@article {pmid42000775,
year = {2026},
author = {Ou, YN and Liu, X and Gao, PY and Yang, L and Feng, JF and Tan, L and Yu, JT and Song, JH},
title = {Associations of oral contraceptives and hormone replacement therapy with incident dementia risk: a population-based cohort study.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04007-4},
pmid = {42000775},
issn = {2158-3188},
support = {82071201, 82071997//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82501704//National Natural Science Foundation of China (National Science Foundation of China)/ ; tsqn202408400//Taishan Scholar Project of Shandong Province/ ; ZR2025QC957//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; },
abstract = {The relationships between exogenous hormones and dementia, as well as cognitive function in females, remains debated. This study aimed to investigate the associations of exogenous hormone exposure (oral contraceptives [OC] and hormone replacement therapy [HRT]) with incident dementia risk, cognitive function and changes in brain structures. Multivariate Cox proportional hazard regression models were used to assess the associations between exogenous hormone exposure and dementia incidence. Linear regression models were employed to explore the relationships of exogenous hormone exposure and cognitive performances. Mediation models were conducted to explore the underlying mechanisms driven by brain structures. A total of 233,896 female participants from the UK Biobank were included. In fully adjusted models, OC use was associated with reduced risks of all-cause dementia (ACD) (HR [95% CI], 0.806 [0.724-0.897]), Alzheimer's disease (AD) (HR [95%CI], 0.767 [0.659-0.893]) and vascular dementia (VaD) (HR [95%CI], 0.735 [0.578-0.934]). HRT was associated with decreased risks of ACD (HR [95%CI], 0.897 [0.811-0.992]) and AD (HR [95%CI], 0.804 [0.696-0.928]). Duration of OC use showed a non-linear (J-shaped) association with the risks of ACD and AD. In addition, brain structures, including the bilateral pallidum and left thalamus proper were identified as potential mediators in the relationships between the duration of OC use and cognitive performance. To summarize, exogenous hormone use is associated with reduced dementia risk and better cognitive function, with pallidum and thalamus possibly mediating the associations.},
}

@article {pmid42000813,
year = {2026},
author = {Farinas, MF and Chen, Y and Zeng, X and Nafash, MN and Cohen, AD and Lopez, OL and Karikari, TK},
title = {Evaluation of serum as an alternative matrix to plasma for NULISA‑based proteomic blood biomarker measurements.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-46409-w},
pmid = {42000813},
issn = {2045-2322},
}

@article {pmid42001186,
year = {2026},
author = {Zheng, W and Geng, D and Wang, A and Li, Z and Liu, A and Chen, S and Wang, Q and Su, C and Yan, Z and Yin, Y and Xu, G},
title = {Gamma low field magnetic stimulation ameliorates pathophysiological damage and cognitive impairments in AD mice.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02052-1},
pmid = {42001186},
issn = {1758-9193},
support = {52277230//National Natural Science Foundation of China/ ; SJZZXB24006//Science and Technology Cooperation Special Project of Shijiazhuang/ ; 25292001D//Hebei Province Provincial Science and Technology Programme Project International Science and Technology Co-operation Special Project/ ; 2022YFC2402203//National Key R&D Program of China/ ; },
abstract = {BACKGROUND: The normal functioning of gamma rhythms is crucial for maintaining brain health, while their abnormalities are closely associated with various neurological disorders, particularly Alzheimer's disease. Gamma stimulation modalities including auditory, visual, electrical, and strong magnetic approaches have all demonstrated potential therapeutic effects for AD, with substantial research findings continuously emerging. However, 40 Hz gamma low field magnetic stimulation(gamma-LFMS) remains unexplored.

METHODS: To investigate this question, we applied pulsed magnetic fields with a magnetic field strength of 10 mT and frequency of 40 Hz (2 × 30 min/day) to 9-month-old APP/PS1 double transgenic AD model mice for 18 consecutive days, and evaluated changes in spatial memory capacity, hippocampal neural network characteristics, and amyloid protein 42 content in AD mice.

RESULTS: Gamma-LFMS significantly enhanced spatial memory performance in AD mice, increased theta-gamma phase-amplitude coupling and gamma band power in the hippocampal CA1 region, showed a trend toward desynchronization in low gamma, and effectively reduced hippocampal β-amyloid42 burden.

CONCLUSIONS: This study demonstrates for the first time that gamma-LFMS effectively ameliorates pathophysiological alterations and spatial memory deficits in AD mice. These findings address a critical knowledge gap regarding the effects of gamma-LFMS on AD pathology and provide a theoretical foundation for developing cost-effective home-based prevention and treatment devices applicable throughout the lifespan.},
}

@article {pmid42001246,
year = {2026},
author = {Grondona, C and Russo, E and Tasso, B},
title = {Exploring the Hydrazone Group in Multifunctional Approaches for Alzheimer's Disease Therapy.},
journal = {ChemMedChem},
volume = {21},
number = {8},
pages = {e202501097},
doi = {10.1002/cmdc.202501097},
pmid = {42001246},
issn = {1860-7187},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Hydrazones/chemistry/pharmacology/therapeutic use ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; Molecular Structure ; *Neuroprotective Agents/chemistry/pharmacology ; Cholinesterases/metabolism ; Animals ; Structure-Activity Relationship ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder in which numerous interconnected pathological processes, such as cholinergic deficits, Aβ and tau aggregation, oxidative stress, metal dyshomeostasis, mitochondrial dysfunction, and neuroinflammation, synergistically drive neuronal damage and cognitive decline. This heterogeneity has limited the effectiveness of the clinically available single-target therapies which only provide symptomatic relief and underscores the need for molecular frameworks capable of addressing multiple pathogenic pathways simultaneously to stop the progression of the disease. Hydrazones have emerged as highly versatile scaffolds in medicinal chemistry thanks to their straightforward synthesis, structural adaptability, and rich repertoire of interaction modes with different biological targets. In recent literature, an increasing number of hydrazone-based molecules have been designed as multitarget-directed ligands (MTDLs) to modulate key enzymes and pathological mechanisms relevant to AD. This review provides a comprehensive and critical overview of hydrazone-containing compounds reported over the last years (2020-2025) with potential application in AD therapy, highlighting their activity on classical targets, especially cholinesterases (ChEs), as well as emerging targets including carbonic anhydrase, BACE1, and α-glycosidase. Particular emphasis is placed on structure-activity relationships (SARs), multitarget profiles, and rational design strategies aimed at exploiting the hydrazone moiety to address the multifactorial nature of AD.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Hydrazones/chemistry/pharmacology/therapeutic use
*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use
Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
Molecular Structure
*Neuroprotective Agents/chemistry/pharmacology
Cholinesterases/metabolism
Animals
Structure-Activity Relationship

@article {pmid42001284,
year = {2026},
author = {Hu, Y and Jiang, J and Shen, G and Ding, X},
title = {Polypharmacy and cognitive outcomes in elderly inpatients with Alzheimer's disease: A three-year retrospective study.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {6},
pages = {1792-1801},
doi = {10.36721/PJPS.2026.39.6.170.1},
pmid = {42001284},
issn = {1011-601X},
mesh = {Humans ; *Polypharmacy ; *Alzheimer Disease/drug therapy/psychology/mortality ; Retrospective Studies ; Male ; Female ; Aged ; Aged, 80 and over ; *Cognitive Dysfunction/epidemiology ; *Cognition/drug effects ; Inpatients ; Incidence ; Accidental Falls/statistics & numerical data ; Hospitalization ; Cholinergic Antagonists/adverse effects/therapeutic use ; Disease Progression ; Propensity Score ; },
abstract = {BACKGROUND: Inpatient care for Alzheimer's disease (AD), often complicated by comorbidities, frequently involves polypharmacy (≥5 medications). The profile and cognitive consequences of sustained polypharmacy in these elderly inpatients require further investigation.

OBJECTIVES: To investigate the status of polypharmacy in elderly inpatients with AD and its correlation with three-year cognitive outcomes, so as to provide a basis for clinical optimization of medication regimens.

METHODS: This study was a retrospective propensity score matching (PSM) cohort study. 300 AD inpatients who were hospitalized from March 2022 to March 2025 were included. Patients were stratified into polypharmacy and non-polypharmacy groups according to their polypharmacy status. The primary outcome was the incidence of cognitive decline (MMSE decline ≥3 points) at 3 years. Secondary outcomes were the association of CDR progression, rate of decline in MoCA, incidence of falls, all-cause rehospitalization, all-cause mortality and anticholinergic drug burden with cognitive outcomes.

RESULTS: After PSM, baseline characteristics were balanced (p>0.05). At the 3-year follow-up, the polypharmacy group had a significantly higher incidence of cognitive decline than the non-polypharmacy group (64.0% vs. 38.0%; RR=1.68, 95% CI: 1.33-2.13, p<0.001). Polypharmacy was also associated with faster CDR progression, a greater annual rate of MoCA decline and increased risks of falls (RR=1.82, p<0.01) and all-cause rehospitalization (RR=1.67, p<0.001). A high anticholinergic burden (ACB score ≥3) was identified as an independent predictor of cognitive decline (OR=2.5, 95%CI: 1.7-3.7, p<0.001).

CONCLUSIONS: Our findings highlight polypharmacy as a key, modifiable risk for cognitive decline in AD, calling for structured medication management to mitigate this risk.},
}

Humans
*Polypharmacy
*Alzheimer Disease/drug therapy/psychology/mortality
Retrospective Studies
Male
Female
Aged
Aged, 80 and over
*Cognitive Dysfunction/epidemiology
*Cognition/drug effects
Inpatients
Incidence
Accidental Falls/statistics & numerical data
Hospitalization
Cholinergic Antagonists/adverse effects/therapeutic use
Disease Progression
Propensity Score

@article {pmid42001306,
year = {2026},
author = {Thakur, A and Rana, M and Vanjani, S and Liou, KC and Taliyan, R and Nepali, K and Yang, CH},
title = {Multi-Targeting Ligands as Prospective Therapeutics for Alzheimer's Disease, a Prevalent Neurodegenerative Disorder: Mechanistic Insights, Emerging Targets and Drug Discovery Campaigns.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.70047},
pmid = {42001306},
issn = {1098-1128},
support = {NSTC 112-2320-B-038-018-MY3//National Science and Technology Council, Taiwan/ ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive impairment, memory deterioration, and neuronal dysfunction. Its complex pathophysiology involves multiple interlinked processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, synaptic dysfunction, and cholinergic deficits. Current FDA-approved therapies provide only symptomatic relief and fail to halt disease progression, highlighting the urgent need for more effective treatment strategies. This review provides a comprehensive overview of the pathological mechanisms underlying AD and the emerging therapeutic targets for the design of tractable anti-AD scaffolds, namely, acetylcholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β (GSK3β), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), histone deacetylases (HDACs), and soluble epoxide hydrolase (sEH). Emphasis is placed on the paradigm shift from single-target therapies to multitarget-directed ligands (MTDLs), which are increasingly recognized as promising tools to tackle AD's multifactorial pathology. We also discuss recent advances in medicinal chemistry and structure-guided drug discovery campaigns aimed at developing pharmacologically optimized, BBB-penetrant MTDLs. By consolidating mechanistic insights with therapeutic innovation, this review aims to facilitate the development of next-generation therapeutics with enhanced efficacy and disease-modifying potential in AD.},
}

@article {pmid42001319,
year = {2026},
author = {Romandini, M and Hajishengallis, G and Curtis, M and Baima, G},
title = {Periodontal Medicine Rewired: Mechanisms Linking Periodontitis to Systemic Diseases.},
journal = {Journal of periodontal research},
volume = {},
number = {},
pages = {},
doi = {10.1111/jre.70099},
pmid = {42001319},
issn = {1600-0765},
abstract = {Periodontitis is now recognized not merely as a localized oral condition but as a systemic disease linked to over 70 communicable and non-communicable conditions. This Review explores the key mechanistic pathways-or "gum-shots"-underpinning the systemic impact of periodontitis. Seven interwoven mechanisms are identified. The first, microbial translocation, involves oral pathobionts and virulence factors breaching anatomical barriers and gaining systemic access via hematological, respiratory, and enteral routes, contributing to tissue damage at extra-oral sites. The second, systemic (meta)inflammation, implicates both the spillover of inflammatory mediators from periodontal tissues into circulation and the immune response to translocated pathogens, fueling pro-inflammatory processes. The third, maladaptive myelopoiesis, involves the periodontitis-associated maladaptive trained immunity and aging-related clonal hematopoiesis of indeterminate potential in the bone marrow, leading to myeloid cells with heightened proinflammatory potential. The fourth, immune players trafficking, centers on the systemic repercussions of periodontally generated autoantibodies, translocated orally primed inflammatory cells, and other local immune events. The fifth, masticatory dysfunction-mediated dietary alterations, involves compromised chewing efficiency that alters dietary intake, resulting in nutritional and metabolic imbalances. The sixth, functional dysregulation of the oral microbiome, describes how periodontitis alters the metabolic activity of this densely populated microbial "superorganism", with downstream effects on both oral and systemic physiology. The final mechanism, shared underlying vulnerabilities, refers to background entities-such as biological aging, oxidative stress, psychosocial stress, (epi)genetic predispositions, certain viral infections, and potentially other as-yet-unknown contributors-that drive multi-morbidity, including periodontitis. By dissecting these interconnected pathways, this critical Review challenges the traditional dichotomy of direct versus indirect mechanisms, revealing a more intricate and dynamic interplay.},
}

@article {pmid42001798,
year = {2026},
author = {Kurihara, M and Ihara, R and Sato, K and Iwata, A},
title = {Cost analyses of plasma p-tau217 versus p-tau217/Aβ42 ratio using two-step approach in the Japanese health care system.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100572},
doi = {10.1016/j.tjpad.2026.100572},
pmid = {42001798},
issn = {2426-0266},
abstract = {Plasma p-tau217 may offer a cost-saving effect in diagnosing Alzheimer's disease. However, each healthcare system has different costs, and its impact on evaluating anti-amyloid β (Aβ) therapies in Japan remains unclear. We conducted cost analyses using a two-step approach with a recently released application, assuming that measuring two analytes (p-tau217/Aβ42) would reduce the intermediate zone to 7%, despite doubling the price. Plasma biomarker costs were simulated from 100 to 800 USD. Cost savings ranged 34-79% compared with positron electron tomography (PET) and -5.6%-74% compared with in-patient cerebrospinal fluid (CSF) Aβ42/40 when 14.7% were in the intermediate zone. Savings were comparably high by measuring two analytes at 100 or 200 USD per analyte and gradually differed (one analyte better savings than two) as the cost per analyte increased. Both plasma p-tau217 and p-tau217/Aβ42 showed substantial cost-saving effects, with comparably high savings at lower costs (100, 200 USD) per analyte.},
}

@article {pmid42001941,
year = {2026},
author = {Chen, AP and Pandey, H and Hancock, WO},
title = {Oxidative stress impairs processive motility of the axonal transport motor KIF1A.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {111471},
doi = {10.1016/j.jbc.2026.111471},
pmid = {42001941},
issn = {1083-351X},
abstract = {The kinesin-3 family member, KIF1A is an essential motor protein that carries out intracellular transport in neurons. Previous work has established that: 1) intracellular transport can be impaired in neurodegenerative diseases such as Alzheimer's and Parkinson's; and 2) oxidative stress is elevated in neurodegenerative diseases and during aging. To date there has not been a systematic study of the effects of reactive oxygen species on kinesin motor proteins. We hypothesized that oxidative stress can damage kinesin, leading to decreased motility. To test our hypothesis, we treated KIF1A in vitro with varying concentrations of hydrogen peroxide (H2O2), a common reactive oxygen species, and characterized the impacts on KIF1A function. Pretreatment of KIF1A with H2O2 at concentrations of 1 mM and higher decreased motility in microtubule gliding assays. In single-molecule assays KIF1A was impacted in two ways: a fraction of motors moved with slowed velocity, while a fraction of motors moved only diffusively with no net directionality. Non-reducing SDS-PAGE of oxidized kinesin showed higher molecular weight bands, consistent with disulfide-bonded dimers and higher-order species. Treating oxidized motors with reducing agents reversed this crosslinking and partially restored motility. Replacing cysteine residues in the motor domain reduced the effects of moderate oxidation but did not prevent the severe degradation of motility at the highest H2O2 concentrations, indicating there is irreversible oxidative damage beyond only cysteine residues. Our results suggest that KIF1A can be impacted by oxidative stress and raise the possibility that oxidized KIF1A may be involved in the pathogenesis of neurodegenerative diseases.},
}

@article {pmid42001982,
year = {2026},
author = {Shiino, A and Tanigaki, K and Oki, M and Watanabe, Y},
title = {Advancing Brain Age Estimation: Normative Deviation Mapping (NDM) for Sensitive Detection of Pathological Aging.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121927},
doi = {10.1016/j.neuroimage.2026.121927},
pmid = {42001982},
issn = {1095-9572},
abstract = {Brain age is a valuable neuroimaging-based biomarker for assessing brain health, typically estimated using machine learning (ML) models. However, ML approaches suffer from inherent bias, requiring post-hoc correction, and may mask age-related biological variation, limiting their sensitivity to detect subtle biological aging. To overcome these limitations, we proposed a normative deviation mapping (NDM) model as an alternative to conventional ML. We analyzed MRI-derived volumes of 223 brain regions from 10,539 participants (aged 4-98 years). The NDM model assumes a normal distribution for age-specific volumes to calculate regional deviations, which are then aggregated across the brain to determine the final brain age. Compared to standard ML models (e.g., neural networks, extreme gradient boosting), the NDM model effectively eliminated regression bias. Consequently, the NDM model mitigated the underestimation of brain age in older adults, significantly enhancing the detection of pathological changes associated with neurodegenerative diseases, such as Alzheimer's disease. Furthermore, in healthy individuals, the NDM model showed a stronger correlation with cognitive function than chronological age. Our findings indicate that the use of ComBat-GAM for data harmonization could unintentionally mitigate the pathological associations of the brain age gap, suggesting a need for caution to preserve vital biological information. Overall, our model outperforms conventional ML in detecting pathological changes and reflecting biological brain age, while revealing the effects of amyloid accumulation and lifestyle habits on brain health, offering a more robust and biologically meaningful biomarker.},
}

@article {pmid42002234,
year = {2026},
author = {Tang, Y and Guo, T and He, H and Deng, Y},
title = {Beyond acid-base dyshomeostasis: Dynamic instability of neuronal lysosomal pH as a pathogenic mechanism and therapeutic target in neurological diseases.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117990},
doi = {10.1016/j.bcp.2026.117990},
pmid = {42002234},
issn = {1873-2968},
abstract = {The precise maintenance of the intra-lysosomal acidic microenvironment is vital for neuronal functions, including protein degradation, metabolic regulation, and organelle quality control. This review systematically elucidates the dynamic regulatory network governing neuronal lysosomal pH homeostasis, transcending the classical proton pump-leak model. We highlight a multifaceted system integrating vacuolar-type H[+]-ATPase (V-ATPase)-driven active proton pumping, proton leakage mediated by channels such as transmembrane protein 175 (TMEM175) and solute carrier family 7 member 11 (SLC7A11), membrane potential buffering by the Cl[-]/H[+] exchanger ClC-7, and regulatory signaling pathways involving AMP-activated protein kinase (AMPK)-mechanistic target of rapamycin complex 1 (mTORC1)-transcription factor EB (TFEB). Crucially, pH dysregulation-manifesting as hyperacidification, alkalinization, or the increasingly recognized and potentially more deleterious phenomenon of dynamic instability-emerges as a fundamental pathogenic mechanism in neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD). Such disruption impairs autophagic flux and mitochondria-lysosome crosstalk, triggering neuroinflammation and ultimately leading to neuronal dysfunction and death. Building upon these mechanistic insights, we discuss emerging therapeutic strategies, advocating a paradigm shift from merely correcting acid-base imbalance toward restoring intrinsic lysosomal pH homeostatic resilience. Finally, we outline critical challenges for clinical translation, including deciphering neuron subtype-specific mechanisms, identifying dynamic in vivo pH biomarkers, and developing brain-penetrant therapeutics. Overcoming these hurdles through interdisciplinary innovation is essential to advance lysosomal pH-targeted therapies into clinical practice.},
}

@article {pmid42002260,
year = {2026},
author = {Oh, J and Oda, K and Chiriac, G and Fraser, GE and Sirirat, R and Sabaté, J},
title = {Egg intake and the incidence of Alzheimer's disease in the Adventist Health Study-2 cohort linked with Medicare data.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101541},
doi = {10.1016/j.tjnut.2026.101541},
pmid = {42002260},
issn = {1541-6100},
abstract = {BACKGROUND: A substantial knowledge gap remains regarding the relationship between modifiable dietary factors and Alzheimer's disease risk. Eggs are a source of key nutrients that support brain health.

OBJECTIVE: Our aim was to investigate the association between egg consumption and incidence Alzheimer's disease.

METHODS: Data were drawn from the Adventist Health Study-2, a large, prospective cohort of U.S. Seventh-day Adventists, linked with Medicare records to identify Alzheimer's disease diagnosis. Diet and lifestyle factors were assessed using a validated food frequency questionnaire. Egg consumption was categorized by frequency ranging from never/rarely to ≥5 times/week. The analytic sample included 39,498 participants (mean follow-up: 15.3 years), among whom 2,858 developed Alzheimer's disease. Multivariable-adjusted Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline analysis was conducted using continuous egg intake (g/day).

RESULTS: Egg consumption was inversely associated with Alzheimer's disease risk. Compared to never/rarely consuming eggs, HRs (95% CIs) after adjusting for demographic, lifestyle, food groups, and comorbidities were: 0.83 (0.75-0.92) for 1-3 times/month, 0.83 (0.74-0.94) for once/week, 0.80 (0.71-0.90) for 2-4 times/week, and 0.73 (0.60-0.89) for ≥5 times/week. In the spline model, zero egg intake was curvilinearly associated with an adjusted HR of 1.22 (1.11-1.34) compared to 10 g/day.

CONCLUSIONS: In this health-conscious population, moderate egg consumption was associated with a significantly lower risk of Alzheimer's disease. These findings suggest a potential neuroprotective benefit of nutrients found in eggs when consumed as part of a balanced diet.},
}

@article {pmid42002722,
year = {2026},
author = {Gorniak-Walas, M and Telugu, NS and Rudolph, IM and Diecke, S and Willnow, TE},
title = {Alzheimer's disease risk single nucleotide polymorphism rs11218343 is linked to functional expression of SORL1 in microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71390},
doi = {10.1002/alz.71390},
pmid = {42002722},
issn = {1552-5279},
support = {NNF18OC0033928//Novo Nordisk Foundation/ ; },
mesh = {*Polymorphism, Single Nucleotide/genetics ; *Microglia/metabolism ; Humans ; *Alzheimer Disease/genetics ; *LDL-Receptor Related Proteins/genetics/metabolism ; *Membrane Transport Proteins/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Genetic Predisposition to Disease ; Alleles ; },
abstract = {INTRODUCTION: The rs11218343 is a non-coding variant of genome-wide significance for sporadic Alzheimer's disease (AD) with one of the most protective effects known to date. It localizes to SORL1, encoding the AD risk factor Sortilin-related receptor with A type repeats (SORLA). Still, the functional significance of rs11218343 for AD-related processes remains unclear.

METHODS: We used induced pluripotent stem cell (iPSC) lines from donors, or genome-engineered to carry major and minor rs11218343 alleles, to study the impact of rs11218343 on cellular activities.

RESULTS: We show that rs11218343 is uniquely linked to functional expression of SORLA in microglia, with increased expression in the protective allele correlating with reduced pro-inflammatory responses. These anti-inflammatory effects are seen in donor lines but not in single nucleotide polymorphism (SNP) -engineered isogenic lines, arguing that this polymorphism alone is insufficient but acting context-dependent.

DISCUSSION: Our data infer genetically defined expression of SORL1 in microglia as a determinant of protection from pro-inflammatory stimulation, a function likely encoded by a haplotype linked to rs11218343.},
}

*Polymorphism, Single Nucleotide/genetics
*Microglia/metabolism
Humans
*Alzheimer Disease/genetics
*LDL-Receptor Related Proteins/genetics/metabolism
*Membrane Transport Proteins/genetics/metabolism
Induced Pluripotent Stem Cells/metabolism
Genetic Predisposition to Disease
Alleles

@article {pmid42002723,
year = {2026},
author = {Sukreet, S and Kim, EK and Petersen, M and Zhang, F and O'Bryant, SE and Rafii, MS and Rissman, RA},
title = {Precision medicine for Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71398},
doi = {10.1002/alz.71398},
pmid = {42002723},
issn = {1552-5279},
support = {AG073979//NIH/NIA/ ; R61/R33AG066543//NIH/NIA/ ; },
mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/drug therapy/diagnosis/blood/complications ; *Precision Medicine/methods ; Male ; Female ; Biomarkers/blood ; Middle Aged ; *Vitamin E/therapeutic use ; Proteomics ; Aged ; Neuropsychological Tests ; Support Vector Machine ; Extracellular Vesicles/metabolism ; },
abstract = {INTRODUCTION: Down syndrome (DS) exhibits a genetic form of Alzheimer's disease (AD). We used a blood-based proteomic algorithm to predict cognitive status, treatment responders, and change to vitamin E in DS adults from a completed clinical trial, "Vitamin E in Aged Persons with Down Syndrome," which originally showed no significant cognitive benefit using the primary endpoint cognition (Brief Praxis Test [BPT]).

METHODS: Plasma and extracellular vesicle (EV; astrocytic and neuronal) biomarkers were assayed at baseline and 36 months (n = 138 each). Cognitive response was measured using combined scores from the BPT, vocabulary, and behavior and function DS tests. Support vector machine (SVM) analyses predicted diagnostic and treatment responders and change accuracy.

RESULTS: SVM classified demented versus non-demented with up to 99% accuracy and predicted treatment response and changes with up to 100% accuracy in plasma and EV.

DISCUSSION: Our study supports blood-based screening and precision diagnostics for AD therapy in DS.},
}

Humans
*Down Syndrome/complications
*Alzheimer Disease/drug therapy/diagnosis/blood/complications
*Precision Medicine/methods
Male
Female
Biomarkers/blood
Middle Aged
*Vitamin E/therapeutic use
Proteomics
Aged
Neuropsychological Tests
Support Vector Machine
Extracellular Vesicles/metabolism

@article {pmid42002809,
year = {2026},
author = {Yang, M and Abdulsalam, R and Shi, Y and Fan, W and Manson, SM and Corrada, MM and O'Connell, J and Jiang, L},
title = {Alzheimer's disease and related dementias and related health conditions among American Indian and Alaska Native Medicare beneficiaries.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71385},
doi = {10.1002/alz.71385},
pmid = {42002809},
issn = {1552-5279},
support = {U54MD000507/MD/NIMHD NIH HHS/United States ; P30AG015292/AG/NIA NIH HHS/United States ; R01AG061189/AG/NIA NIH HHS/United States ; CDPH #24-10131//California Department of Public Health/ ; HealthEquityScholarship//University of California, Irvine, Joe C. Wen School of Population and Public Health/ ; },
mesh = {Humans ; Male ; Female ; United States/epidemiology ; *Alzheimer Disease/epidemiology/ethnology ; Aged ; *Medicare/statistics & numerical data ; *Alaska Natives/statistics & numerical data ; Prevalence ; Aged, 80 and over ; *Dementia/epidemiology/ethnology ; Risk Factors ; *American Indian or Alaska Native/statistics & numerical data ; *Indians, North American/statistics & numerical data ; },
abstract = {INTRODUCTION: Alzheimer's disease and related dementias (ADRD) and its associated factors are not well understood in the American Indian and Alaska Native (AI/AN) population.

METHODS: We analyzed Medicare 2019 data for 112,280 AI/AN and 1,010,862 White beneficiaries aged 68+, examining the prevalence of ADRD-related health conditions and their associations with ADRD through logistic regressions.

RESULTS: AI/AN beneficiaries had higher age-adjusted ADRD prevalence (15.6% vs. 13.3%), and a higher prevalence of 5 of 9 Lancet risk factors: diabetes, alcohol use disorder (AUD), tobacco use disorder, visual and hearing impairments. Traumatic brain injury (TBI), AUD, and visual and hearing impairments had stronger associations with ADRD among AI/AN beneficiaries, while depression, diabetes, and hypertension had stronger associations among White beneficiaries.

DISCUSSION: Our findings highlight disparities in ADRD and related health conditions between AI/AN and White beneficiaries, potentially due to social and systematic health-care inequalities. Addressing these gaps requires culturally tailored prevention and care strategies.},
}

Humans
Male
Female
United States/epidemiology
*Alzheimer Disease/epidemiology/ethnology
Aged
*Medicare/statistics & numerical data
*Alaska Natives/statistics & numerical data
Prevalence
Aged, 80 and over
*Dementia/epidemiology/ethnology
Risk Factors
*American Indian or Alaska Native/statistics & numerical data
*Indians, North American/statistics & numerical data

@article {pmid42002820,
year = {2026},
author = {Mi, X and Zhang, YC and Zhang, XJ and He, HB and Chen, XC and Dai, XM},
title = {The impact of APOE genotype, age, and sex on gut microbiota in a mouse model of Alzheimer's Disease: an exploration of their interactions.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00905-w},
pmid = {42002820},
issn = {2042-6410},
abstract = {BACKGROUND: As an important interface between the peripheral environment and the central nervous system, the gut microbiota varies greatly between patients or animals with Alzheimer's disease (AD) and their respective non-AD counterparts; however, it remains unexplored whether the apolipoprotein E (APOE) genotype, age, and sex may interactively influence the characteristics of gut microbiota in AD animals.

METHODS: APOE genotype, age, and sex were enrolled as independent variables, with genotype distinguished into APOE3 and APOE4, age into 3 and 10 months, and sex into female and male. The composition, structure, and potential functions of gut microbiota were systematically analyzed by 16S rRNA gene amplicon sequencing to evaluate the individual and interactive effects of APOE genotype, age and sex.

RESULTS: Significant interactions were observed among APOE genotypes, ages, and sexes, with different factor combinations exhibiting distinct effect on microbiotic composition and functional potential. APOE genotype exerted the most significant influence on gut microbiota, followed by age and sex with a relatively minor effect, highlighting the dominant role of host genetic background. Functional prediction analysis indicated that the functional profiles were mainly concentrated in basic metabolic pathways, including the biosynthesis of secondary metabolites and amino acids, and carbon metabolism.

CONCLUSION: APOE genotype, age, and sex are jointly associated with the structure and potential function of the gut microbiota in AD model mice. These findings provide a perspective of multi-factor interaction into the alterations in gut microbiota in AD and offer new microecological evidence for understanding APOE4-related AD susceptibility, as well as a conceptual basis for future stratified microecological intervention studies.},
}

@article {pmid42003023,
year = {2026},
author = {Everix, L and Miranda, A and Akkermans, J and Khetarpal, V and Liu, L and Bard, J and Staelens, S and Bertoglio, D},
title = {Comparing kinetic profiles of SV2A radiotracers [[18]F]SynVesT-1 and [[18]F]UCB-J using PET imaging in mice.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261435323},
doi = {10.1177/0271678X261435323},
pmid = {42003023},
issn = {1559-7016},
abstract = {Deficits in the synaptic vesicle protein 2A (SV2A) have been reported in various neurodegenerative diseases including Alzheimer's and Huntington's disease (HD). SV2A levels can be investigated using positron emission tomography (PET) radioligands such as [[11]C]UCB-J, [[18]F]UCB-J, and [[18]F]SynVesT-1. To compare the in vivo performance of the PET radioligands [[18]F]UCB-J and [[18]F]SynVesT-1 in terms of brain penetration, binding profile, and SV2A quantification, we here report a head-to-head study in a mouse model of HD. Dynamic µPET/CT scans (60 min) were acquired in 17-month-old heterozygous (HET, n = 20) zQ175DN and wild-type (WT, n = 19) mice. Brain time-activity curves and image-derived input function were extracted and kinetic modeling was performed using Logan and the two-tissue compartmental model (2TCM). Intra-animal comparison between both radioligands revealed significantly higher K1 (p < 0.01) but equal k2 for [[18]F]SynVesT-1 compared to [[18]F]UCB-J. VT(IDIF) (Logan) quantification found significantly higher values for [[18]F]SynVesT-1 compared to [[18]F]UCB-J regardless of genotype (e.g. striatum WT: 22.4 ± 2.7 vs 18.6 ± 1.8 mL/cm[3]). Regional analyses comparing the average VT(IDIF) between genotypes showed no significant differences; however, voxel-based VT(IDIF) analyses revealed significant SV2A alterations in several subregions of the brain for both radioligands. Overall, [[18]F]SynVesT-1 and [[18]F]UCB-J showed agreement across analyses, demonstrating the equal applicability of both radioligands for SV2A PET imaging.},
}

@article {pmid42003207,
year = {2026},
author = {Fang, ZH and Grant, RH and Vitale, D and Hernandez, CF and Hong, S and Leonard, HL and Makarious, MB and Lange, LM and Solomonson, M and Heutink, P and Dilliott, AA and Galvelis, KG and Nalls, MA and Singleton, AB and Blauwendraat, C and , },
title = {The Global Parkinson's Disease Genetics (GP2) Genome Browser.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70309},
pmid = {42003207},
issn = {1531-8257},
support = {//This project was supported by the Global Parkinson's Genetics Program (GP2, https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF)./ ; },
abstract = {BACKGROUND: Large-scale sequencing initiatives have generated extensive genomic resources essential for variant interpretation, yet their effective use often requires bioinformatics expertise. To support identification of Parkinson's disease (PD) risk and disease-causing variants, we developed an open-access, summary-level genomic data browser.

METHODS: We performed uniform joint variant calling to harmonize whole-genome sequencing (WGS) data from AMP-PD Release 4, GP2 Data Releases, and additional controls from the Alzheimer's Disease Sequencing Project. Clinical-exome sequencing (CES) data from GP2 Release 8 were also included.

RESULTS: The integrated dataset included 31,665 WGS and 9,559 CES samples, spanning 11 ancestries and over 300 million variants.

CONCLUSIONS: The GP2 Genome Browser is a lightweight, flexible platform providing intuitive gene- and variant-level summaries with ancestry-stratified allele frequencies and functional annotations. It is open source and freely accessible at https://gp2.broadinstitute.org, enabling broad access to PD genomic data and supporting global research efforts. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42003218,
year = {2026},
author = {Yauk, J and Dobbs, D and Peterson, LJ and Meng, H},
title = {Assisted Living Staff Perspectives on End-Of-Life Care for Residents Living With Dementia: A Qualitative Study.},
journal = {The American journal of hospice & palliative care},
volume = {},
number = {},
pages = {10499091261444002},
doi = {10.1177/10499091261444002},
pmid = {42003218},
issn = {1938-2715},
abstract = {BackgroundAlzheimer's disease and related dementia (ADRD) affect nearly half of assisted living (AL) residents, the majority of whom have palliative care (PC) needs at the end of life (EOL). AL staff are well positioned to provide PC with appropriate training; however, little is known about their experiences delivering EOL care.ObjectiveTo explore AL staff perspectives on providing quality PC at the EOL for residents with ADRD.MethodsThis qualitative study analyzed secondary data from 17 staff across six AL communities in southwest Florida who participated in the Palliative Care Education in Assisted Living for Dementia Care Providers (PCEAL-DCP) study (2019-21). As part of the training, staff completed two homework assignments: (1) defining what constitutes a good death for residents with dementia, and (2) identifying one resident and at least one action to address EOL care needs. Responses were analyzed using hybrid deductive-inductive thematic analysis. A priori codes were based on the physical, social, emotional, and spiritual domains of PC.ResultsTwenty-two homework assignments were analyzed. Care planning coordination with family emerged as an overarching theme. Staff described family involvement in all four a priori PC themes physical, social, emotional, and spiritual care, with particularly prominent roles in social and emotional aspects of care.ConclusionAL staff emphasized person-centered PC that is responsive to residents' and families' needs, underscoring the multidimensional nature of EOL care and the central role of staff-family collaboration in meeting residents' PC needs at EOL.},
}

@article {pmid42003348,
year = {2026},
author = {Morris, C and Mok, PLH and Robinson, DL and Ashcroft, DM and Blakeman, T and Kontopantelis, E},
title = {How does diagnostic subtype affect the quality of primary care for people with dementia? A retrospective cohort study in 1490 English general practices.},
journal = {Age and ageing},
volume = {55},
number = {4},
pages = {},
doi = {10.1093/ageing/afag101},
pmid = {42003348},
issn = {1468-2834},
mesh = {Humans ; Retrospective Studies ; Male ; Female ; Aged ; *Primary Health Care/standards ; *Dementia/diagnosis/therapy/classification ; Aged, 80 and over ; *General Practice/standards/statistics & numerical data ; England/epidemiology ; Inappropriate Prescribing/statistics & numerical data ; *Quality of Health Care ; *Healthcare Disparities ; },
abstract = {INTRODUCTION: Diagnostic subtype has been suggested as a determinant of inequity for people with dementia; its impact on primary care provision is underexplored. This study investigated the association between dementia subtype and likelihood of receiving guideline-consistent primary care.

METHOD: Retrospective cohort study using Clinical Practice Research Datalink (Aurum) database, 1.1.2006-30.06.2024. We examined potential inequity with eight dementia subtypes: Alzheimer's disease (AD), Lewy body dementia (LBD), vascular, frontotemporal, unspecified, other and two mixed categories. Six outcomes were examined: care plan or medication review (both within 24 months of index) and four indicators of potentially inappropriate prescribing (PIP) (high anti-cholinergic burden drugs, z-drugs, benzodiazepines and anti-psychotics). Cox-regression models were used, adjusting for: age, sex, comorbidities, deprivation and ethnicity.

RESULTS: A total of 571 663 people were included and 72.1% received a care plan; 79.4% received a medication review within 24 months. Compared to AD: people with mixed dementias were more likely to receive a care plan [hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.26-1.32 for mixed including AD/LBD, HR 1.37, 1.32-1.43 for mixed non-AD/LBD]. All other subtypes were less likely to receive a care plan. Individuals with mixed AD/LBD (HR 1.28, 1.26-1.32), mixed non-AD/LBD (HR 1.35, 1.26-1.45), vascular (HR 1.05, CI 1.04-1.07), LBD (HR 1.02, 1.01-1.04) and unspecified (HR 1.02, 1.01-1.03) were more likely to receive medication reviews. Compared to AD, all other subtypes were more likely to experience PIP across all four indicators.

CONCLUSION: We found greater likelihood of PIP in people with non-AD dementias, a novel finding. Further research is needed, especially with new AD drugs potentially widening disparities.},
}

Humans
Retrospective Studies
Male
Female
Aged
*Primary Health Care/standards
*Dementia/diagnosis/therapy/classification
Aged, 80 and over
*General Practice/standards/statistics & numerical data
England/epidemiology
Inappropriate Prescribing/statistics & numerical data
*Quality of Health Care
*Healthcare Disparities

@article {pmid42003377,
year = {2026},
author = {Ding, C and Zhang, Y and Chen, Z and Li, W and Wu, S and Qin, Z and Huang, Y},
title = {Five-in-One Neurodetoxification-Guardian-Type Near-Infrared Carbon Dots for Synergistic Blockade of Alzheimer's Disease Pathological Cascade.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c00295},
pmid = {42003377},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) involves multiple interconnected pathologies, including amyloid-β (Aβ) aggregation, Cu[2+] accumulation, oxidative stress, and mitochondrial dysfunction. Single-target therapies show limited efficacy, and most probes lack combined multipathology modulation and real-time imaging─often requiring extensive surface modifications for modest effects. Here, we report a simple five-in-one neuroprotective-guardian near-infrared luminescent carbon dots (NGN-CDs) synthesized via a glutathione-assisted solvothermal method in formamide. NGN-CDs enable simultaneous intervention in AD pathology and real-time monitoring without complex functionalization. Their strong negative surface charge suppresses Aβ aggregation and disaggregates preformed fibrils, reducing plaque deposition. The carboxyl-rich structure allows high-affinity Cu[2+] chelation, blocking Cu[2+]-induced Aβ aggregation and reactive oxygen species (ROS) generation by inhibiting peroxidase-like activity. NGN-CDs also show dose-dependent broad-spectrum antioxidant activity, effectively scavenging ROS and alleviating oxidative stress. They selectively target mitochondria and preserve membrane potential under H2O2 or Aβ-Cu[2+] challenge, protecting neuronal organelles. Their intrinsic near-infrared fluorescence at 685 nm enables stable, real-time visualization of AD-related processes. Standing out for its multifunctional synergy, this nanoprobe integrates five key functions─Aβ antiaggregation, Cu[2+] detoxification, antioxidant activity, mitochondrial protection, and NIR imaging─into a single platform. This work presents an innovative strategy for synergistic AD intervention and a rational design framework for nanotheranostics in neurodegenerative diseases.},
}

@article {pmid42003482,
year = {2026},
author = {Duran-Aniotz, C and Pizarro, M and Migeot, J and Salazar-Londoño, S and Santamaría-García, H and O'Bryant, SE and Ibanez, A},
title = {Contextualizing Blood-Based Biomarkers for Dementia Globally.},
journal = {Journal of neurochemistry},
volume = {170},
number = {4},
pages = {e70443},
doi = {10.1111/jnc.70443},
pmid = {42003482},
issn = {1471-4159},
support = {1210622//ANID/FONDECYT Regular/ ; 1250091//ANID/FONDECYT Regular/ ; 1210176//ANID/FONDECYT Regular/ ; 1220995//ANID/FONDECYT Regular/ ; AARGD-24-1310017/ALZ/Alzheimer's Association/United States ; SG-20-725707/ALZ/Alzheimer's Association/United States ; //National Agency for Research and Development (ANID)/ ; NIH R01/GF/NIH HHS/United States ; R01 AG057234/GF/NIH HHS/United States ; R01 AG075775/GF/NIH HHS/United States ; R01 AG21051/GF/NIH HHS/United States ; R01 AG083799/GF/NIH HHS/United States ; GBHI ALZ UK-23-971135//Global Brain Health Institute and Alzheimer Association/ ; CARE-2025-0883490149//Wellcome Leap CARE Program/ ; },
mesh = {Humans ; *Biomarkers/blood ; *Dementia/blood/diagnosis/epidemiology ; Alzheimer Disease/blood/diagnosis ; },
abstract = {Blood-based biomarkers (BBMs) are transforming the diagnostic landscape of Alzheimer's disease by enabling scalable, less invasive, and potentially earlier biological characterization. However, most evidence supporting their performance, interpretation, and clinical integration derives from highly selected cohorts in high-income settings, raising concerns about external validity, threshold transportability, and equitable implementation across diverse populations. In this Opinion, we argue that advancing BBMs from analytical validity to real-world use requires a shift from biomarker-centric accuracy toward context-aware interpretation frameworks that explicitly account for social, environmental, and health system determinants. Using the amyloid, tau, and neurodegeneration (AT(N)) system as a conceptual anchor, we discuss how BBMs should be positioned according to clearly defined contexts of use, including triage, diagnostic support, prognosis, and clinical trial readiness, rather than treated as universal diagnostic substitutes. We examine how social determinants of health, life-course exposures, and the cumulative exposome interact with comorbidity burden, systemic physiological stress, and health system readiness to shape biomarker distributions, trajectories, and clinical meaning. Evidence from Latin America and other underrepresented settings illustrates how cardiometabolic, vascular, and inflammatory load can modify baseline biomarker levels, challenging the uncritical transfer of cutoffs, reference ranges, and predictive models developed in high-income settings. We conclude that BBMs hold substantial potential to expand access to biological characterization of Alzheimer's disease, but their responsible adoption depends on aligning biological signals with clinical context, social and environmental conditions, and system capacity. Without this alignment, large-scale deployment risks misclassification, inequitable access to care, biased trial enrollment, and distorted estimates of disease burden.},
}

Humans
*Biomarkers/blood
*Dementia/blood/diagnosis/epidemiology
Alzheimer Disease/blood/diagnosis

@article {pmid42003556,
year = {2026},
author = {Chin, D and Luo, Y and Lau, Y and Dutta, N and He, Z and Yin, C and Williams, RM and Balachandran, S and Vicens, Q and Dröge, P and Luo, D},
title = {Cryo-EM structures of anti Z-DNA antibodies in complex with antigen reveal distinct recognition modes of a left-handed geometry.},
journal = {Nucleic acids research},
volume = {54},
number = {7},
pages = {},
doi = {10.1093/nar/gkag325},
pmid = {42003556},
issn = {1362-4962},
support = {//Singapore Ministry of Education/ ; MOET32023-0003//Singapore Ministry of Education Academic Research Fund Tier 3/ ; RT22/23//Education Academic Research Funds Tier 1/ ; RG84/21//Education Academic Research Funds Tier 1/ ; R01AI135025//Education Academic Research Funds Tier 1/ ; R01CA269975//Education Academic Research Funds Tier 1/ ; MOET32023-0003//Academic Research Fund Tier 3/ ; RG84/21//Academic Research Funds Tier 1/ ; RT22/23//Academic Research Funds Tier 1/ ; },
mesh = {Cryoelectron Microscopy ; *DNA, Z-Form/chemistry/immunology/ultrastructure ; *Antibodies, Monoclonal/chemistry/ultrastructure/immunology ; Nucleic Acid Conformation ; Immunoglobulin Fab Fragments/chemistry ; Models, Molecular ; Humans ; *Antibodies, Antinuclear/chemistry/ultrastructure/immunology ; *Antigens/chemistry/immunology ; },
abstract = {Double-stranded nucleic acids can undergo transitions from canonical B/A-forms to alternate left-handed Z-DNA/Z-RNA (Z-NAs). Z-NAs are implicated in processes such as neuroinflammation in Alzheimer's disease, Lupus Erythematosus, microbial biofilms, and type I interferon-mediated human pathologies. Since endogenous Z-NA sensors like the Zα domain can induce B-to-Z transitions, monoclonal antibodies (mAbs) Z-D11 and Z22 have been regarded as conformation-specific tools to confirm Z-NA in situ, although high-resolution structural information remain unavailable. Here, we employed single-particle cryo-electron microscopy to determine structures of Z-D11 and Z22 bound to synthetic d(CG)6 12mer Z-DNA duplex. Both mAbs form filamentous trimers around the Z-DNA axis, further stabilized by Fab-Fab interactions. The mAbs achieve specificity through multiple backbone-dominated contacts to both Z-form backbone strands and the exposed guanine/cytosine bases in the major groove. This mode of recognition is dictated by shape complementarity rather than sequence specificity, sensing the alternating syn/anti backbone torsions and the phosphate zig-zag geometry unique to Z-DNA. Our data also suggest that these mAbs do not induce B-to-Z transitions under normal physiological conditions. Finally, comparison to other double-stranded NA-binding mAbs defines a similar structural logic adapted to different helical geometry recognition patterns, thus providing a framework for engineering highly specific nucleic acid probes.},
}

Cryoelectron Microscopy
*DNA, Z-Form/chemistry/immunology/ultrastructure
*Antibodies, Monoclonal/chemistry/ultrastructure/immunology
Nucleic Acid Conformation
Immunoglobulin Fab Fragments/chemistry
Models, Molecular
Humans
*Antibodies, Antinuclear/chemistry/ultrastructure/immunology
*Antigens/chemistry/immunology

@article {pmid42003793,
year = {2026},
author = {Hu, D and Li, T and He, J and Jiang, Y and Wang, Y and Sun, J},
title = {Dual Physiological Barriers Bypassed by a Silk-Based Supramolecular Protein Delivery Platform for Neuroinflammation Mitigation in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e75342},
doi = {10.1002/advs.75342},
pmid = {42003793},
issn = {2198-3844},
support = {32301143//National Natural Science Foundation of China/ ; AM2022016//Macao Youth Scholars Program/ ; 2022A1515110329//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {Delivering protein therapeutics to the brain through nanocarriers requires overcoming both the blood-brain barrier (BBB) and intracellular lysosomal degradation. Here, we report a silk-based supramolecular protein delivery platform that addresses these dual physiological barriers. Two phenolic compounds are grafted onto silk sericin (SS), a biocompatible and bioactive natural protein, yielding phenolic SS capable of assembling with protein cargos via supramolecular interactions. To facilitate BBB penetration, the iRGD peptide is incorporated to enable transcytosis via the bystander effect. Phenolic modification alters the ratio of amino to carboxyl groups on SS, thereby tuning its isoelectric point. In acidic lysosomes, the nanocomplex undergoes a surface charge reversal from negative to positive, promoting lysosomal escape and cytosolic release of catalase. In parallel, phenolic SS exhibits intrinsic anti-inflammatory activity, repolarizing activated microglia toward an anti-inflammatory phenotype. In APP/PS1 transgenic mice, systemic administration of the nanocomplex reduces oxidative stress and neuroinflammation, leading to significant improvements in cognitive function, compared to a non-charge-reversal control. Collectively, this strategy provides a versatile and translatable framework for engineering protein-based nanocarriers to deliver protein therapeutics for neurodegenerative disease treatments.},
}

@article {pmid42003838,
year = {2026},
author = {Zhao, M and Li, Q and Li, Y and Zhao, L and An, W and Li, G and Li, Q and Miao, Q},
title = {Unimolecular Organic Afterglow Luminophore With Anti-Kasha/Kasha Emission for in Vivo Activatable Imaging.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e3863987},
doi = {10.1002/anie.3863987},
pmid = {42003838},
issn = {1521-3773},
support = {22274107//National Natural Science Foundation of China/ ; 32471428//National Natural Science Foundation of China/ ; 32571592//National Natural Science Foundation of China/ ; BK20230009//National Natural Science Foundation of China/ ; },
abstract = {Afterglow luminescence holds great promise for biomedical imaging by eliminating tissue autofluorescence. Unimolecular afterglow systems avoid the need for nanoencapsulation, providing enhanced simplicity and structure flexibility as well as in vivo stability over common nanoparticle-based designs. However, rational design remains challenging, and only a few unimolecular systems have been reported. These systems often exhibit low signal intensity, which restricts their biomedical applications. To resolve it, we design a hemicyanine-based unimolecular organic afterglow platform (CyIA) with high afterglow brightness and structural tunability for in vivo activatable imaging. CyIA displays anti-Kasha/Kasha dual-emission with bright afterglow signal in aqueous solution, up to 10[8] p/s/cm[2]/sr, which is nearly three orders of magnitude higher than previously reported unimolecular organic afterglow probes. Leveraging the structural flexibility, a butyrylcholinesterase (BChE)-activatable afterglow probe (CyIAB-T) is fabricated. This probe enables a specific and sensitive detection of BChE in Alzheimer's disease (AD) model mice with higher contrast relative to fluorescence imaging. Importantly, this probe permits dynamic tracking of the age-dependent upregulation of BChE during AD progression. Therefore, this study establishes a versatile unimolecular organic afterglow scaffold with high intensity and structural flexibility for developing activatable afterglow probes for high-contrast biomedical imaging.},
}

@article {pmid42004206,
year = {2026},
author = {Denève, A and Dauchez, R and Lebouvier, T and D'Hondt, F and Bertoux, M},
title = {AI-powered analysis of affective dimensions in speech and its relevance for FTD diagnosis.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70300},
pmid = {42004206},
issn = {2352-8729},
abstract = {INTRODUCTION: Affective disturbances are common across behavioral variant frontotemporal degeneration (bvFTD), primary psychiatric disorders (PPD), and Alzheimer's disease (AD). Objective markers are needed for differential and transdiagnostic characterization. We tested whether artificial intelligence (AI)-based analysis of natural speech could provide such markers.

METHODS: Speech from 112 participants (bvFTD = 31, AD = 28, PPD = 15, controls = 39) was analyzed using a fine-tuned speech emotion recognition model estimating valence, arousal, dominance, and entropy. Group differences were assessed with analyses of covariance, diagnostic utility with logistic regression, and neuroanatomical correlates with voxel-based morphometry.

RESULTS: Group-specific affective profiles emerged. Overall, PPD exhibited a lower valence. bvFTD and AD showed a reduced arousal and a higher dominance. Affective dimensions predicted bvFTD with 80.4% accuracy (area under the curve  =  0.732) and mapped onto fronto-insular and temporal networks. Entropy was identified as a transdiagnostic marker.

DISCUSSION: AI-based speech analysis provides objective, scalable biomarkers for differential diagnosis, transdiagnostic characterization, and disease monitoring.},
}

@article {pmid42004234,
year = {2026},
author = {Leszko, M},
title = {Beyond the Physical Demands: Loneliness and Social Isolation Among Female Spousal Caregivers of Persons with Alzheimer's Disease.},
journal = {Psychology research and behavior management},
volume = {19},
number = {},
pages = {534558},
pmid = {42004234},
issn = {1179-1578},
abstract = {BACKGROUND: Adjusting to Alzheimer's disease diagnosis is a complex process. Caregivers tend to experience feelings of loneliness and isolation, which in turn may have adverse effects on their well-being. The purpose of this study was to explore and describe the perspectives of female older adult caregivers of individuals with AD concerning the social isolation and loneliness.

METHODS: The study uses a mixed methods design (N = 48), combining qualitative and quantitative research components to provide a more comprehensive understanding of the phenomenon.

RESULTS: Based on the analysis, three main themes were derived: "social isolation due to caregiving responsibilities", "changes in social circle" and "balancing caregiving and social connection". There were significant negative associations between loneliness and depression.

CONCLUSION: While the detrimental effects of caregiving on psychological and physical health are well-documented, further research is needed to fully understand the multifaceted nature of the caregiving experience, particularly regarding loneliness and social isolation. This study addresses this gap by exploring the often-neglected aspect of loneliness among caregivers. The findings provide valuable insights for psychologists and healthcare professionals, enhancing their understanding of the challenges and needs of this population.},
}

@article {pmid42004236,
year = {2026},
author = {Zhang, B and Zhang, M},
title = {Metabolic Regulatory Networks in Ferroptosis During Alzheimer's Disease, Mechanisms of Glial Cell Action, and Pathological Correlations with Neuritic Plaques.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {596584},
pmid = {42004236},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathological mechanism, which is still poorly understood. Ferroptosis is a type of non-apoptotic programmed cell death. Many recent studies have found that ferroptosis is closely related to the occurrence and development of AD. This article explains the main theoretical basis of ferroptosis in the pathological development of AD, and systematically analyzes the synergistic pathological network of multiple pathways caused by iron metabolism disorder, abnormal lipid peroxidation, and abnormal amino acid metabolism. This article mainly focuses on the dual regulation mechanism and molecular mechanism of microglia, astrocytes, and oligodendrocytes in the process of ferroptosis. This article studies the two-way relationship between neuritic plaques (NP) and ferroptosis, and the relationship between NP and dystrophic neurites, inflammatory response, and abnormal tau phosphorylation. Based on the existing research, we propose several unanswered questions and possible targeted research directions to provide a theoretical reference for the study of AD pathogenesis and the exploration of intervention strategies.},
}

@article {pmid42004264,
year = {2026},
author = {Bortoluzzi, M and Cencini, A and Rutigliano, L and Rilievo, G and Cecconello, A and Tonolo, F and Molinari, S and Sacchetto, R and Carotti, M and Sandonà, D and Martinello, T and Ugolotti, J and Fresch, B and Litti, L and Vianello, F and Magro, M},
title = {Nanohybridization as a Route to a Water-Friendly Therapeutic Tool for Rescuing Misfolded Proteins.},
journal = {ACS nanoscience Au},
volume = {6},
number = {2},
pages = {191-200},
pmid = {42004264},
issn = {2694-2496},
abstract = {Misfolded proteins cause several threatening pathologies, ranging from Alzheimer's disease to cystic fibrosis. Although several protein folding correctors were tested, their delivery is usually inadequate. Here, via a self-assembly wet reaction, colloidal γ-Fe2O3 was used to immobilize two correctors (C4 and C17) for a cystic fibrosis-associated transmembrane protein. The as-obtained core-shell magnetic nanohybrids were extensively characterized, revealing high drug loading and remarkable chemical stability in water. In addition, a dedicated computational study revealed that the whole organic multilayer is involved in a long-range polarization on the nanoconjugate surface, showing sufficient colloidal stability for its application in cells and in contrast with the cargo's hydrophobic nature. Experiments conducted in HEK293 cells, expressing a mutated subunit of α-sarcoglycan, showed a positive effect on protein complex recovery. This study represents the first in vitro example of a multifunctional nanochaperone for the structural recovery of misfolded proteins.},
}

@article {pmid42004516,
year = {2026},
author = {Vafadar Moradi, E and Rezvani Kakhki, B and Yazdanpanah, Z and Jalali, J and Ghasemzadeh Rahbardar, M},
title = {Rosemary (Rosmarinus officinalis L.) and nervous system disorders: New findings on its neuroprotective properties.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {2},
pages = {155-180},
pmid = {42004516},
issn = {2008-3866},
abstract = {Rosemary (Rosmarinus officinalis L.) has gained recognition for its neuroprotective potential, offering therapeutic benefits for various nervous system disorders. Its main components, including rosmarinic acid, carnosic acid, and ursolic acid, exhibit anti-oxidant, anti-inflammatory, neurotransmitter-modulating, and mitochondrial-stabilizing effects. This updated narrative review explores recent advancements in the mechanisms of action of rosemary and its therapeutic applications in various neurodegenerative diseases. Peer-reviewed studies published between 2020 and 2025 were analyzed using electronic databases, including Scopus, Google Scholar, and PubMed. Research assessing the pharmacological properties of rosemary and its main components, molecular pathways, and clinical implications was reviewed to provide a comprehensive evaluation of its neuroprotective potential.Findings reinforce the neuroprotective potential of rosemary and its main components in Alzheimer's disease, anxiety, depression, epilepsy, pain, and Parkinson's disease. They modulate key molecular pathways, including NF-κB, Nrf2, BDNF, NO/cGMP/KATP, and autophagic clearance, leading to reduced oxidative stress, neuro-inflammation, and apoptosis. They also affect neurotransmitter balance and protein aggregation. The ability of these compounds to enhance cholinergic activity, stabilize mitochondrial integrity, and regulate neuro-immune signaling supports cognitive resilience and neuronal protection. Rosemary also exhibits synergistic potential when combined with conventional treatments, such as analgesics and neuroprotective agents, improving therapeutic efficacy while minimizing adverse effects. This updated review consolidates current findings on the neuroprotective effects of rosemary and its active components, offering insights into its therapeutic applications for nervous system disorders. Future research should focus on clinical trials to validate its efficacy and optimize its use in neurological health management.},
}

@article {pmid42004570,
year = {2026},
author = {Shajahan, SR and Hein, ZM and Muhammad, H and Mustafa, MZ and Kumari, Y and Jazuli, I and Zulkapli, A and Shari, N and Nassir, CMNCM and Ramli, MDC},
title = {Stingless bee honey alleviates cognitive deficits and hippocampal neurodegeneration in an Alzheimer's model: Behavioural, neurochemical, and histological analyses.},
journal = {AIMS neuroscience},
volume = {13},
number = {1},
pages = {1-28},
pmid = {42004570},
issn = {2373-7972},
abstract = {Stingless bee honey (SBH), widely consumed in Southeast Asia, is traditionally valued for its medicinal and nutritional properties, particularly in promoting brain health. However, its neuroprotective potential against Alzheimer's disease (AD) remains underexplored. In this study, we investigated the therapeutic effects and safety of SBH in a rat model of AD. A total of sixty-three adult male Sprague-Dawley rats (180-200 g) were used: Fifteen were assigned to three toxicity groups (500, 750, 1000 mg/kg; n = 5) and forty-eight to six therapeutic groups (n = 8): Normal control, AD (AlCl3 + D-gal), AD + Donepezil (1.5 mg/kg), and three SBH-treated groups (500, 750, 1000 mg/kg). Alzheimer-like pathology was induced by aluminium chloride (150 mg/kg) and D-galactose (300 mg/kg), followed by 14 days of treatment. Toxicity was evaluated through liver and kidney histopathology, while behavioural performance was assessed using the Open Field Test and Morris Water Maze. Serum dopamine, serotonin, corticosterone, and acetylcholinesterase activity were quantified via ELISA, and hippocampal morphology was examined histologically. SBH administration produced no signs of systemic toxicity and significantly improved exploratory activity and spatial learning, with the most pronounced effects at 750 mg/kg. Biochemical assays showed reduced acetylcholinesterase and corticosterone levels alongside increased dopamine and serotonin concentrations. Histological analysis confirmed neuronal preservation and reduced hippocampal damage. Inclusion of Donepezil as a positive control enabled comparison with a standard pharmacological treatment. These findings demonstrated that SBH is a safe and promising natural therapeutic capable of alleviating cognitive deficits associated with AD.},
}

@article {pmid42004692,
year = {2026},
author = {Sin, MK and Allman, RM and Lin, Y and Choupani, F and Ahmed, A and Faselis, C},
title = {Risk of a Dementia Diagnosis in Community-Dwelling Older Adults With Normal MMSE Scores in the United States.},
journal = {American journal of medicine open},
volume = {15},
number = {},
pages = {100129},
pmid = {42004692},
issn = {2667-0364},
abstract = {BACKGROUND: The Mini-Mental State Examination (MMSE) is commonly used in clinical and research settings to assess cognitive function and scores 27-30 are considered normal. Whether individuals with lower MMSE scores within this normal range are at increased risk for Alzheimer's disease and related dementias (ADRD) remains unclear. We sought to examine this question in the current study.

METHODS: In the Cardiovascular Health Study (CHS), 4433 community-dwelling adults ≥ 65 years had MMSE 27-30: MMSE-30 (n = 1228), MMSE-29 (n = 1353), MMSE-28 (n = 1079) and MMSE-27 (n = 773). HR (95% CI) for incident ADRD during 23 years of follow-up associated with MMSE-29, MMSE-28, and MMSE-27 were estimated, adjusting for 27 baseline characteristics including activities of daily living (ADL) impairment. ADRD was defined using International Classification of Diseases (ICD) codes.

RESULTS: Individuals with MMSE-30, MMSE-29, MMSE-28, and MMSE-27 had mean ages of 71.1, 71.9, 72.6, and 73.4 years, and mean ADL impairment scores of 0.06, 0.08, 0.12 and 0.16, respectively (both p < 0.001). Overall, 59% were women and 10% African American. ADRD occurred in 8.5%, 11.4%, 12.5% and 13.6% of those with MMSE-30, MMSE-29, MMSE-28, and MMSE-27, respectively. Compared with MMSE-30, HR (95% CI) for incident ADRD for MMSE-29, MMSE-28, and MMSE-27 were 1.48 (1.16-1.90), 1.82 (1.42-2.35) and 2.15 (1.64-2.82), respectively. These associations varied by age, sex, race, education, and self-reported general health.

CONCLUSIONS: These findings suggest that among community-dwelling older adults with normal MMSE, lower scores were associated with impaired ADL and significant, independent, and incrementally higher risk of ADRD.},
}

@article {pmid42004890,
year = {2026},
author = {Lv, Z and Liu, X and Huang, Q and Liu, H and Xu, Z and Xu, P},
title = {The multifaceted roles of the transcription factor SP1 in the pathogenesis of Alzheimer's disease: From molecular regulation to therapeutic targets.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70211},
pmid = {42004890},
issn = {2352-8737},
abstract = {UNLABELLED: Alzheimer's disease (AD) is driven by interrelated pathologies, including the accumulation of amyloid β (Aβ), tau pathology, chronic neuroinflammation, and oxidative stress (OS). These pathological processes collectively lead to progressive neurodegeneration. The transcription factor specificity protein 1 (SP1) functions as a key transcriptional regulator in AD pathogenesis. By binding to GC-box elements, SP1 promotes Aβ production and tau hyperphosphorylation. It also activates microglia, perpetuating neuroinflammation; disrupts oxidative balance; and ultimately induces neuronal death through ferroptosis and apoptosis. Furthermore, environmental toxins exacerbate AD progression by enhancing SP1-DNA binding activity via epigenetic mechanisms such as DNA methylation and histone modifications. SP1 activity is tightly controlled by diverse post-translational modifications, which adds another layer of complexity to its function. Small-molecule inhibitors, natural compounds, and epigenetic interventions can modulate the SP1-regulated network, thereby ameliorating key pathological features and demonstrating broad therapeutic potential. Future efforts must address developing brain-targeted delivery systems and precise epigenetic editors for effective clinical translation.

HIGHLIGHTS: SP1 functions as a master transcriptional hub in Alzheimer's disease, simultaneously driving amyloid beta production, tau hyperphosphorylation, neuroinflammation, oxidative stress, and ferroptotic cell death.Environmental toxins epigenetically activate SP1 via altered DNA methylation and histone modifications, establishing a molecular link between external risk factors and late-onset Alzheimer's pathogenesis.Post-translational modifications and microRNAs tightly regulate SP1 activity; their dysregulation in AD amplifies pathogenic gene expression networks.Small-molecule inhibitors and natural compounds targeting SP1 demonstrate multi-pathway therapeutic potential in preclinical Alzheimer's models.Cell-type-specific SP1 functions, compensatory upregulation of SP3/SP4 family members, and limited blood-brain barrier penetration present major challenges for clinical translation.},
}

@article {pmid42005278,
year = {2026},
author = {Soelistiono, S},
title = {A longitudinal and explainable 2.5D deep learning framework for Alzheimer's disease progression using ADNI MRI.},
journal = {Neuroimage. Reports},
volume = {6},
number = {2},
pages = {100342},
pmid = {42005278},
issn = {2666-9560},
abstract = {Early identification of Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI), is important for timely clinical assessment and disease management. Structural T1-weighted magnetic resonance imaging (MRI) captures macroscopic neurodegenerative changes associated with disease progression; however, developing deep learning models that are both methodologically rigorous and clinically interpretable remains challenging. This study presents an explainable deep learning framework for longitudinal classification of cognitively normal (CN), MCI, and AD subjects using MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). A two-and-a-half-dimensional (2.5D) convolutional neural network based on a modified ResNet-18 architecture was used to incorporate contextual information from adjacent sagittal slices while remaining computationally efficient. To preserve longitudinal validity and reduce potential information leakage, multiple follow-up visits per subject were included and a strict subject-level data splitting strategy was adopted. Under this evaluation protocol, the proposed model achieved moderate classification performance, highlighting the difficulty of three-class longitudinal neurodegenerative disease classification under a stringent split design. To further examine the effect of split level, we additionally evaluated the same framework using a scan-level splitting strategy. In our implementation, scan-level splitting did not produce a substantial performance improvement, supporting the use of subject-level splitting primarily as a methodological choice for longitudinal validity. To enhance transparency, Gradient-weighted Class Activation Mapping (Grad-CAM) was used to interpret model predictions. The resulting explanations showed plausible temporo-frontal attention patterns in correctly classified AD cases and more heterogeneous responses in MCI cases. Overall, this work demonstrates that combining longitudinal MRI analysis with explainable deep learning under a rigorous evaluation framework can provide an interpretable and reproducible baseline for Alzheimer's disease research. By jointly emphasizing interpretability, temporal consistency, and evaluation validity, the proposed framework contributes toward the development of more trustworthy AI methods in neuroimaging, while also highlighting the remaining challenges in robust AD classification.},
}

@article {pmid42005438,
year = {2026},
author = {Fleig, K and Haslinger, L and Dawczynski, C and Kolassa, IT},
title = {Omega-3 fatty acids in mental disorders: from neurobiological and metabolic mechanisms to therapeutic potential.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1748196},
pmid = {42005438},
issn = {2296-861X},
abstract = {Nutritional psychiatry is an emerging field. Micro- and macro-nutrients play a role in energy metabolism and the regulation of inflammation; particularly, an insufficient dietary intake of omega-3 fatty acids and an imbalanced intake of omega-6/omega-3 fatty acids, with a shift toward increased inflammation, are of relevance for the pathophysiology of mental disorders. This review summarizes evidence on the role of omega-3 fatty acids in the pathophysiology of mental disorders (schizophrenia, affective and anxiety disorders, post-traumatic stress disorder, and eating disorders), neurodevelopmental disorders (attention-deficit/hyperactivity disorder and autism spectrum disorder) and neurodegenerative disorders (Alzheimer's disease) and explores potential treatment implications. In addition, the underlying neurobiological mechanisms through which omega-3 fatty acids might exert a protective effect are also discussed. Despite methodological variability and heterogeneous results, an increasing body of evidence suggests that omega-3 deficiency and altered fatty acid profiles are modifiable risk factors and potential biomarkers for mental disorders. The integration of omega-3 supplementation as an adjuvant to state-of-the-art therapy offers the potential for a low-risk intervention with meaningful clinical outcomes. However, clinical monitoring is recommended to avoid adverse effects and to adjust the dosage according to individual and disease-specific factors.},
}

@article {pmid42005580,
year = {2026},
author = {Imran, S and Patel, M and Noroozifar, M and Kerman, K},
title = {Recent advances towards BACE1 drug discovery and therapeutics design.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42005580},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. A key feature of AD is the accumulation of amyloid beta (Aβ) peptides in the form of extracellular plaques. The amyloid cascade hypothesis suggests that the pathogenesis of AD is initiated by the cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Numerous therapeutic approaches have been pursued to target BACE1 due to its crucial role in AD. However, the complexity of AD and the localization of BACE1 in the brain have posed challenges, leading to the failure of clinical trials and, in some cases, even exacerbating disease progression. Specifically, the blood-brain barrier (BBB) prevents the entry of many molecules, making BACE1 a difficult target to approach. Recent advancements in BACE1 therapy have shifted the focus from traditional enzyme inhibitor-based therapeutics to modulators, antibody therapy, and gene therapy. These approaches offer several advantages, including the ability to efficiently cross the BBB and provide targeted treatment. In this review, we explore the latest developments in modulators, antibody therapy, and gene therapy targeting BACE1 to combat AD. These approaches offer a promising avenue to mitigate the progression of AD and provide a novel therapeutic strategy.},
}

@article {pmid42006040,
year = {2026},
author = {Zhang, P and Jin, W and Lyu, X and Zhu, S and Lu, Y and Chen, Y and Han, L and Tao, M and Li, L},
title = {Research on the imbalance of metal homeostasis and ferroptosis mechanisms in neurodegenerative diseases.},
journal = {Global medical genetics},
volume = {13},
number = {2},
pages = {100108},
pmid = {42006040},
issn = {2699-9404},
abstract = {OBJECTIVE: To investigate the associations between urinary and serum metal levels and neurodegenerative diseases (NGDs) as well as all-cause mortality, and identify research trends through bibliometric.

METHODS: This study first analyzed data from a large-scale national cross-sectional survey (2005-2018) involving 6288 participants. Multivariable regression models were used to assess the associations of urinary metals (Ba, Cd, Co, Cs, Mo, Pb, Sb, Tl, W) and serum metals (Fe, Cd, Pb, Hg) with the risk of neurodegenerative diseases (NGDs) and all-cause mortality. Subsequently, a bibliometric analysis was conducted on literature pertaining to "metals" and "NGDs" retrieved from the Web of Science Core Collection to identify research trends and key underlying mechanisms.

RESULTS: Epidemiological analyses revealed significant associations between several metals-such as Cd, Cs, Mo, Hg, and Pb-and either NGDs risk or all-cause mortality, with some exhibiting nonlinear patterns (e.g.L-shaped or inverted U-shaped relationships). Subsequent bibliometric analysis of 34,313 publications identified "iron" as a central hub keyword linking "metal exposure" to "neurodegenerative diseases". Mechanisms related to Fe-including "oxidative stress" and "lipid peroxidation"-emerged as research hotspot keywords. Notably, the cluster labeled "ferroptosis" demonstrated substantial scale in co-citation clustering. Research trajectories have evolved from broad pathological observations toward molecular-level investigations of the NLRP3 inflammasome, glutathione peroxidase 4 (GPX4), ultimately converged on the ferroptosis pathway.

CONCLUSION: Exposure to multiple metals is significantly associated with the risk and prognosis of NGDs. Integrated bibliometric evidence highlights ferroptosis as the central mechanism bridging metal dyshomeostasis and neuronal injury, offering a cohesive evidence chain from population data to mechanistic insights.},
}

@article {pmid42006102,
year = {2025},
author = {Manescu, MD and Catalin, B and Mateescu, VO and Rosu, GC and Boboc, IKS and Istrate-Ofiteru, AM and Liliac, IM and Busuioc, CJ and Pirici, D},
title = {AQP4 Drives Gliotic Changes in an APPPS1 Mouse Model of Alzheimer's Disease.},
journal = {Current health sciences journal},
volume = {51},
number = {4},
pages = {543-551},
pmid = {42006102},
issn = {2067-0656},
abstract = {Alzheimer's disease (AD) is the most common form of dementia, accounting for most of the cases, especially in individuals aged 65 and older. While the existence of genetic factors has helped us create animal models of AD that mimic APP and Ab overproduction, sporadic cases represent the bulk casuistry, and most probably their pathology is related to a loss of function towards the clearance of Ab rather than consecutive the overproduction of Ab alone. It is known that aquaporin 4 (AQP4) facilitation amplifies the perivascular Ab clearance route and decreases Ab deposits in animal models of AD, however it is now known how the glial component of the CNS responds to this treatment. We have aimed here to assess the glial response in a APPPS1 transgenic mouse model of AD, after one month of pharmacological facilitation or inhibition of AQP4. To this extent, we have utilized APPPS1 mice of 2 months of age, treated daily for 28 days with either TGN-020 AQP4 inhibitor or the TGN-073 AQP4 facilitator, and compared their GFAP expression in the brain with that of untreated APPPS1 and wild-type animals. Our image analysis of the GFAP immunohistochemical pattern, showed that AQP4 facilitation increases GFAP expression in the brains of APPPS1 animals, compared to untreated APPPS1 animals, but complexity-lacunarity morphological patterns resemble in fact those of wild-type animals, rather than that of the APPPS1 untreated animals, suggesting that this GFAP reactivity might represent a benefic amyloid-clearance astrocytic profile.},
}

@article {pmid42006158,
year = {2026},
author = {Wang, G and Duan, X and Ouyang, D and Zhou, J and Zhang, H and Ding, Y},
title = {Nose-to-brain delivery of donepezil within a small dose improves bioavailability and efficacy for Alzheimer's disease treatment.},
journal = {Asian journal of pharmaceutical sciences},
volume = {21},
number = {2},
pages = {101130},
pmid = {42006158},
issn = {2221-285X},
abstract = {Oral administration of donepezil (Don) is the first-line medication for Alzheimer's disease (AD); however, the dysphagia of elderly patients and severe gastrointestinal side effects substantially restrict administration compliance. Herein, we exploit a nose-to-brain pathway for Don administration to obtain smaller dosage but higher intracerebral bioavailability (BA), thereby achieving inhibition of acetylcholinesterase (AChE) activity and avoiding side effects. With respect to the intranasal administration design, a patient-friendly Don nasal spray without preservatives was developed. The administration of Don nasal spray demonstrated good nasal deposition and mucosa permeation ability comparable to that of the model drug propranolol. The mice intranasally administered Don at an equivalent oral dose (0.65 mg/kg) demonstrated rapid brain distribution (∼5 min) and long-lasting AChE inhibition effects (72 h). To obtain the optimal intranasal dose, a dose-descending study was conducted by cascading the oral dosage at a 1:3 ratio. The results demonstrated that intranasal administration of Don at 0.07 mg/kg resulted in intracerebral BA and AChE inhibition comparable to oral administration at 0.65 mg/kg, suggesting an 89% dose reduction. Compared with oral administration, anti-AD effectiveness was evaluated in AD model mice after 34-d- intranasal administration of Don, resulting in a shorter onset time, higher intracerebral drug concentration, and a longer duration of AChE inhibition (0.07 mg/kg). The nasal and systemic safety of intranasal administration of Don was confirmed in an allergic rhinitis mouse model after 4 weeks of intranasal administration. Thus, a small dose of Don exhibits improved intracerebral BA and AChE inhibition via intranasal administration, thereby offering better compliance and reducing side effects in AD treatment.},
}

@article {pmid42006342,
year = {2026},
author = {Li, H and Liu, S and Miao, D and Chen, L and Sun, Y and Wang, G and Zhu, Z and Li, X and Lu, Q},
title = {Decoding unchanged transcriptome of Alzheimer's disease reveals an NCAM1 mRNA switch as a potential biomarker.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115456},
pmid = {42006342},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD), a neurodegenerative disease primarily affecting older adults, is characterized by changes in memory, behavior, and language. Although gene expression varies during AD progression, the molecular mechanisms underlying this variation remain unclear. RNA sequencing indicates that most genes exhibit minimal gene-level differential expression in AD but may relate to neuronal function. Our comprehensive analysis revealed that neural cell adhesion molecule 1 (NCAM1) underwent alternative splicing (AS) in AD. Notably, an isoform switch occurred from the long isoform (L-NCAM1), typical under normal conditions, to the short isoform (S-NCAM1) in AD. S-NCAM1 lacked the intracellular domain in L-NCAM1. Additionally, the S-NCAM1-to-L-NCAM1 ratio increased in the hippocampus of amyloid precursor protein (APP)/PS1 mice compared to wild-type mice. Single-nucleus sequencing determined that this change in NCAM1 isoforms occurred predominantly within reactive astrocytes. Hence, AS may play a key role in AD development, while the L-NCAM1-to-S-NCAM1 ratio could serve as a biomarker.},
}

@article {pmid42006351,
year = {2026},
author = {Abskharon, R and Jiang, YX and Sawaya, MR and Ge, P and Zhang, J and Boyer, DR and Dolinsky, JL and Pi, J and Cascio, D and Guo, F and Eisenberg, DS},
title = {Structural evidence that RNA contributes to polymorphism of tau amyloid fibrils.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115501},
pmid = {42006351},
issn = {2589-0042},
abstract = {RNA colocalizes with tau deposits in Alzheimer's disease (AD) and drives tau aggregation in vitro. Previously, we determined a cryogenic-electron microscopy (cryo-EM) structure of fibrils of full-length tau bound to unfractionated mammalian RNA, revealing a small tau C-terminal core. Here, we present the cryo-EM structure of fibrils of full-length recombinant tau bound to unfractionated mammalian RNA seeded by AD-extracted tau fibrils. This structure reveals an expanded tau C-terminal core resembling AD tau fibrils. RNA sequencing identified 18S ribosomal RNA as the primary fibril-bound species. Next, we determined the cryo-EM structure of fibrils of full-length recombinant tau bound to mammalian 18S ribosomal RNA, revealing a core that consists of the R2 to R4 repeat domains previously seen in pathological tau fibrils. All our recombinant RNA-tau fibrils dissolve upon RNase treatment. Tau fibrils adopt distinct folds in the presence of different RNAs, suggesting RNA is a cofactor capable of shaping tau fibril polymorphism.},
}

@article {pmid42006409,
year = {2026},
author = {Davidson, MH and Hsieh, A and de Kleer, M and Szarek, MS and Scheltens, P and Vijverberg, E and Johnson, A and Ditmarsch, M and Kastelein, JJP},
title = {The emerging role of CETP inhibition in the prevention of Alzheimer's disease.},
journal = {American journal of preventive cardiology},
volume = {26},
number = {},
pages = {101442},
pmid = {42006409},
issn = {2666-6677},
abstract = {We recently showed that patients with atherosclerotic cardiovascular disease (ASCVD) carry a substantial but largely unrecognized burden of early Alzheimer's disease (AD) pathology. In the BROADWAY pivotal phase 3 lipid-lowering trial, nearly half of participants with high-risk ASCVD had plasma p-tau217 concentrations above thresholds associated with preclinical AD, yet none had undergone evaluation for cognitive impairment. In this population, apolipoprotein E ε4 (APOE4) carriers were disproportionately represented among those with the highest p-tau217 levels. These findings expose a critical gap between cardiovascular care and dementia prevention and raise the question whether interventions targeting shared pathophysiology could address both conditions simultaneously. Cholesteryl ester transfer protein (CETP) inhibition has emerged as a candidate for this dual role. In BROADWAY, obicetrapib reduced p-tau217 progression across the study population, with effects most pronounced in APOE4 carriers. In fact, treatment differences favoring obicetrapib were observed across all measured AD biomarkers in high-risk subgroups, including neurofilament light chain, glial fibrillary acidic protein, and the amyloid-beta (Aβ) 42:40 ratio. Unlike approaches that target downstream pathology, such as amyloid plaques already deposited in the brain or the inflammatory consequences of established disease, CETP inhibition may address the upstream processes involved in initiating the pathological cascade: lipid dysregulation, cholesterol ester accumulation in glial cells, impaired cholesterol efflux, lipid peroxidation, oxysterol formation, and deficient antioxidant transport. This review examines the biological rationale linking APOE4 status to disordered lipid metabolism in both peripheral and central compartments, the genetic and epidemiological evidence supporting CETP as a therapeutic target, the mechanisms through which CETP inhibition might confer neuroprotection, and the clinical data suggesting obicetrapib as the first oral agent associated with favorable changes in AD biomarkers across both amyloid and tau axes in individuals at high genetic risk for the development of AD.},
}

@article {pmid42006781,
year = {2026},
author = {Raikes, AC and Garza, M and Murrell, AN and Brinton, RD},
title = {Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.07.26350339},
pmid = {42006781},
abstract = {IMPORTANCE: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A [2] ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A [2] ND glucose dysregulation spatial signature remains undescribed.

OBJECTIVE: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A [2] ND.

DATA SOURCES: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).

STUDY SELECTION: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.

DATA EXTRACTION AND SYNTHESIS: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.

MAIN OUTCOMES AND MEASURES: Cluster peak and subpeak coordinates, cluster-wise t-or Z-values, and annotations indicating the disease of interest, whether the outcome was for hyper-(disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.

RESULTS: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A [2] ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A [2] ND which included both hypo-and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A [2] ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.

CONCLUSIONS AND RELEVANCE: These data demonstrate dysregulated glucose metabolism as a common A [2] ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A [2] ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.},
}

@article {pmid42006785,
year = {2026},
author = {Yang, D and Yang, Y and Ray, NR and Li, M and Benchek, P and Crawford, DC and O'Toole, JF and Sedor, JR and Reitz, C and Lynn, A and Zhu, X and Haines, JL and , and Bush, WS},
title = {Shared Genetic Architecture Between Kidney Function and Alzheimer Disease Across Ancestries.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.04.26350158},
pmid = {42006785},
abstract = {Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two conditions remains largely unexplored beyond genome-wide correlation analyses. Here, we conducted the first comprehensive, multi-ancestry, large-scale genetic investigation to identify shared genetic components between kidney function and Alzheimer disease. We leveraged large-scale genome-wide association study summary statistics for estimated glomerular filtration rate (N≈1.5 million European, N≈145,000 African ancestry) and late-onset Alzheimer disease (N=63,926 and N=398,058 in two European cohorts; N=9,168 in African ancestry) corrected for competing risk bias. We deployed a novel analytical framework integrating linkage disequilibrium score regression and polygenic risk score analysis, local analysis of [co]variant association, conjunctional false discovery rate analysis with Bayesian colocalization and fine-mapping, and bidirectional cis-Mendelian randomization to identify vertical pleiotropy. Despite the absence of genome-wide genetic correlation (r g ≈ 0, p > 0.1), local genetic analysis uncovered striking regional heterogeneity. Sixteen pleiotropic loci were identified in individuals of European ancestry (conjunctional false discovery rate < 0.05), including APOE , PICALM , SPI1 , and EFTUD1 , alongside 15 loci with significant local genetic correlations. Fine-mapping revealed that most pleiotropic loci harbored distinct causal variants for kidney function and Alzheimer disease, indicating horizontal pleiotropy. An APOE ε4-defining allele (rs429358) was the sole variant with shared causality across both traits. We identified vertical pleiotropy using cis-Mendelian randomization at the PICALM and EFTUD1 loci, providing evidence that kidney function-related genetic variants can causally affect Alzheimer disease risk at specific genomic loci. In contrast, loci such as CD2AP , MAT1A , and SYMPK demonstrated horizontal pleiotropy, reflecting shared upstream biological pathways rather than direct causal mediation. Notably, APOE was the only pleiotropic locus shared between European and African ancestry groups, underscoring marked ancestry-specific genetic architectures with critical implications for risk prediction and therapeutic translation. Alzheimer disease and kidney function share genetic components at specific loci rather than genome-wide, with mixed directional effects and horizontal pleiotropy explaining the absent global correlation despite strong local signals. At a subset of loci, we identified directional effects linking kidney genetic determinants to Alzheimer disease risk using cis-Mendelian randomization, supporting a complex kidney-brain genetic axis. Most overlap reflects horizontal pleiotropy, with limited loci showing vertical pleiotropy. APOE was the only shared locus across ancestries, underscoring ancestry-specific architectures with implications for risk prediction. The multi-scale approach used here also provides a methodological framework for dissecting complex disease relationships missed by traditional genome-wide analyses.},
}

@article {pmid42006950,
year = {2026},
author = {Lu, Y and Zhang, X and Zhou, L and Ye, F},
title = {Global research trends on thyroid hormones and neurodegenerative diseases: a bibliometric study from 2015 to 2025.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1780027},
pmid = {42006950},
issn = {1663-4365},
abstract = {OBJECTIVE: Despite extensive research on the role of thyroid hormone (TH) in neurodegenerative diseases (NDs), no bibliometric study has been conducted to evaluate their interrelationship. To fill this gap, this study conducts an analysis of literature published between 2015 and 2025, aiming to uncover research trends and emerging hotspots and to offer valuable guidance for subsequent investigations.

METHODS: Publications from 2015 to 2025 were collected from the Web of Science (WoSCC) and Scopus databases and subsequently analyzed with R software, VOSviewer, and CiteSpace.

RESULTS: This study included 820 papers retrieved from the WoSCC database and 2,039 relevant papers retrieved from the Scopus database. The annual publication output in this field increased steadily from 2015 to 2025, reflecting growing scholarly interest. Among all contributing countries, China produced the greatest number of publications, followed successively by the United States, Italy, Japan, and Brazil. Furthermore, China not only led in research productivity but also demonstrated the strongest international collaborative networks. The Journal of Clinical Endocrinology and Metabolism had the highest number of publications and citation rate. Comprehensive analysis results indicate that research hotspots in this field mainly focus on the epidemiological evidence of TH secretion abnormalities and NDs, the mechanisms of TH in NDs, and the role of thyroid hormone-mediated remyelination and neural regeneration in diseases such as MS.

CONCLUSION: In the past decade, research on TH and NDs has attracted increasing global attention, reflecting growing scholarly interest in this field. The present bibliometric analysis systematically identified the key research hotspots and evolving trends of TH in NDs. These findings provide a comprehensive overview of the current research landscape and may serve as a reference framework for future investigations in this area.},
}

@article {pmid42000570,
year = {2026},
author = {Da Cunha, E and Manera, V and Chorin, F and Lemaire, J and Plonka, A and Mouton, A and Zory, R and Gros, A},
title = {Speech-based digital biomarkers for early etiological stratification of Alzheimer's disease and frontotemporal degeneration: a biomarker-confirmed prospective study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100573},
doi = {10.1016/j.tjpad.2026.100573},
pmid = {42000570},
issn = {2426-0266},
abstract = {BACKGROUND: Early differentiation between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is a prerequisite for secondary prevention and targeted trial enrollment, yet remains challenging at disease onset. We investigated whether automated speech analysis could serve as a digital biomarker for early etiological stratification across clinically heterogeneous presentations.

METHODS: In this prospective biomarker-confirmed prognostic study, 172 participants (108 patients with biomarker-confirmed AD or FTLD and 64 controls) completed a standardized speech protocol at initial clinical assessment. Acoustic, temporal, and phonatory features were automatically extracted. Machine learning models and a stacking ensemble were trained using stratified, repeated 5-fold cross-validation to discriminate between AD and FTLD pathology, with exploratory analysis extending to atypical and rare phenotypes crossed with physiopathology, including primary progressive aphasia (PPA) variants.

RESULTS: Speech-based models achieved high sensitivity and specificity in distinguishing physiopathology independently (mean area under the curve (AUC)=0.986) and crossed phenotype and physiopathological diagnostic association (mean AUC=0.966).The ensemble identified 82% of cases with clinicopathological discordance. Interpretability analyses revealed distinct speech signatures: AD was associated with global speech slowing and phonatory instability, while FTLD was characterized by reduced verbal output and acoustic hypo-expressivity.

CONCLUSIONS: Automated speech analysis provides a promising non-invasive digital biomarker for the early etiological stratification of AD and FTLD, including atypical phenotypes, with high accuracy in a monocentric biomarker-confirmed cohort. These findings support the feasibility of speech-based etiological stratification and its potential to complement existing biomarker frameworks, particularly in cases of clinicopathological discordance. External validation is required before clinical deployment can be considered.},
}

@article {pmid42000571,
year = {2026},
author = {Liao, ZB and Hu, ZC and Zeng, GH and Chen, J and Li, XP and Liu, YH and Yao, XQ and Wang, YR and , },
title = {The association between omega-3 supplementation and cognitive decline in older adults.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100569},
doi = {10.1016/j.tjpad.2026.100569},
pmid = {42000571},
issn = {2426-0266},
abstract = {BACKGROUND: While omega-3 fatty acid supplementation is widely used for cognitive protection, its efficacy remains controversial, and its impact on core Alzheimer's disease (AD) pathologies in humans is not well-established.

METHODS: This longitudinal study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We employed linear mixed-effects models to assess the association between omega-3 supplementation and longitudinal cognitive decline, and mediation analyses to examine whether this relationship was mediated by core AD pathologies (Aβ-PET, tau-PET, T1-MRI, FDG-PET).

RESULTS: Omega-3 supplementation was associated with significantly accelerated cognitive decline, as evidenced by a faster decrease in MMSE scores (β = -0.266, p < 0.001) and a faster increase in both ADAS-Cog13 (β = 0.823, p < 0.001) and CDR-SB scores (β = 0.205, p < 0.001). This association was not mediated by Aβ deposition, tau pathology, or gray matter atrophy. Instead, longitudinal FDG hypometabolism within AD-vulnerable regions served as a significant mediating pathway, accounting for 30.8%, 40.8%, and 19.0% of the total effect on the decline in MMSE, ADAS-Cog13, and CDR-SB, respectively.

CONCLUSIONS: Omega-3 supplementation may be associated with accelerated cognitive decline in older adults, potentially through adverse effects on cerebral synaptic function rather than classical AD proteinopathies. These findings challenge the prevailing view of omega-3 as uniformly beneficial and highlight the need for a cautious reassessment of its widespread use for cognitive protection.},
}

@article {pmid41997807,
year = {2026},
author = {Washer, SJ and Frith, M and Cowan, E and Dempster, E and Mill, J and Farrow, SL},
title = {Epigenetic biomarkers in neurodegenerative diseases: from molecular signatures to therapeutic targets.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.03.004},
pmid = {41997807},
issn = {1878-108X},
abstract = {Collectively, neurodegenerative diseases impose an escalating global health burden, representing one of the leading causes of death and disability worldwide. Despite their growing prevalence, diagnosis and treatment remain major challenges, partly due to the absence of specific and reliable biomarkers for early detection, disease monitoring, and prognosis. Epigenetic biomarkers are emerging as promising clinical tools, although their potential in the context of neurodegenerative diseases is not yet fully realised. In this review, we provide an overview of advances in the understanding of DNA modifications and chromatin architecture in neurodegeneration, highlighting translational relevance for biomarker discovery and therapeutic development. Finally, building on insights from other diseases where epigenetic biomarkers are already applied, we discuss the key steps required to enable implementation in neurodegenerative diseases.},
}

@article {pmid41997899,
year = {2026},
author = {Tian, MM and Tiong, JWC and Gabathuler, R and Martens, G and Humphrey, EC and Jefferies, WA},
title = {Lipid-anchored melanotransferrin mediates transferrin-independent iron uptake and ferritin storage in mammals.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03043-9},
pmid = {41997899},
issn = {2058-7716},
abstract = {Non-transferrin-bound iron (NTBI) transport constitutes a critical pathway for cellular iron uptake in the kingdom Animalia that remains mechanistically unresolved. Its physiological importance is underscored by atransferrinemia, a rare disorder in which individuals lacking plasma transferrin nonetheless retain the capacity to distribute dietary iron to essential organs, implying the presence of compensatory iron transport routes. Melanotransferrin (MFI2; also designated p97 or CD228) is an evolutionarily conserved iron-binding protein that exists in both a secreted form and a glycosylphosphatidylinositol (GPI)-anchored membrane-bound form, suggesting a fundamental role in iron homeostasis. In mammals, the secreted isoform mediates iron transport across the blood-brain barrier, whereas GPI-anchored MFI2 is expressed by microglia in proximity to β-amyloid plaques in Alzheimer's disease, implicating it in neuroinflammatory processes. Moreover, it is also recognized as a tumor-associated antigen in melanoma, indicating a potential role in tumor progression. In the present study, we delineate a previously uncharacterized NTBI internalization pathway mediated by GPI-MFI2. Using human melanoma cells, we demonstrate that GPI-MFI2, together with its bound iron, undergoes caveolae-dependent internalization followed by trafficking through a Rab5-mediated endosomal pathway. The internalized iron is subsequently trafficked to ferritin, underscoring its functional importance in maintaining intracellular iron stores. These findings establish the first molecularly defined pathway for transferrin-independent iron uptake in mammalian cells, providing a framework to interrogate MFI2's role in iron mobilization and dysregulation in neurodegeneration and cancer.},
}

@article {pmid41997924,
year = {2026},
author = {Lattmann, R and Vockert, N and Bernal, J and Wesenberg, J and Suksangkharn, Y and Yakupov, R and Schütze, H and Glanz, W and Incesoy, E and Butryn, M and Lüsebrink, F and Schmid, M and Stark, M and Kleineidam, L and Spottke, A and Coenjaerts, M and Brosseron, F and Fliessbach, K and Schneider, A and Dechent, P and Scheffler, K and Hetzer, S and Ramirez, A and Laske, C and Sodenkamp, S and Altenstein, S and Schneider, LS and Gref, D and Spruth, EJ and Lohse, A and Schott, BH and Wiltfang, J and Kilimann, I and Goerss, D and Rostamzadeh, A and Priller, J and Peters, O and Hellmann-Regen, J and Teipel, S and Wagner, M and Jessen, F and Maass, A and Ziegler, G and Düzel, E},
title = {Dysfunction of the episodic memory network in the Alzheimer's disease cascade.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {41997924},
issn = {2041-1723},
support = {BN012//Deutsches Zentrum für Neurodegenerative Erkrankungen (German Center for Neurodegenerative Diseases)/ ; },
mesh = {*Alzheimer Disease/physiopathology/diagnostic imaging/metabolism ; Humans ; *Memory, Episodic ; Magnetic Resonance Imaging ; Male ; Female ; Aged ; Disease Progression ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Longitudinal Studies ; *Brain/physiopathology/diagnostic imaging ; tau Proteins/metabolism ; Aged, 80 and over ; Biomarkers/metabolism ; Middle Aged ; Cognition ; *Nerve Net/physiopathology/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.},
}

*Alzheimer Disease/physiopathology/diagnostic imaging/metabolism
Humans
*Memory, Episodic
Magnetic Resonance Imaging
Male
Female
Aged
Disease Progression
*Cognitive Dysfunction/physiopathology/diagnostic imaging
Longitudinal Studies
*Brain/physiopathology/diagnostic imaging
tau Proteins/metabolism
Aged, 80 and over
Biomarkers/metabolism
Middle Aged
Cognition
*Nerve Net/physiopathology/diagnostic imaging
Amyloid beta-Peptides/metabolism

@article {pmid41998449,
year = {2026},
author = {Chauhan, P and Wadhwa, K and Singh, G},
title = {Geraniol and Z-guggulsterone co-treatment attenuates Alzheimer's disease in adult zebrafish by targeting oxidative damage, neuroinflammation, mitochondrial stress, and synaptic dysfunction.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41998449},
issn = {1568-5608},
abstract = {Given the multifactorial pathogenesis of Alzheimer's disease (AD) and the limited efficacy of single-target drug therapy, there is a growing scientific need for combination regimens to concurrently target various AD-associated cascades. Currently, plant-derived phytoconstituents, with their intrinsic multi-target properties, represent a promising component for combination therapy, offering translational potential with enhanced neuroprotection. In this avenue, the current study aimed to explore the combined neuroprotective effects of geraniol (a monoterpenoid alcohol) and Z-guggulsterone (a phytosterol) in streptozotocin (STZ)-induced AD model of adult zebrafish (4-6 months old). Following intracerebroventricular STZ injection, zebrafish were treated with geraniol and Z-guggulsterone per se and in combination for 28 consecutive days. On day 27, a novel tank diving test and a light/dark preference test were performed to evaluate locomotive and cognitive impairments. Afterwards, the fish were evaluated for numerous blood parameters, including blood glucose and serum cholesterol levels, followed by biochemical assessment of oxidative stress markers, mitochondrial complexes, neuroinflammatory cytokines, and neurotransmitter levels. Results demonstrated that co-therapy of geraniol and Z-guggulsterone significantly ameliorated cognitive deficits, reduced anxiety-like behaviours, impeded acetylcholinesterase activity, regulated neurotransmitter levels (glutamate and acetylcholine), mitigated oxidative stress markers, and prevented mitochondrial dysfunction, compared to monotherapies. Additionally, downregulation of TNF-α was also observed, affirming suppression of detrimental neuroinflammatory processes. Collectively, these findings support the neuroprotective potential of geraniol and Z-guggulsterone co-therapy in the zebrafish model of AD; however, future research is warranted to explore the potential clinical application of this combination therapy in AD.},
}

@article {pmid41998740,
year = {2026},
author = {Tort-Colet, N and Stankeviciute, L and Fernández-Arcos, A and Soldevila-Domenech, N and Sánchez-Benavides, G and Shekari, M and Vállez García, D and Altomare, D and Barkhof, F and Boada, M and Buckley, C and Collij, LE and den Braber, A and Farrar, G and Ford, L and Frisoni, GB and Gismondi, R and Gispert, JD and Grootoonk, S and Hanseeuw, BJ and Jessen, F and Luckett, ES and Manber, R and Marquié, M and Mett, A and Quenon, L and Ritchie, C and Schmidt, ME and Schöll, M and Stephens, AW and Vandenberghe, R and Visser, PJ and Wolz, R and Grau-Rivera, O and , },
title = {Self-reported sleep quality and longitudinal amyloid burden in clinically unimpaired adults from the AMYPAD PNHS study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02049-w},
pmid = {41998740},
issn = {1758-9193},
support = {CP23/00039 (Miguel Servet contract)//Instituto de Salud Carlos III (ISCIII)/ ; PID2020-119556RA-I00//Ministerio de Ciencia e Innovación/ ; IJC2020-043417-I//Ministerio de Ciencia e Innovación/ ; PI19/00117//Instituto de Salud Carlos III/ ; },
}

@article {pmid41999085,
year = {2026},
author = {Weiner, J and Akhavan, M and Raja, M and Buoncore, J and Sobecki, A and Beatty, B},
title = {Arterial Calcification Alters Lumen Surface Roughness of Branches of the Circle of Willis.},
journal = {Clinical anatomy (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/ca.70106},
pmid = {41999085},
issn = {1098-2353},
abstract = {Atherosclerotic lesions within carotid and cerebral vessels are likely to influence hemodynamics and manifest into vascular pathologies, including Alzheimer's Disease and ischemic stroke. Hemodynamics are influenced by changes in luminal diameter of vessels and wall shear stress derived from vortex formation which directly relates to the surface topography of the lumen. In this study, we performed a quantitative assessment of surface metrology of carotid and cerebral arteries in relation to calcification, vessel size and location among individuals. We speculate intracranial vessels will follow suit of extracranial vessels, with increased surface roughness in larger-diameter vessels. Samples of the internal carotid, common carotid, and multiple branches of the Circle of Willis were collected at 18 different sites from 10 human whole body donors. For each vessel, arterial calcification was quantified from image analyses of Alizarin red stained histological sections. The arterial surface metrology of the adjacent parts of the same segments was opened and gently cleaned, and then analyzed using a Sensofar S Neox 3D optical profiler, from which scale-sensitive fractal analyses (SSFA) were analyzed using SensoMap software. ANOVAs testing for the influence of calcification percentage, vessel identity, vessel size, individual differences, age, sex, and the role of cardiovascular disease in the donor's cause of death found no significant differences in SSFA variables for vessel identity, individuals, age, sex, and cause of death. The most significant differences are correlated with vessel calcification percentage, though surface roughness appears also greater in the larger vessels. These findings support ideas that calcification plays a role in alterations of vortex formation and wall shear stresses in intracranial vessels as they do in coronaries. With further research in this field, the pathophysiology of intracranial atherosclerosis and the role of atherosclerosis in neurodegenerative disorders might be understood at another, more granular level.},
}

@article {pmid41999183,
year = {2026},
author = {Zuber, M and Borate, SN and Tan, CJ and Li, N},
title = {Health Care-Related Tasks of Informal Dementia Caregivers in the U.S.: A Systematic Review with Narrative Synthesis.},
journal = {Inquiry : a journal of medical care organization, provision and financing},
volume = {63},
number = {},
pages = {469580261438330},
doi = {10.1177/00469580261438330},
pmid = {41999183},
issn = {1945-7243},
mesh = {Humans ; *Caregivers/statistics & numerical data/psychology ; *Dementia/nursing/therapy ; United States ; },
abstract = {Health care-related tasks (e.g., making appointments, talking to providers) performed by informal caregivers caring for older adults with dementia have become increasingly common, yet the evidence on caregiving task profiles remains fragmented and has not been comprehensively synthesized. This is a systematic review with narrative synthesis of the patterns of health care-related tasks and the characteristics of caregivers who performed them. We searched PubMed, Embase, PsychInfo, Web of Science, and CINAHL databases. The identified tasks were grouped into health and medical care, advocacy and care coordination, and surrogate tasks. We also reported caregiver characteristics. We included 12 studies. Only 5 studies reported on racial and ethnic minority caregivers. Medication management was the most common health and medical care task. Only 1 study reported surrogate tasks, and 2 studies reported caregivers performing advocacy and care coordination tasks. This study is particularly timely given the recent implementation of the Centers for Medicare and Medicaid Services (CMS) Guiding an Improved Dementia Experience (GUIDE) Model, which includes caregiver support and education as core components of dementia care delivery. Systematically characterizing the health care-related tasks performed by dementia caregivers can inform the design, targeting, and evaluation of the GUIDE Model.},
}

Humans
*Caregivers/statistics & numerical data/psychology
*Dementia/nursing/therapy
United States

@article {pmid41999218,
year = {2026},
author = {Lange-Maia, BS and Vialle, RA and Wang, T and Zammit, AR and Farfel, J and Seyfried, NT and Bennett, DA and Buchman, AS},
title = {Proteome-wide association study of cortical proteins that may provide resilience for late-life disability.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag101},
pmid = {41999218},
issn = {1758-535X},
abstract = {Disabilities are common and untreatable in many older adults. This proteome-wide discovery study identified cortical proteins that may provide resilience for disabilities in older adults. Participants were 850 decedents (mean age 89.3 years [SD: 6.6] at death, 67% female) from two longitudinal cohort studies with proteome-wide data collected from the dorsal lateral prefrontal cortex, indices of 10 Alzheimer's disease and related dementia (ADRD) pathologies, and measures of mobility disability, instrumental activities of daily living (IADLs), and activities of daily living (ADLs) prior to death. Linear regression models adjusting for demographics identified proteins related to each disability phenotype correcting for multiple comparisons (p < 5 × 10-6). Resilience proteins-operationalized as proteins related to residual disability after adjusting for ADRD pathologies-were aggregated into resilience index scores for each disability instrument and their associations with adverse health outcomes were tested. Exploratory functional enrichment analyses identified molecular pathways associated with resilience proteins. We identified 12 resilience proteins related to mobility disability, 215 for IADL and 291 for ADL disability. Models with resilience index scores accounted for an additional 2.7%, 3.3%, and 3.5% of the variance of mobility, IADL, and ADL disability, respectively, compared to 1.7%, 2.7% and 2.0%, for ADRD pathologies. In exploratory analyses, key enriched Gene Ontology terms were predominantly related to mitochondrial function. Further work targeting these cortical proteins is needed to demonstrate that they provide resilience for disability in older adults and can facilitate functional independence in old age, though future work is needed to demonstrate protective mechanisms. Ultimately, targeting these proteins may lead to therapies that maintain functional independence in aging adults.},
}

@article {pmid41999403,
year = {2026},
author = {Liu, X and Mi, X and Yu, X and Deng, N and Lei, Y and Shu, J and Tang, J},
title = {The burden and trends of late-onset multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias among adults aged 55 and older, spanning from 1990 to 2021, with projections through 2050.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {5},
pages = {},
pmid = {41999403},
issn = {1590-3478},
support = {82204861//National Natural Science Foundation of China/ ; CSTB2024NSCQ-MSX0609//Natural Science Foundation of Chongqing/ ; Chongqing Traditional Chinese Medicine No. 16 (2021)//Chongqing Key Discipline of Traditional Chinese Medicine (Traditional Chinese Medicine Encephalopathy) Project/ ; Chongqing Traditional Chinese Medicine No. 23 (2023)//Chongqing Bayu Qihuang Scholars Support Program/ ; Discipline Hierarchical and Classified Construction Project of Traditional Chinese Medicine Encephalopathy in Chongqing Hospital of Traditional Chinese Medicine//Discipline Hierarchical and Classified Construction Project of Traditional Chinese Medicine Encephalopathy in Chongqing Hospital of Traditional Chinese Medicine/ ; },
}

@article {pmid41999476,
year = {2026},
author = {Ding, TJ and Hsu, HY and Chen, JC and Yao, CY and Yao, ZF and Tseng, TA},
title = {Map-based spatial perspective taking reveals frontal late negativity loss and posterior delta gain in mild cognitive impairment.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41999476},
issn = {2509-2723},
support = {112-2410-H-007-018-MY2//National Science and Technology Council/ ; CMUHCHNTHU- 113-004//China Medical University Hospital/ ; CMUHCH-DMR-114-005//China Medical University Hospital/ ; },
abstract = {Spatial disorientation represents a clinically meaningful vulnerability during aging and is an early manifestation along the Alzheimer's disease continuum. Understanding how aging-related central nervous system (CNS) changes affect the neural computations required for spatial perspective taking (SPT) is essential for characterizing early neurodegenerative processes. In this study, older adults with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) completed a simplified map-based SPT paradigm while electroencephalography (EEG) was recorded. Although behavioral accuracy was largely preserved, MCI participants demonstrated globally slower responses. Crucially, high-demand egocentric-allocentric transformations (180°) revealed a marked loss of frontal N400 modulation in MCI, together with increased posterior delta-band synchronization. This pattern indicates an aging-related frontal-posterior reweighting in spatial integration networks, consistent with early compensatory recruitment as frontal conflict-monitoring mechanisms decline. These findings provide mechanistic insight into how aging and MCI jointly alter CNS function during spatial cognition, and they highlight the translational potential of low-burden SPT-EEG paradigms for detecting subtle neurophysiological changes relevant to clinical neurology, geriatric assessment, and the early monitoring of neurodegenerative disease.},
}

@article {pmid41999828,
year = {2026},
author = {Chen, L and Ye, Y and Guo, X and Li, R and Xia, S and Chen, F and Wang, S and Cao, Y and Hu, Z and Qiu, Y and Wang, L and Chi, D and Yang, M and Tao, J and Liu, W},
title = {High-intensity interval training and moderate-intensity continuous training improve hippocampal synaptic plasticity in Alzheimer's disease via differential lactylation.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115782},
doi = {10.1016/j.expneurol.2026.115782},
pmid = {41999828},
issn = {1090-2430},
abstract = {While both high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are known to benefit physical health, their comparative effects on cognitive function in Alzheimer's disease (AD) remain unclear. Here, using equal number 3.5 months old male (28 ± 2 g) and female (24.0 ± 1.1 g) 5 × FAD transgenic mice, we demonstrate that HIIT and MICT improve AD pathology and cognitive performance, as evidenced by reduced amyloid-β deposition and enhanced hippocampal synaptic plasticity. Both exercise modalities significantly elevated lactate levels in the blood and hippocampus of AD mice. The functional consequences of this increase, however, were not linear. We found that while low lactate (2 mM) universally enhanced excitatory postsynaptic potentials in the hippocampus, high lactate (7 mM) was inhibitory, with no significant effects observed at intermediate concentrations (4 and 6 mM), an effect independent of genotype. To mechanistically link lactate dynamics to functional benefits, we performed lactylation-based proteomics. This revealed that HIIT and MICT differentially modulated protein lactylation-both reduced lactylation of glutamatergic synaptic proteins, but HIIT specifically upregulated lactylation of necroptosis-related proteins (CypA/Cyp40), while MICT downregulated proteasome-related proteins (Psmc1/Psmα7). Our findings suggest that exercise-induced lactate dynamically regulates brain function via protein lactylation, offering a novel therapeutic avenue for AD.},
}

@article {pmid41999930,
year = {2026},
author = {Azadovich, AP and Oralov, B and Sherzod, K and Kudeshova, G and Feruza, A and Umida, B and Kambarova, O and Farkhod, R and Baxtiyor, S and Jurabek, Y and Narzikulova, K and Nazirova, S and Egamberdieva, S},
title = {Cerebrospinal fluid biomarkers in Alzheimer's disease: enhancing diagnostic precision and guiding therapeutic strategies.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121010},
doi = {10.1016/j.cca.2026.121010},
pmid = {41999930},
issn = {1873-3492},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a growing global impact. Early and accurate diagnosis is crucial for effective management and therapeutic development. Cerebrospinal fluid (CSF) biomarkers have revolutionized AD diagnostics, reflecting core pathological hallmarks such as amyloid plaques and neurofibrillary tangles. Core CSF biomarkers, including amyloid-beta 42 (Aβ42), total tau (T-tau), and phosphorylated tau (p-tau), demonstrate high diagnostic accuracy, identifying AD even in early stages and predicting the conversion from mild cognitive impairment (MCI) to dementia. These biomarkers are invaluable not only for diagnosis but also for monitoring therapeutic responses in clinical trials and assessing the biochemical effects of disease-modifying treatments. This narrative review synthesizes the evolving role of CSF biomarkers in AD, focusing on their strategic application in enhancing diagnostic precision, enabling therapeutic monitoring, and facilitating clinical implementation. We explore the established utility of core CSF biomarkers, the development of novel markers, and the ongoing efforts to standardize assays and integrate these tools into routine clinical practice, ultimately aiming to improve patient outcomes and accelerate the development of effective AD interventions.},
}

@article {pmid42000003,
year = {2026},
author = {Zou, F and Ren, X and Huo, G and Peng, L and Sun, C},
title = {Tianwang Buxin Pill improves cognitive function in APP/PS1 mice by reducing neuronal damage and regulating synaptic plasticity.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121683},
doi = {10.1016/j.jep.2026.121683},
pmid = {42000003},
issn = {1872-7573},
abstract = {As a progressive neurological degenerative disorder, Alzheimer's disease (AD) remains a significant concern, with the lack of effective cures burdening healthcare resources and posing ongoing obstacles for scientific research in neuroscience. Tianwang Buxin Pills (TWBXP) is a traditional Chinese medicinal formula long employed for treating amnesia and cognitive decline, and has shown promising potential in AD treatment. Nevertheless, the detailed mechanisms responsible for these effects warrant further investigation.

AIM OF THE STUDY: This study seeks to systematically evaluate the impact of TWBXP on cognition, neuronal damage, and synaptic plasticity in AD mice, while clarifying its underlying therapeutic mechanisms.

MATERIALS AND METHODS: HPLC-UV was employed to ensure the quality of TWBXP. APP/PS1 mice were administered TWBXP (0.43, 0.85, 1.70 g/kg) for 8 weeks, and cognitive performance was assessed using behavioral tests. AD-related pathology was evaluated by Immunohistochemistry (IHC), Western blotting, ELISA, Transmission electron microscopy (TEM), and Immunofluorescence (IF). The integration of Network Pharmacology and Proteomics was conducted for the exploration of potential mechanisms.

RESULTS: TWBXP markedly improved cognitive performance and reduced cerebral Aβ burden. It promoted microglial polarization toward an M2 phenotype, dampened neuroinflammation, and enhanced microglia-associated Aβ clearance. TWBXP also exerted marked neuroprotective and synaptic protective effects by increasing NeuN, MAP2, and MBP levels, restoring synaptic proteins (PSD95, SYP) and neurotrophic factors (BDNF, NGF), reducing neuronal loss and functional impairment, and improving synaptic plasticity. Such effects might be associated with the enhanced activity of the cAMP/PKA/NR2B/CaMKⅡ signaling axis.

CONCLUSIONS: TWBXP significantly ameliorated cognitive impairment and AD-related pathological changes in APP/PS1 mice, accompanied by improvements in neuronal injury and synaptic plasticity. Its therapeutic effects may be associated with the regulation of microglial function and the cAMP/PKA/NR2B/CaMKII signaling axis.},
}

@article {pmid42000006,
year = {2026},
author = {He, M and Zhao, H and Liu, M and Wang, Y},
title = {Advanced Extraction to Targeted Delivery: A Holistic Review of Technological Innovations and Therapeutic Mechanisms of Ginkgo biloba Extract.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121703},
doi = {10.1016/j.jep.2026.121703},
pmid = {42000006},
issn = {1872-7573},
abstract = {Ginkgo biloba L., a 'living fossil' with an evolutionary history spanning over 200 million years, occupies a prominent place in traditional medicine systems. Historical records, including the Chinese pharmacopoeia Ben Cao Gang Mu, document its use for treating various ailments related to the respiratory, circulatory, and cognitive systems. Modern pharmacological research has validated these traditional applications, identifying Ginkgo biloba extract (GBE) as a valuable phytomedicine for neurodegenerative, cardiovascular, and metabolic diseases.

AIM OF STUDY: This comprehensive review aims to synthesize recent advances in GBE research, with a primary focus on literature from the past three years in GBE research, critically evaluating four key areas: 1) innovations in green extraction and purification technologies; 2) novel organelle-level mechanisms of action; 3) the development and application of nano-delivery systems for targeted therapy; and 4) clinical evidence and toxicological studies supporting GBE's therapeutic use and safety profile.

MATERIALS AND METHODS: This holistic review was conducted through a systematic literature search (covering 2003.8.15-2026.2.22) in databases including PubMed, Web of Science, and Scopus, using keywords related to GBE's extraction technologies, nano-delivery systems, organelle-level mechanisms, and clinical applications. The retrieved literature was screened and critically evaluated to synthesize recent advances, with a focus on identifying emerging trends, convergent evidence, and knowledge gaps across the four key areas outlined in the review's aim.

RESULTS: Significant improvements in the sustainability and efficiency of GBE extraction have been achieved through recent technological innovations. DESs have emerged as tunable platforms for the selective and efficient extraction of bioactive compounds, while physical field-assisted methods enhance yields. Mechanistic studies reveal that GBE orchestrates cellular homeostasis by synchronously modulating mitochondrial bioenergetics, endoplasmic reticulum stress, and autophagic-lysosomal activity. Nano-delivery systems, such as liposomal nanoparticles and chitosan-coated carriers, effectively enhance the bioavailability and targeting precision of GBE's bioactive components, including quercetin. Clinically, standardized formulations like Ginkgo Diterpene Lactone Meglumine Injection (GDLI) show promise in improving cognitive outcomes in ischemic stroke and Alzheimer's disease, and in managing cardiovascular diseases. However, potential toxic side effects, primarily from ginkgolic acids (GA) and 4'-O-methylpyridoxine (MPN), necessitate rigorous quality control, with advanced methods like enzymatic degradation being developed for detoxification.

CONCLUSION: GBE represents a promising, multifaceted therapeutic agent that effectively bridges traditional medicine and modern scientific innovation. Its broad-spectrum efficacy stems from the synergistic interactions of its bioactive constituents and their system-level regulatory mechanisms. To fully harness GBE's potential as a precision therapeutic agent, future research should focus on a coordinated technological strategy: employing green extraction methods such as DES to ensure sustainable and efficient compound isolation; developing standardized nano-formulations to overcome key pharmacokinetic limitations like low bioavailability and poor targeting; and applying multi-omics approaches to elucidate its organelle-level mechanisms of action. Validating these integrated innovations in large-scale clinical trials will be essential. Ultimately, the convergence of green chemistry, nanomedicine, and systems biology is key to translating GBE's multifaceted bioactivity into targeted and reliable clinical therapies.},
}

@article {pmid42000084,
year = {2026},
author = {Alonso-López, E and Silva-Llanes, I and Díez-Tejedor, E and Lastres-Becker, I},
title = {TARGETING PYROPTOSIS IN TAUOPATHIES: A REDOX-DRIVEN AXIS OF NEUROINFLAMMATION AND NEURODEGENERATION.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.04.029},
pmid = {42000084},
issn = {1873-4596},
abstract = {Tauopathies encompass a diverse group of neurodegenerative disorders characterized by abnormal TAU accumulation, synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Beyond its role as a pathological hallmark, increasing evidence indicates that TAU actively drives neurodegeneration by disrupting mitochondrial function, promoting oxidative stress, and triggering maladaptive innate immune responses. In this context, pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasome activation and GASDERMIN pore formation, has emerged as a critical mechanism linking TAU pathology to chronic neuroinflammation and neuronal damage. This review summarizes current advances on the molecular crosstalk between TAU pathology, redox imbalance, inflammasome signaling, and pyroptotic cell death across primary and secondary tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). We discuss how pathological TAU induces mitochondrial dysfunction and reactive oxygen species generation, providing key priming and activation signals for inflammasomes, particularly NLRP3, in microglia and other brain cells. Pyroptosis is highlighted as a downstream effector that amplifies neuroinflammation through the release of pro-inflammatory cytokines and danger-associated molecular patterns, thereby sustaining TAU propagation and neurodegeneration. Special attention is paid to the redox-sensitive transcription factor NRF2 as a central regulatory node capable of counteracting oxidative stress, inflammasome activation, and pyroptosis. Finally, we examine emerging therapeutic strategies targeting pyroptotic and redox pathways, discussing their translational potential and current limitations. Overall, this review positions pyroptosis-driven redox-immune dysregulation as a promising yet underexplored therapeutic target in TAU-driven neurodegenerative diseases.},
}

@article {pmid42000101,
year = {2026},
author = {Leśniewski, M and Dutkiewicz, R and Targońska, M and Waleron, K and Wasąg, B and Liwo, A and Jasiecki, J},
title = {Structural and aggregation studies of the butyrylcholinesterase signal peptide combining in vitro experiments and in silico simulations.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112082},
doi = {10.1016/j.cbi.2026.112082},
pmid = {42000101},
issn = {1872-7786},
abstract = {Structural characterization of proteins is essential for understanding their function, stability, and role in disease. Butyrylcholinesterase (BChE), expressed in the brain and localized within amyloid-β plaques, may generate an extended 69-amino acid, cysteine-rich signal peptide capable of self-aggregation and iron binding. In this study, we investigated the structure and aggregation of the BChE signal peptide using far-UV circular dichroism (CD) spectroscopy combined with in silico modelling via AlphaFold and coarse-grained replica-exchange molecular dynamics simulations with the UNRES force field. CD spectra revealed a predominance of β-sheet structure, with additional α-helices and statistical coil contributions. These experimental results were qualitatively consistent with AlphaFold and UNRES predictions, which revealed mixed α and β secondary structure in oligomeric assemblies. UNRES also predicted a substantial statistical coil content. Thermal CD analyses revealed marked differences in stability between variants. The p.C31Y signal peptide showed no significant spectral changes after heating, indicating exceptional resistance to thermal unfolding. In contrast, the wild-type peptide exhibited partial structural change under identical conditions. To refine structural interpretation, three short fragments of the BChE signal sequence (P1-P3) were analyzed by far-UV CD. P1 and P3 were largely disordered, whereas P2 displayed mixed secondary structure. An equimolar mixture of all three fragments produced an approximately additive CD spectrum, suggesting minimal conformational interference. Notably, P1 and P2 improved the solubility of the hydrophobic P3 fragment. Overall, these findings support a stable, aggregation-prone architecture for the extended BChE signal peptide and provide molecular insights into its potential role in promoting Alzheimer's pathology.},
}

@article {pmid42000213,
year = {2026},
author = {Littmann-Crites, V and Marrache, AM and Tan, C and Nightingale, N and Neish, CS and Therrien, F and Ismail, Z},
title = {Treatment patterns of agitation associated with Alzheimer's dementia (AAD) patients in Canada.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100209},
doi = {10.1016/j.inpsyc.2026.100209},
pmid = {42000213},
issn = {1741-203X},
abstract = {OBJECTIVES: Explore treatment patterns of Canadian patients with AAD to understand variability in clinical management.

DESIGN: This retrospective study used public claims data from Ontario and New Brunswick in IQVIA databases.

SETTING: Inferred patients with AAD were identified through claims for cognitive enhancers and medications used off-label to treat AAD, i.e., antipsychotics (AP), anticonvulsants (AC), antidepressants (ADT), benzodiazepines (benzo).

PARTICIPANTS: Patients (≥55 years) were identified between 2011-2018, indexed on their first AP/AC/AD/benzo and followed until the earlier of their fourth line (4L) of therapy or September 30, 2023. An all-history lookback to 2003 was used to ensure no prior claims for these therapies.

MEASUREMENTS: Descriptive analyses explored treatment utilization patterns.

RESULTS: 23,732 patients with AAD were identified, mostly from Ontario (98.7%). Patients with AAD tended to move to long-term care, with these increasing with more treatment trials from 24% (1 L therapy) to 54% (4 L therapy). Patients received between 500 and 2000 unique combinations across therapy lines. Citalopram, escitalopram, gabapentin, lorazepam, mirtazapine, pregabalin, quetiapine, risperidone, sertraline, and trazodone ranked in the top 10 therapies. Risperidone accounted for 7.2% of claims and ranked as the 6th most common 1 L therapy. Although trazodone remained the most common therapy for patients with AAD, it had one of the lowest persistence rates. Most patients remained on their 3 L - 4 L therapy, and ≥ 80% were adherent across all therapy lines. Average daily doses were lower than those described in the product monographs.

CONCLUSIONS: AAD treatment varies widely, underscoring the need for approved treatments and enhanced clinical education.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid42000233,
year = {2026},
author = {Hung, C},
title = {A tanycytic route for tau clearance in Alzheimer's disease.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.03.012},
pmid = {42000233},
issn = {1878-108X},
abstract = {In a recent study, Sauvé et al. identified hypothalamic tanycytes as a route for tau transport from cerebrospinal fluid to blood and suggested that disruption of this pathway contributes to Alzheimer's disease pathology. The work broadens current models of tau clearance and raises new questions about how tanycytic dysfunction contributes to neurodegeneration.},
}

@article {pmid42000400,
year = {2026},
author = {O'Connell, A and Kwakowsky, A},
title = {Rebalancing inhibition: α5 GABAA receptor positive and negative allosteric modulation in Alzheimer's disease.},
journal = {Experimental and molecular pathology},
volume = {146},
number = {},
pages = {105045},
doi = {10.1016/j.yexmp.2026.105045},
pmid = {42000400},
issn = {1096-0945},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive and memory decline. An imbalance in the excitatory/inhibitory (E/I) neurotransmitter systems is hypothesized to play a significant role in the pathological mechanisms underlying this cognitive failure. As therapies targeting the excitatory side of this E/I balance provide only mild symptomatic relief, modulating inhibitory GABAergic neurotransmission has emerged as a potential therapeutic strategy for AD. α5 GABA type A receptors (α5-GABAARs) are of particular interest given their high expression in the hippocampus and involvement in learning and memory processes. Positive and negative allosteric modulators of α5-GABAARs have been developed with the converging aim of cognitive enhancement. This perspective explores the current literature on positive and negative allosteric modulators of α5-GABAARs in AD and proposes a model where two drug classes with opposing mechanisms can both offer therapeutic potential. Current evidence suggests that α5-GABAAR modulation may play divergent, circuit-dependent roles, such that negative allosteric modulators could enhance cognition in conditions of excessive inhibition, while positive allosteric modulators may be beneficial in hyperexcitable circuits. Ultimately, the successful clinical translation of α5-GABAAR positive and negative allosteric modulators will require careful phenotyping of neuronal activity and E/I balance to align pharmacological strategies with circuit state.},
}

@article {pmid42000569,
year = {2026},
author = {Schelter, BO and Shiells, H and Lo, S and Nazlee, N and Evans, E and Bentham, P and Gauthier, S and Zetterberg, H and Wilcock, GK and Froelich, L and Burns, A and MacSweeney, E and Ballard, C and Yu, JT and Choon, TS and Asvatourian, V and Muehlemann, N and Priel, J and Kook, K and Sullivan, T and Downie, D and Miller, S and Pringle, C and Storey, JMD and Baddeley, T and Harrington, CR and Staff, R and Sandu, AL and Hull, C and Stefanacci, R and Wischik, CM and , },
title = {Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer's disease with hydromethylthionine mesylate using external control data.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100560},
doi = {10.1016/j.tjpad.2026.100560},
pmid = {42000569},
issn = {2426-0266},
abstract = {BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.

OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039.

PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567).

INTERVENTION: HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.

RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.

CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.},
}

@article {pmid41991301,
year = {2026},
author = {Guo, SF and Wang, EL and Zeng, JX and Hou, YQ},
title = {[Research progress on the pathogenesis of Alzheimer's disease related to infectious pathogens].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {60},
number = {4},
pages = {631-639},
doi = {10.3760/cma.j.cn112150-20250607-00522},
pmid = {41991301},
issn = {0253-9624},
support = {2024ZDXK0065//Key Discipline Project of Shanghai Municipal Health Commission/ ; 24SJYXZDA06//Key Discipline Project of Shanghai Songjiang District Municipal Health Commission/ ; 23ZR1457300//Project supported by the Shanghai Committee of Science and Technology/ ; 82401655//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/microbiology/etiology ; Blood-Brain Barrier ; },
abstract = {Alzheimer's disease (AD), one of the most prevalent neurodegenerative disorders, is clinically characterized by progressive memory decline and cognitive impairment, predominantly affecting the elderly population. The pathogenesis of AD remains incompletely elucidated, and effective curative treatments are currently lacking. Notably, China has become the country with the highest number of AD cases globally. Growing evidence suggests that infections may play a crucial role in the initiation and progression of AD, though the precise mechanisms remain unclear. This review systematically examines how infectious agents participate in AD pathogenesis through key pathways including: driving neuroinflammatory responses, disrupting the blood-brain barrier and mediating central nervous system invasion, programmed cell death, and modulating epigenetic regulation and gene expression. We focus on recent advances in understanding the associations between AD and diverse pathogens including viruses, bacteria, fungi, and parasites. Finally, we discuss current anti-infective therapeutic strategies and outline future research priorities, aiming to provide novel theoretical foundations and investigative approaches for AD prevention and treatment.},
}

Humans
*Alzheimer Disease/microbiology/etiology
Blood-Brain Barrier

@article {pmid41991602,
year = {2026},
author = {Um, JH and Choi, SM and Kim, YY and Shin, DJ and Yoo, E and Maeng, HJ and Nathan, ABP and Jo, J and Cho, JH and Yun, J},
title = {Allyl-substituted ALT001 promotes alternative mitophagy and improves therapeutic outcomes in Alzheimer's disease models.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-48974-6},
pmid = {41991602},
issn = {2045-2322},
support = {RS-2024-00335192//Ministry of Health & Welfare and Ministry of Science and ICT/ ; RS-2025-00554128//National Research Foundation of Korea/ ; 2021R1A6C101A425//Korea Basic Science Institute/ ; },
abstract = {The impairment of mitophagy plays a key role in the pathology of Alzheimer's disease (AD). We previously demonstrated that ALT001 induces mitophagy via the alternative mitophagy pathway and ameliorates mitochondrial dysfunction and cognitive deficits in AD models. In this study, we synthesized a novel derivative, namely, ALT001-4a, by introducing an allyl group at the C13 position of ALT001. Compared with ALT001, ALT001-4a exhibited an approximately fivefold lower EC50 for inducing mitophagy, while maintaining low cytotoxicity, and it exerted this effect via the alternative mitophagy pathway. Similarly, ALT001-4a induced mitophagy in the hippocampus of mice at a fourfold lower dose than ALT001. Importantly, ALT001-4a successfully restored mitochondrial and cognitive function in both a cellular AD model and a 5xFAD AD model. These findings suggest that the structural modification of ALT001 can generate derivatives with superior potency and potential for treating Alzheimer's disease and that further optimization could enable the development of ALT001-4a as a viable therapeutic agent for AD.},
}

@article {pmid41991715,
year = {2026},
author = {Wei, P and Zhu, T and Hashimoto, K and Jia, M and Yang, JJ},
title = {Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41991715},
issn = {1476-5578},
support = {82571352//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82571374//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades.},
}

@article {pmid41991786,
year = {2026},
author = {Flores-Melivilu, D and Carrazana, E and García, N and Alarcón, S and Caru-Ruiz, M and Chacón-Fuentes, M and Santos, N and Ahumada, M and Nova, E and Diaz-Espinoza, R and Sanhueza, M and Hormazábal, E and Salvadores, N},
title = {Aristotelia chilensis Fruit Extracts Exhibit Neuroprotective Properties Against Alzheimer's Disease Related Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41991786},
issn = {1559-1182},
mesh = {*Plant Extracts/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Fruit/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Animals ; Cell Survival/drug effects ; Humans ; Glutamic Acid/toxicity ; Acetylcholinesterase/metabolism ; Neurons/drug effects/metabolism/pathology ; *Elaeocarpaceae/chemistry ; },
abstract = {Aristotelia chilensis (maqui) extracts have garnered interest for their potential bioactivity, yet their specific effects on Alzheimer's disease (AD) pathology remain understudied. This study evaluated the neuroprotective properties of white and black maqui fruit extracts against glutamate-induced excitotoxicity and β-amyloid (Aβ) fibrillogenesis in vitro. Pre-treatment with maqui extracts significantly mitigated glutamate toxicity, increasing cell viability from 26.8% in glutamate-treated cells to 49.9% and 48.8% for white and black maqui, respectively. Furthermore, the extracts reduced Fluorojade C-positive degenerating neurons by up to 86.4% compared to the glutamate control. The extracts also exhibited potent anti-fibrillogenic activity, suppressing Aβ fibril formation by up to 77% in the ThT assay. Electron microscopy confirmed this inhibitory effect by showing a reduction in fibrillar structures. In contrast, neither extract inhibited acetylcholinesterase nor butyrylcholinesterase activity. Together, these results indicate that maqui fruits contain compounds capable of modulating key pathological features of AD in vitro, supporting their potential for further investigation.},
}

*Plant Extracts/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/metabolism
*Fruit/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Animals
Cell Survival/drug effects
Humans
Glutamic Acid/toxicity
Acetylcholinesterase/metabolism
Neurons/drug effects/metabolism/pathology
*Elaeocarpaceae/chemistry

@article {pmid41991821,
year = {2026},
author = {White, T and Rowlands, S},
title = {Cogninet: an explainable deep learning model for multi-class MRI-based Alzheimer's disease staging.},
journal = {International journal of computer assisted radiology and surgery},
volume = {},
number = {},
pages = {},
pmid = {41991821},
issn = {1861-6429},
abstract = {PURPOSE: Alzheimer's Disease (AD) is a neurodegenerative condition which presents significant challenges in early diagnosis and clinical decision-making. This paper seeks to address key limitations in existing research-namely, a reliance on binary classification, a lack of model interpretability, and minimal consideration for clinical usability.

METHODS: This paper presents CogniNet, a novel convolutional neural network (CNN) architecture specifically designed for the classification of Alzheimer's progression using magnetic resonance imaging (MRI) data. CogniNet combines the architectural depth of VGGNet19 with the feature reuse and gradient efficiency of DenseNet201, mitigating vanishing gradients while promoting richer internal representations. Trained on axial slices from preprocessed T1-weighted MRI scans, the model performs four-way classification and uses gradient-weighted class activation mapping (Grad-CAM) to generate class-specific attention maps to visually highlight regions most influential to improve interpretability.

RESULTS: CogniNet was tested on 3,200 unseen axial MRI slices using standard performance metrics achieving 98% accuracy and 98% sensitivity. This paper compared CogniNet's performance against several established CNN architectures and prior research and demonstrates improved performance.

CONCLUSION: These results highlight CogniNet as a high-performing and explainable deep learning model suitable for AI-assisted neuroimaging diagnostics. Beyond quantitative performance, the model provided interpretable outputs through Grad-CAM attention maps, allowing end users to visually audit which regions of the brain influenced predictions-an essential step toward clinical trust and adoption.},
}

@article {pmid41992103,
year = {2026},
author = {Hegerath-Segler, FM and Giehl, C and Vollmar, HC and Otte, IC},
title = {'Take care of it, general practitioner' - a qualitative study about barriers and needs in general practice caring for people newly diagnosed with dementia.},
journal = {BMC primary care},
volume = {27},
number = {1},
pages = {},
pmid = {41992103},
issn = {2731-4553},
}

@article {pmid41992240,
year = {2026},
author = {Bhargavan, B and Annadurai, N and Kanmogne, GD},
title = {Effects of HIV and azidothymidine on Alzheimer's-like pathology and amyloid beta transporters in hu-PBL-NSG mice, brain endothelial amyloid beta uptake and endothelial barrier integrity.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00807-4},
pmid = {41992240},
issn = {2045-8118},
}

@article {pmid41992414,
year = {2026},
author = {Micocci, S and Parisotto, S and Alberti, D and Lanfranco, A and Bitonto, V and Renzi, P and Salmi, M and Bello, FD and Pagano, K and Ragona, L and Protti, N and Deagostino, A and Geninatti Crich, S},
title = {Carboranyl-Curcuminoids for the Neutron Capture-Based Treatment of Amyloid Aggregates in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e21701},
doi = {10.1002/advs.202521701},
pmid = {41992414},
issn = {2198-3844},
support = {D13C22003520001//Dipartimenti di Eccellenza/ ; D13C25000220007)//Compagnia di San Paolo/ ; 964934//H2020 Future and Emerging Technologies/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. The aggregation of amyloid-beta (Aβ) peptides into oligomers and fibrils is central to its pathogenesis. While oligomers represent the most neurotoxic species, larger aggregates serve as reservoirs, maintaining pathological Aβ levels. To our knowledge, this study is the first to investigate Boron Neutron Capture Therapy (BNCT) as a method to selectively destabilize Aβ aggregates. This is achieved by inducing structural modifications in the Aβ peptide, aiming to convert fibrils into innocuous species. The approach utilizes [10]B-enriched monocarbonyl analogs of curcumin (BMACs), a novel molecule that binds to Aβ fibrils and enables the site-specific release of high-linear-energy-transfer (LET) α particles and lithium ions upon neutron exposure. In vitro, Aβ aggregates were characterized using FESEM and Thioflavin T staining. The binding affinities of BMACs were determined through competition assays, with inhibition constants calculated using the Cheng-Prusoff equation. Post-irradiation analysis by [1]H-NMR and mass spectrometry demonstrated selective oxidation of histidine residues, a chemical modification capable of inducing fibril destabilization. This study provides proof of concept that not only offers future perspectives for Alzheimer's treatment but also enhances the understanding of radiation effects on proteins, particularly within the context of amyloidosis.},
}

@article {pmid41992461,
year = {2026},
author = {Sharma, D and Jain, D and Bhatia, D},
title = {Unveiling the Modern Therapeutic Properties and Folk Medicinal Riches of Rubia cordifolia.},
journal = {Recent patents on biotechnology},
volume = {20},
number = {3},
pages = {342-354},
pmid = {41992461},
issn = {2212-4012},
mesh = {Humans ; *Rubia/chemistry ; *Plant Extracts/therapeutic use/chemistry/pharmacology ; Medicine, Ayurvedic ; Patents as Topic ; Plants, Medicinal/chemistry ; Animals ; Antioxidants/therapeutic use/pharmacology/chemistry ; Medicine, Traditional ; Anti-Infective Agents/pharmacology/therapeutic use/chemistry ; Phytotherapy ; },
abstract = {Rubia cordifolia (Manjishtha), a perennial herb of the Rubiaceae family, has been valued in traditional medicine for its diverse pharmacological properties. Predominantly cultivated in hilly regions, its roots have been historically used for their red pigment and therapeutic applications in Ayurveda. R. cordifolia has been traditionally employed for skin diseases, menstrual disorders, snake bites, herpes, eye diseases, haemorrhoids, and fractures. Modern research highlights its potent antioxidant, antimicrobial, and hepatoprotective properties, with evidence supporting its role in managing acne, inflammation, cancer, diabetes, Alzheimer's disease, and infectious diseases. Furthermore, its integration into various Ayurvedic formulations emphasizes its clinical significance. A comprehensive literature review highlights its bioactive compounds and their therapeutic relevance in modern medicine. The review aims to provide a comprehensive knowledge of the pharmacological impacts, the active components, and the medicinal applications of R. cordifolia. It uncovers new bioactive compounds, mechanisms of action, or novel formulations, patent protection becomes essential.},
}

Humans
*Rubia/chemistry
*Plant Extracts/therapeutic use/chemistry/pharmacology
Medicine, Ayurvedic
Patents as Topic
Plants, Medicinal/chemistry
Animals
Antioxidants/therapeutic use/pharmacology/chemistry
Medicine, Traditional
Anti-Infective Agents/pharmacology/therapeutic use/chemistry
Phytotherapy

@article {pmid41992726,
year = {2026},
author = {Evers, A and Watson, K and Abbasi, F and Haque, K and Verma, A and Eitan, E and Rasgon, N},
title = {Insights from changes in NDEV biomarkers of metabolism: Effects of PPARγ and GLP1 receptor agonists on brain metabolism.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1210/clinem/dgag176},
pmid = {41992726},
issn = {1945-7197},
abstract = {BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD).

METHODS: We analyzed biological samples from two cohorts of clinical trial participants: 1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and 2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups.

RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all p ≤ 0.02) compared to placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; p = 0.04 and p = 0.025, respectively) compared to placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test.

DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.},
}

@article {pmid41992789,
year = {2026},
author = {Ling, Y and Sun, J and Hu, L and Zhao, M and Chen, J and Zheng, Y},
title = {Diagnostic Value of Inflammatory Biomarkers in Differentiating Vascular Dementia From Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71341},
doi = {10.1002/brb3.71341},
pmid = {41992789},
issn = {2162-3279},
support = {2024ZL1138//mechanism of regulating microglia mitochondria autophagy of Ginseng Yangrong Decoction to improve cognitive ability of Alzheimer's disease/ ; 2023A14029//mechanism of the NLRP3caspase-1GSDMD pathway mediated by miR-146a-5p to regulate the progression of Alzheimer's disease based on the inflammatory microenvironment/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Dementia, Vascular/diagnosis ; Biomarkers/blood ; Diagnosis, Differential ; *Inflammation/metabolism ; },
abstract = {INTRODUCTION: Dementia encompasses distinct subtypes characterized by different underlying mechanisms-most notably, Alzheimer's disease (AD), driven by neurodegeneration, and vascular dementia (VaD), stemming from cerebrovascular pathology. Growing evidence emphasizes the critical role of neuroinflammatory processes in both conditions, highlighting inflammatory biomarkers as potential tools for differential diagnosis. This study assesses the diagnostic accuracy of inflammatory biomarkers in distinguishing AD from VaD.

METHOD: A systematic search of PubMed, EMBASE, Web of Science, and Cochrane Library databases was conducted in November 2025 to identify eligible studies. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to compare inflammatory marker levels between AD and VaD groups. Random-effects models were applied for all meta-analyses.

RESULTS: Fifteen observational studies involving 1728 participants were included. Pooled analyses showed no significant differences in IL-6 (SMD: -0.13; 95% CI: -0.44 to 0.19; p = 0.433), TNF-α (SMD: -0.22; 95% CI: -0.71 to 0.28; p = 0.388), or CRP (SMD: 0.73; 95% CI: -0.17 to 1.62; p = 0.111) between AD and VaD overall. However, subgroup analyses indicated context-dependent variations: IL-6 and TNF-α levels were lower in patients with AD in studies conducted in Eastern regions, with larger sample sizes (≥100 participants), older populations (≥70 years), or higher methodological quality. CRP showed similar patterns in larger or higher-quality studies. Importantly, IL-1β levels were significantly higher in patients with AD compared to patients with VaD (SMD: 0.48; 95% CI: 0.18 to 0.79; p = 0.002).

CONCLUSIONS: Exploratory analyses suggest IL-1β as a promising candidate for differentiating AD from VaD, warranting validation in larger, prospective studies. The preliminary, context-dependent signals for IL-1β, IL-6, and TNF-α indicate that inflammatory pathways differ between these dementias but are substantially influenced by methodological and population factors.

 INPLASY platform (number: INPLASY202570068).},
}

Humans
*Alzheimer Disease/diagnosis
*Dementia, Vascular/diagnosis
Biomarkers/blood
Diagnosis, Differential
*Inflammation/metabolism

@article {pmid41992810,
year = {2026},
author = {Park, S and Lee, J and Park, SJ and Song, J and Kim, HJ and Kim, SM and Lee, H and Kim, J and Lee, SK and Cho, HJ and Kim, KH and Park, SM},
title = {Association Between Change in Dental Hygiene Practices and Incidence of Dementia.},
journal = {Journal of clinical periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jcpe.70128},
pmid = {41992810},
issn = {1600-051X},
support = {//Seoul National University Hospital Research Fund/ ; //National Research Foundation of Korea/ ; },
abstract = {AIM: To investigate whether changes in toothbrushing frequency influence the incidence of dementia.

MATERIALS AND METHODS: This is a retrospective cohort study using the Korean National Health Insurance Service database. Among 91,978 adults who received two oral health screenings between 2002 and 2005, 74,156 were included after exclusions. Participants were followed until 2019. Participants were categorised into nine groups based on toothbrushing frequency (≤ 1, 2, ≥ 3 times/day) at each screening. Main outcomes such as incidence of overall dementia, Alzheimer's disease (AD) and vascular dementia (VaD) were assessed using Cox proportional hazards models, adjusting for potential confounders.

RESULTS: Individuals who increased their toothbrushing frequency to ≥ 3 times/day showed reduced risks of overall dementia (aHR 0.79, 95% CI 0.64-0.99) and AD (aHR 0.76, 95% CI 0.59-0.96). Those who decreased their brushing to ≤ 1 time/day had a higher risk of AD (aHR 1.31, 95% CI 1.05-1.65). A decrease from moderate brushing frequency was associated with elevated VaD risk (aHR 1.32, 95% CI 1.02-1.70).

CONCLUSION: Improvements in dental hygiene practices may lower dementia risk, even among those with poor baseline habits. Conversely, lapses in oral care among previously consistent brushers may increase dementia risk.},
}

@article {pmid41992956,
year = {2026},
author = {Liu, Y and Zhao, Y and Yao, Y and Liu, D and Sun, Y and Xu, W and Yu, H and Chi, L},
title = {SRSF1 as a promising biomarker and key player in the pathogenesis of Alzheimer's disease.},
journal = {Molecular medicine reports},
volume = {33},
number = {6},
pages = {},
doi = {10.3892/mmr.2026.13882},
pmid = {41992956},
issn = {1791-3004},
mesh = {*Alzheimer Disease/genetics/metabolism/diagnosis/pathology ; *Serine-Arginine Splicing Factors/genetics/metabolism ; Animals ; Humans ; Biomarkers/metabolism/blood ; Mice ; Disease Models, Animal ; Male ; Female ; Aged ; Amyloid beta-Peptides ; Signal Transduction ; Gene Expression Profiling ; },
abstract = {Given the unclear pathogenesis and insidious progression of Alzheimer's disease (AD), the aim of the present study was to identify reliable diagnostic markers for AD detection using a combination of bioinformatics analysis, animal experiments and clinical patient validation. Gene expression profiles were retrieved from the GSE95587 dataset. Weighted gene co‑expression network analysis combined with four machine learning algorithms identified two signature genes: Serine/Arginine Rich Splicing Factor 1 (SRSF1) and NADH: Ubiquinone oxidoreductase subunit B5 (NDUFB5), and a diagnostic model with moderate efficiency in differentiating AD was established. The AD diagnostic signature genes (SRSF1 and NDUFB5) were associated with specific immune cell infiltration. SRSF1 was significantly enriched in the p38MAPK and AKT1/mTOR signalling pathways. Notably, in an Aβ1‑42‑induced mouse model, SRSF1 expression was upregulated in the hippocampus and cerebral cortex. Moreover, in patients with AD, SRSF1 mRNA levels in peripheral blood mononuclear cells showed a strong negative correlation with mini‑mental state examination and Montreal cognitive assessment scores and a positive correlation with clinical dementia rating scores, indicating a notable association between elevated SRSF1 expression and cognitive decline. Furthermore, SRSF1 levels were positively associated with plasma levels of p‑tau217, p‑tau181 and glial fibrillary acidic protein. These findings underscore the strong association between SRSF1 and AD pathology. The newly identified genes, particularly SRSF1, show potential as candidate biomarkers of AD progression and may provide insights into AD pathogenesis, but require further validation in a larger prospective cohort.},
}

*Alzheimer Disease/genetics/metabolism/diagnosis/pathology
*Serine-Arginine Splicing Factors/genetics/metabolism
Animals
Humans
Biomarkers/metabolism/blood
Mice
Disease Models, Animal
Male
Female
Aged
Amyloid beta-Peptides
Signal Transduction
Gene Expression Profiling

@article {pmid41993066,
year = {2026},
author = {Joshi, H and Nair, G and Roy, AA and Havanur, S and Rangarajan, SK and Sreeraj, VS and Sinha, P and Narayanan, M and Kumar, JK and Sinha, S and Saini, J and Thangaraju, SP and Varghese, M and Thompson, P and Venkatasubramanian, G and John, JP},
title = {A functional MRI and magnetoencephalography study of the cognitive modulatory effect of transcranial direct current stimulation in early Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1767772},
pmid = {41993066},
issn = {1662-5161},
abstract = {OBJECTIVE: Anodal transcranial direct current stimulation (tDCS) is known to improve cognition in patients with mild cognitive impairment (MCI) and Alzheimer's disease (mild AD).

METHODS: We aimed to examine the brain functional alterations accompanying improvement in cognitive performance following anodal tDCS at the left dorsolateral prefrontal cortex (DLPFC) in a sample of patients with early AD (N = 40; MCI, n = 19, and mild AD, n = 21) using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG).

RESULTS: Significant (p-FDR < 0.05) reduction in seed(left middle frontal gyrus, lMFG)-to-voxel resting-state functional connectivity (rsFC) with precuneus and posterior cingulate gyrus (PCC) was noted following tDCS intervention, while task-based fMRI (tbfMRI) analysis revealed significant (p-FDR < 0.05) increases in blood oxygen level-dependent (BOLD) activations at PCC and right MFG (rMFG) during episodic memory encoding and retrieval tasks, respectively. Furthermore, a significant decrease (p-FDR < 0.05) in resting-state MEG (rsMEG) gamma power at the right occipital cortex and an increase in phase (theta) and amplitude (gamma) coupling at the left entorhinal cortex were observed post-tDCS.

CONCLUSION: The findings of this comprehensive study using resting fMRI and MEG, as well as task-based fMRI, provide mechanistic insights regarding brain functional alterations that underlie the cognitive modulatory effects of anodal tDCS in early AD.},
}

@article {pmid41993142,
year = {2026},
author = {Soussi, C and Chauveau, L and de Flores, R and Cabé, N and Laniepce, A and Coulbault, L and Boudehent, C and de la Sayette, V and Chételat, G and Segobin, S and Pitel, AL},
title = {Dissecting medial temporal lobe from diencephalic sub-volumes: The amnesia dichotomy revisited.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41993142},
issn = {2837-6056},
abstract = {Severe episodic memory deficits have historically been categorized as diencephalic amnesia, like in Korsakoff's Syndrome (KS), or as medial temporal lobe (MTL) amnesia, like in Alzheimer's Disease (AD). However, recent research has highlighted that both MTL and thalamus contribute to episodic memory. We aimed to challenge the traditional distinction by assessing whether subregional volume loss in the MTL and diencephalon reflects the distinct amnesia profiles traditionally associated with KS and AD. This cross-sectional observational study includes 203 subjects, comprising 81 healthy control participants. Of the 122 patients, 42 had amnesia: 18 patients with KS and 24 patients with AD at a dementia stage (dAD); and 80 had mild cognitive disorders: 50 patients with severe alcohol use disorder (AUD) without KS and 30 patients with amnestic mild cognitive impairment (aMCI). High-resolution T1-weighted MRI was used to quantify MTL subregions (anterior/posterior hippocampus, entorhinal cortex, parahippocampal cortex) using the ASHS-T1 pipeline and key diencephalic structures (anterior/mediodorsal thalamic nuclei, mammillothalamic tract) using the HIPS-THOMAS toolbox. Volume loss among patients and regions were compared using a linear mixed model. For each region, correlations between episodic memory and volumes loss were assessed and compared between aMCI/dAD and AUD/KS patients. Results showed no volume difference between patient groups for the anterior and posterior hippocampus and parahippocampal cortex. Entorhinal cortex was more altered in aMCI and dAD than in AUD and KS. KS and AUD patients showed disproportionate structural alterations in thalamic nuclei and mammillothalamic tracts compared with MTL subregions. KS patients showed more severe alterations than all other groups, except for anterior thalamic nuclei for which volume did not differ between KS and dAD. Episodic memory performance of AUD and KS patients correlated with volumes loss in the anterior and mediodorsal thalamic nuclei and mammillothalamic tract, while that of aMCI and dAD patients correlated with volume loss in the anterior hippocampus. Alterations in the MTL and diencephalon are not as clearly dissociated as traditionally proposed in the classification of amnesia. While KS pathology is characterized by more severe diencephalic alterations, only the entorhinal cortex is more damaged in AD than in KS. Neither hippocampal nor anterior thalamic volume loss appears to distinguish between the two types of amnesia, suggesting that structural changes in these two regions jointly participate to the pathophysiology of amnesia whatever the etiology. However, these alterations are not similarly involved in memory deficits, which suggests different architectural and/or functional implications of same-scale volume loss.},
}

@article {pmid41993246,
year = {2026},
author = {Pattanashetty, SG and Serrano, PA and Rockwell, P and Xie, L and Figueiredo-Pereira, ME},
title = {Terazosin drives sex-dependent adrenergic-bioenergetic reprogramming to restore network function in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716175},
pmid = {41993246},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) has long been defined by amyloid-β plaques and hyperphosphorylated tau, yet disease-modifying therapies remain critically limited. Growing evidence reframes AD as a system-level failure driven by early dysregulation of synaptic, metabolic, and neuroimmune pathways, preceding overt protein aggregation and originating in selectively vulnerable circuits, including the locus coeruleus (LC)-hippocampal noradrenergic axis. This complexity underscores the need for therapeutic strategies that engage the disease at a network level, early in its trajectory. To this end, using a machine learning-based systems pharmacology framework for drug repurposing applied to human AD transcriptomic datasets, we identified terazosin (TZ) as a candidate predicted to reverse AD-associated molecular signatures. TZ is an FDA-approved α1-adrenergic receptor antagonist and phosphoglycerate kinase-1 activator. It was administered chronically via the diet (0.5 mg/kg bw/day) to male and female TgF344-AD rats and wild-type littermates from 5 to 11 months of age, preceding overt pathology. Bulk hippocampal RNA sequencing revealed sex-specific transcriptional remodeling in transgenic rats, strongly conserved with human AD datasets. Male TgF344-AD rats exhibited suppression of synaptic and transcriptional maintenance pathways with concurrent activation of metabolic, proteostatic, extracellular matrix, and vascular stress responses; females showed suppression of survival and vascular structural signaling alongside heightened DAM-like immune activation, amyloid-associated stress, and cell death programs. TZ reversed these signatures in a sex-dependent manner: males showed enhanced immune surveillance and reduced proteostasis burden, while females showed reinforcement of synaptic, survival, and metabolic pathways. TgF344-AD rats displayed selective LC-derived hippocampal noradrenergic axonopathy without global neuronal loss. TZ preserved fiber integrity preferentially in females and partially reversed LC vulnerability-associated transcriptional signatures in both sexes. TZ also reduced amyloid-β plaque burden in both sexes, attenuated hyperphosphorylated tau exclusively in females, and induced microglial morphological shifts in males. Finally, TZ restored wild-type spatial learning in transgenic animals, with females appearing to derive the greater cognitive benefit. Together, these findings demonstrate that TZ induced systems-level reprogramming of AD-relevant molecular pathways and preserved vulnerable noradrenergic circuitry in a sex-dependent manner. Moreover, TZ rescued spatial cognition in transgenic rats, with cognitive gains seemingly more pronounced in females. These results support adrenergic-bioenergetic modulation as a translational strategy for early-stage AD and underscore the necessity of sex as a biological variable in disease-modifying treatment development.},
}

@article {pmid41993387,
year = {2026},
author = {Marchi, A and Anwer, D and Kerkhoven, E and Montaldo, NP and Gilis, J and Polster, A},
title = {Cell-Type-Resolved Pseudobulk Classification Across Independent Cohorts Identifies Microglial PTPRG as a Transcriptional Hub in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.07.717029},
pmid = {41993387},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and widespread cerebral pathology. Understanding cell-type-specific molecular mechanisms underlying AD is critical for identifying precise therapeutic targets. We applied a supervised machine learning approach to single-nucleus RNA sequencing data from the ROSMAP cohort, aggregating gene expression profiles into pseudobulk representations across six major brain cell types. Systematic evaluation of all possible cell-type combinations identified microglia and astrocytes as the most discriminative cell types for AD classification. A logistic regression model trained on 228 highly variable genes achieved robust classification performance on held-out ROSMAP samples (balanced accuracy 0.87, AUC 0.89) and generalized to an independent cohort from the Seattle Alzheimer's Disease Brain Cell Atlas (balanced accuracy 0.86, AUC 0.92), demonstrating cross-cohort reproducibility that remains uncommon in computational AD research. Among the 72 genes selected by the model, microglial PTPRG exhibited the highest absolute coefficient. Gene Set Enrichment Analysis (GSEA) revealed that microglia-expressed genes were enriched for chronic immune activation and inflammatory signaling, while astrocyte-associated genes implicated protein homeostasis stress and HSF1-mediated chaperone pathways. Weighted Gene Co-expression Network Analysis (WGCNA) further showed that PTPRG operates within fundamentally different gene network contexts in AD and NCI microglia, with AD networks characterized by inflammatory dysregulation and NCI networks reflecting homeostatic immune surveillance. Cell-cell communication analysis identified established AD risk genes including APOE, GRN, PSEN1, and CLU among the top neuronal ligands predicted to regulate microglial PTPRG, positioning it as a convergence point for disease-relevant neuronal signals. Correlation analysis further revealed that excitatory and inhibitory neurons couple to microglial PTPRG through distinct biological processes, implicating divergent mechanisms of AD-associated microglial dysregulation. Collectively, these findings establish microglial PTPRG as a central hub integrating neuronal signaling and inflammatory dysregulation in AD pathology.},
}

@article {pmid41993389,
year = {2026},
author = {Negida, A and , },
title = {Alpha-synuclein co-pathology amplifies amyloid-driven tau accumulation across Braak stages without modifying tau-cognition associations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.713304},
pmid = {41993389},
issn = {2692-8205},
abstract = {INTRODUCTION: Alpha-synuclein (αSyn) is the most common co-pathology in Alzheimer's disease (AD), yet its role within the amyloid-tau-neurodegeneration (ATN) cascade is unknown.

METHODS: We analyzed 636 ADNI participants with CSF αSyn seed amplification assay, amyloid PET, regional tau PET (Braak I-VI), structural MRI, and cognitive composites. Interaction models tested whether αSyn modifies the amyloid-tau and tau-cognition associations.

RESULTS: αSyn positivity (19.0%) amplified the amyloid-tau association across all Braak stages (meta-temporal interaction β = 0.258, 95% CI 0.104-0.411, p = 0.001), with strongest effects in Braak III-IV. αSyn did not modify tau-cognition associations in any domain (all interaction p > 0.18).

DISCUSSION: αSyn co-pathology selectively amplifies amyloid-driven tau propagation without modifying downstream tau-cognition relationships, identifying a node-specific effect within the ATN cascade with implications for patient stratification.

RESEARCH IN CONTEXT: Systematic review: We searched PubMed for studies combining α-synuclein seed amplification assays with amyloid and tau PET in Alzheimer's disease. One recent study (Franzmeier et al., 2025) demonstrated that α-synuclein co-pathology accelerates amyloid-driven tau accumulation. No study has examined whether α-synuclein modifies the downstream tau-cognition relationship or assessed regional tau specificity across all Braak stages.Interpretation: In 636 ADNI participants, α-synuclein co-pathology amplified the amyloid-tau association across all Braak stages but did not modify tau-cognition relationships. This dissociation identifies α-synuclein as a node-specific modifier of the ATN cascade, acting at the amyloid-to-tau transition.Future directions: Longitudinal studies with serial tau PET and α-synuclein SAA are needed to establish temporality. Clinical trials should evaluate whether α-synuclein stratification improves prediction of anti-amyloid treatment response.},
}

@article {pmid41993400,
year = {2026},
author = {Kammala, AK and Tatiparthy, M and Sreenivasmurthy, SGS and Garza, KH and Budhwani, S and Richardson, L and Menon, R and Krishnan, B},
title = {Exofection as a Therapeutic Modality: Restoring P-gp Activity via Trophoblast-Derived EV in Neuroinflammatory Disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716001},
pmid = {41993400},
issn = {2692-8205},
abstract = {BACKGROUND: P-glycoprotein (P-gp/ABCB1) is a key efflux transporter that maintains barrier integrity by clearing xenobiotics and toxic metabolites. At the feto-maternal interface, trophoblast-derived extracellular vesicles (CTC-EVs) naturally and transiently transfer functional P-gp to maternal decidual cells, restoring lost and or reduced P-gp function (exofection) to sustain pregnancy homeostasis. A similar loss of P-gp at the blood brain barrier (BBB) contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease. We investigated whether CTC-EV-mediated exofection could restore P-gp function in human brain endothelial cells (hBECs) and enhance Aβ clearance under inflammatory and neurodegenerative conditions.

METHODS: CTC-EVs were isolated and characterized by nanoparticle tracking analysis and western blotting for P-gp and EV markers. Transcriptomic profiling of CTC-EVs identified enrichment of transporter-related genes, including solute carriers and ABC transporters, along with inflammatory mediators. Network analysis revealed coordinated modules linking EV cargo to transporter regulation, endocytosis/trafficking pathways, and inflammatory remodeling processes converging on BBB efflux activity. hBECs were exposed to LPS (500 ng/mL, 48 h) with or without CTC-EVs. P-gp expression was assessed by immunofluorescence (mean fluorescence intensity, MFI) and western blotting, while functional efflux was measured using Calcein-AM assays. Aβ oligomer transport was evaluated using a transwell hBEC model. In vivo, 3xTg-AD mice received intravenous CTC-EVs (1×10L/day for 5 days), followed by assessment of P-gp expression, Aβ burden, and neuroinflammatory markers. Pharmacokinetic studies in P-gp knockout mice were conducted to confirm functional transporter recovery.

RESULTS: LPS exposure significantly reduced P-gp expression in hBECs (41.3% decrease in MFI, p=0.0084), which was restored by CTC-EVs (46.7% increase vs. LPS, p=0.0121). Exofection increased P-gp by a 2.1-fold following EV treatment as determined by western blot. Functional assays demonstrated enhanced efflux, with a 38.5% reduction in intracellular Calcein fluorescence (p<0.001). Network-informed mechanisms supported coordinated regulation of transporter and trafficking pathways. CTC-EVs improved Aβ transport across inflamed hBEC monolayers. In vivo, EV-treated 3xTg-AD mice exhibited increased P-gp expression in the frontal cortex (38.6%) and hippocampus (42.1%), reduced Aβ plaque burden (27.9%), and decreased inflammatory markers (IL-1β and TNF-α, p<0.05). In P-gp knockout mice, EVs reduced brain drug accumulation by 22.4% (p=0.032), confirming restoration of transporter function.

CONCLUSION: CTC derived EVs are natural carriers of functional transporter proteins and restore efflux capacity in compromised endothelial barriers. Integration of transcriptomic and network analyses highlights coordinated regulation of transporter, trafficking, and inflammatory pathways underlying exofection. This reproductive biology inspired strategy offers a promising therapeutic approach for enhancing Aβ clearance and mitigating neuroinflammation in Alzheimer's disease.},
}

@article {pmid41993440,
year = {2026},
author = {Martínez-Flores, R and Martín-Sobrino, I and Falgàs, N and Grau-Rivera, O and Suárez-Calvet, M and Cristi-Montero, C and Ibañez, A and Supèr, H},
title = {Cognitive Vergence and Pupil Response During Oddball Task are Associated With Alzheimer's Disease Cerebrospinal Fluid Neurodegenerative Biomarkers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.10.717637},
pmid = {41993440},
issn = {2692-8205},
abstract = {BACKGROUND: Alzheimer's disease (AD) can be diagnosed using cerebrospinal fluid (CSF) biomarkers reflecting amyloid and tau pathology. However, it provides no information about functional network status. We aimed to determine whether CSF biomarkers (Aβ42, p-Tau, t-Tau, and Aβ42/p-Tau ratio) are associated with altered stimulus differentiation in vergence and pupil responses during an oddball task, and to evaluate oculomotor metrics as predictors of CSF core AD biomarkers in patients at mild cognitive impairment (MCI) stage.

METHODS: Thirty-eight participants with abnormal CSF core AD biomarkers at MCI stage completed a visual oddball task while oculomotor responses were recorded. Linear mixed-effects models examined condition × biomarker interactions, controlling for sex, age, and MMSE. Temporal and magnitude features were tested as predictors using linear regression.

RESULTS: Higher p-Tau levels were negatively associated with target-distractor differentiation in cognitive vergence (β = -0.035, p < 0.001) and pupil responses (β = - 0.060, p < 0.001). Higher Aβ42 and Aβ42/p-Tau showed positive associations with vergence differentiation but opposite effects on pupil responses. Oculomotor features predicted p-Tau levels (R [2] = 0.20-0.21).

CONCLUSION: Oculomotor differentiation metrics capture functional signatures of tau-related network dysfunction, positioning them as accessible biomarkers complementing CSF measures for detecting network disruption at MCI stage.},
}

@article {pmid41993450,
year = {2026},
author = {Manninen, E and Comrie, CJ and Serrano, GE and Beach, TG and Hutchinson, EB and Benjamini, D},
title = {Separable multidimensional MRI signatures of cellular and structural pathology in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716156},
pmid = {41993450},
issn = {2692-8205},
abstract = {Cognitive decline in Alzheimer's disease (AD) reflects progressive disruption of cellular and microstructural organization, yet the biological specificity of MRI signals remains incompletely understood. Multidimensional diffusion-relaxation MRI (MD-MRI) resolves sub-voxel tissue heterogeneity, offering a potential framework to link imaging signals to underlying pathology. We tested the hypothesis that neuronal, glial and white matter pathologies in AD occupy separable regions of diffusion-relaxation space and generate spatially organized imaging signatures linked to cognitive impairment. We integrated ex vivo MD-MRI with co-registered histology from 12 human donors spanning a range of Braak stages and pathological severity. Using nested cross-validated elastic net modeling, we predicted voxelwise Aβ, pTau, microglia and myelin burden from the multidimensional diffusion-relaxation density distribution. Regional associations were assessed across hippocampal subfields and white matter, and clinical relevance was evaluated by relating MRI-predicted pathology to Mini-Mental State Examination (MMSE) scores. Distinct diffusion-relaxation components were preferentially associated with different pathological markers, indicating separable microstructural signatures. Voxelwise MRI-derived predictions were significantly associated with histological measures of myelin (ρ = 0.77), pTau (ρ = 0.62), and microglia (ρ = 0.61), with weaker correspondence for Aβ (ρ = 0.45). Regionally, predicted pathology recapitulated known patterns of selective vulnerability, with elevated pTau and microglial signal in hippocampal subfields and dominant myelin-associated signal in white matter (p < 0.0001). Importantly, higher predicted pTau density in the hippocampus was strongly associated with worse cognitive performance (ρ = -0.88, p = 0.0014), with a moderate association in white matter (ρ = -0.66, p = 0.036), suggesting that tau-related microstructural alterations within both gray and white matter contribute to cognitive impairment. By directly linking multidimensional MRI signatures to histologically verified cellular pathology, this study demonstrates that AD-related processes manifest as distinct and spatially organized diffusion-relaxation signatures. These findings provide mechanistic insight into the microstructural basis of MRI contrasts and support the potential of MD-MRI to map regionally specific neuropathological processes in AD. As clinically feasible MD-MRI acquisition protocols continue to emerge, translation of these spectral signatures to in vivo imaging may enable more mechanistically informed assessment of aging and dementia.},
}

@article {pmid41993458,
year = {2026},
author = {Wu, Q and Brigande, AM and Lutz, MW and Shi, P and Disney, AA},
title = {Integrated metabolomics and proteomics from voxelated cortical hemispheres of adult rhesus monkeys.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.04.716423},
pmid = {41993458},
issn = {2692-8205},
abstract = {The spatial organization of molecular networks across cortex likely contributes to differences in local circuit vulnerability in aging and Alzheimer's disease; yet many existing molecular datasets sacrifice spatial structure, sampling only a handful of regions per brain. Here, we present a framework for generating spatially registered, paired metabolomic and proteomic maps across an entire cortical hemisphere of an adult rhesus monkey, at millimeter resolution. One hemisphere each from two animals was harvested under controlled conditions, approximately flattened, and hand dissected at different sampling resolutions (roughly 2.5 and 4 mm/side) into tissue voxels. Each voxel was split after homogenization and extraction to provide matched aliquots for targeted metabolomics and deep untargeted proteomics. To handle these high dimensional data, we developed PChclust, a principal component guided feature clustering algorithm. For cross omic integration, we developed a spatially regularized sparse canonical correlation analysis (sr-sCCA), which incorporates spatial neighborhood structure via graph Laplacian smoothing. We recover meaningful biology: Molecular similarity between neighboring voxels decayed with distance in both modalities, confirming that voxelation captures spatially organized biological variance. The sr-sCCA identified joint proteome-metabolome components with coherent cortical gradients that were conserved across animals. Pathway enrichment analysis recovered brain relevant ontologies and reconstructed complete metabolic circuits from single voxels.},
}

@article {pmid41993473,
year = {2026},
author = {Fatima, U and Padala, A and Barger, SW},
title = {Insulin Growth Factor 1 affects glutamate receptor activity differently in primary cultures of neocortical versus hippocampal neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.04.716504},
pmid = {41993473},
issn = {2692-8205},
abstract = {Insulin-like growth factor-1 (IGF-1) plays a critical role in neuronal signaling. Disrupted insulin/IGF-1 signaling is implicated in Alzheimer's disease, among other conditions, yet its specific influence on glutamate receptor-mediated calcium responses remains unclear. We examined the impacts of IGF-1 on glutamate receptor function in primary rat neurons monitored for intraneuronal calcium following stimulation with glutamate, AMPA, or NMDA/glycine. Pharmacological blockers (CNQX for AMPA receptors, APV for NMDA receptors, and nimodipine for L-type calcium channels) were applied to define receptor-specific contributions. In hippocampal neurons, IGF-1 and insulin altered responses to glutamate in different directions, with IGF-1 tending to evoke and enhanced response. In neocortical neurons, by contrast, IGF-1 consistently reduced glutamate- and AMPA-evoked calcium peaks, suggesting an inhibitory effect on AMPA receptors. To rule out effects on voltage-gated calcium channels downstream of AMPA receptors, we tested effects of IGF-1 on depolarization with potassium chloride; calcium elevation in this case was unaffected by IGF-1. Likewise, IGF-1 did not inhibit responses to NMDA/glycine; and IGF-1 did not affect glutamate responses in the presence of CNQX, a selective AMPA receptor blocker. These findings, combined with the observation that IGF-1 effects persisted in the presence of APV (an NMDA receptor antagonist), indicate that the inhibition of glutamate responses by IGF-1 is mediated by suppression of AMPA receptor activity. IGF-1 may thus contribute to normal neurophysiology, and given the role that glutamate receptors play in excitotoxicity, IGF-1 may confer neuroprotection in the neocortex. Disruption of IGF-1 signaling, as seen in states resembling insulin resistance, may therefore worsen glutamate-driven excitotoxicity and contribute to adverse outcomes.},
}

@article {pmid41993514,
year = {2026},
author = {Ekanayake, A and Hwang, SN and Peiris, S and Elyan, R and Tulchinsky, M and Wang, J and Eslinger, PJ and Yang, Q and Ghulam, M and Karunanayaka, P},
title = {A DERIVED RELAXATION CONTRAST FROM SYNTHETIC MRI FOR DETECTING NETWORK MICROSTRUCTURAL VULNERABILITY.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.08.717271},
pmid = {41993514},
issn = {2692-8205},
abstract = {BACKGROUND: Odor identification impairment is an early marker of Alzheimer's disease (AD) that predicts memory decline, yet its underlying microstructural basis remains unclear. We hypothesized that mild cognitive impairment (MCI) involves early myelin and lipid disruption within olfactory and limbic circuits, detectable using a synthetic MRI derived contrast that provides complementary sensitivity to myelin volume fraction (MVF).

METHODS: Methods: Thirty three older adults (healthy controls [HC], n = 16; mild cognitive impairment [MCI], n = 17) completed olfactory and cognitive testing and underwent 3T brain MRI using a QALAS sequence. An MVF map and synthetic FLAIR and DIR images were generated, and a FLAIR and DIR derived metric (FD) was computed as FD = (FLAIR - DIR) / FLAIR. We investigated ROI-based group differences in olfactory and limbic gray-matter regions and associated white matter tracts, voxel wise regressions investigating FD odor identification associations, and ROI based MCI vs HC classification using cross validated logistic regression models.

RESULTS: Compared with HC, MCI showed significantly lower FD across olfactory and limbic gray matter regions and white matter pathways including hippocampus, amygdala, orbitofrontal cortex, thalamus, and corpus callosum whereas MVF differences were more limited. FD achieved moderate discrimination, with baseline performance comparable to MVF. Voxel wise analyses revealed that better odor identification was associated with higher FD in the hippocampus/parahippocampal and insula; the association persisted after adjusting for voxel wise MVF. MVF also showed significant positive voxel-wise associations with odor identification in the insula and genu of the corpus callosum.

CONCLUSION: FD is a practical, myelin- and lipid-sensitive contrast derived from routinely acquired synthetic FLAIR & DIR images that complement quantitative MVF. It captures behaviorally relevant variance beyond local myelin content and may improve detection of early olfactory and limbic microstructural changes in MCI. These findings support FD as a scalable candidate marker linking early network disruption to olfactory symptoms across the AD continuum.},
}

@article {pmid41993524,
year = {2026},
author = {Turcu, AL and Oken, AC and Griñán-Ferré, C and Durner, A and Sierra-Marquez, J and Hinz-Kowalik, S and Nagel, J and Lee, SD and Tzortzini, E and Georgiou, K and Bhol, M and Baz, Z and Llop, J and Schneider, M and Barbaraci, C and Kim, GR and Barniol-Xicota, M and Val, C and Brea, J and Loza, MI and Pérez, B and Naesens, L and Kolocouris, A and Kim, YC and Müller, CE and Nicke, A and Pallàs, M and Mansoor, SE and Vázquez, S},
title = {A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.06.716621},
pmid = {41993524},
issn = {2692-8205},
abstract = {The ATP-gated P2X7 receptor (P2X7R) activates inflammatory signaling pathways in the central nervous system. In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimer's disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-β plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.},
}

@article {pmid41993560,
year = {2026},
author = {Gunter, JL and Preboske, GM and Persons, BD and Przybelski, SA and Schwarz, CG and Low, A and Vemuri, P and Petersen, RC and Jack, CR},
title = {Multi-Contrast MRI Inputs Enable Self-Consistent Tissue Segmentation & Robust Perivascular Space Identification.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.03.716409},
pmid = {41993560},
issn = {2692-8205},
abstract = {Different MRI image contrasts are designed to highlight various tissue properties and combining them allows extension of probabilistic segmentation beyond the commonly used "gray-white-CSF" models. This work describes a fully automated method that combines T1-weighted, T2-FLAIR, and conventional T2-weighted images to provide internal consistency across prediction of tissue segmentations including segmentation of superficial and deep gray matter, white matter hyperintensities, and MR-visible perivascular spaces. Results from 773 imaging datasets from 403 participants in the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center (ADRC) are presented.},
}

@article {pmid41993970,
year = {2026},
author = {Huang, Y and Xi, J and Su, B and Wang, P and Xie, C and Yuan, Y and Yin, X and Bao, B},
title = {Syntaxin1A in synaptopathies: From molecular mechanisms to therapeutic implications in neurological disorders (Review).},
journal = {Biomedical reports},
volume = {24},
number = {5},
pages = {65},
pmid = {41993970},
issn = {2049-9442},
abstract = {Syntaxin1A (STX1A) is a presynaptic membrane protein that is abundantly expressed in the central nervous system. It is a key member of the soluble N-ethylmaleimide sensitive factor attachment protein receptor protein family. Notably, STX1A acts as a 'molecular hub' in neural networks by regulating presynaptic membrane fusion with synaptic vesicles and the subsequent release of neurotransmitters. In addition to this function, STX1A is crucial for neuronal development, synaptic plasticity, and ion channel regulation. The deficiency or variation of STX1A not only directly disrupts neurotransmitter transmission but also contributes to pathological processes in neurological disorders such as Alzheimer's disease, epilepsy, autism spectrum disorder, and ischemic stroke by interfering with excitatory-inhibitory balance, inducing neuroinflammation, and triggering neuronal apoptosis. The present review summarizes the structure and physiological functions of STX1A, highlights its mechanisms in the pathogenesis of various neurological diseases, and examines its potential as a diagnostic biomarker and therapeutic target for these diseases.},
}

@article {pmid41993974,
year = {2026},
author = {Han, H and Hou, L and Lu, J and Sun, H and Ning, W and Liang, Y and Gu, Y and Yin, H and Gao, Q},
title = {The intellectual landscape of cognitive impairment in type 2 diabetes: knowledge structure, research focuses and rising trends.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1809245},
pmid = {41993974},
issn = {1664-2392},
mesh = {*Diabetes Mellitus, Type 2/complications/psychology ; Humans ; *Cognitive Dysfunction/etiology/epidemiology/psychology ; Bibliometrics ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent worldwide, with cognitive dysfunction emerging as a significant complication. Despite extensive research into its pathological mechanisms and clinical management, the knowledge structure, research priorities, and developmental trends within this field remain unsystematically integrated.

METHODS: To ensure comprehensive coverage and compatibility with bibliometric analysis tools, relevant publications on type 2 diabetes mellitus (T2DM) and cognitive dysfunction were primarily retrieved from the Web of Science Core Collection (WOSCC) database from its inception to November 5, 2025. Searches were also conducted in PubMed and Scopus to verify completeness, but the final dataset was derived mainly from WOSCC due to its optimal export format for CiteSpace (plain text with full records and cited references) and high overlap after deduplication. Employing bibliometric methods and tools such as CiteSpace (version 6.4 Advanced) and SCImago Graphica (version 1.0.39), we conducted visual analyses of publication trends, country/region collaboration, institutional distribution, author contributions, journal impact, co-cited references, and keywords.

RESULTS: A total of 1,752 publications were included. Annual publication volume exhibited a marked upward trend, accelerating particularly after 2018. China, the United States, and the United Kingdom were the primary contributing nations, with close inter-institutional collaboration. High-frequency keywords included 'type 2 diabetes mellitus', 'Alzheimer's disease', and 'cognitive impairment'. Research focus has shifted from early risk factors to microscopic levels, including neuroimaging, gut microbiota, and molecular mechanisms.

CONCLUSION: Research on cognitive dysfunction in T2DM exhibits multidisciplinary characteristics, balancing fundamental research with clinical translation. Future efforts should enhance multidimensional integration of mechanism studies to advance early screening and personalised treatment strategies.},
}

*Diabetes Mellitus, Type 2/complications/psychology
Humans
*Cognitive Dysfunction/etiology/epidemiology/psychology
Bibliometrics
*Biomedical Research/trends

@article {pmid41994122,
year = {2026},
author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A},
title = {On the accuracy of image registration in portable low-field 3D brain MRI.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8255109/v1},
pmid = {41994122},
issn = {2693-5015},
abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those of Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three representative approaches: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.},
}

@article {pmid41994193,
year = {2026},
author = {Jiang, T and Yan, F and Liu, B and Li, Q and Wang, K and Ru, X and Hao, Y and Guan, Y and Wang, Y},
title = {Intraventricular hemorrhage, suspected EBV reactivation, and TBA-positive epilepsy after deep cervical lymphovenous anastomosis in Alzheimer's disease: a case report.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1791011},
pmid = {41994193},
issn = {1663-4365},
abstract = {Lymphovenous anastomosis (LVA) is emerging as a potential surgical intervention to ameliorate cervical lymphatic outflow and enhance glymphatic clearance in Alzheimer's disease (AD). However, the spectrum of neurological sequelae associated with this procedure remains poorly characterized. We report the case of a 67-years-old male with amyloid PET-confirmed AD who underwent bilateral deep cervical LVA. Twenty-three days postoperatively, he presented with high-grade fever and altered consciousness. Head CT revealed acute hemorrhage in the posterior horn of the left lateral ventricle (∼2 mL). Cerebrospinal fluid (CSF) analysis demonstrated lymphocytic pleocytosis and significantly elevated protein levels; the fluid was uniformly bloody, confirming intraventricular hemorrhage. Plasma metagenomic next-generation sequencing (mNGS) identified Epstein-Barr virus (EBV), with serology supporting reactivation. Following antiviral and empirical antibiotic therapy, the patient's condition stabilized, and the hemorrhage resolved. Four months postoperatively, he developed new-onset generalized seizures. Despite negative results from a conventional autoimmune encephalitis antibody panel in both serum and CSF, a tissue-based assay (TBA) proved positive in both samples. Seizures were successfully controlled with levetiracetam. This case suggests a potential association between invasive lymphatic procedures and a hemorrhage-infection-immune cascade in highly vulnerable AD patients with preexisting metabolic and neurodegenerative risk factors.},
}

@article {pmid41994275,
year = {2026},
author = {Yu, T and Yu, Y and Zhao, J and Li, H and Lu, H and Li, Y and Peng, Y and Wang, S and Wei, W and Cheng, X},
title = {Qifuyin improves physiological frailty by regulating the intestinal flora in 3xTg-AD mice.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1753643},
pmid = {41994275},
issn = {1664-302X},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is often accompanied by motor dysfunction, impaired limb strength, and gut microbiota disturbances. This study aimed to evaluate the effects of Qifuyin (QFY), a traditional Chinese medicine formula, on motor deficits, limb strength, aging, and gut microbiota composition in 3xTg-AD mice, a widely used model of AD.

METHODS: Male and female 3xTg-AD mice were administered QFY at low, medium, or high doses. Motor function was assessed using grip strength and rotarod tests. Aging was evaluated through aging scores. Gut microbiota composition was analyzed at the phylum, family, genus, and species levels. Functional profiling of microbiota was performed using KEGG, eggNOG, and carbohydrate-active enzyme (CAZyme) databases. Pearson correlation analyses were conducted to explore relationships between microbiota composition and motor performance.

RESULTS: QFY treatment significantly improved both absolute and normalized grip strength in male and female 3xTg-AD mice. Similarly, motor coordination, as assessed by latency to fall on the rotarod, was significantly enhanced in the groups of QFY. Aging scores were significantly reduced after the treatment of QFY. Microbiome analysis revealed that QFY treatment restored species diversity and improved the overall composition of gut microbiota, with significant increases in Muribaculaceae and decreases in Alcaligenaceae, Rhodanobacteraceae, and Spirochaetaceae. Principal component analysis (PCA) indicated that the gut microbiota composition of the QFY group resembled that of the control (Con) group. Functional analyses showed that treatment of QFY restored microbial pathways related to metabolism and genetic information processing, with significant correlations between microbial alterations and improved motor outcomes. Additionally, QFY modulated the abundance of key carbohydrate-active enzymes, including GH43 and GH35, which were positively correlated with grip strength and rotarod performance.

CONCLUSION: Qifuyin improves motor function, reduces aging-related deficits, and restores gut microbiota homeostasis in 3xTg-AD mice. These findings suggest that QFY may offer therapeutic potential for addressing frailty and motor dysfunction in AD, in association with alterations in gut microbiota composition and predicted microbial functions.},
}

@article {pmid41994333,
year = {2026},
author = {Stein, DN and Gendelman, HE},
title = {CAR Treg therapies for neurodegenerative diseases.},
journal = {iScience},
volume = {29},
number = {3},
pages = {114988},
pmid = {41994333},
issn = {2589-0042},
abstract = {Regulatory T cells (Tregs) promote immune tolerance by recognizing non-foreign self-antigens. Consequently, Tregs suppress chronic immune responses and prevent autoimmunity. Chimeric antigen receptor Tregs (CAR Tregs) enhance Treg responses by genetic modification for cell-specific targeting. This can lead to effective treatments for autoimmune diseases, transplant rejection, and graft-versus-host disease. An extension of CAR Tregs involves their potential ability to regulate immune responses to misfolded and aggregated proteins, which drive neurodegenerative diseases. These protein aggregates can trigger immune responses that lead to neural injury. Early preclinical and translational strategies suggest CAR Treg therapies can treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In each case, a Treg-based approach transforms a neurotoxic, inflammatory environment through neurotrophic responses. By doing so, CAR Tregs may restore brain balance and slow disease progression. This review highlights ongoing efforts to develop CAR Treg strategies as potential therapies for neurodegenerative disorders.},
}

@article {pmid41994569,
year = {2026},
author = {Li, X and Zhou, W and Yang, S and Huang, X and Zheng, K},
title = {Pharmacological interventions targeting the gut-brain axis in neurological disorders: mechanisms and translational applications.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1806532},
pmid = {41994569},
issn = {1662-4548},
abstract = {The microbiota-gut-brain axis represents a complex bidirectional communication network linking the gastrointestinal system and the central nervous system and has been increasingly recognized as a key contributor to neurological and psychiatric disorders. Growing evidence indicates that alterations in gut microbiota composition and function can influence brain development and function through neural, immune, endocrine, and metabolic pathways, thereby modulating neuroinflammation, neurotransmission, and blood-brain barrier integrity. Dysregulation of this axis has been implicated in a range of conditions, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism spectrum disorder, depression, anxiety, and stroke. Recent pharmacological advances have identified the microbiota-gut-brain axis as a promising therapeutic target. Current strategies focus on modulating shared pathophysiological mechanisms rather than disease-specific endpoints and include microbiota-directed interventions, immune-inflammatory modulators, neurotransmitter-targeting agents, and approaches aimed at restoring intestinal and blood-brain barrier function. In this review, we summarize the core mechanisms underlying microbiota-gut-brain axis dysfunction and organize existing pharmacological strategies according to their primary targets. By integrating evidence across multiple disorders, we provide a mechanism-oriented framework to support future drug development and precision therapeutic approaches for brain disorders.},
}