations confirmed stable ligand-protein complexes stabilized by hydrogen-bond networks and deep binding within catalytic pockets. Overall, these findings highlight T. triptera and its dimeric proanthocyanidins as promising multi-target candidates for anti-Alzheimer drug development.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification
Molecular Docking Simulation
Butyrylcholinesterase/chemistry/metabolism
*Terminalia/chemistry
Acetylcholinesterase/chemistry/metabolism
Humans
*Plant Extracts/chemistry/pharmacology
Molecular Structure
Computer Simulation
Alzheimer Disease/drug therapy

@article {pmid41976241,
year = {2026},
author = {Shen, X and Ming, K and Shi, H and Li, J and Yang, Y and Zhang, W and Cui, X and Yang, X},
title = {Recent Progress in the Regioselective Biotransformation and Multitarget Therapeutic Potential of Ginsenoside Rd.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {7},
pages = {},
pmid = {41976241},
issn = {1420-3049},
support = {32460114//National Natural Science Foundation of China/ ; KKXX202526073//Xingdian Talents Support Program of Yunnan Province/ ; },
mesh = {*Ginsenosides/pharmacology/chemistry/therapeutic use/metabolism ; Humans ; Biotransformation ; Animals ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; },
abstract = {Ginsenoside Rd, a protopanaxadiol (PPD)-type tetracyclic triterpenoid saponin, has emerged as a promising bioactive constituent for multitarget therapeutic interventions. However, its natural abundance in the source plant is extremely low, making direct extraction both costly and inefficient. This review systematically summarizes the latest research progress on regioselective biotransformation strategies for Rd production since 2022. Furthermore, it comprehensively reviews recent advances in the diverse pharmacological activities of Rd. Beyond its well-recognized neuroprotective effects against neurological disorders including Alzheimer's disease and Parkinson's disease, we also highlight its antitumor activity and multitarget protective effects in liver diseases. This review provides a theoretical basis for developing Rd as a high-value nutraceutical and therapeutic candidate for systemic health.},
}

*Ginsenosides/pharmacology/chemistry/therapeutic use/metabolism
Humans
Biotransformation
Animals
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use

@article {pmid41976259,
year = {2026},
author = {Kukla, J and Olejnik, P and Kasarełło, K},
title = {Exploring the Evolving Role of Scopolamine in Pharmacotherapy: From Cognitive Impairment to Neuroplasticity?-A Narrative Review.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {7},
pages = {},
pmid = {41976259},
issn = {1420-3049},
mesh = {*Scopolamine/pharmacology/therapeutic use/chemistry ; Humans ; *Neuronal Plasticity/drug effects ; *Cognitive Dysfunction/drug therapy/metabolism ; Animals ; },
abstract = {Scopolamine, also known as hyoscine, is a naturally occurring tropane alkaloid derived from plants of the Solanaceae family. Clinically, the compound has long been used for the prevention of motion sickness and postoperative nausea and vomiting, as well as for ophthalmological procedures requiring mydriasis and cycloplegia. However, beyond these established indications, increasing attention has been directed toward its broader neuropharmacological actions. This narrative review aims to summarise current knowledge regarding the pharmacological properties of scopolamine, with particular emphasis on its mechanisms of action and emerging implications in neuroscience and neuropsychiatric disorders. Scopolamine acts as a non-selective antagonist of muscarinic receptor subtypes M1-M5, interfering with cholinergic neurotransmission. Experimental and clinical studies demonstrate that scopolamine induces transient cognitive impairment. This property has led to its widespread use as a pharmacological model of Alzheimer's disease, enabling investigation of cholinergic contributions to cognitive decline. More recently, several early clinical studies suggested that intravenous administration may produce rapid reductions in depressive symptoms, possibly through modulation of glutamatergic neurotransmission and activation of mTORC1-dependent synaptic plasticity pathways in the prefrontal cortex. Nevertheless, subsequent trials have yielded inconsistent results, and the therapeutic relevance of these findings remains uncertain. Current evidence indicates that scopolamine's neuropsychiatric effects likely arise from complex interactions between cholinergic, glutamatergic, and neurotrophic signalling systems. Taken together, scopolamine represents both a valuable experimental tool for studying cholinergic function and a mechanistic framework for the development of novel therapeutics targeting rapid neuroplastic processes in neuropsychiatric disorders.},
}

*Scopolamine/pharmacology/therapeutic use/chemistry
Humans
*Neuronal Plasticity/drug effects
*Cognitive Dysfunction/drug therapy/metabolism
Animals

@article {pmid41976506,
year = {2026},
author = {Chen, T and Shahidin, and Zhu, Q and Wang, Y and Wu, Y and Wu, X and Yuan, W and Sheng, J and Zi, C},
title = {Phytochemical Diversity, Mechanistic Pharmacology, and Therapeutic Potential of Alpinia oxyphylla.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
pmid = {41976506},
issn = {2304-8158},
support = {ZDYF2025SXLH005//Hainan Provincial Key Research and Development Program/ ; 202101BD070001-028//Yunnan Province Agricultural Basic Research Joint Foundation/ ; 31960075//National Natural Science Foundation of China/ ; YNWR-QNBJ-2020-178//Yunnan Ten Thousand Talents Plan Young & Elite Talents Project/ ; },
abstract = {Alpinia oxyphylla Miquel is a perennial medicinal plant widely cultivated in the provinces of Fujian, Guangdong, and Hainan in China. The dried mature fruit of A. oxyphylla, officially recorded as Alpiniae Oxyphyllae Fructus in the pharmacopoeia of the People's Republic of China (since 2012), is one of the four primary southern medicinal materials in traditional Chinese medicine (TCM). In TCM, the fruit is traditionally used to support kidney function, regulate urination, and alleviate gastrointestinal disorders such as diarrhea. Its continued use across Southeast Asia underscores its enduring ethnopharmacological relevance. The plant is rich in bioactive constituents, including terpenoids, flavonoids, diphenylheptanes, and sterols, which exhibit diverse biological activities, including antioxidant, anti-inflammatory, anticancer, neuroprotective, and gastrointestinal protective effects. Information on Alpinia oxyphylla was collected from multiple databases, including Web of Science, Google Scholar, PubMed, Baidu Scholar, ScienceDirect, CNKI, and the Pharmacopoeia of the People's Republic of China. The search strategy included keywords related to A. oxyphylla, its chemical constituents, biological activities, pharmacological effects, traditional medicinal uses, and safety. A bibliometric analysis of 217 English-language publications (2014-2025) using CiteSpace revealed a marked increase in global research interest, with keyword clustering and burst analyses highlighting oxidative stress, Alzheimer's disease, and cognitive enhancement as emerging research hotspots. Moreover, 692 patents were identified, demonstrating substantial technological innovation related to A. oxyphylla, particularly in essential oil formulations, functional foods, and health-promoting applications. Overall, this review integrates phytochemical, pharmacological, bibliometric, and patent perspectives to provide a holistic understanding of A. oxyphylla and its medicinal fruit, offering a solid scientific foundation for future research, standardization, and translational development.},
}

@article {pmid41977262,
year = {2026},
author = {Mîndreanu, R and Chiș, IC and Sevastre-Berghian, A and Login, C and Stan, A and Stan, T and Clichici, S and Suciu, Ș},
title = {N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073076},
pmid = {41977262},
issn = {1422-0067},
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy ; Translational Research, Biomedical ; Antioxidants/therapeutic use ; Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Multiple Sclerosis/drug therapy ; Brain Injuries, Traumatic/drug therapy ; },
abstract = {N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer's disease (AD, n = 5), Parkinson's disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment.},
}

*Acetylcysteine/therapeutic use/pharmacology
Humans
*Nervous System Diseases/drug therapy
*Neuroprotective Agents/therapeutic use
Parkinson Disease/drug therapy
Translational Research, Biomedical
Antioxidants/therapeutic use
Alzheimer Disease/drug therapy
Oxidative Stress/drug effects
Amyotrophic Lateral Sclerosis/drug therapy
Multiple Sclerosis/drug therapy
Brain Injuries, Traumatic/drug therapy

@article {pmid41977275,
year = {2026},
author = {Zhu, Y and Zhao, L and Li, Y and Tian, M and Liao, Y and Huang, J and Guo, P and Xie, Y},
title = {Disruption of Synaptic Vesicle Trafficking in Alzheimer's and Parkinson's Disease: Mechanisms and Therapeutic Implication.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073089},
pmid = {41977275},
issn = {1422-0067},
support = {82060823//National Natural Science Foundation of China/ ; 82074421//National Natural Science Foundation of China/ ; 202501AS070139//Natural Science Foundation of Yunnan Province/ ; 2024Y395//Yunnan Provincial Department of Education/ ; 202105AG070012XS25032//Yunnan Science and Technology Talent and Platform Program/ ; N/A//Yunnan Collaborative Innovation Center for the Application of Aromatic Chinese Medicine/ ; },
mesh = {*Synaptic Vesicles/metabolism/pathology ; Humans ; *Alzheimer Disease/metabolism/pathology/therapy ; *Parkinson Disease/metabolism/pathology/therapy ; Animals ; Endocytosis ; Protein Transport ; Amyloid beta-Peptides/metabolism ; alpha-Synuclein/metabolism ; },
abstract = {Alzheimer's (AD) and Parkinson's disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca[2+]-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions.},
}

*Synaptic Vesicles/metabolism/pathology
Humans
*Alzheimer Disease/metabolism/pathology/therapy
*Parkinson Disease/metabolism/pathology/therapy
Animals
Endocytosis
Protein Transport
Amyloid beta-Peptides/metabolism
alpha-Synuclein/metabolism

@article {pmid41977297,
year = {2026},
author = {Kurma, SH and Adarvez-Feresin, C and Parravicini, O and Garro, A and Stepankova, S and Hosek, J and Pauk, K and Lisicic, J and Jampilek, J and Enriz, RD and Imramovsky, A},
title = {Structure-Based Design of New Series of Sulfonates with Potent and Specific BChE Inhibition and Anti-Inflammatory Effects.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073109},
pmid = {41977297},
issn = {1422-0067},
support = {DKRVO RO0523//Ministry of Agriculture/ ; //Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)/ ; //National University of San Luis/ ; APVV-24-0341//Slovak Research and Development Agency/ ; },
mesh = {*Butyrylcholinesterase/chemistry/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; Humans ; Molecular Dynamics Simulation ; *Anti-Inflammatory Agents/chemistry/pharmacology ; Drug Design ; *Sulfonic Acids/chemistry/pharmacology ; Structure-Activity Relationship ; Animals ; },
abstract = {In the present work, a novel series of eleven sulfonate derivatives with potent inhibitory activity against butyrylcholinesterase (BChE) is reported. Of these, compounds 2-[(E)-(2-Benzoylhydrazinylidene)methyl]phenyl 5-(dimethylamino)naphthalene-1-sulfonate (5c, IC50 = 1.11 µM) and tert-butyl (2E)-2-[(2-{[5-(dimethylamino)naphthalene-1-sulfonyl]oxy}p
henyl)methylidene]hydrazine-1-carboxylate (5b, IC50 = 11.51 µM) exhibit stronger inhibitory activity than rivastigmine, the reference compound, and exhibit high selectivity for BChE over AChE (e.g., selectivity index 57 for 5c). Interestingly, compound 5c also exhibited anti-inflammatory effects, which is important for potential therapeutic applications, especially in Alzheimer's disease. These new compounds were designed through a structure-based approach using molecular modeling techniques (docking, molecular dynamic (MD) simulations, and QTAIM (quantum theory of atoms in molecules) calculations). The most promising compounds show no detectable toxic effects and satisfy Lipinski's rule of five, indicating that they represent attractive starting structures for the design of new derivatives acting as specific BChE inhibitors. In addition, our results indicate that relatively simple computational techniques such as docking calculations and toxicity prediction programs can be valuable when properly used in the search of new candidates for this particular target. Docking calculations show that the more active compounds of this series reach the bottom region of the gorge interacting with residues within the active site of BChE. However, our data further suggest that the use of more precise techniques, such as MD simulations and QTAIM analysis, is necessary to obtain detailed insight into ligand-enzyme interactions. Regarding QTAIM calculations, they demonstrate that such computations are very useful to evaluate the molecular interactions of the different molecular complexes. In summary, we report a new series of sulfonate derivatives as promising starting structures for the development of new selective BChE inhibitors.},
}

*Butyrylcholinesterase/chemistry/metabolism
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
Humans
Molecular Dynamics Simulation
*Anti-Inflammatory Agents/chemistry/pharmacology
Drug Design
*Sulfonic Acids/chemistry/pharmacology
Structure-Activity Relationship
Animals

@article {pmid41977314,
year = {2026},
author = {Neamțu, M and Petreuș, T and Olinici, DT and Stoica, L and Arcan, OD and Stoica, BA and Moșoiu, C},
title = {The NLRP3 Inflammasome in Neuropsychiatric Disorders: Molecular Mechanisms and Emerging Therapeutic Strategies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073127},
pmid = {41977314},
issn = {1422-0067},
mesh = {Humans ; *Inflammasomes/metabolism/immunology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Mental Disorders/metabolism/immunology/therapy ; Animals ; },
abstract = {Inflammasomes are cytosolic multiprotein complexes that detect pathogens, cellular stress, and damage-associated molecular signals, thereby orchestrating innate immune responses. Increasing evidence suggests that dysregulated inflammasome activation contributes to persistent neuroinflammation and to a wide range of neuropsychiatric disorders, including mood disorders, schizophrenia, Alzheimer's disease, and autism spectrum disorders. Together, these findings emphasize the critical role of neuroimmune interactions in the pathophysiology of mental disorders. Recent molecular studies have substantially advanced our understanding of the crosstalk among neurons, microglia, astrocytes, and peripheral immune cells, uncovering complex regulatory networks mediated by cytokines, neurotrophins, and neurotransmitters. By examining key inflammatory mediators and cell type-specific mechanisms, this review consolidates current knowledge and proposes conceptual frameworks to guide future investigations and facilitate the development of targeted therapeutic strategies for neuropsychiatric disorders.},
}

Humans
*Inflammasomes/metabolism/immunology
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Mental Disorders/metabolism/immunology/therapy
Animals

@article {pmid41977320,
year = {2026},
author = {Toledano-Pinedo, M and Porro-Pérez, A and Schäker-Hübner, L and Diez-Iriepa, D and Iriepa, I and Siwek, A and Wolak, M and Satała, G and Bojarski, AJ and Doroz-Płonka, A and Handzlik, J and Godyń, J and Dallemagne, P and Rochais, C and Davis, A and Since, M and Pérez, B and Bellver-Sanchis, A and Irisarri, A and Pallàs, M and Solana-Manrique, C and López-Muñoz, F and Ismaili, L and Griñán-Ferré, C and Paricio, N and K Hansen, F and Więckowska, A and Marco-Contelles, J},
title = {Polyfunctionalized N-Arylsulfonyl Indoles: Identification of (E)-N-Hydroxy-3-{3-[(5-(3-(piperidin-1-yl)propoxy]-1H-indol-1-yl)sulfonyl]phenyl}a
crylamide (MTP150) for the Epigenetic-Based Therapy of Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073135},
pmid = {41977320},
issn = {1422-0067},
support = {PID2019-105813RB-C21//AEI (Government of Spain/ ; },
mesh = {Animals ; *Parkinson Disease/drug therapy/genetics/metabolism ; *Indoles/pharmacology/chemistry/therapeutic use ; Disease Models, Animal ; Caenorhabditis elegans/drug effects/genetics ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Epigenesis, Genetic/drug effects ; Oxidative Stress/drug effects ; *Acrylamides/pharmacology/chemistry ; },
abstract = {Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease.},
}

Animals
*Parkinson Disease/drug therapy/genetics/metabolism
*Indoles/pharmacology/chemistry/therapeutic use
Disease Models, Animal
Caenorhabditis elegans/drug effects/genetics
Humans
*Neuroprotective Agents/pharmacology/chemistry
*Epigenesis, Genetic/drug effects
Oxidative Stress/drug effects
*Acrylamides/pharmacology/chemistry

@article {pmid41977389,
year = {2026},
author = {Tiwari, S and Yadav, SK and Kumari, M and Dhakal, T and Puranik, N},
title = {Neuropeptides in the Management of Alzheimer's Disease: From Pathophysiology to Therapeutic Opportunities.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073206},
pmid = {41977389},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology ; *Neuropeptides/therapeutic use/metabolism/pharmacology ; Animals ; Vasoactive Intestinal Peptide/therapeutic use ; *Neuroprotective Agents/therapeutic use/pharmacology ; Pituitary Adenylate Cyclase-Activating Polypeptide/therapeutic use/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral changes, ultimately leading to a loss of independence and reduced quality of life. Although understanding of the molecular basis of AD has advanced, effective disease-modifying therapies remain scarce. Neuropeptides are small protein-like signaling molecules that regulate diverse physiological processes, including mood, memory, and neuronal function. Growing evidence indicates that neuropeptides are promising therapeutic candidates for AD, particularly through modulation of neuroinflammation, synaptic plasticity, and amyloid-beta (Aβ) aggregation. Preclinical AD models show that neuroprotective neuropeptides, such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP), exert neuroprotective effects, enhance memory, and attenuate cognitive decline. This review summarizes current research on neuropeptide-based therapies for AD, detailing their molecular mechanisms, therapeutic actions, and the barriers to their clinical translation. We specifically highlight neuropeptides whose clinical potential in AD remains comparatively underrecognized, discuss strategies for optimizing their delivery and overcoming pharmacokinetic limitations, and outline future perspectives for integrating neuropeptide-based interventions into AD therapy.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/physiopathology
*Neuropeptides/therapeutic use/metabolism/pharmacology
Animals
Vasoactive Intestinal Peptide/therapeutic use
*Neuroprotective Agents/therapeutic use/pharmacology
Pituitary Adenylate Cyclase-Activating Polypeptide/therapeutic use/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid41977405,
year = {2026},
author = {Foncea-Bitrán, A and Barros-Osorio, C and Arriaza, F and Ramírez-López, C and Ruiz, LM and Barreto, M and Ortiz, FC and Cornejo, F and Gómez, GI},
title = {Connecting the Dots: Neurobiological Interplay Between Type 2 Diabetes and Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073225},
pmid = {41977405},
issn = {1422-0067},
support = {1250485//Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *Diabetes Mellitus, Type 2/metabolism/complications/pathology ; Biomarkers/metabolism ; Animals ; tau Proteins/metabolism ; Insulin Resistance ; Amyloid beta-Peptides/metabolism ; Insulin/metabolism ; Cognitive Dysfunction/metabolism ; },
abstract = {Diabetes Mellitus is a chronic metabolic disorder characterized by impaired insulin production and/or action, leading to persistent hyperglycemia and insulin resistance. It has been associated with several comorbidities, including cognitive dysfunction, affecting functions such as attention, memory, and processing speed. Mounting evidence indicates a complex relationship between type 2 Diabetes Mellitus (DM2) and neurodegenerative disorders such as mild cognitive impairment and Alzheimer's disease (AD). Beyond the conventional hallmarks of each pathology, patients with DM2 face an increased risk of neuronal degeneration, while AD is characterized by a marked reduction in insulin receptor density. Although aging, neuroinflammation, and vascular dysfunction have been recognized as key risk factors in AD, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. Various studies have been conducted to identify reliable biomarkers that elucidate the connection between DM2 and AD, including insulin dysregulation, neuroinflammation, amyloid-β aggregation, and tau hyperphosphorylation. Investigation of these biomarkers is still ongoing, and they may serve not only as diagnostic tools but also as therapeutic targets. Here, we review the current evidence supporting a convergent biological framework between DM2 and AD. Clarifying these shared pathways may improve early detection and guide the development of targeted therapeutic strategies aimed at reducing neurodegeneration in metabolically vulnerable populations.},
}

Humans
*Alzheimer Disease/metabolism/pathology/etiology
*Diabetes Mellitus, Type 2/metabolism/complications/pathology
Biomarkers/metabolism
Animals
tau Proteins/metabolism
Insulin Resistance
Amyloid beta-Peptides/metabolism
Insulin/metabolism
Cognitive Dysfunction/metabolism

@article {pmid41977406,
year = {2026},
author = {Lin, L and Pratt, AE and Hoffman, DA},
title = {DPP6 Loss Causes Age-Dependent Sleep Dysregulation and Depression-like Phenotypes Linked to Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073224},
pmid = {41977406},
issn = {1422-0067},
support = {ZIA HD008755/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Mice, Knockout ; Mice ; *Depression/genetics/metabolism ; Phenotype ; *Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/deficiency/metabolism ; *Aging ; Sleep ; *Neurodegenerative Diseases/genetics ; Male ; *Sleep Wake Disorders/genetics/metabolism ; Circadian Rhythm ; Mice, Inbred C57BL ; Disease Models, Animal ; },
abstract = {Sleep disturbances are early hallmarks of Alzheimer's disease (AD) and other dementias, yet the molecular mechanisms remain poorly understood. We previously showed that dipeptidyl aminopeptidase-like protein 6-knockout (DPP6-KO) mice exhibit accelerated neurodegeneration with synaptic loss, neuronal death, and circadian dysfunction resembling AD pathology. Here, we investigate whether DPP6 deficiency directly causes sleep dysregulation and assess age-dependent effects using wireless EEG/EMG telemetry, behavioral monitoring, and body temperature recordings. We found striking age-dependent sleep phenotypes in DPP6-KO mice. Adult (3-month) DPP6-KO mice showed hyperactivity-driven REM sleep increases, while aged (12-month) DPP6-KO mice developed insomnia with fragmented sleep architecture. Critically, aged DPP6-KO mice exhibited decreased REM latency, a biomarker of depression, which we confirmed by behavioral assays. Conversely, DPP6 overexpression in aged wild-type mice increased NREM duration and reduced sleep fragmentation, demonstrating a protective effect. Throughout aging, DPP6-KO mice showed dysregulated locomotor activity and body temperature rhythms, suggesting broader disruption of circadian and metabolic homeostasis. These findings establish DPP6 as a critical regulator of sleep architecture whose loss recapitulates key sleep disturbances observed in AD/dementia. The progressive nature of sleep dysfunction in DPP6-KO mice, from REM abnormalities to insomnia, parallels human disease progression and positions DPP6 as a potential therapeutic target for sleep-related symptoms in neurodegenerative disorders.},
}

Animals
Mice, Knockout
Mice
*Depression/genetics/metabolism
Phenotype
*Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/deficiency/metabolism
*Aging
Sleep
*Neurodegenerative Diseases/genetics
Male
*Sleep Wake Disorders/genetics/metabolism
Circadian Rhythm
Mice, Inbred C57BL
Disease Models, Animal

@article {pmid41977439,
year = {2026},
author = {Bougea, A},
title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073260},
pmid = {41977439},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; *RNA, Untranslated/genetics ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics ; Genetic Therapy/methods ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.},
}

Humans
*Neurodegenerative Diseases/genetics/therapy
Animals
*RNA, Untranslated/genetics
MicroRNAs/genetics
RNA, Long Noncoding/genetics
Genetic Therapy/methods

@article {pmid41977460,
year = {2026},
author = {Taboada-Jara, T and Ribalta, M and Romero-Becerra, F and Muixí, J and Bellver-Sanchis, A and Griñán-Ferré, C and Escolano, C and Pallàs, M},
title = {Usefulness of C. elegans Models of Alzheimer's and Huntington's Disease to Evaluate Novel Imidazoline I2 Receptor Ligands.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073282},
pmid = {41977460},
issn = {1422-0067},
support = {PDC2022-133441-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00357//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PID2022-138079OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; N° 19/2015//Ministerio de Economía y Finanzas and Programa Nacional de Becas "Don Carlos Antonio López"/ ; //Càtedra UB Dr. Antoni Esteve i Subirana de Recerca en Farmacologia/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Huntington Disease/metabolism/drug therapy/genetics ; Disease Models, Animal ; *Imidazoline Receptors/metabolism ; Ligands ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Oxidative Stress/drug effects ; Humans ; Animals, Genetically Modified ; Caenorhabditis elegans Proteins/metabolism/genetics ; Amyloid beta-Peptides/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's (AD) and Huntington's (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics
*Huntington Disease/metabolism/drug therapy/genetics
Disease Models, Animal
*Imidazoline Receptors/metabolism
Ligands
*Alzheimer Disease/metabolism/drug therapy/genetics
Oxidative Stress/drug effects
Humans
Animals, Genetically Modified
Caenorhabditis elegans Proteins/metabolism/genetics
Amyloid beta-Peptides/metabolism/genetics
*Neuroprotective Agents/pharmacology

@article {pmid41977467,
year = {2026},
author = {Nilewar, SS and Chavan, AD and Pradhan, AR and Tripathy, AA and Bandaru, N and Dudhe, PB and Kumar, PK and Lodha, S and Muteeb, G and Peredo-Valderrama, I and Naranjo-Redondo, AJ and Pawar, TJ},
title = {Dual-Site Acetylcholinesterase Inhibition and Multiscale Stability of Fused Quinoline Sulfonamides: A Chemoinformatic GA-MLR and Molecular Dynamics Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073286},
pmid = {41977467},
issn = {1422-0067},
support = {UAG-CI-00001//Universidad Anáhuac Querétaro/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Dynamics Simulation ; *Quinolines/chemistry/pharmacology ; *Acetylcholinesterase/chemistry/metabolism ; Molecular Docking Simulation ; Quantitative Structure-Activity Relationship ; *Sulfonamides/chemistry/pharmacology ; Humans ; Catalytic Domain ; Cheminformatics/methods ; },
abstract = {Alzheimer's disease (AD) represents an escalating global neuropharmacological crisis, with prevalence in high-growth demographic regions such as India projected to exceed 14 million by 2040. This study addresses the urgent need for high-potency, dual-site acetylcholinesterase (AChE) inhibitors through an integrated computational pipeline. We address the failure of mono-target paradigms by designing scaffolds capable of simultaneously anchoring the Catalytic Active Site (CAS) and the Peripheral Anionic Site (PAS). A robust GA-MLR QSAR model was developed from 115 quinoline analogs using 11,135 descriptors. Lead candidates were prioritized via cavity directed molecular docking (7XN1) and 100 ns molecular dynamics (MD) simulations. The five-descriptor model (R[2] = 0.7569, QLOO2 = 0.7244) was validated by an external set of 8 experimental compounds (Rext2 = 0.8620). Lead Compound 19 emerged as a superior candidate (ΔG = -11.1 kcal/mol), exhibiting a stable MD trajectory (PL-RMSD ≈ 2.4 Å) and preserving essential Gly121-His447 catalytic anti-correlations. This study provides a statistically validated scaffold and computational mechanistic foundation for future in vitro experimental validation, advancing the high throughput screening of neuroprotective agents on a global scale.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology
Molecular Dynamics Simulation
*Quinolines/chemistry/pharmacology
*Acetylcholinesterase/chemistry/metabolism
Molecular Docking Simulation
Quantitative Structure-Activity Relationship
*Sulfonamides/chemistry/pharmacology
Humans
Catalytic Domain
Cheminformatics/methods

@article {pmid41977473,
year = {2026},
author = {Bivona, G and Ghersi, G},
title = {Microglia-Astrocyte Cooperation and Peripheral T Cells in Alzheimer's Disease: State-of-the-Art and Treatment Perspectives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073295},
pmid = {41977473},
issn = {1422-0067},
mesh = {*Alzheimer Disease/immunology/therapy/pathology/metabolism ; Humans ; *Microglia/metabolism/pathology/immunology ; *T-Lymphocytes/immunology/metabolism ; *Astrocytes/metabolism/pathology/immunology ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder first described more than one century ago. Over this time, many features of the disease have been discovered and, consequently, many different approaches in the diagnosis and treatment of AD have been developed. A major assumption has guided research on AD in the past: this fatal form of cognitive decline is believed to have a pathogenic basis in the deposition of amyloid beta (Aβ) aggregates throughout the brain. Consequently, a main goal of AD therapy is to reduce Aβ load, and several monoclonal antibodies targeting amyloid are among the most recent approaches to AD treatment. However, the effectiveness of these drugs is limited, as they cannot block the progression of the disease; they only slow it down in certain conditions. Many other causative factors are known to promote the development of the disease, with immune system involvement being the most investigated. Indeed, it has been well documented that the microglial response enhances the deposition of other altered proteins, such as Tau, and induces a neurotoxic microenvironment that promotes neuronal loss. In this scenario, the interaction between microglia and astrocytes is known to accelerate pathogenic processes, and a possible role for peripheral T lymphocytes in AD pathology has also been described. An interesting hypothesis is that immune cells driving chronic inflammation might worsen AD progression and, therefore, could represent a target for treatment strategies in this disease. Thus, this review article aims to summarise the role of brain and peripheral immune molecules and cells in AD. Also, immune-based treatments for AD are described, including those targeting microglia and T cells.},
}

*Alzheimer Disease/immunology/therapy/pathology/metabolism
Humans
*Microglia/metabolism/pathology/immunology
*T-Lymphocytes/immunology/metabolism
*Astrocytes/metabolism/pathology/immunology
Animals
Amyloid beta-Peptides/metabolism

@article {pmid41977515,
year = {2026},
author = {Angelopoulou, E and Papatriantafyllou, J and Papageorgiou, S and Villa, C},
title = {Elucidating the Neurobiological Underpinnings of Mild Behavioral Impairment in Tauopathies: Clinical and Molecular Insights.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073341},
pmid = {41977515},
issn = {1422-0067},
mesh = {Humans ; *Tauopathies/metabolism/pathology ; tau Proteins/metabolism ; Biomarkers ; Animals ; Alzheimer Disease/metabolism ; *Cognitive Dysfunction ; },
abstract = {Mild behavioral impairment (MBI) is a clinical syndrome characterized by the late-life onset and persistence of neuropsychiatric symptoms (NPSs), representing a change from longstanding behavior or personality and considered a potential prodrome of neurodegenerative disease. MBI is classified into five domains: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and psychotic symptoms. In this narrative review, we synthesize clinical, neuroanatomical, and molecular evidence linking MBI to the spectrum of tauopathies, including Alzheimer's disease (AD), frontotemporal spectrum disorders (FTSDs), and primary four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Emerging evidence suggests that early behavioral symptoms associated with MBI may reflect the selective vulnerability of frontolimbic, salience, default mode, and frontostriatal networks to tau-mediated neurodegeneration. Mechanistically, converging findings support roles for tau-related synaptic dysfunction, including synaptotoxic soluble tau species, cytoskeletal and axonal transport disruption, monoaminergic neurotransmitter imbalance in brainstem systems, and neuroinflammatory and glial pathways. We also highlight genotype-related behavioral profiles in genetic frontotemporal lobar degeneration and discuss how scalable blood-based biomarkers, including neurofilament light chain, glial fibrillary acidic protein, and plasma phospho-tau species, may complement MBI-based phenotyping for differential diagnosis and prognostic stratification in clinical research.},
}

Humans
*Tauopathies/metabolism/pathology
tau Proteins/metabolism
Biomarkers
Animals
Alzheimer Disease/metabolism
*Cognitive Dysfunction

@article {pmid41977873,
year = {2026},
author = {Zinser, ALV and Zahrebelnei, F and Winiarski, JP and Picciani, PHS and Wohnrath, K and Pessôa, CA},
title = {Electrochemical Detection of miR-29a and miR-34a Using AuNPs Immobilized by a Silsesquioxane Polyelectrolyte: Potential Early Alzheimer's Disease Biomarkers Detection.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/s26072089},
pmid = {41977873},
issn = {1424-8220},
support = {465572/2014-6//National Institute of Organic Electronics (INEO)/ ; 406008/2022-1//National Council for Scientific and Technological Development/ ; 22.027.260-5//Fundação Araucária/ ; },
mesh = {*MicroRNAs/isolation & purification/genetics ; *Alzheimer Disease/diagnosis/genetics ; Humans ; *Biosensing Techniques/methods ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; *Electrochemical Techniques/methods ; Biomarkers/blood ; Organosilicon Compounds/chemistry ; Polyelectrolytes/chemistry ; Electrodes ; Limit of Detection ; },
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia worldwide, and early diagnosis is crucial to minimize neurological damage and loss of quality of life. Here, we report an electrochemical biosensor for detecting miRNAs 29a and 34a, potential non-invasive biomarkers associated with AD. The biosensor consisted of a glassy carbon electrode (GCE) modified with a novel nanohybrid of gold nanoparticles stabilized by 3-n-propyl(4-dimethylaminopyridinium) silsesquioxane chloride (AuNPs-Si4DMAP[+]Cl[-]). Thiolated anti-miRNA probes were immobilized separately on the GCE/AuNPs-Si4DMAP[+]Cl[-], followed by BSA blocking. Target miRNAs were detected via hybridization with complementary probes using electrochemical impedance spectroscopy. The nanohybrid, characterized by spectroscopic and morphological techniques, significantly enhanced the electrochemical response and was effective detecting both miRNAs, showing suspension stability over 600 days. LOD and LOQ were 1.79 pM and 5.87 pM for miRNA-29a, and 2.21 pM and 11.01 pM for miRNA-34a. These results highlight the platform's potential for electrochemical detection of these miRNAs in blood, supporting earlier detection of AD and other neurodegenerative diseases.},
}

*MicroRNAs/isolation & purification/genetics
*Alzheimer Disease/diagnosis/genetics
Humans
*Biosensing Techniques/methods
*Gold/chemistry
*Metal Nanoparticles/chemistry
*Electrochemical Techniques/methods
Biomarkers/blood
Organosilicon Compounds/chemistry
Polyelectrolytes/chemistry
Electrodes
Limit of Detection

@article {pmid41978186,
year = {2026},
author = {Castro, CB and Gardener, SL and Jahan, F and Chen, J and Brown, BM and Loo, RL and Taddei, K and Rainey-Smith, SR and Weinborn, M and Dos Reis, ACR and Verma, S and Carrigan, N and Inderjeeth, C and Doré, V and Garg, ML and Martins, RN and Sohrabi, HR},
title = {Dietary Patterns and Cerebral Glucose Metabolism in Older Adults: Findings from the Western Australian Memory Study.},
journal = {Nutrients},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/nu18071136},
pmid = {41978186},
issn = {2072-6643},
support = {#324100; Molecular and Neuropsychological Predictive Markers of Cognitive Decline)//NHMRC/ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Diet, Western/adverse effects ; *Glucose/metabolism ; Prospective Studies ; Longitudinal Studies ; Positron-Emission Tomography ; *Brain/metabolism/diagnostic imaging ; Aged, 80 and over ; Western Australia ; Alzheimer Disease/metabolism ; Fluorodeoxyglucose F18 ; *Diet ; },
abstract = {UNLABELLED: Alzheimer's disease (AD) is characterized by significant reductions in glucose metabolism, reflecting underlying synaptic dysfunction, correlating with cognitive decline. We aimed to explore the impact of dietary patterns on the change in glucose metabolism.

METHODS: This longitudinal, prospective study included 132 community-dwelling older adults without a diagnosed dementia history enrolled in the Western Australian Memory Study (WAMS). Participants completed a food frequency questionnaire at baseline and underwent [[18]F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging at baseline and at up to two follow-up assessments scheduled approximately 18 months apart, over a maximum follow-up period of 43 months. Principal component analysis yielded two dietary patterns-named Western Diet and Prudent Diet. Linear mixed-effect models evaluated the association between dietary adherence and glucose metabolism, including potential confounders. Analysis was repeated stratified by sex.

RESULTS: Adherence to a Western Diet, characterized by high sugars and saturated fats, was associated with faster decline in glucose metabolism in the left fusiform gyrus (β = -0.00062; SE = 0.00025; FDR-adjusted p = 0.043), neocortex (β = -0.00063; SE = 0.00026; FDR-adjusted p = 0.047), left ventrolateral prefrontal (β = -0.00083; SE = 0.00032; FDR-adjusted p = 0.045 and inferior parietal region (β = -0.00344; SE = 0.00129; FDR-adjusted p = 0.033) in females. A Prudent Diet, characterized by a high intake of fruits, vegetables, and whole grains, showed no significant effects.

CONCLUSIONS: Our study highlights the following: (a) The potential detrimental impact of a Western Diet on brain glucose metabolism, particularly for females, who are at higher risk for AD. The decline was observed in regions essential for cognitive functions, including visual processing and facial recognition, emphasizing the role of diet in brain health. (b) No significant associations were observed between adherence to a Prudent dietary pattern and changes in glucose metabolism.},
}

Humans
Female
Male
Aged
*Diet, Western/adverse effects
*Glucose/metabolism
Prospective Studies
Longitudinal Studies
Positron-Emission Tomography
*Brain/metabolism/diagnostic imaging
Aged, 80 and over
Western Australia
Alzheimer Disease/metabolism
Fluorodeoxyglucose F18
*Diet

@article {pmid41978265,
year = {2026},
author = {Lázaro, B and Tadeo, FJ and Rodríguez, A and Ayuso-Molina, L and Martínez-Láinez, JM and Quandt, E and Bernard, M and Borghi, F and Saiardi, A and Juan-Mateu, J and Jiménez, J and Clotet, J and Bru, S},
title = {Nuclear speckle dynamics are controlled by polyphosphate inhibition of CLK proteins.},
journal = {Nucleic acids research},
volume = {54},
number = {7},
pages = {},
doi = {10.1093/nar/gkag309},
pmid = {41978265},
issn = {1362-4962},
support = {//Ministerio de Ciencia e Innovación/ ; PID2021-127302NB-I00//Spanish Government/ ; PID2024-158824NB-I00//Spanish Government/ ; //Universitat Internacional de Catalunya/ ; },
mesh = {Humans ; *Polyphosphates/metabolism ; RNA Splicing/genetics ; *Cell Nucleus/metabolism/genetics ; *Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors/genetics ; *Protein-Tyrosine Kinases/metabolism/genetics ; Phosphorylation ; HeLa Cells ; Serine-Arginine Splicing Factors/metabolism/genetics ; RNA-Binding Proteins/metabolism ; HEK293 Cells ; },
abstract = {Nuclear speckles (NS) are membraneless nuclear organelles that act as critical hubs for pre-messenger RNA splicing. Defects in splicing are linked to several human diseases, including cancer, Alzheimer's disease, and dystrophies. While CLK kinases regulate the mobilization of splicing factors from NS, the molecular mechanisms underlying NS assembly and dissolution remain unclear. Using an adaptation of the Biotinylation by Antibody Recognition technique, we identified polyphosphate (polyP) as a novel and essential regulator of NS dynamics. Polyphosphate, a highly conserved polyanion composed of a chain of phosphate molecules, is involved in several functions in mammalian cells. Here, we show that polyP interacts with the NS core component SRRM2, and its depletion disrupts NS organization releasing splicing factors into the nucleoplasm. RNA-seq analysis reveals that polyP depletion increases exon exclusion, particularly in transcripts with multiple isoforms, highlighting its role in splicing regulation. Mechanistically, we demonstrate that polyP acts as a physiological inhibitor of CLK3 kinase, preventing the phosphorylation of SR proteins and thereby maintaining NS stability. Our findings not only expand our understanding of NS biology but also provide new insights into the polyP involvement in splicing-related diseases.},
}

Humans
*Polyphosphates/metabolism
RNA Splicing/genetics
*Cell Nucleus/metabolism/genetics
*Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors/genetics
*Protein-Tyrosine Kinases/metabolism/genetics
Phosphorylation
HeLa Cells
Serine-Arginine Splicing Factors/metabolism/genetics
RNA-Binding Proteins/metabolism
HEK293 Cells

@article {pmid41978701,
year = {2026},
author = {Long, S and Li, R and Yang, J and Cheng, R and Wang, Y and Dong, Y},
title = {SIRT1 decreases Aβ-induced IL-1β production by suppressing NLRP3 inflammasome activation and M1 microglial polarization.},
journal = {Cytotechnology},
volume = {78},
number = {3},
pages = {85},
pmid = {41978701},
issn = {0920-9069},
abstract = {Microglia polarize into the proinflammatory M1 phenotype drive Alzheimer's disease (AD) pathogenesis through NLRP3 inflammasome-dependent maturation of interleukin (IL)-1β. Silent information regulator-1 (SIRT1) regulates a large number of cellular pathways and is related to aging and age-associated diseases, however, there were limited studies investigated whether SIRT1 can affect NLRP3 inflammasome and microglial activation and subsequent IL-1β production in AD. Here, we identified SIRT1 over-expression attenuated the release of IL-1β in amyloid-β (Aβ) treated microglia. Furthermore, our findings also revealed that NLRP3 inflammasome were less activated while the SIRT1 has been up-regulated. In addition, SIRT1 considerably alleviated the polarization of microglia toward to M1 phenotype mediated by Aβ, and the inhibitory on M1 polarization accompanied with the up-regulation of phosphorylated AMPK. This study demonstrated that SIRT1 can reduce IL-1β production by inhibiting the activation of NLRP3 and microglial phenotype toward M1, which suggesting SIRT1 may represent a potential strategy for modulating neuroinflammation in AD.},
}

@article {pmid41978790,
year = {2026},
author = {Koenig, LN and Huber, H and Chongtham, A and Di Molfetta, G and Andrews, RD and Lukic, A and Shafiian, N and Fillit, HM and Blennow, K and Ashton, NJ and Zetterberg, H and Matthews, DC and Pereira, AC},
title = {Plasma p-tau217 and glucose metabolism correlate in neocortical association areas in Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag074},
pmid = {41978790},
issn = {2632-1297},
abstract = {While the biomarkers available for Alzheimer's disease are continually expanding, including clinically approved blood tests, not all of the relationships between various biomarkers have been fully elucidated. In this study, we explore how regional brain metabolism, as measured by fludeoxyglucose-18 (FDG)-PET, relates to plasma biomarkers such as p-tau217, Glial fibrillary acidic protein (GFAP), phosphorylated-tau (p-tau)217/beta-amyloid (Aβ) 42, and Aβ42/40 in a cohort of participants with early symptomatic Alzheimer's disease. P-tau217 showed a consistent pattern of participants with higher p-tau217 levels having increased hypometabolism in Alzheimer's disease-related regions in neocortical association areas such as the lateral temporal cortex, the precuneus and inferior parietal cortex and atrophy accompanied by greater cognitive impairment. GFAP also related to regional hypometabolism and atrophy in regions known to be affected in Alzheimer's disease, though with a slightly different regional pattern. We additionally observed that participants with equivalent biomarker levels still exhibited diverse patterns of FDG-PET and atrophy. This suggests that, despite the above correlations, imaging provides additional information. These findings support and extend our knowledge of how plasma p-tau217 relates to other Alzheimer's disease biomarkers and cerebral metabolism, helping to contextualize both the benefits and limitations of these plasma biomarkers.},
}

@article {pmid41978992,
year = {2026},
author = {Bouchoucha, K and Collin, L and Coquette, C and Colmant, L and Boyer, E and Huyghe, L and Quenon, L and Gerard, T and Salman, Y and Hox, V and Kienlen-Campard, P and Hanseeuw, B and Decottignies, A and Huart, C},
title = {Olfactory decline tracks central-to-peripheral spread of tau pathology in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71402},
doi = {10.1002/alz.71402},
pmid = {41978992},
issn = {1552-5279},
support = {//Fondation Louvain/ ; //StopAlzheimer Foundation/ ; //FRFS-Welbio/ ; //Télévie-FNRS/ ; CCL40010417//Fonds De La Recherche Scientifique - FNRS/ ; //UCLouvain/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/complications/metabolism ; *tau Proteins/metabolism ; Male ; Female ; Aged ; *Olfactory Bulb/pathology/metabolism ; *Olfaction Disorders/pathology/etiology ; Aged, 80 and over ; Middle Aged ; Disease Progression ; },
abstract = {INTRODUCTION: Olfactory decline often precedes cognitive symptoms in Alzheimer's disease (AD) and is linked to tau pathology. Yet, whether tau aggregates start in peripheral olfactory structures or spread from central regions remains debated.

METHODS: We analyzed 34 post mortem human olfactory bulb (OB) and 2 neuroepithelium (ONE) samples across Braak stages, combined with ex vivo nasal swabs and standardized olfactory testing in 88 clinically characterized participants.

RESULTS: Tau aggregates appeared in the anterior olfactory nucleus layer of the OB from Braak stage III, spreading to peripheral layers only in late stages. Olfactory identification declined in the preclinical phase and was linked to central tau pathology. Discrimination worsened during the prodromal stage, while threshold impairment appeared only in dementia, reflecting the anatomical progression of tau pathology.

DISCUSSION: This anatomical-functional link supports a central-to-peripheral spread of tau pathology in the olfactory system, with stage-specific deficits suggesting targeted smell tests as early AD biomarkers.},
}

Humans
*Alzheimer Disease/pathology/complications/metabolism
*tau Proteins/metabolism
Male
Female
Aged
*Olfactory Bulb/pathology/metabolism
*Olfaction Disorders/pathology/etiology
Aged, 80 and over
Middle Aged
Disease Progression

@article {pmid41978994,
year = {2026},
author = {Li, J and Yi, Y and Gan, L and Bezgin, G and Chan, T and Rahmouni, N and Wang, YT and Aumont, E and Hosseini, SA and Hall, BJ and Trudel, L and Therriault, J and Macedo, AC and Socualaya, KMQ and Arias, JF and Zheng, Y and Olivia-Lopez, D and Hopewell, R and Hsiao, CH and Zou, T and Soucy, JP and Gauthier, S and Vitali, P and Pascoal, TA and Razlighi, QR and Montembeault, M and Li, R and Rosa-Neto, P},
title = {Elevation in network dynamics amplifies amyloid-dependent tau pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71354},
doi = {10.1002/alz.71354},
pmid = {41978994},
issn = {1552-5279},
support = {//Weston Brain Institute/ ; MOP-11-51-31/CAPMC/CIHR/Canada ; RFN 152985/CAPMC/CIHR/Canada ; 159815/CAPMC/CIHR/Canada ; 162303/CAPMC/CIHR/Canada ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090//the Alzheimer's Association/ ; NIRP-12-259245//the Alzheimer's Association/ ; CFI Project 34874//Brain Canada Foundation/ ; 33397//Brain Canada Foundation/ ; Chercheur Boursier 2020-VICO-279314//the Fonds de Recherche du Québec-Santé/ ; 2024-VICO-356138//the Fonds de Recherche du Québec-Santé/ ; 2022ZD0208903//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 823720853//National Natural Science Foundation of China/ ; LGL-1630-05//Lingang Laboratory/ ; //Fondation Brain Canada/ ; //Consortium canadien en neurodégénérescence associée au vieillissement/ ; },
mesh = {Humans ; Male ; *tau Proteins/metabolism ; Female ; Cross-Sectional Studies ; *Amyloid beta-Peptides/metabolism ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Aged ; *Brain/diagnostic imaging/metabolism/pathology ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Middle Aged ; *Nerve Net/diagnostic imaging ; Biomarkers ; },
abstract = {INTRODUCTION: The role of brain network dynamics in relation to amyloid beta (Aβ) and tau pathology across Braak stages remains unclear.

METHODS: In this cross-sectional study of 216 participants from Translational Biomarkers of Aging and Dementia (TRIAD) cohort, we analyzed resting-state functional magnetic resonance imaging using a multilayer modularity algorithm to assess brain network dynamics across 10 predefined functional networks, stratified by amyloid and tau positron emission tomography biomarkers and Braak stages.

RESULTS: Switching rates were significantly elevated in Aβ-positive/tau-positive individuals relative to Aβ-negative/tau-negative individuals, and increased progressively with advancing Braak stages. Elevated switching rates were strongly correlated with Aβ and tau burden in dorsal attention network and sensorimotor network, as well as with cognitive severity. Importantly, the interaction between network switching rate and Aβ burden synergistically contributed to accelerated tau accumulation in Braak stage III to V regions.

DISCUSSION: These findings support the framework that increased network switching may amplify Aβ-related tau load and cognitive deterioration in Alzheimer's disease.},
}

Humans
Male
*tau Proteins/metabolism
Female
Cross-Sectional Studies
*Amyloid beta-Peptides/metabolism
Magnetic Resonance Imaging
Positron-Emission Tomography
Aged
*Brain/diagnostic imaging/metabolism/pathology
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Middle Aged
*Nerve Net/diagnostic imaging
Biomarkers

@article {pmid41979006,
year = {2026},
author = {Caro, I and Pérez, G and Bize, JV and Ponferrada, J and Ferrante, FJ and Welford, AS and Gauder, L and Olavarría, L and Henríquez, F and Ramos, T and Besnier, C and Ferrer, L and Gorno-Tempini, ML and Slachevsky, A and Ibañez, A and García, AM},
title = {Benchmarking speech biomarkers of Alzheimer's against cognitive and neural measures.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71365},
doi = {10.1002/alz.71365},
pmid = {41979006},
issn = {1552-5279},
support = {1231839//Fondecyt Regular/ ; ACT210096//PIA Anillos/ ; //NIH/ ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; SG-20-725707/ALZ/Alzheimer's Association/United States ; //Rainwater Charitable Foundation - Tau Consortium, and Global Brain Health Institute/ ; //Fogarty International Center [FIC]/ ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; 2P01AG019724/AG/NIA NIH HHS/United States ; R01 AG075775/AG/NIA NIH HHS/United States ; R01 AG21051/AG/NIA NIH HHS/United States ; R01 AG083799/AG/NIA NIH HHS/United States ; CARDS-NIH/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; //Rainwater Charitable Foundation - The Bluefield Project to Cure FTD/ ; //Global Brain Health Institute/ ; 1250091//ANID/FONDECYT Regular/ ; 1250317//ANID/FONDECYT Regular/ ; 1220995//ANID/FONDECYT Regular/ ; ACT210096//ANID/PIA/ANILLOS/ ; DISCeRN 2025//JPI JPND-Care/ ; //Health and Social Care Research with a Focus on the Moderate and Late Stages of Neurodegenerative Diseases/ ; ID20I10152//FONDEF/ ; 15150012//ANID/FONDAP/ ; /WT_/Wellcome Trust/United Kingdom ; 335293/Z/25/Z//BRAIN-CLIMA: Investigating the Combined Impact of Heat and Air Pollution on Blood-Brain Barrier Integrity and Brain Aging in Latin America/ ; CARE-2025-0883490149//Wellcome Leap CARE Program/ ; 101236426//Advancing Female-Specific Predictive Models and Risk Assessment Tools for Alzheimer's Disease in the US and Latin America, and the CliCBrain/ ; //Marie Skłodowska-Curie Actions - MSCA/ ; R01AG075775//NIA of the NIH/ ; R01AG083799//NIA of the NIH/ ; 2P01AG019724//NIA of the NIH/ ; FONDAP ID15150012//ANID/ ; FONDAP ID15150012//ANID/ ; FONDECYT Regular 1250317 1250091//ANID/ ; 01-PICTE-2022-05-00103//Agencia Nacional de Promoción Científica y Tecnológica/ ; /TW/FIC NIH HHS/United States ; //The Bluefield project to cure FTD/ ; //Rainwater Charitable Foundation/ ; //Tau Consortium/ ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; 2P01AG019724/AG/NIA NIH HHS/United States ; FONDECYT Regular 1250091//Agencia Nacional de Investigación y Desarrollo/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology ; Male ; Female ; Magnetic Resonance Imaging ; Biomarkers ; Aged ; Neuropsychological Tests/statistics & numerical data ; *Benchmarking ; *Speech/physiology ; Executive Function/physiology ; Middle Aged ; Brain/diagnostic imaging ; *Cognition/physiology ; Machine Learning ; Hispanic or Latino ; Memory, Episodic ; White ; },
abstract = {INTRODUCTION: Digital speech biomarkers (DSBs) support the detection and monitoring of Alzheimer's disease (AD) in Latinos. However, they have not been benchmarked against standard cognitive and neuroimaging measures, missing a critical validation milestone.

METHODS: Thirty-three AD patients and 33 healthy controls completed verbal fluency tasks, episodic memory and executive tests, and magnetic resonance imaging (MRI) (volume) and functional MRI (fMRI) (connectivity) scans. Between-group machine learning classification was compared among fluency-derived DSBs, episodic and executive test scores, MRI, and fMRI measures.

RESULTS: The fluency classifier's performance (area under the curve [AUC] = 0.84) was comparable (p > 0.14) to the episodic (AUC = 0.90), executive (AUC = 0.79), and structural (AUC = 0.90) classifiers and superior to the functional classifier (AUC = 0.65, p = 0.002). Top discriminating features were word length and frequency, both associated with right (pre)frontal volume upon adjusting for sociodemographic factors.

DISCUSSION: DSBs appear non-inferior to standard cognitive and imaging measures, supporting scalable AD assessments in Latinos.

HIGHLIGHTS: We examined digital speech biomarkers (DSBs) for detecting AD in Latinos. DSBs were benchmarked against cognitive and neuroimaging features. DSB-based classifiers matched or outperformed cognitive and brain classifiers. Top DSBs included word length, phonological neighborhood, and frequency. Word length and frequency correlated with right (pre)frontal brain volume.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology
Male
Female
Magnetic Resonance Imaging
Biomarkers
Aged
Neuropsychological Tests/statistics & numerical data
*Benchmarking
*Speech/physiology
Executive Function/physiology
Middle Aged
Brain/diagnostic imaging
*Cognition/physiology
Machine Learning
Hispanic or Latino
Memory, Episodic
White