@article {pmid41814325,
year = {2026},
author = {Zhang, J and Zhou, Y and Mei, X and Yan, S and Mao, J and Li, Y and Bian, Z and Li, L and Ji, D and Lu, T and Chen, J and Su, L},
title = {Molecular mechanisms and therapeutic potential of tryptophan metabolism in gut-brain signaling transduction: a narrative review.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41814325},
issn = {1742-2094},
support = {2023YFC3504200//National Key Research and Development Program of China/ ; ZYXYL2024-006//The "leading plan" project of the first-class discipline of Nanjing University of Chinese Medicine/ ; 82304723//National Natural Science Foundation of China/ ; },
abstract = {As an essential amino acid, tryptophan (Trp) serves as a pivotal mediator in gut-brain axis (GBA) communication through three primary metabolic pathways: kynurenine (Kyn), indole, and serotonin (5-HT), which together regulate neuroimmune and neuroendocrine homeostasis via the vagus and spinal afferent nerves, circulatory system, and hypothalamic-pituitary-adrenal (HPA) axis. This review systematically examines Trp metabolism’s critical roles in GBA, emphasizing molecular pathways, rate-limiting enzymes, and receptor-mediated signaling. We discuss the bidirectional interplay between gut microbiota and host Trp metabolism, encompassing microbial modulation of host enzyme activities such as indoleamine 2,3-dioxygenase and direct production of bioactive indole derivatives like indole-3-propionic acid. Characteristic disruptions in Trp metabolism patterns are identified across GBA-associated disorders including irritable bowel syndrome, inflammatory bowel disease, depression, Alzheimer’s disease, schizophrenia and Parkinson’s disease, marked by aberrant neurotoxic to neuroprotective metabolite ratios and enzymatic dysregulation. The aryl hydrocarbon receptor (AhR) emerges as a molecular hub connecting Trp metabolites to GBA functions, with distinct metabolites eliciting opposing effects through AhR activation. Therapeutic strategies targeting Trp metabolism are critically evaluated, including fecal microbiota transplantation, probiotic supplementation, metabolite administration, and enzyme inhibitors. Future research directions address mechanistic gaps and translational challenges in restoring GBA homeostasis via Trp pathway modulation.},
}

@article {pmid42007396,
year = {2026},
author = {Al Khzem, AH and Gomaa, MS},
title = {Peptide-Based Therapeutics for Alzheimer's Disease: Medicinal Chemistry, AI-Guided Computational Design, and Blood-Brain Barrier Delivery.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {597087},
pmid = {42007396},
issn = {1177-8881},
mesh = {Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; *Drug Delivery Systems ; Chemistry, Pharmaceutical ; *Artificial Intelligence ; *Peptides/chemistry/pharmacology/administration & dosage ; Animals ; },
abstract = {Alzheimer's disease (AD) represents a pressing challenge in modern medicine, with current therapeutics offering only symptomatic relief. Peptide-based therapeutics have emerged as promising candidates owing to their target specificity, favorable safety profiles, and ability to modulate protein-protein interactions inaccessible to small molecules. This narrative review evaluates medicinal chemistry and artificial intelligence (AI)-driven approaches that are reshaping peptide drug discovery for AD, spanning target selection, sequence design, synthesis optimization, and central nervous system (CNS) delivery. Peptides targeting key AD pathological mechanisms-including amyloid-β (Aβ) aggregation inhibition, tau hyperphosphorylation disruption, and neurotrophic signaling enhancement-are discussed alongside strategies such as cyclization, D-amino acid incorporation, PEGylation, and peptidomimetic design to improve metabolic stability and blood-brain barrier (BBB) penetration. We review automated fast-flow peptide synthesis with inline UV-vis monitoring as a platform for rapid, high-fidelity preparation of complex sequences suitable for translational development. Delivery platforms-including cell-penetrating peptides, intranasal formulations, and nanocarrier systems-which primarily increase systemic exposure or fundamentally alter CNS distribution mechanisms are presented. AI and machine-learning (ML) technologies, molecular simulations, and structure-prediction systems are examined as an integrated pipeline that supports end-to-end design, validation, and optimization, with emphasis on rigorous QSAR and docking/MD validation practices. Clinical translation is analyzed through peptide repurposing (e.g. GLP‑1 receptor agonists, intranasal insulin, oxytocin), dedicated peptide candidates, and evolving regulatory expectations. Finally, we outline concrete design checklists for CNS ready peptides, discuss key translational bottlenecks, and propose priorities for the next 5-10 years of peptide-based AD therapy development.},
}

Humans
*Blood-Brain Barrier/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism
*Drug Design
*Drug Delivery Systems
Chemistry, Pharmaceutical
*Artificial Intelligence
*Peptides/chemistry/pharmacology/administration & dosage
Animals

@article {pmid42007400,
year = {2026},
author = {Ueda, M and Erskine, D and Thomas, A and Hamilton, C and Donaghy, PC},
title = {Association between angiotensin receptor blocker use and postmortem dementia pathology: analysis of the UK Brain Banks Network dataset.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001342},
pmid = {42007400},
issn = {2632-6140},
abstract = {BACKGROUND: Angiotensin receptor blockers (ARB) may be associated with a lower risk of a clinical dementia diagnosis. This study investigated the association between ARB use during life and postmortem dementia neuropathology, compared with angiotensin-converting enzyme inhibitors (ACEI) use.

METHOD: Cases with documented ACEI (n=257) or ARB (n=102) use, regardless of dementia pathology, were selected from the UK Brain Banks Network dataset. Pathology was categorised as either 'significant' pathology (Thal amyloid phase >3, Braak neurofibrillary tangle stage >3, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score of moderate/high density and Lewy body (LB) Braak >0 or cortical/limbic/neocortical LB pathology) or 'not significant'.

RESULTS: The ARB group was less likely to have Alzheimer's disease (AD) pathology compared with the ACEI group: Thal amyloid (adjusted OR (AOR) 0.59 (95% CI 0.36 to 0.97), p=0.038), Braak neurofibrillary tangle (AOR 0.61 (95% CI 0.38 to 0.98), p=0.041) and CERAD neuritic plaque (AOR 0.58 (95% CI 0.35 to 0.96), p=0.035). LB pathology did not differ significantly between ARB and ACEI groups, though use of either ACEI or ARB was associated with a lower likelihood of LB pathology (AOR 0.27 (95% CI 0.21 to 0.36), p<0.001).

CONCLUSION: ARB use is associated with a lower risk of AD pathology. The association between ARB/ACEI use and LB pathology requires further investigation.},
}

@article {pmid42007415,
year = {2025},
author = {Crenshaw, KH and Ortega, A and Curiel Cid, RE and Zheng, DD and Carrasquillo, MM and Crocco, E and Ramirez, S and Frydman, A and Remedios, S and Morales, YV and Vaillancourt, DE and Wang, WE and Garcia, DF and de Rivero Vaccari, JP and Ertekin-Taner, N and Kuchenbecker, L and Duara, R and Loewenstein, DA},
title = {Detecting Cognitive Impairment in African American Older Adults Using the LASSI-L and Plasma P-Tau217.},
journal = {Advances in Alzheimer's disease},
volume = {14},
number = {2},
pages = {23-37},
pmid = {42007415},
issn = {2169-2459},
support = {R01 AG077677/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) disproportionately affects Black/African American (B/AA) older adults, yet this group remains underrepresented in research. Traditional neuropsychological assessments, often developed on predominantly White populations, may not be reliable for B/AA individuals. The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) have been shown to effectively differentiate individuals with amnestic mild cognitive impairment (aMCI) from cognitively unimpaired (CU) individuals. This study examines the relationship between LASSI-L performance and plasma p-tau217 levels to explore early detection methods for AD in B/AA populations.

METHODS: Fifty-six older adults received clinical and cognitive evaluations and were deemed cognitively unimpaired (CU) and p-tau217 negative (n = 35) or met criteria for amnestic mild cognitive impairment (aMCI) and p-tau217 positive (n = 21). All participants were administered the LASSI-L to compare groups, but it was not used for group allocation to avoid circularity.

RESULTS: After adjusting for age and MMSE score, the aMCI p-tau217+ group performed significantly worse than the CU p-tau217- group on both free recall on List B (Free B1 Recall) and frPSI (correct responses on Cued B2). These differences remained statistically significant after covariate adjustment (p < 0.001). In addition, four other outcomes remained statistically significant following covariate adjustment: the aMCI p-tau217+ group exhibited a higher percentage of intrusion errors (PIE) on both Cued B1 and Cued B2, along with poorer performance on maximal learning ability (Cued A2) and PSI (correct responses on Cued B1). However, after applying the Bonferroni correction, only PIE on Cued B2 remained statistically significant among these measures. Notably, performance on LASSI-L Free B1 Recall and PIE for List Cued B2 were significant predictors distinguishing aMCI p-tau217+ from CU p-tau217- groups, with high sensitivity (80%) and specificity (91.7%). ROC analysis of these predictors yielded an area under the curve of 0.872 (SE = 0.055; p < 0.001), with a 95% confidence interval ranging from 0.765 to 0.979.

CONCLUSION: The study highlights the utility of the LASSI-L in conjunction with plasma biomarkers, particularly p-tau217, for early AD detection in B/AA older adults. The LASSI-L demonstrated strong sensitivity to cognitive impairment, effectively differentiating between CU and aMCI groups based on plasma p-tau217 levels. These findings suggest that combining cognitive assessments with plasma biomarkers can enhance early diagnosis and improve timely interventions, addressing health disparities in AD diagnosis and care.},
}

@article {pmid42007489,
year = {2026},
author = {Yang, F and Wang, F and Jiang, Y and Qian, D and Chen, L},
title = {Role of the WNT signalling pathway in physiological and pathological blood-brain barrier.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2657638},
doi = {10.1080/07853890.2026.2657638},
pmid = {42007489},
issn = {1365-2060},
mesh = {*Blood-Brain Barrier/pathology/metabolism/physiopathology/physiology ; Humans ; *Wnt Signaling Pathway/physiology ; Animals ; Induced Pluripotent Stem Cells ; Cell Differentiation ; Wnt Proteins/metabolism ; },
abstract = {BACKGROUND: The blood-brain barrier (BBB) is essential for maintaining central nervous system (CNS) homeostasis and protecting neural tissue. The wingless-type MMTV integration site family (WNT) signalling pathway has emerged as a key regulator of BBB development, maintenance, and repair. Dysregulation of this pathway is implicated in BBB dysfunction associated with various neurological disorders.

METHODS: We conducted a comprehensive review of recent literature integrating data from animal models, human induced pluripotent stem cell (iPSC)-derived BBB systems, and disease-specific mechanistic studies. The role of canonical and non-canonical WNT signalling in BBB formation, maturation, and pathological alteration was systematically analyzed.

RESULTS: WNT7a/b ligands activate β-catenin-dependent signalling to drive cerebral angiogenesis and BBB differentiation, with G protein‑coupled receptor 124 (GPR124), Reversion‑inducing cysteine‑rich protein with Kazal motifs (RECK), and SRY‑related HMG‑box transcription factor 17 (Sox17) identified as critical co-regulators. In the mature BBB, WNT activity is suppressed epigenetically to maintain barrier stability. In diseases such as ischaemic stroke, Alzheimer's disease, multiple sclerosis, and glioblastoma, WNT signalling is disrupted, leading to BBB breakdown. Pharmacological activation of WNT/β-catenin signalling (e.g. lithium, Glycogen synthase kinase 3β (GSK-3β) inhibitors and engineered WNT ligands) restores BBB integrity in preclinical models. Additionally, modulation of WNT signalling can enhance drug delivery across the BBB, offering therapeutic advantages in brain tumours and neurodegenerative diseases.

CONCLUSIONS: WNT signalling is a central molecular axis governing BBB integrity under both physiological and pathological conditions. Targeted modulation of this pathway represents a promising therapeutic strategy for restoring BBB function and improving CNS drug delivery. Further mechanistic and translational studies are warranted to advance clinical applications.},
}

*Blood-Brain Barrier/pathology/metabolism/physiopathology/physiology
Humans
*Wnt Signaling Pathway/physiology
Animals
Induced Pluripotent Stem Cells
Cell Differentiation
Wnt Proteins/metabolism

@article {pmid42007524,
year = {2026},
author = {Bao, N and Zhang, M and Tang, M and Shen, Z and Wang, S and Jiang, G},
title = {Ketogenic diet regulates Uch-L1(C) to improve cerebral energy metabolism and cognitive function in Alzheimer's disease mice.},
journal = {European journal of histochemistry : EJH},
volume = {70},
number = {2},
pages = {},
doi = {10.4081/ejh.2026.4548},
pmid = {42007524},
issn = {2038-8306},
mesh = {Animals ; *Alzheimer Disease/metabolism/diet therapy ; *Diet, Ketogenic ; *Energy Metabolism ; Mice ; *Ubiquitin Thiolesterase/metabolism ; Male ; *Cognition ; Hippocampus/metabolism ; *Brain/metabolism ; GTP Phosphohydrolases/metabolism ; Oxidative Stress ; Apoptosis ; },
abstract = {The ketogenic diet (KD), a high-fat, low-carbohydrate diet, can effectively regulate energy metabolism in the brain. The regulation of cerebral energy metabolism in patients with Alzheimer's disease (AD) has attracted the attention of researchers. Recent studies have shown that ubiquitin carboxyl terminal hydrolase L1 (Uch-L1) deficiency leads to neurodegeneration by increasing energy demand and endoplasmic reticulum stress. However, the effect of Uch-L1 on AD remains to be explored. This study first combined Uch-L1 with cerebral energy metabolism to explore its role in long-term KD in AD. We found that AD mice with long-term KD showed better spatial recognition and working memory. KD promoted Uch-L1(C) and Mfn2 expression by inhibiting oxidative stress in the hippocampus of mice, improved mitochondrial function, increased ATP content, and significantly reduced neuronal apoptosis. In conclusion, KD can increase Uch-L1(C) and Mfn2 expression in the brain, and improve cerebral energy metabolism and cognitive function in AD mice.},
}

Animals
*Alzheimer Disease/metabolism/diet therapy
*Diet, Ketogenic
*Energy Metabolism
Mice
*Ubiquitin Thiolesterase/metabolism
Male
*Cognition
Hippocampus/metabolism
*Brain/metabolism
GTP Phosphohydrolases/metabolism
Oxidative Stress
Apoptosis

@article {pmid42007542,
year = {2026},
author = {Cao, P and Zhang, J and Shen, Y and Xing, Z and Han, F and Chen, X and Jiang, N},
title = {MechMemDyn: Coupling Frustration Analysis with Membrane Dynamics to Target the TREM2-DAP12 Complex Interface.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.5c03239},
pmid = {42007542},
issn = {1549-960X},
abstract = {The transmembrane complex formed by TREM2 (Triggering Receptor Expressed on Myeloid cells 2) and DAP12 (DNAX-activating protein of 12 kDa) constitutes a pivotal therapeutic target for Alzheimer's disease. However, the intrinsic plasticity of its interface poses a formidable challenge for structure-based discovery of protein-protein interaction stabilizers (PPI stabilizers). Conventional approaches, ranging from static molecular docking to geometric deep learning, fail to capture the subtle interfacial energetics required for stabilizing this assembly, often leading to erroneous activity predictions. Here, we present MechMemDyn, a novel predictive framework that uniquely integrates protein frustration analysis with membrane-embedded molecular dynamics (MD) simulations. To our knowledge, this is the first systematic application of frustration analysis to rationalize PPI-stabilizing activity and guide ligand design. By mapping the local frustration landscape, we identify critical, minimally frustrated contact networks at the protein interface, which are essential for stabilizing the PPI. We demonstrate that the ability of a ligand to dampen distance fluctuations within these key networks, a metric rooted in thermodynamic rigor, correlates strongly with experimental potency. This method outperforms conventional static docking, AI-driven dynamic docking approaches, and standard molecular simulations, providing a more accurate and reproducible basis for cross-ligand comparison. This work not only resolves the intractability of the TREM2-DAP12 complex but also establishes a physics-driven paradigm for targeting dynamic transmembrane interfaces via frustration-optimized PPI stabilizers.},
}

@article {pmid42007885,
year = {2026},
author = {Zheng, S and Liu, Y and Zhong, B and Chu, H and Gong, Z and Zhao, B and Cheng, M and Liang, Z and Zhang, Y and Zhao, Q and Zhang, L},
title = {Orthogonal Ionic Liquid-Based Extraction Strategy Enables Amyloid-Specific Profiling of Aggregate Proteome.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23685},
doi = {10.1002/advs.202523685},
pmid = {42007885},
issn = {2198-3844},
support = {2024YFC3405403//National Key R&D Program of China/ ; 2021YFA1301501//National Key R&D Program of China/ ; 22322411//National Natural Science Foundation/ ; 22274150//National Natural Science Foundation/ ; 32088101//National Natural Science Foundation/ ; 22393931//National Natural Science Foundation/ ; DICP I202529 DICP I202413//Innovation program of science and research from the Dalian institute of chemical physics, Chinese Academy of sciences/ ; 2024RJ009//Dalian Science Foundation for Distinguished Young Scholars/ ; },
abstract = {Amyloid deposits, composed of insoluble cross-β-sheet fibrils, are pathological hallmarks of many neurodegenerative diseases. However, their structural heterogeneity and extreme insolubility hinder characterization of their molecular composition and deposition mechanisms. Here, an orthogonal ionic liquid-based extraction strategy (Orth-iEA) was developed to selectively enrich amyloid aggregates from complex biological samples. Systematic screening identified tetramethylguanidine tetrafluoroborate (TMGBF4) as a potent ionic liquid capable of disrupting hydrogen bonds within cross-β-sheet structures, thereby solubilizing amyloid aggregates. In contrast, 1-dodecyl-3-methylimidazolium chloride (C12ImCl) preferentially solubilized non-amyloid proteins through hydrophobic interactions. In combination, these two reagents constitute the orthogonal extraction system, enabling the highly selective enrichment of amyloid aggregates from complex biological samples while remaining compatible with downstream LC-MS/MS proteomic workflows after mild desalting. Application of Orth-iEA to hippocampal tissue from 12-month-old 3xTg Alzheimer's disease model mice identified numerous amyloid-associated proteins enriched in mitochondrial components, which was further confirmed by immunofluorescence co-localization analysis. Functional and network analyses converged on pathways involving protein transport, mitochondrial translation, intracellular signaling, and apoptosis, revealing previously unrecognized molecular links between amyloid pathology and Alzheimer's disease. Therefore, Orth-iEA provides a versatile chemical platform for selective isolation and molecular profiling of amyloid aggregates.},
}

@article {pmid42007924,
year = {2026},
author = {Maestri, S and Scalzo, D and Zobel, M and Besusso, D and Cattaneo, E},
title = {Towards AI-driven prediction of HTT CAG size in super-expanded human spiny projection neurons from Huntington disease donors.},
journal = {Journal of Huntington's disease},
volume = {},
number = {},
pages = {18796397261443137},
doi = {10.1177/18796397261443137},
pmid = {42007924},
issn = {1879-6400},
abstract = {Somatic instability (SI) of the CAG tract in HTT is a major driver of neurodegeneration of Spiny Projection Neurons (SPNs), the primary neuronal subtype affected in Huntington's disease (HD). SPNs can accumulate hundreds of CAG repeats during a patient's lifetime, and once the expansion exceeds ∼150 CAGs, they acquire distinct, cell-autonomous transcriptional alterations that ultimately contribute to degeneration. Here, we developed the "HD-Phase-Model", a mathematical framework designed to identify "super-expanded" SPNs without repeat sizing, by leveraging the only available single-nucleus HD post-mortem dataset that provides both transcriptional profile and matched HTT CAG sizes. After validating model performance on the test data, we applied it to independent single-nucleus datasets lacking CAG sizing information and across multiple brain regions. In all cases, the model consistently detected SPNs populations with convergent transcriptional dysregulation signatures indicative of extreme CAG expansion.Importantly, although the model was trained on caudate SPNs, we observed highly similar dysregulation patterns in putamen and accumbens, while no evidence of super-expansion was found in SPNs from Alzheimer's and Parkinson's disease donors.Together, these findings demonstrate that transcriptional profiles alone can serve as predictors of HTT CAG size, enabling systematic identification of super-expanded SPNs and providing insights into HD-specific neurodegenerative mechanisms.},
}

@article {pmid42008214,
year = {2026},
author = {Abuhassan, Q and Ardah, MT and Menon, SV and Maharana, L and Inbathamizh, L and Mukherjee, G and Sinha, A and Khodzhiyeva, S and , },
title = {Stage-dependent associations of plasma clusterin with reduced brain volume, tau pathology, and cognitive impairment across the Alzheimer's disease spectrum.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42008214},
issn = {2240-2993},
abstract = {Clusterin, a multifunctional glycoprotein involved in proteostasis, amyloid-β clearance, and neuroinflammation, has been proposed as a biomarker in Alzheimer's disease (AD), but its stage-specific links to brain structure, tau pathology, and cognition remain unclear. This study evaluated plasma clusterin across the AD spectrum, its associations with brain volumes and CSF tau/p-tau, and whether structural brain measures mediate its cognitive effects. Data from 333 participants (CN = 38, MCI = 207, AD = 88) were analyzed using FDR-corrected regression, Pearson correlations, and mediation analyses, adjusting for demographic factors and APOE ɛ4 status. Results showed that plasma clusterin was highest in mild cognitive impairment (MCI) compared to cognitively normal (CN) and AD, suggesting a peak during early neurodegeneration. In CN participants, higher clusterin was associated with lower whole-brain volume, but it was not significantly related to hippocampal volumes or tau/p-tau. In MCI, clusterin was modestly associated with reduced whole-brain volume and elevated CSF tau, while associations with hippocampal volumes and p-tau were nonsignificant. In AD, higher clusterin was significantly associated with smaller left and right hippocampal volumes, with a trend toward lower whole-brain volume; no significant associations with tau or p-tau were observed. Based on the mediation analysis, in CN participants, no significant mediation effects of brain volumes were observed between plasma clusterin and cognitive function. In the MCI group, higher plasma clusterin was associated with lower whole-brain volume, and this volumetric measure showed significant indirect effects linking plasma clusterin to cognitive performance, consistent with indirect-only (full mediation) patterns. This suggests an indirect association whereby higher clusterin may be linked to poorer cognitive function through its association with reduced global brain volume. Likewise, in the AD group, higher clusterin levels were associated with lower whole-brain and right hippocampal volumes. Both measures significantly mediated the relationship between clusterin and cognitive performance, indicating that higher clusterin may be linked to poorer cognitive function through its association with reductions in global and region-specific brain volumes. Future studies should clarify the temporal and mechanistic pathways linking clusterin to neurodegeneration to determine its value as a biomarker and therapeutic target.},
}

@article {pmid42008257,
year = {2026},
author = {Fowler, NR and Perkins, AJ and Gao, S and Bakas, T and Head, KJ and Higbie, A and Baucco, C and Callahan, CM and Williams-Farrelly, MM and Boustani, MA},
title = {Benefits and Harms of Dementia Screening for Family Members of Older Adults: A Randomized Clinical Trial.},
journal = {JAMA internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2026.0844},
pmid = {42008257},
issn = {2168-6114},
abstract = {IMPORTANCE: Early detection of Alzheimer disease and related dementias (ADRD) may influence outcomes for both patients and their family members, yet the risks and benefits of screening for family members are not established.

OBJECTIVE: To evaluate the benefits and risks of ADRD screening for family members of older adults screened in primary care (PC).

This multisite randomized clinical trial was conducted in 29 PC clinics from October 2018 to September 2023. Dyads of patients aged 65 years and older and a family member were randomized into 1 of 3 groups: screening only, screening plus referral for diagnostic follow-up, and no-screening control. Data were collected at baseline and at 6, 12, 18, and 24 months.

INTERVENTIONS: Cognitive screening was conducted in-person, by telephone, or secure video using the Mini-Cog, the Memory Impairment Screen Telephone version (MIS-T), or the MIS-T with the clock drawing test.

MEASURES: The primary outcome was family member health-related quality of life at 24 months measured using the Short Form Health Survey (SF-36) physical and mental component summary scores. Secondary outcomes included family member depressive and anxiety symptoms, caregiver preparedness, and caregiving self-efficacy, as well as patient health-related quality of life and depressive and anxiety symptoms.

RESULTS: A total of 1808 dyads completed baseline assessments. Mean (SD) patient age was 73.7 (5.7) years and 959 (53%) were female. Among family members, 1171 (64.8%) were spouses, 1224 (67.7%) were female, and mean [SD] age was 64.2 [12.9] years. Overall, 62 patients (5.1%) screened positive for cognitive impairment. Among dyads assigned to screen plus, 10 (35.7%) did not pursue diagnostic follow-up. There were no significant differences between the combined screening groups and no-screening group in SF-36 physical (24-month predicted difference, -0.21; 95% CI, -1.26-0.85) or mental (24-month predicted difference, 0.58; 95% CI, -0.18-1.33) component scores. No differences were observed in patient secondary outcomes at 24 months.

DISCUSSION: This randomized clinical trial found that ADRD screening in PC was not associated with improvement in family member health-related quality of life, caregiver preparedness, or caregiving self-efficacy. Screening was also not associated with increased family member depression or anxiety. Low rates of positive screening and high rates of refusal for follow-up diagnostic assessment may help explain these findings.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03300180.},
}

@article {pmid42008282,
year = {2026},
author = {Burns, JM and Woodward, JL and Morris, JK and Townley, RA},
title = {Reimagining Care Delivery for Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0801},
pmid = {42008282},
issn = {2168-6157},
}

@article {pmid42008377,
year = {2026},
author = {Siddiqui, A and Kathiresan, T and Opler, M and Cohen, A and Alber, J and Snyder, PJ and Vogel, AP},
title = {The utility of Speech and Language analytics for screening Alzheimer's Disease.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-26},
doi = {10.1159/000552094},
pmid = {42008377},
issn = {1660-2862},
abstract = {BACKGROUND: Effective screening and cohort enrichment remain major challenges in clinical trials for Alzheimer's disease (AD), where traditional diagnostic pathways rely on costly, invasive, and time-consuming procedures. Speech and language analysis has emerged as a scalable, low-burden approach for detecting subtle cognitive-linguistic and motor-speech changes that may appear early in the disease course.

SUMMARY: This review synthesizes current evidence on acoustic, prosodic, lexical, semantic, and syntactic speech features associated with AD and mild cognitive impairment (MCI) and evaluates their reported utility across a range of elicitation tasks including picture description, verbal fluency, narrative recall, spontaneous speech, and reading. Across studies, machine-learning models trained on speech and language features have reported consistent performance, although results vary substantially depending on task design, feature sets, and cohort characteristics. Task-dependent variability is evident, with picture description and verbal fluency tasks capturing lexical-semantic and timing markers, while narrative and spontaneous speech tasks capture impairments in coherence, information content, and prosody. Hybrid approaches integrating hand-crafted and machine-extracted features have also been explored to improve interpretability and model performance. Speech and language analytics may support digital pre-screening, cohort enrichment, and quality-assurance monitoring within clinical trials; however, their application depends on methodological considerations and validation across diverse settings.

KEY MESSAGES: Despite encouraging findings, several methodological challenges persist, including inter-individual variability, limited dataset sizes, differences in recording conditions, and limitations in automatic speech recognition performance in cognitively impaired populations. Continued development of standardized protocols, disorder-adapted speech models, and multimodal analytic pipelines is needed to support clinical translation. Collectively, current evidence suggests that speech and language features represent candidate digital markers that may improve screening efficiency and support clinical trial enrichment in AD, although further validation is required to establish their reliability and generalizability.},
}

@article {pmid42008415,
year = {2026},
author = {Ou, C and Chen, B and Deng, J and Long, H},
title = {Deciphering the molecular network of Trichostatin A in regulating Alzheimer's disease screening of core genes and mechanistic investigation based on multidimensional bioinformatics and molecular simulation.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0347532},
doi = {10.1371/journal.pone.0347532},
pmid = {42008415},
issn = {1932-6203},
mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism ; *Hydroxamic Acids/pharmacology/chemistry/therapeutic use ; Humans ; *Histone Deacetylase Inhibitors/pharmacology ; *Computational Biology/methods ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Gene Regulatory Networks/drug effects ; Machine Learning ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Histone deacetylases (HDACs) regulate neuroprotection; however, Trichostatin A (TSA), an HDAC inhibitor, lacks clear molecular mechanisms and core targets in Alzheimer's disease (AD), limiting clinical translation. This study aimed to decipher TSA's AD-regulating network, screen core genes, and support AD early diagnosis and multi-target therapies.

METHODS: TSA targets were computationally predicted. Five GEO AD datasets were analyzed for differential genes and core modules, and 130 machine learning algorithms were employed to identify core genes. Functional annotation, immune cell analysis, and single-cell expression profiling were conducted. Molecular docking and 100 ns molecular dynamics simulations verified TSA-protein interactions.

RESULTS: 949 potential TSA targets were identified, overlapping with AD differential genes and enriching key pathways such as GABAergic synapse and tau phosphorylation. Eight machine learning-identified core genes (EFNA1, GABRB2, GABARAPL1, EGR1, CDK5, KCNC2, MET, GRIA2) exhibited a distinct AD expression pattern: synergistic downregulation of protective genes and unique upregulation of pathological EFNA1. These genes are implicated in neurotransmission, synaptic plasticity, tau clearance, and immune-neural crosstalk. Molecular dynamics simulations suggested TSA may not stably bind these candidates, implying its regulation relies on epigenetic mechanisms via HDAC1-3/6 inhibition, potentially restoring gene network balance and disrupting neuroinflammation-neurodegeneration cycles. Complex regulatory modes and cell type-specific expression were also observed.

CONCLUSION: This study provides preliminary insights into TSA's putative mechanisms in AD intervention, highlighting the eight candidate core genes' potential diagnostic and therapeutic value as AD biomarkers, supporting TSA's multi-target therapy. All findings are computationally derived and require experimental verification.},
}

*Alzheimer Disease/genetics/drug therapy/metabolism
*Hydroxamic Acids/pharmacology/chemistry/therapeutic use
Humans
*Histone Deacetylase Inhibitors/pharmacology
*Computational Biology/methods
Molecular Docking Simulation
Molecular Dynamics Simulation
*Gene Regulatory Networks/drug effects
Machine Learning
Gene Expression Profiling

@article {pmid42008483,
year = {2026},
author = {Zhang, X and Wang, Z and Sun, M and Bao, Q and Chen, Z and Liu, Y and Wang, Z and Ye, F and Yang, Z and Du, X and Zhang, H and Mou, X and He, X and Li, D and Wu, K and Yao, J and Zhong, W and Xu, P and Yang, S and Zhao, L and Yin, Z and Liang, F},
title = {Acupuncture for amnestic mild cognitive impairment: Study protocol for a multicenter, single-blinded, long-term, randomized controlled trial.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346717},
doi = {10.1371/journal.pone.0346717},
pmid = {42008483},
issn = {1932-6203},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Single-Blind Method ; Aged ; Female ; Male ; Treatment Outcome ; *Amnesia/therapy ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), a common neurodegenerative disease affecting older adults, has garnered significant research interest over the past few years. While previous studies have suggested that acupuncture holds promise as a clinical intervention to improve cognitive function in patients with aMCI, the long-term effect of acupuncture treatment for aMCI remains unclear.

METHODS: This is a multicenter, single-blinded, randomized controlled trial (RCT) with a long-term follow-up.166 patients diagnosed with aMCI will be randomly divided into acupuncture group (AG) and sham acupuncture group (SA). The intervention will last for 12 weeks (2 sessions per week), follow-up for 48 weeks, and the study will last a total of 60 weeks. The primary outcomes are the changes in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score from baseline to week 12 and from baseline to week 60. Generalized estimating equations (GEE) will be used to assess the impact of the acupuncture intervention on outcome variables over time at baseline and weeks 12, 24, 48, and 60.

DISCUSSION: This protocol outlines a detailed procedure for a multicenter RCT designed to further evaluate the long-term effect of acupuncture in managing aMCI. We anticipate that the findings of this research will provide valuable insights and evidence-based recommendations for the clinical management of this patient population.

TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry on 28 May 2024 (Number: ChiCTR2400084932).},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods
Single-Blind Method
Aged
Female
Male
Treatment Outcome
*Amnesia/therapy
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Middle Aged
Aged, 80 and over

@article {pmid42008564,
year = {2026},
author = {Al-Anbari, E and Karshenas, H and Shoushtarian, B},
title = {Normalizing flow based neural processes for Alzheimer's disease progression prediction.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0345958},
doi = {10.1371/journal.pone.0345958},
pmid = {42008564},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Aged ; Male ; Female ; Neuroimaging ; },
abstract = {As one of the most common neurodegenerative diseases, Alzheimer's accounts for serious health problems worldwide. Accurate detection and prediction of this disease contribute to the health system for better prevention and interventions in the treatment plans. However, traditional models designed for prediction and classification face several challenges, including handling complex data, which neglects many data points for the diagnosis. To overcome this challenge, we propose a novel model based on the integration of Neural Processes (NPs) and Normalizing Flows (NFs). The dataset used for this study is the Alzheimer's Disease Prediction of Longitudinal Evolution (TADPOLE). We selected various features to build an efficient model, including cognitive, neuroimaging, genetic, and demographic data. which contains three classes: Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD. The proposed model is able to capture the temporal dependencies present in the complex distribution. The stochastic processes were modeled by NPs, while NF was able to transform the Gaussian distributions from simple to complex distributions, allowing them to model a wide range of data distributions. The prediction performance and robustness have been enhanced since this framework is able the adapt to every patient trajectory and generalizing across different populations. The model was compared with other models, such as SNP, deep geometric learning, Manifold DCNN, and other models. Our model (SNP-NF) made an improvement regarding mAUC, Precision, and Recall, approximately 3%,1%, and 0.7%, respectively from our previous model, which utilized only NP. These results demonstrate the capability of the proposed approach to provide early detection and personal treatment plans for patients suffering from this disease.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics
Disease Progression
Cognitive Dysfunction/diagnosis
Aged
Male
Female
Neuroimaging

@article {pmid42008601,
year = {2026},
author = {Alvi, AM and Siuly, S and De-Cola, MC and Wang, H},
title = {CDR-Net: A computerized framework to detect Alzheimer's diseases and mild cognitive impairment.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346576},
doi = {10.1371/journal.pone.0346576},
pmid = {42008601},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Electroencephalography/methods ; Aged ; Male ; Female ; Machine Learning ; *Diagnosis, Computer-Assisted/methods ; Aged, 80 and over ; *Neural Networks, Computer ; Brain/physiopathology/diagnostic imaging ; },
abstract = {Alzheimer's disease (AD) and mild cognitive impairment (MCI) are two dementia-related brain illnesses that are prevalent among elders in the twenty-first century. MCI is treated as the initial stage of AD, and once the illness reaches the AD stage, there is no escape from certain death. The accuracy and efficacy of current multiclass computer-based approaches to diagnose AD and MCI are constrained by traditional machine learning (ML) classifiers due to their shallow architecture. This makes it challenging to make a prompt and accurate diagnosis of AD and MCI. This research proposes a framework employing electroencephalography (EEG) to diagnose MCI, AD, and healthy subjects (HSs) to boost multiclass performance and efficacy. EEG is a portable, non-invasive, and affordable means to identify brain problems as compared to expensive and time-consuming techniques like computed tomography (CT) scans, positron emission tomography (PET), magnetic resonance imaging (MRI), and the mini-mental state examination (MMSE). To circumvent these issues, the Cognitive Decline Recognition Network (CDR-Net) architecture has been developed to identify MCI, AD, and healthy individuals using EEG data. The proposed architecture allows for the acquisition of EEG data, data preprocessing (down-sampling, noise cleaning, segmentation, and digital picture construction), feature extraction and classification using CDR-Net, as well as performance assessment and cross-validation stages. Our suggested CDR-Net architecture produced better multiclass accuracy, sensitivity, and specificity of 99.25%, 99.13%, and 99.32%, respectively. By using 10 folds and leave-one-out cross validations, stability, consistency, and data overfitting and underfitting concerns are addressed. This framework will serve as a foundation for future systems designed to detect multiple brain disorders.},
}

Humans
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Electroencephalography/methods
Aged
Male
Female
Machine Learning
*Diagnosis, Computer-Assisted/methods
Aged, 80 and over
*Neural Networks, Computer
Brain/physiopathology/diagnostic imaging

@article {pmid42008670,
year = {2026},
author = {Lindberg, M and Hu, J and Thacker, D and Sparr, E and Linse, S},
title = {The temperature dependence of amyloid β solubility reveals the hydrophobic effect as the main driving force for fibril formation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {17},
pages = {e2531916123},
doi = {10.1073/pnas.2531916123},
pmid = {42008670},
issn = {1091-6490},
support = {2015-00143//Vetenskapsrådet (VR)/ ; 2019-02397//Vetenskapsrådet (VR)/ ; AdG 101097824//EC | European Research Council (ERC)/ ; 2022-0059//Knut och Alice Wallenbergs Stiftelse (kawforskning)/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Solubility ; Hydrophobic and Hydrophilic Interactions ; Temperature ; Humans ; *Peptide Fragments/chemistry/metabolism ; Circular Dichroism ; *Amyloid/chemistry ; Thermodynamics ; Protein Aggregates ; Kinetics ; Alzheimer Disease/metabolism ; },
abstract = {The aggregation of amyloid proteins into fibrillar and oligomeric aggregates is linked to a number of neurodegenerative diseases. While the disease onset remains elusive in many cases, an understanding of the driving forces for the aggregation may help finding possible causes. While effects on amyloid formation kinetics are more commonly studied, gaining insights into these driving forces require a thermodynamic approach with equilibrium measurements. Here we investigate the temperature dependence of the solubility of the amyloid beta peptide, Aβ42, related to Alzheimer's disease, using high-performance liquid chromatography coupled to a mass spectrometer and circular dichroism spectroscopy. Samples of 8 to 50 μM Aβ42 were incubated for up to 168 h at pH 8.0 and moderate ionic strength at multiple temperatures in the range of 5 to 80 [°]C. The remaining monomer concentration was measured after 48 to 168 h, with little change in between suggesting that equilibrium is approached at 168 h. The lowest solubility of 20 ± 10 nM is found around body temperature, with higher solubility at both lower and higher temperatures. This nonmonotonic temperature dependence is indicative of the hydrophobic effect being a major driving force for the fibril formation of this peptide.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Solubility
Hydrophobic and Hydrophilic Interactions
Temperature
Humans
*Peptide Fragments/chemistry/metabolism
Circular Dichroism
*Amyloid/chemistry
Thermodynamics
Protein Aggregates
Kinetics
Alzheimer Disease/metabolism

@article {pmid42008697,
year = {2026},
author = {Xin, Y and Liu, D and Ma, Y and Zhang, Z and Chen, P and Wu, M and Li, Y and Chen, S and Yan, S and Song, G and Chen, L and Wang, Q and Geng, J and Sun, K},
title = {Simultaneous Profiling and Quantification of Tau and Its Phosphorylated Isomers Using Engineered FraC Nanopores.},
journal = {Nano letters},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.nanolett.6c00368},
pmid = {42008697},
issn = {1530-6992},
abstract = {Tau aggregation and hyperphosphorylation are key pathological hallmarks and early diagnostic biomarkers of Alzheimer's disease (AD). However, the simultaneous profiling and quantitative analysis of Tau and its phosphorylated isoforms remain technically challenging. Here, by introducing an acidic aspartate residue at the G6 site of FraC[G13F], we engineered a high-resolution FraC[G6DG13F] nanopore with enhanced temporal resolution for protonated polypeptide detection. Integrated with machine-learning algorithms, our nanopore-based workflow enabled the real-time identification of 12 tryptic peptides from native Tau (2N4R) protein with over 91.1% accuracy. Furthermore, positional phosphorylation isomers at either S400 or S402 of Tau (2N4R) were precisely resolved and quantified in mixed digestion samples, achieving classification accuracy exceeding 93% and sensitivity comparable to that of microgram-level mass spectrometry. This study demonstrates a promising advancement of global analysis of phosphorylated Tau in nanopore-based methods, highlighting its potential for high-resolution characterization and accurate quantification of proteins with PTMs.},
}

@article {pmid42008717,
year = {2026},
author = {Neltner, AM and Shahidehpour, RK and Hall, ME and Ning, X and Fister, S and Kang, H and Anderson, S and Jicha, GA and Lee, TL and Abner, EL and Fardo, DW and Nelson, PT},
title = {Locus coeruleus TDP-43 pathology in a community-based cohort: Clinical and pathological correlates.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag035},
pmid = {42008717},
issn = {1554-6578},
support = {P30 AG072946/GF/NIH HHS/United States ; R01 NS118584/GF/NIH HHS/United States ; RF1 AG082339/GF/NIH HHS/United States ; P01 AG078116/GF/NIH HHS/United States ; R01 AG076932/GF/NIH HHS/United States ; },
abstract = {The locus coeruleus (LC) is the source of norepinephrinergic innervation in the human brain. Locus coeruleus pathology has been linked to clinical conditions such as cognitive impairment and behavioral and psychiatric symptoms of dementia (BPSD). However, phosphorylated TDP-43 (pTDP-43) pathology in the LC has been understudied, particularly in the contexts of aging and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Here, a convenience sample (n = 134) of autopsied participants from the University of Kentucky Alzheimer's Disease Research Center community-based cohort was analyzed for LC pTDP-43 and phosphorylated tau (pTau) pathologies. Locus coeruleus pTDP-43 pathology was found in 28/134 (20.9%) brains and was generally sparse when present. Locus coeruleus pTDP-43 lesions typically appeared as round granular structures that measured ∼3-12 µm in diameter. Locus coeruleus pTDP-43 pathology was increased with aging and was imperfectly correlated with LATE-NC staging; it showed no correlation with cortical pTau pathology in ADNC or PART. In terms of clinical-pathological correlations, LC pTDP-43 pathology was associated with depressive symptoms but not with global cognition or with other BPSDs. Locus coeruleus pTau pathology was positively correlated with cortical pTau pathologic severity and with LATE-NC stages. In conclusion, LC pTDP-43 pathology is a common feature of brain aging, associated with LATE-NC.},
}

@article {pmid42008720,
year = {2026},
author = {Calderón-Garcidueñas, L and Nalbantoglu, OU and González-Maciel, A and Torres-Jardón, R},
title = {Alzheimer neuropathological change, α-synuclein and transactive response DNA-binding protein of 43 kDa expression in children and young adult brains from forensic autopsies: Value for early measurement of abnormal protein expression prevalence in neurodegenerative diseases.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag028},
pmid = {42008720},
issn = {1554-6578},
abstract = {Alzheimer disease (AD) neuropathologic change (ADNPC), Parkinson disease (PD) α-synuclein (α-Syn), and TAR DNA-binding protein 43 (TDP-43) pathology overlap in a continuum in fine particulate matter (PM2.5)-exposed Metropolitan Mexico City (MMC) children and young adult forensic autopsy brains. This report focuses on a forensic targeted immunohistochemistry protocol to assess ADNPC, α-Syn and TDP-43 in ≤40y subjects, and to define their relationship with cumulative PM2.5 (CPM) exposures. We proposed an early measurement of abnormal protein expression to evaluate neurodegenerative disease prevalence in exposed PM2.5 urban young populations. We studied 189 autopsies average age 26±10y, including 179 MMC ≤40y olds and 10 low pollution controls. Among MMC adults 18-40y, 11.3% exhibited ADNPC alone; 50% had ADNPC + PD, 32.0% had ADNPC + PD + TDP-43 and 6.7% had ADNPC + TDP-43 pathology. In 37 children (13.0±4.8y), 24.3% had ADNPC, 37.8% had ADNPC + PD, 32.4% had ADNPC + PD + TDP-43; 5.4% had ADNPC + TDP-43 pathology. The overlapping children's neuropathology was documented under low CPM. We suggest that measurements of abnormal protein expression to evaluate neurodegenerative disease in young PM2.5-exposed young urban populations in US autopsies will define the prevalence and overlap of early neurodegenerative biological markers. This information guide preventive medicine, health services, environmental PM2.5 emission control and early neuroprotection from potentially preventable air pollution-associated neurodegenerative diseases.},
}

@article {pmid42008766,
year = {2026},
author = {Ramalingam, SV and Soloman, VG and Ramesh, H and Bakthavatchalam, S and Ramesh, M and Ramachandran, K and Govindasamy, C and Al-Numair, KS and Vinayagam, R},
title = {Bioactive Zoochemicals From Portunus sanguinolentus Shells: A Sustainable Source of Acetylcholinesterase Inhibitors and Antimicrobial Agents.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {4},
pages = {e02610},
doi = {10.1002/cbdv.202502610},
pmid = {42008766},
issn = {1612-1880},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; *Acetylcholinesterase/metabolism ; Animals ; Molecular Docking Simulation ; *Brachyura/chemistry ; Microbial Sensitivity Tests ; Antioxidants/pharmacology/chemistry/isolation & purification ; *Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification ; Dose-Response Relationship, Drug ; Structure-Activity Relationship ; Molecular Structure ; },
abstract = {This study explores the therapeutic potential of methanol extracts from the shells of the marine crab Portunus sanguinolentus, with a focus on inhibiting acetylcholinesterase (AChE) to enhance acetylcholine (ACh) levels, an essential strategy in the management of Alzheimer's disease (AD). GC-MS analysis identified 18 distinct zoochemicals, predominantly fatty acid derivatives, and HPLC analysis confirmed the presence of n-Hexadecanoic acid, while FT-IR spectroscopy confirmed the presence of functional groups typical of polyphenols, alkaloids, and terpenoids. The extract exhibited notable antioxidant activity, with IC50 values of 62.08 µg/mL (DPPH) and 68.05 µg/mL (ABTS), both showing strong dose-dependent responses (R[2] = 0.90). AChE inhibition assays revealed dose-dependent effects with an IC50 of 161.49 µg/mL (R[2] = 0.943). Molecular docking studies further supported the bioactivity, indicating strong interactions between identified zoochemicals and key targets, including AChE (1EVE), Peroxiredoxin 5 (1HD2), Myeloperoxidase (1DNU), and MraY (5CKR). Additionally, the extract demonstrated significant antibacterial efficacy, confirmed through MIC, MBC, zone of inhibition assays, cytoplasmic leakage (DNA and protein), and in silico predictions. These findings suggest that the P. sanguinolentus shell methanol extract contains bioactive zoochemicals with promising AChE-inhibitory, antioxidant, and antibacterial activities. Importantly, the use of crab shells not only contribute to drug development for Alzheimer's disease but also offers a sustainable approach to marine biowaste valorization.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
*Acetylcholinesterase/metabolism
Animals
Molecular Docking Simulation
*Brachyura/chemistry
Microbial Sensitivity Tests
Antioxidants/pharmacology/chemistry/isolation & purification
*Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification
Dose-Response Relationship, Drug
Structure-Activity Relationship
Molecular Structure

@article {pmid42008868,
year = {2026},
author = {Liu, X and Xu, J and Lin, C and Gao, X and Xie, Y and Chen, X and Huang, Q and Ye, R and Shi, H and Zhang, L and Ye, ZC and Wu, C and Zha, D},
title = {Design, synthesis, and biological evaluation of pyranone-carbamate hybrids as selective butyrylcholinesterase inhibitors with anti-neuroinflammatory activity for Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {176},
number = {},
pages = {109887},
doi = {10.1016/j.bioorg.2026.109887},
pmid = {42008868},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which cholinergic dysfunction and chronic neuroinflammation jointly contribute to cognitive decline. To address these converging pathological features, a series of carbamate-pyranone hybrids (E1-E17) were designed using a pharmacophore hybridization strategy that integrates the cholinesterase-inhibitory carbamate motif of Rivastigmine with the anti-neuroinflammatory γ-pyranone scaffold derived from D30. Among these derivatives, E14 emerged as a promising hit compound. E14 inhibited lipopolysaccharide-induced nitric oxide production in BV2 microglial cells (IC50 = 9.76 ± 0.59 μM), while maintaining acceptable cytocompatibility. Enzymatic assays revealed that E14 selectively inhibited butyrylcholinesterase, with IC50 values of 15.59 ± 2.98 μM against eqBuChE and 38.65 ± 3.40 μM against hBuChE, while showing negligible activity against acetylcholinesterase, and kinetic analysis indicated a competitive inhibition mechanism. Consistent with its CNS-oriented design, E14 exhibited high passive blood-brain barrier permeability in a PAMPA-BBB assay (Pe = 11.87 × 10[-6] cm/s) and showed good acute tolerability in mice. In an oligomeric Aβ-induced cognitive impairment mouse model, E14 significantly improved recognition memory and spatial learning performance. Mechanistic investigations demonstrated that E14 attenuated hippocampal glial activation and neuroinflammation, suppressing the TLR4/p38 MAPK signaling pathway and modulating the IL-1β/C3-mediated microglia-astrocyte inflammatory axis. Network pharmacology analyses further suggested multitarget engagement across inflammation- and stress-related pathways relevant to AD pathology. Collectively, these findings identify E14 as a brain-penetrant, BuChE-selective dual-functional compound that integrates cholinesterase inhibition with anti-neuroinflammatory activity, supporting its further development as a multitarget-directed lead for AD intervention.},
}

@article {pmid42008955,
year = {2026},
author = {Yoshikawa, H and Yoshida, E and Matsumoto, T and Sugita, K and Kamiya, S and Ohgita, T and Kobuchi, S and Shimohama, S and Takata, K},
title = {Identification of daurioxoisoporphine D and moringamine I as blood-brain barrier-permeable natural inhibitors of amyloid-β aggregation and neuronal toxicity.},
journal = {Bioorganic & medicinal chemistry},
volume = {138},
number = {},
pages = {118664},
doi = {10.1016/j.bmc.2026.118664},
pmid = {42008955},
issn = {1464-3391},
abstract = {Early Alzheimer's disease (AD) is characterized by extracellular accumulation of amyloid-β (Aβ) peptides and degeneration of basal forebrain cholinergic neurons. Currently, acetylcholinesterase inhibitors and costly anti-Aβ antibodies are used in clinical practice; however, their therapeutic efficacy remains limited. Consequently, disease-modifying therapies that directly target AD pathogenesis and provide neuroprotection-preferably affordable, small-molecule compounds-are urgently needed. To identify seed compounds with potential for clinical translation, screening platforms that accurately recapitulate AD pathophysiology in human-based models are necessary. Therefore, in this study, we employed previously established human induced pluripotent stem cell-derived basal forebrain cholinergic neurons (hiBFChNs). The inhibitory activity against Aβ aggregation was initially evaluated for 129 natural compounds using the thioflavin T assay. Subsequently, the neuroprotective effects of the 65 selected compounds were assessed in human neuroblastoma SH-SY5Y cells and hiBFChNs using the WST-8 and lactate dehydrogenase assays as secondary and tertiary screening steps, respectively. Among these, 17 compounds demonstrated both inhibitory effects against Aβ aggregation and neuroprotective effects. Further evaluation of physicochemical properties relevant to brain penetration, together with confirmation of in vitro blood-brain barrier (BBB) permeability using a monkey BBB kit, identified daurioxoisoporphine D and moringamine I as promising seed compounds for AD drug development. Overall, these results indicate that a unified screening platform capable of seamlessly evaluating Aβ aggregation inhibition, neuroprotection, and brain permeability could facilitate the identification of small-molecule therapeutics that modify disease progression in AD.},
}

@article {pmid42008960,
year = {2026},
author = {Bhattacharya, K and Chanu, NR and Das, D and Khanal, P and Bhattacharjee, A},
title = {NeuroBACE-ML: A reliability-aware screening framework for high-throughput prioritization of potent BACE1 inhibitors.},
journal = {Journal of molecular graphics & modelling},
volume = {146},
number = {},
pages = {109415},
doi = {10.1016/j.jmgm.2026.109415},
pmid = {42008960},
issn = {1873-4243},
abstract = {Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in amyloid-β generation and remains an important target in Alzheimer's disease (AD) drug discovery. Here, we present NeuroBACE-ML, a reliability-aware screening framework for high-throughput prioritization of potent BACE1 inhibitors from small-molecule libraries. Human BACE1 bioactivity records were curated from ChEMBL and standardized on a pIC50 scale using a strict binary definition to reduce label ambiguity: active (IC50 ≤ 100 nM; pIC50 ≥ 7) and inactive (IC50 ≥ 1 μM; pIC50 ≤ 6), while excluding the intermediate grey zone (100-1000 nM; 6 < pIC50 < 7). Molecules were represented using Morgan fingerprints and the primary classifier was built using XGBoost with Optuna-based hyperparameter optimization. On the fixed random held-out test set, NeuroBACE-ML showed high discriminative performance, with AUROC = 0.986, AUPRC = 0.991, MCC = 0.868 and balanced accuracy = 0.943 at the deployed operating threshold of 0.70 (TN = 468, FP = 14, FN = 71, TP = 763). To strengthen reliability for prospective screening, the framework incorporates probability calibration, scaffold-aware robustness assessment, applicability-domain-aware decision support, abstention logic and ensemble uncertainty analysis. In addition, external validation on an independent non-overlapping BindingDB dataset supported generalizability beyond the ChEMBL-derived benchmark (AUROC = 0.969, AUPRC = 0.987, MCC = 0.790). While the framework is intended for early-stage candidate prioritization rather than direct clinical translation, it provides a practical and deployable tool for identifying high-confidence BACE1 inhibitor candidates for downstream medicinal chemistry and experimental follow-up. The exclusion of intermediate compounds may limit real-world applicability by simplifying borderline activity patterns that can occur in practical screening settings. NeuroBACE-ML is available as a web application at https://neurobace-ml.streamlit.app/with supporting code and deployment resources available via GitHub at https://github.com/kunal74/NeuroBACE-ML.},
}

@article {pmid42009011,
year = {2026},
author = {Powell, A and Chan, K and Shepherd, CE and Brodaty, H},
title = {Cognitive resilience in ageing: determinants and interventions.},
journal = {The Lancet. Neurology},
volume = {25},
number = {5},
pages = {492-505},
doi = {10.1016/S1474-4422(26)00027-X},
pmid = {42009011},
issn = {1474-4465},
mesh = {Humans ; *Aging/psychology/physiology ; *Resilience, Psychological ; *Cognition/physiology ; *Cognitive Reserve/physiology ; },
abstract = {Understanding the factors that contribute to the preservation of cognitive abilities into advanced age despite brain injury or disease is a key goal of ageing research. Up until the last two decades, the extent of brain pathology could only be fully appreciated at autopsy. Advances in laboratory and imaging biomarkers now mean that cognitive function can be understood in the context of markers of brain injury and specific pathologies (eg, Alzheimer's disease, Lewy body disease, and cerebrovascular disease). Knowledge on the characteristics of individuals displaying cognitive resilience and its social determinants across the lifespan can inform strategies to enhance resilience at individual and population levels. There is some evidence of the effectiveness of interventions to improve cognitive functioning from high-income countries, supported by biomarker data. Looking ahead, translation of cognitive resilience research to low-income and middle-income countries-the regions with the fastest growth in dementia burden-will require addressing key challenges and seizing opportunities.},
}

Humans
*Aging/psychology/physiology
*Resilience, Psychological
*Cognition/physiology
*Cognitive Reserve/physiology

@article {pmid42009141,
year = {2026},
author = {Liu, Y and Jiang, Y and Zhao, Z and Zhang, H and Li, D and Chai, G and Zhao, P and Xu, B and Jin, Z and Qiu, F and Chen, D and Zhu, E and Shao, W and Zhu, A and Xu, R and Gui, S and Liu, Y and Chen, J and Hu, R and Lu, H},
title = {A Functional Deep Cervical Lymphovenous Anastomosis Model in APP/PS1 Mice Augmenting Cerebral Lymphatic Drainage.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110779},
doi = {10.1016/j.jneumeth.2026.110779},
pmid = {42009141},
issn = {1872-678X},
abstract = {BACKGROUND: Deep cervical lymphatics constitute the final pathway for cerebral lymphatic drainage into the circulatory system. Dysfunction in this pathway inevitably impairs the clearance of cerebral metabolic waste. Recent clinical study has reported the efficacy of deep cervical lymphovenous anastomosis (dcLVA) in Alzheimer's disease (AD) patients. However, the lack of a mouse animal model for LVA has hindered mechanistic research.

NEW METHOD: To address this gap, we established a dcLVA model in APP/PS1 mice. Ten-month-old male APP/PS1 transgenic mice and wild-type (WT) littermates underwent side-to-side anastomosis between deep cervical lymph node and external jugular vein using supermicrosurgical techniques. Indocyanine green (ICG) was injected into the cisterna magna for evaluating cerebrospinal lymphatic drainage via near-infrared fluorescence tracking. Fluorescence intensity of deep cervical lymph node was dynamically recorded at 10min, 30min, 1h, 2h, 3h, and 6h post-ICG injection.

RESULTS: Results revealed significantly impaired ICG drainage in AD mice compared to WT littermates. Notably, dcLVA enhanced ICG drainage from subarachnoid space of cisterna magna in AD mice.

This study is the first to establish a functional LVA model in AD mouse, demonstrating its ability to augment cerebral lymphatic drainage.

CONCLUSIONS: Our findings provide a novel platform for future study to explore the effect and underlying mechanisms of LVA on AD and other neurodegenerative disorders associated with impaired lymphatic function.},
}

@article {pmid42009326,
year = {2026},
author = {Garg, A and Shaw, R},
title = {SSiamese Capsule Network (SNNCap) : Cognitive Analysis for Alzheimer's Disease Classification from MRI Data.},
journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TIP.2026.3683547},
pmid = {42009326},
issn = {1941-0042},
abstract = {Alzheimer's Disease (AD) detection is essential for timely treatment and better patient care. Magnetic Resonance Imaging (MRI) is a technique in which radio waves and magnetic fields are used to capture high-resolution, multi-dimensional representations of brain structures. This high-resolution imaging capability makes MRI a key tool for diagnosing neurological disorders such as Alzheimer's disease. However, the problem is to correctly classify the fresh MRI scans of patients. Researchers have proposed a deep learning-based method for Alzheimer's disease diagnosis using a Siamese Convolutional Neural Network (SCNN) with three ResNet-34 branches trained on structural MRI data. However, this method relies solely on ResNet34 for feature extraction which struggles to preserve spatial relationship due to pooling operations, causing loss of positional information. Other researchers have explored methods like attention mechanisms and 3D convolutional networks to capture spatial dependencies. However, these methods underperform by missing brain complexity or needing high resources without consistent accuracy. In this study, we propose a cognitively inspired approach for classifying MRI images as Non Demented, Very Mild Demented, Mild Demented and Moderate Demented using Siamese Capsule Network (SNNCap). SNNCap uses ResNet-18 for feature extraction and capsule layers to preserve spatial and part-whole relationships in the images. It compares a test image against a few known reference examples per class. This reference-based validation closely mimics cognitive reasoning, improving the system's generaliz-ability. The model achieves strong results on unseen data and demonstrates its effectiveness through classification reports and confusion matrices.},
}

@article {pmid42009653,
year = {2026},
author = {He, Y and Du, Y and Liu, D and Che, P and Wang, Y and Li, J and Wang, C and Zhang, N},
title = {Diagnostic performance of plasma p-tau217 levels measured with different assays for Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04043-0},
pmid = {42009653},
issn = {2158-3188},
abstract = {Plasma tau phosphorylated at threonine 217 (p-tau217) has been recommended as a biomarker for the diagnosis of Alzheimer's disease (AD). We evaluated the diagnostic and differential performance of plasma p-tau217 levels measured with three novel assays in a Chinese population. A total of 233 participants were recruited, including 39 cognitively unimpaired controls (CUCs), 28 individuals with mild cognitive impairment (MCI) due to AD, 57 individuals with AD dementia (ADD), 70 individuals with subcortical ischemic vascular dementia (SIVD), and 39 individuals with frontotemporal lobar degeneration (FTLD). Plasma p-tau217 levels were measured using one assay based on single-molecule techniques (DiSMS), one assay based on digital ELISA (LyMedivh™ AXL), and one assay based on flow cytometry (CBA), as well as a reference assay (ALZpath Simoa). Group differences in plasma p-tau217 levels were assessed using analysis of covariance, and the diagnostic and differential performance of the assays was evaluated via receiver operating characteristic analysis. Partial correlation analysis was used to examine the correlations between the measurements of the three novel assays and those of the reference assay. We found that plasma p-tau217 levels measured with all three novel assays were higher in the ADD group than in the CUC, SIVD, and FTLD groups (all p < 0.05) and effectively discriminated ADD patients from both CUCs and non-AD dementia patients. The diagnostic and differential performances did not significantly differ among the three assays (all p > 0.05). Both the DiSMS and LyMedivh™ AXL assays also revealed elevated plasma p-tau217 levels in the MCI group compared to the CUC group. Moreover, the measurements of the three novel assays demonstrated significant correlations with the ALZpath Simoa measurements (p < 0.01). When using their optimal cutoff values, both the DiSMS and LyMedivh™ AXL assays yielded a specificity of 100% and a sensitivity of 94.4%, and the CBA assay showed a specificity of 100% and a sensitivity of 88.9%. In conclusion, our study demonstrated the diagnostic and differential abilities of plasma p-tau 217 levels measured with three novel assays that can serve as potential alternatives to the currently available testing methods for AD diagnosis.},
}

@article {pmid42009666,
year = {2026},
author = {Moustafa, SA and Mowafi, S and Fawi, G and Othman, M and Heikal, S and Mohamed, AS and Habib, H and Hassan, OA and Meghaed, F and Youssef, AS and Ali, EM and Moustafa, R and Mohamed, M and Moustafa, M and Sweilam, J and Wahdan, M and Ezzeldin, S and Shebl, N and Khella, K and Tantawi, L and Mahmoud, F and Gaballah, Z and Zaki, F and Qansuwa, E and El Taras, M and Sayed, S and El Sayed, M and Srour, I and El Sayed Moustafa, S and Sameer, S and Gad, ES and Sweilam, M and Rizig, M and Meier, I and Narayan, V and Salama, M},
title = {Cohort profile Davos Alzheimer's Collaborative DAC Egypt Cohort.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42009666},
issn = {2731-6068},
abstract = {The Davos Alzheimer's Collaborative (DAC) Egypt Cohort (DAC-Egypt) is a newly established longitudinal study of cognitive aging in a community-based convenience sample of older Egyptian adults. The cohort's purpose is to characterize trajectories of cognitive decline and dementia risk factors in an understudied population, filling a critical gap in aging research in the Middle East. Participants (n = 1,530) aged 55 and above were recruited via regionally diverse convenience sampling, with detailed baseline data collected on demographics, health status, lifestyle, and cognitive function. Cognitive assessments included both traditional neuropsychological testing and innovative digital tools (digital voice/speech & olfactory-sensory assessments) to enable comprehensive monitoring. Key preliminary findings indicated a high prevalence of chronic diseases and notable socioeconomic disparities in cognitive performance among older Egyptians. Blood samples were collected from 98% of participants, and dried blood spot (DBS) cards were obtained for 88% of participants to facilitate future biomarker and genetic research. This study seeks to enrich the scientific field of dementia and Alzheimer's disease and related disorders (ADRD) for early detection and intervention strategies for cognitive health in aging populations.},
}

@article {pmid42009747,
year = {2026},
author = {Chen, P and Fan, M and Lin, H and Chen, Z and Zhang, Q and Cheng, Y and Xu, J},
title = {Identification of small ubiquitin-related modifier (SUMO)-related genes-based biomarkers in Alzheimer's disease based on bioinformatics analysis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49884-3},
pmid = {42009747},
issn = {2045-2322},
support = {2025J011378//Research on Self-Assembled Nano-Biosensors for the Early Diagnosis of Alzheimer's Disease/ ; 2023J011519//Natural Science Foundation of Fujian Province, China/ ; 2024ZY04//Intramural Research Project of Fuzhou Second General Hospital, China/ ; },
abstract = {To investigate the role of small ubiquitin-like modification (SUMO) in Alzheimer's disease (AD) and its pathogenesis, this study employed bioinformatics methods to identify diagnostic biomarkers for AD based on SUMO-related genes (SRGs). It further conducted preliminary explorations into their role in AD pathogenesis and potential therapeutic targets. Datasets related to AD (GSE140831, GSE63060), a dementia dataset (GSE140830), and 189 SRGs were retrieved from public databases. Candidate genes were identified by intersecting differentially expressed genes (DEGs) with SRGs. A protein-protein interaction (PPI) network was constructed to select the top 15 core genes, and the support vector machine-recursive feature elimination (SVM-RFE), least absolute shrinkage and selection operator (LASSO) and boruta random forest (Boruta-RF) identified feature genes. Validation was done using the GSE140831 and GSE63060 datasets, and the nomogram model was assessed by receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis (GSEA) and other analyses were performed. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used for further validation. Overlapping 189 SRGs and 12,853 DEGs identified 107 candidate genes. Six overlapping genes were selected. CREBBP, PIAS1, and TRIM28 were confirmed as AD biomarkers due to their increased expression in AD and strong ROC performance. GSEA highlighted their involvement in pathways such as olfactory transduction, lysosome, and spliceosome. Immune infiltration analysis suggested immune cell involvement in AD progression. Additionally, 21 potential drugs for AD therapy were predicted. RT-qPCR confirmed the over-expression of CREBBP and TRIM28 in AD samples, consistent with dataset trends. CREBBP, PIAS1, and TRIM28 were identified as SRG-based biomarkers for AD diagnosis, providing new insights into AD pathogenesis.},
}

@article {pmid42009901,
year = {2026},
author = {Söylemez, DÖ and Unur, E and Sağır, D},
title = {Protective effects of curcumin and resveratrol on neurodegeneration and cognitive dysfunction in a streptozotocin-induced alzheimer rat model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-48216-9},
pmid = {42009901},
issn = {2045-2322},
support = {TDK-2021-11068//Erciyes University Scientific Research Projects Unit/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by memory loss, cognitive decline, and behavioral disturbances. Given the limited efficacy of current treatments, there is an urgent need for new neuroprotective strategies. In this study, the therapeutic potential of curcumin and resveratrol was evaluated in a rat AD model induced by intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg). Subsequent to model induction, rats were administered curcumin, resveratrol, or a combination of both. The behavioral analyses, which included the Morris water maze, open field, and passive avoidance tests, revealed that both compounds significantly improved learning and memory performance. The histological and immunohistochemical findings demonstrated a decrease in caspase-3 and GFAP immunoreactivity, suggesting reduced neuronal apoptosis and astrocyte activation. The behavioral analyses, which included the Morris water maze, open field, and passive avoidance tests, revealed that both compounds significantly improved learning and memory performance. The histological and immunohistochemical findings demonstrated a decrease in caspase-3 and GFAP immunoreactivity, suggesting reduced neuronal apoptosis and astrocyte activation. Biochemical results showed an increase in total antioxidant status (TAS) and superoxide dismutase (SOD) activity, along with a decrease in total oxidative status (TOS) and TNF-α levels. Stereological evaluation also confirmed partial restoration of hippocampal volume. While curcumin and resveratrol exhibited potent neuroprotective effects when used separately, no synergistic interaction was observed when used in combination. These findings suggest that curcumin and resveratrol may serve as promising therapeutic agents for reducing oxidative stress, neuroinflammation, and neuronal degeneration associated with Alzheimer's disease.},
}

@article {pmid42009978,
year = {2026},
author = {Wang, L and Venkatesh, S and Morris, M and Li, M and Srivastava, R and Visweswaran, S and Lopez, OL and Xia, Z and Cai, T},
title = {Stratification of Alzheimer's disease patients using knowledge-guided unsupervised latent factor clustering with electronic health record data.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01511-y},
pmid = {42009978},
issn = {2730-664X},
abstract = {BACKGROUND: Prognostication for people with Alzheimer's disease (AD) at the point of care could improve clinical management.

METHODS: In this retrospective cohort study using the electronic health record (EHR) data from a large healthcare system (2011-2022), we applied an unsupervised latent factor clustering approach guided by knowledge graph embeddings to stratify AD patients into two groups at diagnosis (baseline) using clinical features in the two years preceding diagnosis. We prognosticated the risk of AD-related outcomes (nursing home admission and mortality) for the clusters in survival analyses adjusted for baseline confounders (age, gender, race, ethnicity, healthcare utilization, and comorbidities). To reflect real-world evolution in clinical trajectories, we updated patient stratification for patients remaining at risk one year post-diagnosis and repeated prognostication.

RESULTS: We stratify 16,411 AD patients into two groups at baseline (41% Group 1, 59% Group 2). Baseline Group 2 has a significantly lower risk of nursing home admission (HR [95% CI] = 0.804 [0.765, 0.844], p < .001) but comparable mortality risk to baseline Group 1 (HR [95% CI] = 1.008 [0.963, 1.056], p = 0.733). We re-stratify the 12,606 patients remaining at risk one year post-diagnosis (46% Group 1, 54% Group 2). Consistent with baseline, the updated Group 2 has a lower risk of nursing home admission (HR [95% CI] = 0.815 [0.766, 0.868], p < .001) but comparable mortality risk (HR [95% CI] = 0.977 [0.922, 1.035], p = .430) to Group 1.

CONCLUSIONS: Patient stratification enables outcome prognosis for AD patients. While baseline prognostication can guide early treatment and tailored management, dynamic prognostication may inform more timely interventions to improve long-term outcomes.},
}

@article {pmid42009995,
year = {2026},
author = {Tan, JY and Retinasamy, T and Lee, VLL and Radhakrishnan, AK and Yeong, KY},
title = {Exploring the role of tocotrienol-rich fraction (TRF) in ameliorating neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42009995},
issn = {1568-5608},
abstract = {Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.},
}

@article {pmid42010082,
year = {2026},
author = {Guo, J and Yang, Z and Luo, S and Li, C and Xu, S},
title = {Alzheimer's disease: disrupted communication between the endoplasmic reticulum and mitochondria.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42010082},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Endoplasmic Reticulum/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Endoplasmic Reticulum Stress/physiology ; },
abstract = {Alzheimer's disease (AD) remains a major, intractable neurodegenerative disorder and a serious threat to human health, characterized by a protracted clinical course, gradual progression, and irreversible cognitive decline. The current therapeutic landscape is characterized by a lack of disease-modifying agents, making the pursuit of early, effective interventions a global priority. Endoplasmic reticulum-mitochondria contact sites (ERMCs), also termed mitochondria-associated ER membranes (MAMs), constitute critical platforms for interorganellar communication, enabling material exchange and signal transduction. Key functions regulated at these junctions include calcium (Ca[2+]) homeostasis, mitochondrial dynamics, and lipid synthesis/transfer. Growing evidence implicates dysregulated ERMCs in the pathogenesis of neurodegenerative diseases, including AD and Parkinson's disease (PD). Recent advances in understanding the physiological and pathological roles of ERMCs have further illuminated their multifaceted contribution to AD, spanning amyloid-β (Aβ) production, Ca[2+] signaling, energy and lipid metabolism, mitochondrial integrity, and endoplasmic reticulum stress (ERs). This review synthesizes current knowledge on ERMCs as a pivotal communication hub in AD and underscores their promising potential as targets for novel therapeutic strategies. Deeper insights into this axis may inform future approaches to improve clinical outcomes.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Endoplasmic Reticulum/metabolism/pathology
*Mitochondria/metabolism/pathology
Animals
Endoplasmic Reticulum Stress/physiology

@article {pmid42010230,
year = {2026},
author = {Liu, Y and Kunutsor, SK},
title = {Brain, benefit, or burden? Revisiting statins and cognitive function in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42010230},
issn = {2509-2723},
abstract = {Statins are among the most widely prescribed medications for the prevention and treatment of cardiovascular disease, particularly in older adults. However, concerns regarding their potential adverse cognitive effects, including memory loss and dementia, have generated substantial debate and regulatory attention. This narrative review critically appraises current evidence on the relationship between statin use and cognitive outcomes in older adults, exploring both potential risks and benefits. We synthesized findings from randomized controlled trials (RCTs), observational cohort studies, meta-analyses, and Mendelian randomization studies. We also examined biological mechanisms, subgroup differences by statin type, and clinical considerations specific to older populations. Most RCTs have not demonstrated a harmful effect of statins on cognition, while observational studies have shown mixed results, including possible protective associations. Mechanistically, statins may exert both neuroprotective and neurotoxic effects, depending on their type, dose, and ability to cross the blood-brain barrier. Mendelian randomization analyses, including those involving over 100,000 individuals from the Danish general population, have largely found no causal effect of genetically proxied statin targets on dementia or neurodegenerative diseases. Importantly, older adults remain underrepresented in trials with cognitive outcomes, and real-world evidence is limited by confounding. Two large-scale randomized trials, PREVENTABLE and STAREE, are currently underway and poised to provide definitive evidence regarding the cognitive effects of statins in older populations. Current evidence does not support discontinuing statin therapy in older adults based solely on concerns about cognitive decline. Instead, decisions should be individualized, weighing cardiovascular benefit against cognitive risk, particularly in those with pre-existing cognitive impairment, polypharmacy, or frailty. Future research should prioritize cognition as a primary outcome in studies involving older populations.},
}

@article {pmid42010343,
year = {2026},
author = {Coomans, EM and Smith, R and Pawlik, D and Oliveira Hauer, K and Palmqvist, S and Stomrud, E and Mattsson-Carlgren, N and Tremblay, C and Serrano, GE and Beach, TG and Rozemuller, AJ and Pijnenburg, Y and van de Giessen, E and Kotari, V and Pontecorvo, M and Shcherbinin, S and Hansson, O and Ossenkoppele, R},
title = {Neuropathological correlates of age and sex differences in 18F-flortaucipir PET.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag136},
pmid = {42010343},
issn = {1460-2156},
abstract = {Among amyloid-positive individuals with symptomatic Alzheimer's disease, older age and male sex have been associated with a lower prevalence of Tau-PET-positivity. Whether Tau-PET-negative older and/or male individuals truly do not harbor widespread tau pathology or whether tangle density is below the PET-detection threshold remains unknown. Therefore, we aimed to investigate the neuropathological correlates of age- and sex-differences in Tau-PET in independent PET-only, autopsy-only, and PET-to-autopsy cohorts. In the PET-only cohort, we included amyloid-β-positive participants with MCI or dementia who underwent [18F]flortaucipir-PET (n=672). In the autopsy-only cohort, we included participants with moderate-to-frequent CERAD scores and MCI or dementia with available data on Braak stage and tangle density (n=945). In the PET-to-autopsy cohort, we included participants who underwent antemortem Tau-PET and had undergone a postmortem assessment of Braak staging (n=85) (median PET-to-post-mortem-interval: 2.6 months). A subset additionally had tangle density data available (n=63). Tau-PET SUVr was calculated in a temporal meta-region, and Tau-PET-positivity was defined using a predefined threshold of 1.36 SUVr. Autopsy cases were categorized as Braak 0-IV versus Braak V-VI. In PET-only-analyses (age: 71.9±8.2, 52.8% male), older age and male sex were associated with a lower prevalence of Tau-PET-positivity and lower Tau-PET SUVr (all p<0.05). In autopsy-only-analyses (age: 82.7±7.9, 54.6% male), older age and male sex were associated with a lower prevalence of Braak-V/VI neuropathology (both p<0.05). Among Braak-V/VI autopsy cases (n=598), older age was associated with lower tangle density (β=-0.38, p<0.001). In PET-to-autopsy-analyses (age: 81.7±9.2, 52.9% male), Tau-PET showed excellent specificity for detecting Braak-V/VI neuropathology (100% across age-stratified and sex-stratified models), while the sensitivity decreased at older age (<83y: 92% [95% confidence interval: 80%-100%] vs ≥83y: 42% [23%-62%]) and in males (females: 85% [69%-96%] vs males: 48% [28%-68%]). Older and male participants with Braak-V/VI neuropathology showed both lower Tau-PET SUVr (age: β=-0.46, p=0.003; sex: β=-0.97, p=0.001), and in the same individuals, older participants showed trend-level lower tangle density (β=-0.31, p=0.053). The lack of age/sex-interactions indicate that the relationship between Tau-PET and tangle density is consistent across ages and sexes. Comprehensive and independent PET, autopsy, and PET-to-autopsy analyses demonstrate that the associations of older age and male sex with lower [18F]flortaucipir-PET uptake and positivity rates can be explained by lower tangle densities. [18F]flortaucipir-PET SUVr thus closely reflects tangle density, which accounts for the lower sensitivity of [18F]flortaucipir-PET for detecting low-density Braak-V/VI tau pathology in older individuals and males.},
}

@article {pmid42010371,
year = {2026},
author = {Malek-Ahmadi, M and Perez, SE and He, B and Rogalski, E and Counts, SE and Ikonomovic, MD and Abrahamson, EE and Ginsberg, SD and Alldred, MJ and Serrano, GE and Belden, CM and Atri, A and Mufson, EJ},
title = {Psychometric criteria for superior cognitive performance in very old adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435166},
doi = {10.1177/13872877261435166},
pmid = {42010371},
issn = {1875-8908},
abstract = {BackgroundThe cellular mechanisms that promote the maintenance of cognitive abilities in very old people designated as successful agers remain under-investigated. Here, we report an episodic memory performance-based criteria that differentiates superior cognitive function from normative cognitive function in adults aged 80 and older.ObjectiveUsing this new criteria, we demonstrate how neuropathological and neurobiological underpinnings of superior cognitive performance can be investigated.MethodsThe most recent verbal episodic memory WMS-R Logical Memory Delayed Recall (LM-DR) score was derived from 144 participants with no cognitive impairment (NCI) 80 years or older participants from the Rush Religious Orders Study classified with Superior Cognitive Performance (SCP, LM-DR ≥ 14) or Normal Cognitive Performance (NCP, LM-DR 13 ≥ 7). Both groups were compared on neuropathological measures for neuritic plaque (NP), diffuse plaque (DP), and neurofibrillary tangle (NFT) load.ResultsNP (p = 0.44), DP (p = 0.27), and NFT (p = 0.28) burden did not differ between SCP and NCP cases. LM-DR scores did not correlate with NP (r = -0.08, p = 0.32), DP (r = -0.14, p = 0.07), or NFT (r = -0.12, p = 0.13) load. Biochemical analysis revealed significantly higher levels of heat-shock protein HSPB6 in SCP compared to NCP (p < 0.001).ConclusionsHeat shock protein differences were observed between NCP and SCP groups. This suggests that our proposed criteria for SCP can help identify neurobiological mechanisms of successful cognitive aging. Our SCP criteria are also concordant with the SuperAger criteria which supports the generalizability of the SCP criteria to other datasets.},
}

@article {pmid42010462,
year = {2026},
author = {Polu, PR},
title = {AI-Driven Chemometrics for Multi-omics Data Integration: Advances, Challenges, and Future Directions.},
journal = {Critical reviews in analytical chemistry},
volume = {},
number = {},
pages = {1-36},
doi = {10.1080/10408347.2026.2657553},
pmid = {42010462},
issn = {1547-6510},
abstract = {The convergence of artificial intelligence and chemometrics has revolutionized multi-omics data integration, enabling unprecedented insights into complex biological systems. This critical review examines AI-driven approaches for integrating genomics, proteomics, metabolomics, and other omics layers, emphasizing developments from 2020 to 2025. We explore fundamental multi-omics challenges including batch effects, high dimensionality, and structural heterogeneity, evaluating how classical chemometric methods have evolved into sophisticated deep learning architectures. Convolutional neural networks, autoencoders, variational autoencoders, and graph neural networks demonstrate remarkable capabilities for non-linear feature extraction and data fusion. Explainable AI frameworks including SHAP and LIME address interpretability concerns critical for analytical chemistry. We review vertical and horizontal integration strategies, highlighting transformer-based attention mechanisms and biological network-informed architectures. Clinical applications in Alzheimer's disease, obesity, and cancer demonstrate 20%-30% performance improvements over traditional approaches. Emerging hyphenated techniques coupling microfluidics with mass spectrometry enable miniaturized analyses. Persistent challenges include computational scalability, overfitting mitigation, regulatory validation gaps, and interdisciplinary collaboration barriers. Future directions encompass federated learning for privacy-preserving analyses, quantum computing applications, and single-cell spatial multi-omics at subcellular resolution. This assessment provides analytical chemists with critical evaluation of available tools, benchmarking strategies, and roadmaps for advancing precision medicine and analytical applications.},
}

@article {pmid42010634,
year = {2026},
author = {Castilla-Silgado, J and Perez-Oliveira, S and Pinto-Hernandez, P and Fernandez-Sanjurjo, M and Corte-Torres, MD and Fernandez-Alvarez, O and Iglesias-Gutierrez, E and Menendez-Gonzalez, M and Alvarez, V and Tomas-Zapico, C},
title = {Connecting HTT intermediate alleles and microRNA dysregulation to enhanced tauopathy in late-onset Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02039-y},
pmid = {42010634},
issn = {1758-9193},
support = {AC20/00017//Instituto de Salud Carlos III/ ; AC20/00017//Instituto de Salud Carlos III/ ; AYUD/2021/5134//Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología/ ; },
}

@article {pmid42010706,
year = {2026},
author = {Chen, Z and Liu, Y and Wang, H and Liu, K and Li, Y and Hu, X and Li, R and Sun, L},
title = {Literature-derived serum miRNA signatures associated with cognitive decline in Alzheimer's disease: integrated analysis and machine learning-based diagnostic modeling.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02048-x},
pmid = {42010706},
issn = {1758-9193},
support = {XYZX0301-12//Capacity Building Project of Xiyuan Hospital, China Academy of Chinese Medical Sciences/ ; },
}

@article {pmid42010774,
year = {2026},
author = {Jin, Y and Topaloudi, A and Drineas, P and Paschou, P},
title = {Risk factors underlying brain structure change rate in cognitive decline: Results from genomewide and phenomewide investigations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71411},
doi = {10.1002/alz.71411},
pmid = {42010774},
issn = {1552-5279},
support = {2006929//Purdue Institute for Drug Discovery/ ; 1715202//Purdue Institute for Drug Discovery/ ; },
mesh = {Humans ; Genome-Wide Association Study ; *Cognitive Dysfunction/genetics/pathology ; *Brain/pathology/diagnostic imaging ; Male ; Risk Factors ; Female ; Aged ; Mendelian Randomization Analysis ; Longitudinal Studies ; Magnetic Resonance Imaging ; Polymorphism, Single Nucleotide ; Apolipoproteins E/genetics ; Atrophy ; Middle Aged ; Genetic Predisposition to Disease ; Aged, 80 and over ; Phenotype ; },
abstract = {INTRODUCTION: The genetic and clinical factors influencing the rate of brain structure change in cognitive decline remain poorly understood. This study aimed to identify genetic variants and risk factors contributing to these changes and explore potential causal relationships.

METHODS: We analyzed data from 2036 individuals across three longitudinal cohorts to assess change rates in 17 brain regions associated with cognitive decline. Genome-wide association studies (GWASs) were followed by phenome-wide association studies (PheWASs), Mendelian randomization (MR), and independent replication.

RESULTS: We identified loci associated with brain structure change, including known Alzheimer's disease genes (apolipoprotein E, APOC1) and novel signals (BEAN1, SDHC). PheWAS and MR analyses in large biobanks suggested potential causal links between brain atrophy and anemia-related traits as well as type 2 diabetes.

DISCUSSION: Our findings highlight genetic contributors and clinical traits associated with brain structure change in cognitive decline. Larger studies with broader cognitive assessments are needed to validate these findings.},
}

Humans
Genome-Wide Association Study
*Cognitive Dysfunction/genetics/pathology
*Brain/pathology/diagnostic imaging
Male
Risk Factors
Female
Aged
Mendelian Randomization Analysis
Longitudinal Studies
Magnetic Resonance Imaging
Polymorphism, Single Nucleotide
Apolipoproteins E/genetics
Atrophy
Middle Aged
Genetic Predisposition to Disease
Aged, 80 and over
Phenotype

@article {pmid42011061,
year = {2026},
author = {Marinou, S and Taler, V},
title = {Age and sex differences in cognitive performance in people with subjective cognitive decline and associated worry: Findings from the Canadian Longitudinal Study on Aging.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70049},
pmid = {42011061},
issn = {1748-6653},
abstract = {Subjective cognitive decline (SCD) refers to self-perceived decline in cognition in the absence of objective impairment and may represent a preclinical stage of Alzheimer's disease, particularly when accompanied by worry. However, limited research has examined the influence of age and sex on cognitive performance among individuals with SCD. This study investigated age- and sex-specific associations between SCD (+/- worry) and cross-sectional cognition in the Canadian Longitudinal Study on Aging (CLSA). Participants were categorized into Controls (n = 5713), SCD-No Worry (n = 3379) and SCD + Worry (n = 3511). Analyses were stratified by age (45-54, 55-64, 65-74, 75+) and sex and adjusted for education and depressive symptoms. Cognitive outcomes included four executive function and two verbal memory measures. Regarding executive function, men with SCD + Worry outperformed controls on letter fluency in the 55-64 and 65-74 groups, and women in both SCD groups outperformed controls on letter fluency in the 65-74 group. In contrast, men aged 75+ with SCD + Worry performed worse than controls on semantic fluency. No group differences emerged on Stroop Interference or the mental alternation task. For memory, men aged 45-54 and 55-64 with SCD-No Worry had higher immediate recall, whereas in the 75+ group, lower delayed recall was observed in men with SCD (+/- worry) and women with SCD-No Worry compared to controls. Overall, the results indicate that the clinical relevance of SCD may increase with age, independent of sex and worry status. These findings may improve the clinical utility of SCD and inform earlier detection of individuals at risk of future cognitive decline.},
}

@article {pmid42011226,
year = {2026},
author = {Weiss, B and Miranda, DR and Arrazati, D and Cao, R and Chen, J and Liu, Y and Brown, D and Marshall, G},
title = {SRN-901, a Novel Longevity Drug, Extends Lifespan and Healthspan by Targeting Multiple Aging Pathways.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {594895},
pmid = {42011226},
issn = {1177-8881},
mesh = {Animals ; *Longevity/drug effects ; Mice ; *Aging/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Niacinamide/analogs & derivatives/pharmacology ; },
abstract = {INTRODUCTION: Developing interventions to delay aging and improve lifespan and healthspan is a critical goal in aging research. Individual geroprotective compounds fail to address the complexity, interconnectedness, and dynamic nature of biological systems, limiting success in significantly extending lifespan and improving health. This study investigates the effects of SRN-901-a novel oral combinatorial drug that consists of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's SRN-820-on lifespan extension, frailty reduction, disease-related gene expression pathways, metabolic aging, and the proteome in 18-month-old mice fed a Western diet.

RESULTS: SRN-901-treated mice showed a significant increase of 33% in median remaining lifespan compared to placebo-treated mice. Cox proportional hazards analysis revealed a hazard ratio of 0.54, indicating that SRN-901 treatment was associated with a 46% reduction in the hazard of death. While rapamycin increased lifespan in adult mice, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) did not show significant differences in median lifespan compared to placebo. SRN-901 protected mice against increased frailty during aging, with baseline-normalized scores rising to 1.17 in treated mice and 1.57 in controls, corresponding to a 70% attenuation of frailty progression between pre-treatment (D-14) and post-treatment (D128; p < 0.001). Transcriptomic analyses revealed that SRN-901 modulates gene expression across pathways implicated in aging biology, including inflammation, apoptosis, and DNA repair, as well as gene sets associated with neurodegenerative disorders, including Alzheimer's disease. Metabolic profiling revealed that SRN-901 was associated with attenuation of several age-related metabolic shifts, resulting in a blood metabolite profile that more closely resembled that of younger mice. The upregulation of glutathione metabolism and other longevity-related pathways underscores SRN-901's role in enhancing cellular defenses against oxidative stress and maintaining metabolic health.

DISCUSSION: These results highlight SRN-901 as a promising multi-compound candidate for extending lifespan and healthspan by targeting multiple aging pathways.},
}

Animals
*Longevity/drug effects
Mice
*Aging/drug effects/metabolism
Male
Mice, Inbred C57BL
Niacinamide/analogs & derivatives/pharmacology

@article {pmid42011258,
year = {2026},
author = {Tong, Y and Hu, G and Liu, L and Zhang, Y and Jiang, N and Zhang, M},
title = {Wavelet Entropy Analysis of EEG Signals During Wake and Sleep in Patients with Alzheimer's Disease: A Pilot Study.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {585445},
pmid = {42011258},
issn = {1176-6328},
abstract = {PURPOSE: Our primary objective is to delve into the wavelet entropy of EEG during wake and sleep in patients with Alzheimer's disease(AD).This is a pilot study aimed at exploring the potential of wavelet entropy as an indicator of EEG complexity in AD patients.

PATIENTS AND METHODS: This study enrolled 30 participants (15 AD patients vs. 15 age-/sex-matched healthy controls). Wavelet entropy analysis was conducted on the electroencephalogram (EEG) signals recorded from all participants across the two groups. A comparative analysis was undertaken between the integral wavelet entropy (En) and individual-scale wavelet entropy (En(a)) during wakefulness and distinct sleep stages in the two patient groups.

RESULTS: Compared with the healthy control group, the entropy of AD group was significantly lower in wakefulness and significantly higher in N3 stage (all P < 0.001). AD patients demonstrated lower En(a) in the β and α frequency bands during wakefulness, compared to the healthy controls (all P <0.001). Conversely, during N3 stage, these patients displayed higher En(a) values across β, α, and θ frequency bands compared to the control cohort (all P <0.001).

CONCLUSION: Wavelet entropy can be used as a reliable indicator of the complexity of EEG signals during waking and different sleep stages in patients with AD. This provides a new insight into the pathophysiological mechanisms of dementia.Due to the limited sample size, larger-scale studies are needed in the future to validate these findings.},
}

@article {pmid42011350,
year = {2026},
author = {Tayarani-Najaran, Z and Hadipour, E and Ramazani, S and Taghizadeh, L and Ramazani, E},
title = {Antioxidant, anti-inflammatory and cytoprotective effects of crocin, a bioactive constituent of saffron, in Alzheimer's and Parkinson's diseases with a focus on molecular mechanisms: A systematic review.},
journal = {Avicenna journal of phytomedicine},
volume = {16},
number = {2},
pages = {13-34},
pmid = {42011350},
issn = {2228-7930},
abstract = {OBJECTIVE: This study assessed the neuroprotective effects of crocin one of the main bioactive compounds of saffron, in Alzheimer's and Parkinson's diseases, by focusing on its anti-oxidative, anti-inflammatory, and cytoprotective properties.

MATERIALS AND METHODS: In this systematic review, we evaluated the efficacy of crocin on in vivo models of Alzheimer's and Parkinson's diseases. Using three online literature databases (PubMed, Scopus, and Google Scholar), we identified studies describing the neuroprotective effects of crocin in Alzheimer's and Parkinson's diseases. A literature search was carried out using a combination of keywords such as crocin, Alzheimer's disease, Parkinson's disease, antioxidant, anti-inflammatory, and cytoprotective. Papers were identified to describe the neuroprotective effects of crocin from 2013 until 2024.

RESULTS: The total number of articles included in the present review is 28. Reducing reactive oxygen species (ROS) and malondialdehyde (MDA) and increasing superoxide dismutase (SOD) levels indicate the anti-oxidant effects of crocin. Crocin can show anti-inflammatory activities via decreasing tumor necrosis factor-alpha (TNF-α) and interleukin levels. Crocin can display cytoprotective effects via down-regulation of p- extracellular signal-regulated kinase (ERK)1/2, and augmentation of phosphoinositide 3-kinases (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling pathway activity.

CONCLUSION: Finally due to a noticeable efficacy of crocin, it is suggested that crocin can be used as a suitable neuroprotective agent against Alzheimer's and Parkinson's diseases.},
}

@article {pmid42011351,
year = {2026},
author = {Mohajeri, M and Hashem-Dabaghian, F and Raeesi, S and Mehroozade, S},
title = {Almond for mild to moderate Alzheimer's disease: A randomized clinical trial.},
journal = {Avicenna journal of phytomedicine},
volume = {16},
number = {2},
pages = {1-12},
pmid = {42011351},
issn = {2228-7930},
abstract = {OBJECTIVE: Almonds are frequently advised as brain tonic and memory enhancers in Persian medicine. There is also scientific evidence to support the effects of almond on memory. This study was designed to assess the effects of almond (Prunus dulcis) on memory and cognitive functions in patients with Alzheimer's disease (AD).

MATERIALS AND METHODS: In this randomized controlled trial, 60 AD patients with mild to moderate cognitive disorder were randomly allocated into an almond group (10 g/day powdered sweet almond plus 1 teaspoon of powdered rock candy along with their previous prescriptions), or the control group (continue previous prescriptions) for 3 months. The Mini-mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and Functional Assessment Staging (FAST) questionnaires were completed at the beginning and the end of the study. The sleep quality was also assessed by the Pittsburg Sleep Quality Index (PSQI).

RESULTS: Thirty participants in each group completed the study, and were analyzed. Age was 71.86±8.04 years in the almond group and 71.3±7.18 years in the control group (p=0.775). Duration of memory deficit was 2.8±0.92 and 3±1.2 months in the almond and control group, respectively (p=0.473). The orientation scale of the MMSE (p=0.024), MOCA (p=0.001), memory scale of MOCA (p=0.005), FAST (p=0.032), and PSQI (p<0.001) in the almond group were significantly improved compared to those in the control group.

CONCLUSION: Almond is a probable safe intervention for memory and sleep enhancement in AD patients. Conducting studies with larger samples, longer follow-up periods, and different control groups are suggested.},
}

@article {pmid42011447,
year = {2026},
author = {Carrillo, N and Poventud, Y and Ramos-Fernandez, M},
title = {When Feeding Tubes Cause Biliary Disease: A Case of Acalculous Cholecystitis Due to Gastrostomy Tube Obstruction.},
journal = {Cureus},
volume = {18},
number = {3},
pages = {e105561},
pmid = {42011447},
issn = {2168-8184},
abstract = {Acute acalculous cholecystitis (AAC) is an inflammatory condition of the gallbladder that occurs in the absence of gallstones and is increasingly recognized among medically complex and long-term care populations. Patients receiving chronic enteral nutrition via gastrostomy tubes may be at risk for biliary complications related to impaired gallbladder emptying or mechanical factors. We describe an 81-year-old female nursing home resident with a previous medical history of hypertension, diabetes mellitus, Alzheimer's dementia, hypothyroidism, and gastrostomy tube dependence who presented with five days of malaise, nausea, vomiting, and right upper quadrant pain. Laboratory evaluation demonstrated a cholestatic liver enzyme pattern without leukocytosis. Bedside ultrasonography revealed gallbladder dilation without gallstones. Contrast-enhanced computed tomography of the abdomen and pelvis demonstrated migration of the balloon-retained gastrostomy tube into the proximal duodenum, causing extrinsic compression of the distal common bile duct, with associated gallbladder distention and intra- and extrahepatic biliary dilatation. Magnetic resonance cholangiopancreatography confirmed obstructive physiology without choledocholithiasis. The gastrostomy tube was deflated, removed, and repositioned, resulting in rapid clinical and biochemical improvement with conservative management. In patients receiving long-term enteral nutrition, reduced physiologic gallbladder stimulation may predispose to bile stasis, creating vulnerability to obstruction when tube malposition occurs. Imaging plays a central role in diagnosis, and early recognition with prompt tube repositioning can reverse obstruction and prevent progression to more severe gallbladder injury. Clinicians should be aware that, in patients with gastrostomy tube dependence, unexplained cholestatic liver enzyme elevation should prompt assessment of tube position and evaluation for possible device-related biliary obstruction.},
}

@article {pmid42011502,
year = {2026},
author = {Sánchez-Soblechero, A and Puertas-López, C and Ibáñez-Royo, MD and Retuerta-Rodríguez, JJ and Grandas, F and Olazarán, J},
title = {Offering and acceptance of plasma p-tau for the diagnosis of Alzheimer's disease: Results and insights from usual practice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443556},
doi = {10.1177/13872877261443556},
pmid = {42011502},
issn = {1875-8908},
abstract = {We conducted a prospective, naturalistic study to assess the offer and acceptance of p-tau217 in capable patients with cognitive symptoms and possible Alzheimer's disease (AD). p-tau217 was offered to 170/221 (76.9%) eligible patients, of whom 126 (74.1%) accepted. Competing medical priorities (31.4%) and personal decision (59.1%) were the most frequent causes for not offering or rejecting the study, respectively. As neurologists gained experience using p-tau217, both offering (OR 2.19 [CI 95% 1.14-4.19]) and acceptance (OR 2.71 [CI 95% 1.33-5.53]) increased. p-tau217 should be offered by experienced clinicians, after considering patient's comorbidity, psychological, and social circumstances. Clear patient decision is mandatory.},
}

@article {pmid42011629,
year = {2026},
author = {Ko, JW and Jeon, S},
title = {Nutritional modulation of the glymphatic system: mechanistic insights and clinical implications.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/10408398.2026.2659866},
pmid = {42011629},
issn = {1549-7852},
abstract = {The glymphatic system is a brain-wide perivascular clearance pathway mediated by aquaporin-4 (AQP4) water channels at astrocytic endfeet and plays a key role in eliminating neurotoxic proteins, including amyloid-β, tau, and α-synuclein. Impaired glymphatic function has been implicated in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. While sleep and physical activity are established modulators of glymphatic activity, the role of nutrition remains less clearly defined. This review summarizes current evidence on how nutritional factors may influence glymphatic-relevant biology and the underlying molecular and physiological mechanisms. Emerging studies suggest that micronutrients, bioactive lipids, and phytochemicals may influence glymphatic-relevant processes by regulating AQP4 expression and polarization, preserving blood-brain barrier integrity, reducing oxidative stress and neuroinflammation, improving cerebrovascular function, and supporting sleep and circadian regulation. In contrast, high-fat diets, excessive alcohol intake, and iron overload are associated with adverse glymphatic-relevant changes, including altered AQP4 regulation and less favorable clearance-related markers. Although mechanistic and preclinical evidence is increasing, large-scale human studies with standardized imaging approaches are still needed to determine whether targeted nutritional strategies can meaningfully alter glymphatic-related biology and whether such changes are accompanied by favorable neuroimaging or clinical outcomes.},
}

@article {pmid42011757,
year = {2026},
author = {Huang, T and Zhang, M and Zhang, Y and Su, C and He, E and Wang, J and Yang, J and Liu, Y and Zeng, Y and Chen, X},
title = {Hippocampal Hap1 down-regulation impairs glucocorticoid receptor nuclear translocation and exacerbates Alzheimer's disease-related neuropathology in APP/PS1 mice.},
journal = {Zoological research},
volume = {47},
number = {2},
pages = {530-546},
doi = {10.24272/j.issn.2095-8137.2025.436},
pmid = {42011757},
issn = {2095-8137},
mesh = {Animals ; *Receptors, Glucocorticoid/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; *Hippocampus/metabolism/pathology ; Mice ; Down-Regulation ; Mice, Transgenic ; *Nerve Tissue Proteins/metabolism/genetics ; Amyloid beta-Protein Precursor/genetics/metabolism ; Presenilin-1/genetics/metabolism ; Male ; Gene Expression Regulation/physiology ; Mice, Inbred C57BL ; },
abstract = {Impaired nuclear translocation of glucocorticoid receptor (GR) has been implicated in hippocampal vulnerability in Alzheimer's disease (AD), yet the molecular basis of this defect remains poorly understood. This study identified Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declined in the hippocampus of APP/PS1 mice with advancing age and pathological burden. Hippocampal Hap1 knockdown induced pronounced cognitive deficits and synaptic deterioration, as indicated by reduced dendritic arborization, decreased spine density, impaired long-term potentiation, and exacerbated amyloid-β deposition. Mechanistic analyses showed that Hap1 deficiency increased GR ubiquitination and proteasomal degradation and, more importantly, disrupted ligand-dependent GR translocation to the nucleus, thereby attenuating GR-dependent brain-derived neurotrophic factor transcription. In parallel, Hap1 knockdown elevated corticosterone concentration and induced depression-like behavior, consistent with hypothalamic-pituitary-adrenal axis dysregulation. Collectively, these findings establish defective GR nuclear trafficking driven by loss of Hap1 function as a key pathomechanism linking intracellular transport failure to synaptic dysfunction in AD and highlight Hap1 as a potential therapeutic target.},
}

Animals
*Receptors, Glucocorticoid/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
*Hippocampus/metabolism/pathology
Mice
Down-Regulation
Mice, Transgenic
*Nerve Tissue Proteins/metabolism/genetics
Amyloid beta-Protein Precursor/genetics/metabolism
Presenilin-1/genetics/metabolism
Male
Gene Expression Regulation/physiology
Mice, Inbred C57BL

@article {pmid42011861,
year = {2026},
author = {Jin, H and Xu, Z and Tang, H and Tang, W and Ma, T and Yu, T and Zhou, H and Deng, Y and Zhang, Y and Li, H and Yin, P},
title = {Simultaneous Visualization of Glutathione and Hydrogen Peroxide with a Dual-Responsive Fluorescent Probe to Elucidate Redox Homeostasis in Alzheimer's Disease Models.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c08155},
pmid = {42011861},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which oxidative stress plays a critical role in pathogenesis. As key reactive species governing oxidative stress, the dynamic interplay between glutathione (GSH) and hydrogen peroxide (H2O2) is tightly coupled to redox homeostasis. To enable simultaneous tracking of these two crucial species, we developed a dual-responsive fluorescent probe, TCS, for the discriminative visualization of GSH and H2O2. TCS features a methylsulfonyl group that is selectively reduced by GSH, triggering green fluorescence at 500 nm, and a boronate ester that is specifically cleaved by H2O2, generating red emission at 680 nm. These two optical channels operate independently with minimal spectral overlap, enabling simultaneous and discriminative detection of GSH and H2O2 without cross-interference. Probe TCS exhibits high sensitivity, excellent selectivity, and good photostability, and is well-suited for real-time imaging of both endogenous and exogenous GSH and H2O2 in complex biosystems. In okadaic acid-induced AD cell and zebrafish models, TCS revealed a time-dependent decrease in GSH levels accompanied by a concomitant increase in H2O2, consistent with progressive oxidative stress. Furthermore, comparative imaging of hippocampal tissues from AD model mice and wild-type mice showed markedly altered levels of both species, underscoring the utility of TCS for visualizing redox imbalance under AD-like pathological conditions. Collectively, this study establishes TCS as a powerful molecular tool for spatiotemporally resolved monitoring of GSH and H2O2 dynamics in living systems and provides a robust analytical platform for elucidating redox mechanisms in AD.},
}

@article {pmid42011957,
year = {2026},
author = {Cheng, S and Wang, W and Zhu, B and Han, R and Luo, X},
title = {A Robust Biosensor Based on the Pd-S Bond-Immobilized Peptide toward Antifouling Electrochemical Detection of an Alzheimer's Disease Biomarker in Serum.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.6c00113},
pmid = {42011957},
issn = {2379-3694},
abstract = {Electrochemical biosensing in complex biological media with biosensors constructed through the Au-S bonding remains a challenge due to the biofouling and biothiol interference. We herein developed an antifouling electrochemical biosensor based on the Pd-S bond for detecting the Alzheimer's disease biomarker Aβ1-42. A multifunctional peptide was designed to integrate the anchoring, antifouling, and recognition sequences, and it was immobilized onto the palladium nanoparticle (PdNP)-modified electrode through the Pd-S bond. Comprehensive characterization and density functional theory calculations reveal that the Pd-S bond exhibits a higher binding energy, shorter bond length, and enhanced electron transfer compared to the conventional Au-S bond. The biosensor based on the peptide immobilized through the Pd-S bond demonstrated exceptional antifouling performance in complex biofluids and exhibited high stability to resist biothiol displacement. For the detection of target Aβ1-42, the biosensor exhibited a wide linear range from 0.1 pg mL[-1] to 1.0 μg mL[-1], with a low detection limit of 0.038 pg mL[-1]. Moreover, the antifouling biosensor maintained consistent performance in buffer and serum, and clinical validation using human serum samples showed excellent agreement with the commercial ELISA kits, underscoring its accuracy and potential for real sample diagnostics. This work not only establishes a generalizable strategy for constructing stable and antifouling biosensing interfaces but also highlights the promise of Pd-S chemistry in biomolecule immobilization.},
}

@article {pmid42011967,
year = {2026},
author = {Nowell, J and Crook, H and de Leon, MJ and Edison, P},
title = {Advances in the drug treatment of Alzheimer's disease: pathophysiology and mechanisms of action.},
journal = {BMJ (Clinical research ed.)},
volume = {393},
number = {},
pages = {78881},
doi = {10.1136/bmj-2023-078881},
pmid = {42011967},
issn = {1756-1833},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/pathology/metabolism ; },
abstract = {Alzheimer's disease, the leading cause of dementia, is a multifactorial disorder involving amyloid beta (Aβ) and tau deposition, impaired glucose metabolism, neuroinflammation, mitochondrial dysfunction, insulin resistance, and progressive brain atrophy. Anti-Aβ therapies have shown clinical efficacy and are licensed in several countries. Amyloid related imaging abnormalities remain a key safety concern, and reimbursement varies across healthcare systems. The mechanisms underlying continued cognitive decline after Aβ clearance remain unclear and might be independent of amyloid pathology. Because Alzheimer's disease involves multiple pathological processes, effective management will likely require combination treatments addressing tau aggregation, neuroinflammation, synaptic loss, and metabolic dysfunction. Numerous compounds targeting these mechanisms are currently in late stage development for both early and advanced disease. These emerging approaches represent a shift toward multimodal, disease modifying strategies designed to improve patient outcomes and quality of life. Here, we review recent therapeutic advances in Alzheimer's disease and provide perspectives on novel treatment strategies.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Brain/pathology/metabolism

@article {pmid42011986,
year = {2026},
author = {Palma, A and Stefanelli, R and Trenta, F and Projetti, C and Massa, G and Canterini, S and Fiorenza, MT},
title = {A Cross-Disease Microglial Transcriptional Program Characterizes Neurodegeneration and Highlights SPP1 as a Biomarker.},
journal = {Glia},
volume = {74},
number = {6},
pages = {e70163},
doi = {10.1002/glia.70163},
pmid = {42011986},
issn = {1098-1136},
support = {RM123188F700A7B2//Sapienza Università di Roma/ ; RG1221816B9646F5//Sapienza Università di Roma/ ; GSP20006_Covid050//Fondazione Telethon/ ; },
mesh = {*Microglia/metabolism/pathology ; Animals ; Humans ; Mice ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Osteopontin/genetics/metabolism ; Biomarkers/metabolism ; Transcriptome ; Cells, Cultured ; },
abstract = {Microglial cells are key players in maintaining brain homeostasis and responding to pathological conditions. Their multifaceted roles in health and disease have garnered significant attention in the context of neurodegeneration. In recent years, single-cell transcriptomic techniques have provided unprecedented insights into microglial heterogeneity, revealing distinct subpopulations and gene expression patterns associated with neuroprotection or neurotoxicity. Here, we dissect the transcriptomic landscape of microglia by leveraging human single-nuclei RNA sequencing datasets from multiple neurodegenerative conditions, including Amyotrophic Lateral Sclerosis, frontotemporal dementia, Alzheimer's disease, aging, and Parkinson's disease. This integrative analysis identifies distinct microglial subpopulations, reflecting functional heterogeneity across diseases and reveals a shared cross-disease microglial transcriptional program associated with inflammatory and neurodegenerative processes. Using a machine learning framework, we further demonstrate that this transcriptional program enables robust discrimination between neurodegenerative and control samples. Experimental validation in primary microglia isolated from a mouse model of Niemann-Pick disease type C, also known as juvenile Alzheimer's disease, supports the conservation of key components of this program and highlights Spp1 as a biomarker of disease-associated microglia states. Overall, this study provides an improved portrait of microglia transcriptional remodeling across neurodegenerative disorders and offers a framework for identifying conserved molecular features that may inform therapeutic strategies aimed at modulating microglial activity to mitigate disease progression and foster neuroprotection.},
}

*Microglia/metabolism/pathology
Animals
Humans
Mice
*Neurodegenerative Diseases/metabolism/genetics/pathology
*Osteopontin/genetics/metabolism
Biomarkers/metabolism
Transcriptome
Cells, Cultured

@article {pmid42012178,
year = {2026},
author = {Gu, F and Saed, B and Naghavi, MH},
title = {Turning defense into damage: HIV-driven amyloidogenesis and neurotoxicity.},
journal = {mBio},
volume = {},
number = {},
pages = {e0308325},
doi = {10.1128/mbio.03083-25},
pmid = {42012178},
issn = {2150-7511},
abstract = {With the continued spread of human immunodeficiency virus 1 (HIV-1) and its ability to enter and persist within the central nervous system (CNS), concerns have arisen regarding its impact on cognitive health. Indeed, during the early stages of the HIV pandemic, when effective treatments were unavailable, severe neurocognitive impairment was common. Although the widespread use of antiretroviral therapy (ART) has markedly reduced the severity, milder forms of HIV-associated neurocognitive disorders (HAND) remain prevalent. Similar to Alzheimer's disease (AD), elevated amyloid-β (Aβ) accumulation has been observed both intracellularly and extracellularly in the brains of HIV-infected individuals, based on autopsy studies. Aβ is generated through the amyloidogenic processing of amyloid precursor protein (APP), which is abundantly expressed in the brain. While the APP's role in AD pathogenesis has been well established, its broader physiological functions, particularly in the context of viral infections such as HIV-1, remain poorly understood. In the CNS, microglia are crucial for maintaining brain homeostasis and defending against viral infections. HIV-1, however, targets microglia, disrupting their antiviral capacity and contributing to neurotoxicity through multiple mechanisms, such as the release of viral proteins and host-derived neurotoxic factors including proinflammatory cytokines and Aβ. Moreover, HIV-infected microglia can influence neighboring cells such as astrocytes and neurons, further amplifying neurodegenerative processes. This review will focus on recent advances in understanding the antiviral role of APP and its processing during HIV-1 infection, highlighting how APP-mediated defense mechanisms intersect with neurotoxic pathways and the intercellular regulatory networks that link APP to HAND.},
}

@article {pmid42012352,
year = {2026},
author = {Bhattacharjee, S and Choi, J and Lee, MQ and Kim, M and Shah, YH and Hadee, A and Cho, CS},
title = {Electromagnetic field induced activation of amyloid-β degrading enzyme, neprilysin, for accelerated Alzheimer's disease therapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444315},
doi = {10.1177/13872877261444315},
pmid = {42012352},
issn = {1875-8908},
abstract = {BackgroundAmyloid-β accumulation and misfolding are key features of Alzheimer's disease (AD), contributing to synaptic dysfunction, neuroinflammation, and neuronal loss. Normally, amyloid-β is cleared by chaperone-assisted folding, enzymes such as neprilysin and insulin-degrading enzyme, and autophagy pathways. In AD, these mechanisms become impaired, leading to toxic aggregation. Enhancing the activity of endogenous degrading enzymes offers a promising therapeutic approach, with electromagnetic (EM) fields emerging as a potential noninvasive method to promote amyloid-β clearance.ObjectiveThis study computationally evaluates whether controlled EM wave exposure (100-900 MHz) delivered through a waveguide can enhance amyloid-β degradation by accelerating enzyme activation and reducing Gibbs free energy barriers.MethodsA mechanistic model linking EM stimulation with cellular stress responses, chaperone activity, enzyme delivery, and autophagy was developed. Quantum-chemical simulations evaluated changes in Gibbs free energy and reaction rates under no EM field, low-intensity EM (1.0 × 10[-][1][1] a.u.), and optimized EM intensity (5.09 × 10[-][1][0] a.u.).ResultsComputational simulations revealed that EM stimulation enhances enzymatic activation by lowering the Gibbs free energy barrier. Without an electric field, ΔG was 66.00 kJ·mol[-][1] with a reaction rate of 56.5 s[-][1]. Low-intensity EM slightly reduced ΔG to 65.87 kJ·mol[-][1] and increased the rate to 67.5 s[-][1]. At optimized EM intensity, ΔG decreased to 52.10 kJ·mol[-][1], raising the reaction rate to 1.18 × 10[4] s[-][1], indicating significantly accelerated enzyme activity and improved amyloid-β degradation potential.ConclusionsThe integrated model shows that optimized EM stimulation enhances enzyme-mediated amyloid-β degradation by lowering energy barriers and increasing reaction rates, supporting a potential noninvasive therapeutic strategy for AD.},
}

@article {pmid42012365,
year = {2026},
author = {Sun, R and Li, W and Liu, N and Ji, X and Zhao, Z and Che, N and Li, A and Hu, W and Zhang, J},
title = {NOTCH3-R544C mutation drives endothelial dysfunction through inflammation, migration impairment, and lipid dysregulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444309},
doi = {10.1177/13872877261444309},
pmid = {42012365},
issn = {1875-8908},
abstract = {BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Previous research has predominantly focused on vascular smooth muscle cell pathology, whereas the role of brain microvascular endothelial cells (BMECs) in the disease remains unclear.ObjectiveTo investigate the impact of the NOTCH3-R544C mutation on BMECs function and to elucidate the underlying mechanisms of endothelial dysfunction in CADASIL.MethodsUsing CADASIL transgenic mice and endothelial cell (EC) models stably expressing NOTCH3-R544C, the impact of the mutation on endothelial function was assessed through immunofluorescence staining, RNA-seq analysis, protein-protein interaction (PPI) network mapping, and lipid and cellular function assays.ResultsSignificant NOTCH3 extracellular domain (NOTCH3ECD) deposition and reduced microvascular density are observed in CADASIL mice. R544C mutant cells exhibit abnormal NOTCH3ECD accumulation alongside pronounced gene expression dysregulation, predominantly enriched in pathways related to inflammation, cell migration. The PPI network centers on CXCL10 as a pivotal hub, forming a core "inflammation-migration" pathological axis. R544C cells exhibit heightened inflammatory responses, cholesterol accumulation, reduced cell viability, and increased sensitivity to inflammatory stimuli.ConclusionsThe NOTCH3-R544C mutation disrupts inflammatory regulation, migratory capacity, and lipid metabolic homeostasis in BMECs, leading to endothelial dysfunction and revealing a key mechanism of endothelial injury in CADASIL.},
}

@article {pmid42012375,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Aso, S and Yasunaga, H and Satake, W and Iwatsubo, T},
title = {Early adoption of lecanemab in Japan (December 2023-December 2024): Pretreatment diagnostic timelines from the DeSC claims database.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443634},
doi = {10.1177/13872877261443634},
pmid = {42012375},
issn = {1875-8908},
abstract = {Using the Japanese DeSC claims database, we described pretreatment timelines for lecanemab initiation during early rollout (December 2023-December 2024). We identified 76 patients (mean age 74.6 years; 34.2% men) from 45 institutions. Mean time to first infusion was 103.9 days from cognitive assessment and 63.1 days from MRI. PET-to-infusion was 30.9 days, whereas cerebrospinal fluid (CSF) sampling-to-infusion was 85.8 days; the post-test interval remained longer after CSF (Bonferroni-adjusted p = 0.015). Although this claims-based snapshot may not represent all practice in Japan, it suggests that the CSF-based pathway can be associated with a longer post-test interval before treatment initiation.},
}

@article {pmid42012386,
year = {2026},
author = {Huang, J and Cho, Y and Wang, C and Beeber, AS and Vu, B and Szanton, SL and Rebok, GW and Li, J},
title = {Daily life experiences of cognitive changes in community-dwelling older adults with subjective cognitive decline: A qualitative study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443974},
doi = {10.1177/13872877261443974},
pmid = {42012386},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD), defined as self-perceived cognitive worsening despite normal performance on standardized tests, is increasingly recognized as a potential early indicator of Alzheimer's disease and related dementias. Older adults with SCD face elevated dementia risk and may benefit from timely intervention or support. To guide such efforts, qualitative research is needed to understand how they experience and perceive cognitive changes in daily life.ObjectiveThis study aims to explore the daily life experiences of community-dwelling older adults with SCD, including how they respond to self-perceived cognitive changes, the impact on daily functioning and well-being, and their perceived factors associated with cognitive performance.MethodsUsing a qualitative descriptive approach, we conducted semi-structured interviews with 16 older adults who reported cognitive decline but showed no objective cognitive impairment. Transcripts were analyzed using thematic analysis to identify key themes related to lived cognitive experiences.ResultsFour major themes emerged: (1) cognitive changes manifesting in everyday tasks across domains such as memory, attention, and executive function; (2) active use of intentional internal and external strategies to manage these changes; (3) varied emotional responses and appraisals shaped by personal expectations and contextual factors; and (4) perceived risk (e.g., aging, stress, poor sleep) and protective factors (e.g., mental stimulation, social engagement) for cognitive function.ConclusionsParticipants with SCD reported cognitive changes that have influenced their daily activities, emotional well-being, and social interactions. Future research may consider person-centered strategies that support cognitive self-management and improve well-being among older adults with SCD.},
}

@article {pmid42012388,
year = {2026},
author = {Hildebrandt, H and Duning, T and Holland-Letz, M},
title = {Is there a cognitive measure of neurodegeneration for amyloid-Aβ-ratio probable Alzheimer's disease patients?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444308},
doi = {10.1177/13872877261444308},
pmid = {42012388},
issn = {1875-8908},
abstract = {BackgroundRecent developments in the assessment of Alzheimer's disease (AD) have centered on differential diagnostic questions. Only a few studies have aimed to identify neuropsychological measures that allow the prediction of disease progression. However, this question is central to informing patients about their diagnosis and to decisions regarding the urgency and timing of treatment escalation.ObjectiveWe analyzed which, if any, neuropsychological test results reflect the extent of neurodegenerative progression.MethodsThis retrospective analysis included 290 patients divided into an Aβ-ratio + group (n = 146; AD biomarker profile) and an Aβ-ratio- group (n = 144; non-AD biomarker profile). The Aβ-ratio + group was further divided into four t-tau quartiles. The Aβ-ratio- group was subdivided into patients with normal (n = 94) or elevated t-tau (n = 50).ResultsRegression and variance analyses demonstrated a correlation between Trail Making Test B (TMT-B) performance and t-tau levels in patients with an Aβ-ratio+, driven by differences between low and high tau values, but not in Aβ-ratio- patients. Several additional statistical control analyses endorsed this finding.ConclusionsWe conclude that, for Aβ-ratio + patients, TMT-B performance may serve as a clinically accessible indicator of tau-related disease activity and the extent of neurodegeneration and may help identify patients at risk of faster progression if replicated in longitudinal studies.},
}

@article {pmid42012391,
year = {2026},
author = {Musaeus, CS and Curnin, CB and Muthupalaniappan, S and Friedman, G and Aslarus, I and Hayashi, T and Smith, MA and Press, DZ},
title = {Feasibility and validity of the D-Cog: A novel digital spatial working memory test for dementia assessment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442078},
doi = {10.1177/13872877261442078},
pmid = {42012391},
issn = {1875-8908},
abstract = {BackgroundCognitive testing is critical for screening, diagnosing, and monitoring neurocognitive disorders, but current tests are limited by long administration times and the need for trained personnel. Digital cognitive testing offers a convenient and highly repeatable alternative to track cognitive decline, which is essential for evaluating patient care and in clinical trials. To address these limitations, we developed a novel digital spatial working memory test called the D-Cog.ObjectiveThis study aimed to assess the feasibility, validity, and diagnostic utility of the D-Cog in a clinical population.MethodsPatients with Alzheimer's disease (AD), Lewy body dementia (DLB), Parkinson's disease (PD), and cognitively normal controls (CN) were included. During clinical visits, a medical assistant administered the D-Cog test, presented as a "serious game" on an iPad.ResultsThe D-Cog showed high participant engagement, although engagement decreased with advancing cognitive impairment. A significant difference in the mean D-Cog score was observed between CN and both AD and DLB/PD groups (p < 0.003). Additionally, a significant correlation between the D-Cog score and the Mini-Mental State Examination was identified (r = 0.65, p < 0.001, 95% CI: 0.52-0.75). The D-Cog demonstrated good discrimination between groups, with AUCs of 0.96 (95% CI: 0.91-1.00) for AD versus healthy controls and 0.88 (95% CI: 0.75-0.97) for MCI versus healthy controls.ConclusionsThe D-Cog is a feasible and valid digital cognitive test with potential clinical utility across neurocognitive disorders. Although engagement was lower in advanced dementia, these findings support further development and exploration of the D-Cog, particularly for potential in-home assessments.},
}

@article {pmid42012394,
year = {2026},
author = {Ottaviani, S and Bozzo, G and De Cesari, F and Peruzzo, S and Tagliafico, L and Nencioni, A and Massa, F and Pardini, M and Monacelli, F},
title = {Frailty in early Alzheimer's disease: Complementary clinical value and prognostic significance in biomarker-defined mild cognitive impairment due to Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443558},
doi = {10.1177/13872877261443558},
pmid = {42012394},
issn = {1875-8908},
abstract = {Frailty, reflecting diminished physiological reserve, may influence how Alzheimer's disease (AD) pathology manifests. This study evaluated the prognostic relevance of frailty in mild cognitive impairment due to AD (MCI-AD). 50 patients underwent frailty assessment using the Clinical Frailty Scale (CFS), with multimorbidity, polypharmacy, and cognition (Mini-Mental State Examination, MMSE) recorded. Participants (median age 74 years; 76% women) exhibited low frailty (median CFS 3). Higher CFS scores correlated with lower baseline MMSE and faster annual decline. In adjusted analyses, CFS independently predicted both poorer cognition and steeper decline, whereas CSF P-tau did not. Frailty thus provides complementary prognostic information to biomarkers in the early stages of AD.},
}

@article {pmid42012422,
year = {2026},
author = {Xu, R and Ma, X and Wu, L and Yin, D and Zhao, L and Zhou, M and Yao, Y and Lin, R and Li, W and Yu, K},
title = {Transcranial Direct Current Stimulation Improves Cognitive Dysfunction in Amyloid Precursor Protein/Presenilin 1 Mice by Promoting Alternative Polarization of Microglia and Amyloid-Β Degradation.},
journal = {Neuromodulation : journal of the International Neuromodulation Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurom.2026.03.007},
pmid = {42012422},
issn = {1525-1403},
abstract = {OBJECTIVE: This study investigated the mechanisms by which transcranial direct current stimulation (tDCS) alleviated Alzheimer's disease (AD) progression.

MATERIALS AND METHODS: Amyloid precursor protein (APP)/human presenilin 1 (PS1) transgenic mice (AD model) received tDCS (0.2 mA, anode electrode placed on the left frontal skull, 20 min/d for two weeks) and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) activator nigericin. Behavior tests evaluated spatial learning, recognition memory, and spontaneous exploration abilities in mice. Histopathologic changes in the hippocampal cornu ammonis area 1 (CA1) region and Aβ1-42 deposition were observed using histologic staining and immunohistochemistry. Enzyme-linked immunosorbent assay was used to measure Aβ1-40 and Aβ1-42 expression. Classical microglia (M1)/alternative microglia (M2) polarization, inflammatory factors, and oxidative stress levels were assessed through immunofluorescence and kits. NLRP3 inflammasome indicators were detected by reverse transcription quantitative polymerase chain reaction and western blot.

RESULTS: After tDCS treatment, APP/PS1 mice exhibited shortened escape latency, increased platform crossings, and an elevated discrimination index. In the open field test, total movement distance and time spent in the center zone increased. The Aβ1-42/40 ratio in the mouse hippocampal CA1 region decreased by 20.8%, whereas neurons and Nissl bodies increased, indicating that tDCS improved cognitive function. tDCS reduced M1 polarization, increased M2 polarization, and reduced neuroinflammation and oxidative stress in the hippocampal CA1 region of APP/PS1 mice. Moreover, tDCS suppressed microglial NLRP3/caspase-1 pathway activation and Aβ deposition in APP/PS1 mice. NLRP3/caspase-1 pathway activation partially reversed effects of tDCS on APP/PS1 mice.

CONCLUSION: This study highlights the potential therapeutic value of tDCS in AD mice. It reveals that tDCS promotes hippocampal microglial M2 polarization and Aβ degradation to curtail NLRP3/caspase-1 inflammasome pathway activation, thereby improving cognitive function in APP/PS1 mice.},
}

@article {pmid42012471,
year = {2026},
author = {Tong, Q and Kwapong, WR and Luan, X and Hu, S and Hu, Y and Guo, Y and Ji, C and Yang, M and Wang, Z},
title = {Retinal Microvascular Dysfunction Reflects Vascular and Alzheimer's-Related Pathology in Dementia With Lewy Bodies.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {4},
pages = {e70891},
doi = {10.1002/cns.70891},
pmid = {42012471},
issn = {1755-5949},
support = {009//Headache Specialty Care Program at the First Affiliated Hospital of Wenzhou Medical University/ ; },
mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Alzheimer Disease/pathology/diagnostic imaging ; *Lewy Body Disease/diagnostic imaging/pathology/complications/physiopathology ; *Retinal Vessels/diagnostic imaging/pathology ; Aged, 80 and over ; *Microvessels/pathology/diagnostic imaging ; Tomography, Optical Coherence ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Biomarkers/blood ; },
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) frequently coexists with cerebrovascular injury and Alzheimer's-related pathology, yet accessible in vivo markers of these processes remain limited. The retinal microvasculature shares structural and physiological characteristics with cerebral small vessels and may provide a non-invasive window into neurovascular and neurodegenerative pathology.

METHODS: In this cross-sectional study, 32 individuals with DLB and 31 age-matched cognitively unimpaired controls (CU) underwent swept-source optical coherence tomography angiography (OCTA), brain MRI, and plasma biomarker assessment. Retinal vessel densities of the superficial vascular complex (SVC), deep vascular complex (DVC), and choriocapillaris (CC) were quantified. Plasma amyloid-β, phosphorylated tau-217 (p-tau217), and glial fibrillary acidic protein were measured. Cerebral small vessel disease (SVD) burden and white matter hyperintensity (WMH) volumes were derived from MRI. Associations with cognition and mediation by WMH burden were evaluated using generalized estimating equations and bootstrapped mediation analyses.

RESULTS: Compared with CU, individuals with DLB exhibited significantly reduced SVC, DVC, and CC vessel densities (all p < 0.001). Lower retinal vessel densities were associated with higher plasma amyloid burden and elevated p-tau217, as well as greater SVD burden and periventricular WMH volume. APOE ε4 carriers demonstrated more pronounced retinal microvascular impairment, higher WMH burden, and elevated p-tau217 levels than non-carriers. Reduced SVC density was associated with worse global cognition, and this relationship was partially mediated by periventricular WMH volume.

CONCLUSIONS: Retinal microvascular impairment measured by OCTA is closely linked to Alzheimer's-related plasma biomarkers, SVD, and cognitive decline in DLB. These findings support retinal OCTA as a scalable, non-invasive biomarker reflecting convergent neurodegenerative and vascular pathology in DLB.},
}

Humans
Male
Female
Aged
Cross-Sectional Studies
*Alzheimer Disease/pathology/diagnostic imaging
*Lewy Body Disease/diagnostic imaging/pathology/complications/physiopathology
*Retinal Vessels/diagnostic imaging/pathology
Aged, 80 and over
*Microvessels/pathology/diagnostic imaging
Tomography, Optical Coherence
Magnetic Resonance Imaging
Amyloid beta-Peptides/blood
tau Proteins/blood
Biomarkers/blood

@article {pmid42012510,
year = {2026},
author = {Uematsu, Y and Iinuma, W and Shimizu, R and Matsuura, H and Yoshinaga, T and Yazaki, M and Yamauchi, K},
title = {Redox status of apolipoprotein E in cerebrospinal fluid: A mechanistically informative biomarker for central nervous system disorders.},
journal = {Bioscience reports},
volume = {},
number = {},
pages = {},
doi = {10.1042/BSR20250388},
pmid = {42012510},
issn = {1573-4935},
abstract = {Apolipoprotein (apo) E is the major cholesterol carrier in the central nervous system (CNS); however, the clinical relevance of its cysteine-thiol redox status in cerebrospinal fluid (CSF) remains unclear. We investigated whether CSF apoE redox indices (redox-IDX-apoE) reflect cholesterol transport efficiency and disease-specific pathologies. We quantified reduced (red), reversibly oxidized (roxi), and irreversibly oxidized (oxi) apoE in CSF and serum using a maleimide-based band-shift assay. We analyzed relationships between redox-IDX-apoE, CSF cholesterol (TC) level, and the TC/apoE ratio (inverse transport efficiency) in patients with apoE3/E3 and identified transport determinants using isometric log-ratio (ILR) regression. Significant but only moderate correlations between CSF and serum indices suggested distinct redox behavior in the two compartments. ApoE3/E4 carriers exhibited higher oxi-apoE, reflecting reduced buffering capacity. In apoE3/E3 CSF, aging increased roxi/total and decreased red/roxi, suggesting a shift toward oxidized forms. CSF TC level positively correlated with roxi-related indices. Conversely, the TC/apoE ratio negatively correlated with red/roxi, indicating that red-apoE supports higher efficiency. ILR analysis confirmed that maintaining the reduced monomeric state, rather than the reversibly oxidized form, was independently associated with improved transport efficiency. Diagnostic groups exhibited distinct signatures: neurodegenerative disorders showed elevated irreversible oxidation, whereas neuroimmunological and infectious conditions exhibited profiles suggestive of reversible and acute oxidation, respectively. The CSF apoE redox status links local redox balance to cholesterol handling and reflects CNS pathophysiology. Maintaining reduced cysteine-thiol appears important for functional capacity, whereas a shift toward oxidation reflects a trade-off between buffering ability and transport efficiency. These indices may serve as potential biomarkers.},
}

@article {pmid42012514,
year = {2026},
author = {Ma, X and Mo, X and Li, B and Xu, Y and Long, L and Dong, Q and Ma, Z and Tian, Q and Chen, X and Qian, J},
title = {Visual working memory is impaired in Alzheimer's disease: evidence from real-world objects and perceptual organization.},
journal = {Experimental brain research},
volume = {244},
number = {6},
pages = {},
pmid = {42012514},
issn = {1432-1106},
support = {22BYY078//National Social Science Fund of China/ ; 32271100//National Natural Science Foundation of China/ ; },
}

@article {pmid42012542,
year = {2026},
author = {Tu, X and Fang, M and Yan, Y and Liu, Y and Yu, J and Chen, L and Zhang, L and Huang, C and Fan, S},
title = {The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.},
journal = {Biogerontology},
volume = {27},
number = {3},
pages = {},
pmid = {42012542},
issn = {1573-6768},
support = {24ZR1466100//Natural Science Foundation of Shanghai Municipality/ ; 25PJD123//Shanghai Magnolia Talent Plan of Shanghai - Pujiang Talents Program/ ; QNKJ2025007//Eastern Talent Program - Science and Technology Platform of Shanghai/ ; },
mesh = {*Histone Deacetylase 6/metabolism ; Animals ; *Triterpenes/pharmacology ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neuroprotective Agents/pharmacology ; Caenorhabditis elegans ; Humans ; *tau Proteins/metabolism/toxicity ; *Stress Granules/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; Caenorhabditis elegans Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by proteostasis collapse driven by amyloid-β (Aβ) plaques and tau tangles. Dysregulation of stress granule (SG) dynamics and aberrant histone deacetylase 6 (HDAC6) activity are emerging as pivotal pathogenic mechanisms promoting neurodegeneration. Here, we identify that Cucurbitacin B (CB), a natural triterpenoid, acts as a potent SG inducer that confers broad-spectrum neuroprotection. Mechanistically, we demonstrate a novel "recruit-and-sequester" model: CB promotes the assembly of HDAC6-recuited SGs, thereby physically sequestering HDAC6 and functionally inhibiting its deacetylase activity. In Caenorhabditis elegans (C. elegans) and mammalian cell models, CB treatment significantly alleviated Aβ oligomer-induced cytotoxicity and tau hyperphosphorylation. Notably, the neuroprotective efficacy of CB was abolished by the genetic knockdown of core SG components (gtbp-1/G3BP1, tiar-1/TIA1) or hda-6/HDAC6, confirming that its therapeutic action relies on the integrity of the HDAC6-SG. Our findings highlight the potential of modulating SG dynamics to spatially regulate HDAC6, offering a novel therapeutic strategy for AD.},
}

*Histone Deacetylase 6/metabolism
Animals
*Triterpenes/pharmacology
*Amyloid beta-Peptides/toxicity/metabolism
*Neuroprotective Agents/pharmacology
Caenorhabditis elegans
Humans
*tau Proteins/metabolism/toxicity
*Stress Granules/metabolism/drug effects
*Alzheimer Disease/metabolism/drug therapy
Caenorhabditis elegans Proteins/metabolism

@article {pmid42012569,
year = {2026},
author = {Belviranlı, M and Okudan, N and Sezer, T},
title = {Exercise-induced GPLD1 is associated with neuroprotection and improvement of hippocampal dysfunction in an Alzheimer's disease model.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42012569},
issn = {1573-7365},
}

@article {pmid42012685,
year = {2026},
author = {Mehta, K and Morton, JI and Chen, L and Anstey, KJ and Carstensen, B and Gregg, EW and Arffman, M and Booth, GL and Chu, LM and Fleetwood, K and Singh-Manoux, A and Fosse-Edorh, S and Guion, M and Kaul, P and Ke, C and Keskimäki, I and Boel Graversen, S and Laurberg, T and Støvring, H and Wild, SH and Shaw, JE and Magliano, DJ},
title = {Age- and sex-specific trends in dementia mortality among people with and without diabetes: a multi-country population-based analysis.},
journal = {Diabetologia},
volume = {},
number = {},
pages = {},
pmid = {42012685},
issn = {1432-0428},
support = {Y18G-MAGD//Diabetes Australia Research Program/ ; 75D30122P14242//US Centers for Disease Control and Prevention/ ; },
abstract = {AIMS/HYPOTHESIS: Large-scale data on age- and sex-specific dementia mortality trends among people with diabetes remain limited, as most previous studies have been restricted to single countries or have not distinguished mortality by diabetes status. We estimated age- and sex-specific time trends in dementia mortality among individuals with and without diabetes from high-income jurisdictions.

METHODS: We analysed aggregated mortality and demographic data using registries and administrative sources in Australia, Canada (Alberta and Ontario), France, Denmark, Finland and Scotland from 2000 to 2023. Poisson regression was used to estimate mortality rates for dementia as the underlying cause of death in people with and without diabetes at 60, 70, 80 and 90 years of age.

RESULTS: A total of 114,559 and 589,706 dementia deaths were identified in over 42 and 244 million person-years of follow-up for individuals with and without diagnosed diabetes, respectively. Dementia mortality trends varied by age and jurisdiction but were generally consistent for both sexes. At younger ages (e.g. 60 and 70 years), the dementia mortality trends did not suggest any meaningful increases or decreases, except for in Scotland, which reported increasing dementia mortality over time only for those with diabetes. At older ages (e.g. 80 and 90 years), however, increases in dementia mortality were observed in most jurisdictions, ranging from 7.6% to 42.4% per 5 years. The magnitude of the increases was generally greater for those with diabetes. Mortality from dementia subtypes (e.g. Alzheimer's disease and vascular dementia) also increased over time in individuals aged 40-89 years, with greater increases in mortality rates for individuals with diabetes, specifically in Australia and Scotland.

CONCLUSIONS/INTERPRETATION: Increases in dementia mortality were observed for those aged 80 years and above and were most marked for people with diabetes. These findings highlight the growing burden of dementia for health systems.},
}

@article {pmid42012729,
year = {2026},
author = {Pandolfi, S and Björklund, G and Ghezzi, C and Paone, FM and Chirumbolo, S},
title = {Spermidine in the aging brain: mechanisms, preclinical evidence, and clinical perspectives.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42012729},
issn = {1573-4978},
}

@article {pmid42013009,
year = {2026},
author = {Botta, D and Bernetti, C and Hutuca, I and Ojeda Esparza, JF and Sveikata, L and Lovblad, KO and Kurz, FT},
title = {Beyond the Leak: Advanced MRI Assessment of the Blood-Brain Barrier in Neurodegeneration.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-25},
doi = {10.1159/000552173},
pmid = {42013009},
issn = {1660-2862},
abstract = {The blood-brain barrier (BBB) is a specialized multicellular interface that maintains the CNS's tightly regulated microenvironment. BBB disruption is increasingly recognized as a key feature of neurodegeneration, documented across disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and cerebral small vessel disease (cSVD). While the extent to which BBB breakdown is a cause or consequence of neuronal pathology remains unclear, its pronounced presence in disease states suggests a significant contributory role in progression. Advances in MRI have revolutionized our ability to visualize and quantify these alterations in vivo. This review provides a neuroradiological overview of advanced MRI approaches and their specific biomarkers, specifically Dynamic Contrast-Enhanced MRI (DCE) with Ktrans and Arterial Spin Labeling (ASL) with kw, detailing disease-specific BBB signatures in major neurodegenerative disorders. Current technological strides, including ultra-high-field MRI and AI-assisted post-processing, are pushing the sensitivity needed to detect subtle BBB changes. Ultimately, with technical refinement and standardization, MRI methods are transitioning from research tools into candidate neurovascular biomarkers with growing potential for early diagnosis, treatment monitoring, and longitudinal follow-up, pending multicenter standardization and normative validation.},
}

@article {pmid42013036,
year = {2026},
author = {Kamiya, M and Osawa, A and Otaka, E and Kato, K and Yoshimi, T and Kagaya, H and Kondo, I},
title = {Correction: Exploring emotion recognition in patients with mild cognitive impairment and Alzheimer's dementia undergoing a rehabilitation program.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0347796},
doi = {10.1371/journal.pone.0347796},
pmid = {42013036},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0322213.].},
}

@article {pmid42013076,
year = {2026},
author = {Jain, S and Tunc, EB and Grossberg, GT},
title = {Pharmacotherapeutic landscape for the management of agitation associated with Alzheimer's disease.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/14656566.2026.2662949},
pmid = {42013076},
issn = {1744-7666},
abstract = {INTRODUCTION: Agitation associated with Alzheimer's disease (AAD) is common, persistent, and strongly linked to caregiver burden, emergency care, and institutionalization. Pharmacologic options have historically been limited by modest efficacy and safety liabilities in the geriatric population, creating a major treatment gap.

AREAS COVERED: This narrative review summarizes established and emerging pharmacotherapies for AAD, emphasizing comparative efficacy, geriatric-relevant safety, and real-world feasibility. A literature search was conducted in PubMed/MEDLINE and ClinicalTrials.gov from database inception through 31 January 2026, prioritizing the most recent decade when applicable, and complemented these searches with hand searches of key trials, meta-analyses, guidelines, and publicly available regulatory or sponsor communications for late-stage programs. Evidence is synthesized qualitatively due to heterogeneity in definitions and outcomes. We discuss antipsychotics, serotonergic agents, drugs with negative trials, and pipeline approaches such as dextromethorphan-based combinations and adrenergic strategies.

EXPERT OPINION: The field is shifting from broad off-label prescribing toward phenotype-informed, trial-validated treatments. Brexpiprazole establishes regulatory feasibility, while dextromethorphan-based combinations, particularly AXS-05, appear promising, including signals for durability. Progress will depend on harmonized outcomes, longer-term safety data, and pragmatic trials that prioritize function, caregiver impact, and crisis prevention.},
}

@article {pmid42013266,
year = {2026},
author = {Yang, Z and Cheng, B and Gan, H and Huang, Z and Zhou, R and Wang, J},
title = {Adaptive Spectral Graph Attention Filtering Network for Alzheimer's Disease Classification Using Multimodal Data.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3686301},
pmid = {42013266},
issn = {2168-2208},
abstract = {Early detection of Alzheimer's Disease (AD) is critical for timely intervention and management. However, existing graph-based approaches often fail to fully leverage the rich spectral-domain information inherent in brain network signals. To address this limitation, we propose an Adaptive Spectral Graph Attention Filtering Network (ASGAFN), which effectively models the spectral structures of functional and structural brain networks to enhance classification performance. Specifically, we first construct structural and functional brain network graphs from diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). Subsequently, a frequency-encoding-guided attention mechanism is designed to learn a shared spectral response function across graphs. This enables the construction of interpretable and adaptive spectral filters while mitigating semantic misalignment across different spectral domains. Furthermore, a spectral energy sensing module is incorporated to facilitate graph-specific adaptation, thereby enhancing flexibility and subject-level discriminability. Finally, the refined spectral signals are transformed back to the spatial domain and fused via a Multimodal Fusion and Enhancement Layer (MFEL). Extensive experiments demonstrate that ASGAFN significantly outperforms multiple baselines in AD-related classification tasks. It achieves accuracies of 96.64% (AD vs. NC), 90.48% (MCI vs. NC), and 91.75% (AD vs. MCI). Additionally, it attains an accuracy of 87.12% in the three-class classification task, underscoring its effectiveness in distinguishing among multiple disease stages. These findings validate the efficacy of spectral-domain modeling and multimodal fusion.},
}

@article {pmid42013560,
year = {2026},
author = {Gosse, M and Oliveira, D and Chiussi, S and Martins, GV and Moreira, F},
title = {Direct electrochemical immunosensing of tau protein using shape-controlled gold nanoparticles for Alzheimer's diagnostics.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {171},
number = {},
pages = {109305},
doi = {10.1016/j.bioelechem.2026.109305},
pmid = {42013560},
issn = {1878-562X},
abstract = {Early diagnosis of Alzheimer's disease (AD) remains challenging, creating an urgent need for sensitive, rapid and non-invasive technologies for the detection of blood-based biomarkers. Here, we report an electrochemical immunosensor for the direct detection of phosphorylated tau protein (tau 181), a key biomarker associated with early-stage AD. The sensing interface combines a redox-active poly(toluidine blue) (p(TB)) layer with gold nanostructures, including spherical nanoparticles (AuNPs) and branched nanostars (AuNSs), enabling external redox probe-free detection. The electropolymerized p(TB) acts as an intrinsic redox mediator, while the nanostructures enhance surface area, antibody immobilization and electron transfer. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) confirmed that interfacial charge transfer processes are strongly dependent on nanostructure morphology, with optimal performance obtained using 0.06 mM AuNPs. Direct quantification of tau 181 was achieved by square wave voltammetry (SWV), providing a wide linear detection range (1 pg/mL-100 ng/mL) and an ultra-low limit of detection of 1.09 pg/mL, which is below the clinically relevant threshold for AD diagnosis (2-4 pg/mL). The immunosensor also demonstrated excellent reproducibility and selectivity. By coupling a redox-active polymer with colloidal gold nanostructures on a disposable electrode platform, this work provides mechanistic insight into nanostructure-mediated electron transfer and establishes a promising biointerface for fast and sensitive AD biomarker detection for clinical screening applications.},
}

@article {pmid42013744,
year = {2026},
author = {Zhao, X and Bao, Y and Wan, X and Miao, R and Li, C and Wang, J and Zhang, H and Xiang, Y and Pang, Y and Miao, Z and Tong, M and Shi, X and Wang, H and Gong, P and Zhao, Y and Hou, Y},
title = {Design, synthesis, and evaluation of dual-target inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH) for the treatment of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {312},
number = {},
pages = {118844},
doi = {10.1016/j.ejmech.2026.118844},
pmid = {42013744},
issn = {1768-3254},
abstract = {In this study, a series of tacrine derivatives featuring a triazole linker with sEH fragment were designed, synthesized, and evaluated for Alzheimer's disease treatment. Among them, compound Z43 exhibited best dual inhibitory activity against AChE and sEH (AChE IC50 = 1.7 nM; sEH IC50 = 0.7 nM) and showed low cytotoxicity in HepG2, SMMC7721 and SH-SY5Y cell lines. In addition, Z43 showed high permeability in PAMPA permeability test. Meanwhile, Z43 protected PC12 cells from H2O2-induced toxicity. Moreover, in LPS-induced BV-2 cell inflammation model, Z43 significantly reduced the levels of TNF-α, IL-1β, IL-6 and iNOS. Acute toxicity tests also indicated a favorable safety profile. In the scopolamine-induced AD mice model, Z43 markedly improved learning and memory deficits, which was significantly better than tacrine and EC5026. In summary, compound Z43 shows promising potential for further research.},
}

@article {pmid42013919,
year = {2026},
author = {Ye, T and Lv, X and Li, Q and Liao, X and Zhan, L and Dai, C and Xiang, K and Lin, X and Sun, J and Liu, J},
title = {Gut microbial metabolite indole-3-acetic acid inhibits microglia-mediated synaptic loss in Alzheimer's disease by targeting CCR4.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106769},
doi = {10.1016/j.bbi.2026.106769},
pmid = {42013919},
issn = {1090-2139},
abstract = {Gut microbial metabolites abnormity links to Alzheimer's disease (AD) progression, yet the mechanism remains unknown. Here, we observed a markedly decreased level of indole-3-acetic acid (IAA) in AD patients, and the IAA level was negatively correlated with cognitive impairment. IAA supplementation improved cognitive dysfunction and synaptic damage, and suppressed microglial activation and synaptic phagocytosis in AD mouse and cell models. RNA sequencing revealed an increase in phagocytosis-associated pathway activity and gene expression, and C-C chemokine receptor 4 (CCR4) was identified as a key regulator of this process. IAA could inhibit the expression level of CCR4, and siRNAs CCR4 markedly inhibited microglia-mediated phagocytosis of synapse. We further demonstrated that microglial CCR4 interacts with aryl hydrocarbon receptor (AHR), a key receptor of IAA, and proposed the hypothesis that AHR binds to the CCR4 promoter, thereby inhibiting its transcriptional activity. Moreover, we further revealed that bacteria producing IAA supplementation inhibited microglia-mediated synaptic loss by down-regulating CCR4, thus delaying Alzheimer's progression. These findings elucidate the mechanisms underlying microbial metabolite IAA's impact on AD, highlighting that targeting CCR4 inhibition in microglia-mediated synaptic phagocytosis represents a promising therapeutic strategy for AD.},
}

@article {pmid42013932,
year = {2026},
author = {Shi, L and Yang, J and Guo, Y and Wei, B and Zhang, S and Wang, H and Li, Y and Zhou, J and Zhang, L and Xiaoxiao, and Guo, Y},
title = {TRPV1-tau axis: A bidirectional regulatory mechanism linking pain sensitization and Alzheimer's disease progression and its potential for intervention.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115780},
doi = {10.1016/j.expneurol.2026.115780},
pmid = {42013932},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by β-amyloid (Aβ) deposition and pathological tau phosphorylation and aggregation, frequently accompanied by chronic pain. Pain sensitization is closely linked to AD progression. Transient receptor potential vanilloid 1 (TRPV1), a key cation channel in pain transduction, is expressed not only in peripheral sensory neurons but also widely in central neurons and glial cells, where it contributes to pain sensitization and neuroinflammation. Emerging evidence indicates a bidirectional regulatory interplay between TRPV1 and tau, forming a "TRPV1-tau axis." This axis acts as a core molecular bridge connecting pain sensitization and AD pathology via calcium dyshomeostasis, mTOR/AMPK, PI3K/Akt/GSK3β, and neuroinflammatory pathways. TRPV1 overactivation promotes tau hyperphosphorylation and aggregation through calcium-dependent kinases, metabolic dysregulation, and inflammatory signaling. Conversely, pathological tau modulates TRPV1 expression and function via transcriptional regulation, protein interactions, and impaired axonal transport, establishing a deleterious feedback cycle. Therapeutic interventions targeting this axis, including TRPV1 modulators, tau-directed agents, anti-inflammatory drugs, and natural compounds, demonstrate potential in alleviating both pain sensitivity and cognitive deficits through multi-target mechanisms. However, clinical translation remains challenging due to issues including blood-brain barrier penetration, target selectivity, and a lack of reliable biomarkers. This review systematically outlines the bidirectional mechanisms of the TRPV1-tau axis, current intervention strategies, and translational challenges, with the goal of informing future development of disease-modifying therapies that concurrently address cognitive decline and chronic pain in AD.},
}

@article {pmid42013956,
year = {2026},
author = {Ou, Q and Dai, Z and Zhou, Y and Li, G and Liu, H and Li, J and He, C and Qin, S and Su, Z},
title = {Microglial heterogeneity in neurological disorders: From dynamic states to druggable targets.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117994},
doi = {10.1016/j.bcp.2026.117994},
pmid = {42013956},
issn = {1873-2968},
abstract = {Once viewed as a homogenous population, microglia are now understood to exist as a dynamic continuum of functionally distinct states whose existence is supported by accumulating evidence from multiple experimental approaches. This heterogeneity, spanning molecular, morphological, and metabolic dimensions, is actively sculpted by brain region, life stage, and a complex microenvironment of neuronal, astrocytic, and systemic signals. In neurological disorders such as Alzheimer's disease, this plasticity leads to context-dependent diversification into discrete subsets-ranging from protective, phagocytic phenotypes to detrimental, inflammatory ones-that critically influence disease progression. Decoding this heterogeneity through single-cell and spatial omics provides a new pharmacological blueprint: it reveals key druggable nodes (e.g., TREM2, CD14) that govern pathogenic state transitions and informs the rational design of subset-selective delivery systems (e.g., ligand-directed nanocarriers). However, translating these insights requires overcoming persistent challenges, including species differences between mouse and human microglia, a lack of tools for causal subset manipulation, and the integration of spatial with temporal dynamics. By framing microglial heterogeneity as a central targetable axis, this review outlines a pathway for developing precise, state-modulating therapeutics to intervene in neurodegeneration and neuroinflammation.},
}

@article {pmid42013966,
year = {2026},
author = {Langerová, T and MacVicar, E and Press, R and Read, FL and Piana, M and Murdoch, S and Innes, J and Wilson, J and Watson, AJM and Waldron, FM and Ramsay, G and Gregory, JM},
title = {Protein misfolding enteropathy predicts and prognosticates neurodegenerative disease years before symptom onset.},
journal = {Gastroenterology},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.gastro.2026.04.003},
pmid = {42013966},
issn = {1528-0012},
abstract = {BACKGROUND: Neurodegenerative disorders are characterized by progressive, irreversible neuronal loss that often advances silently for years before symptoms appear. Disease-modifying therapies are generally less effective once symptoms emerge, as substantial neuronal damage has already occurred. Consequently, there is an urgent need for accessible biomarkers that can predict disease well in advance and serve as reliable target-engagement measures in prevention trials.

METHODS: We analysed archival gastrointestinal (GI) biopsies from 196 individuals with unexplained GI symptoms and 13-15 years of follow-up. Using sensitive histopathological staining, we assessed misfolded TDP-43, tau, and α-synuclein to test whether peripheral proteinopathies can serve as predictive biomarkers for neurodegeneration.

RESULTS: Protein misfolding enteropathy was identified in 60% of cases. Individuals with GI proteinopathy were significantly more likely to develop non-Alzheimer's dementia or α-synucleinopathies, demonstrating >80% sensitivity; however, this performance should be balanced against a low specificity. The presence of two or more proteinopathy markers was associated with a dose-dependent reduction in survival, establishing GI proteinopathy as an independent, life-limiting prognostic factor. Importantly, these pathological changes were present 6.9 years before neurological symptoms emerged.

CONCLUSION: Our findings reveal that neurodegeneration-associated proteinopathies are not confined to the central nervous system but can be detected in routine GI biopsies years before clinical onset. This discovery provides a practical and scalable biomarker platform that could transform early diagnosis, risk stratification, and target-engagement monitoring in clinical trials. Protein misfolding enteropathy represents a new frontier for disease interception in neurodegenerative disorders, enabling intervention at a stage when neuronal damage may still be preventable.},
}

@article {pmid42013989,
year = {2026},
author = {Cui, J and Feng, J and Gong, Y and Huang, X and Chen, H and Hu, W and Li, L},
title = {Phenolic constituents from Raphiocarpus sesquifolius with neuroprotective and cognition-enhancing activities.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114924},
doi = {10.1016/j.phytochem.2026.114924},
pmid = {42013989},
issn = {1873-3700},
abstract = {Raphiocarpus sesquifolius (C. B. Clarke) Burtt is a unique medicinal plant from Sichuan Province, China. Seven phenolic compounds were isolated and identified from the whole herb for the first time: 6,4'-dihydroxy-7-methoxyflavone-5-O-β-D-(6'-acetoxy) glucoside (1), 6,4'-dihydroxy-7-methoxyflavonoid-5-O-β-D-glucoside (2), 4,9-dihydroxy-3-methyl-3,4-dihydroanthracen-1(2H)-one (3), 10-hydroxy-2-methylanthracene-1,4-dione (4), 4',5,6-trihydroxy-7-methoxyflavone (5), isoverbascoside (6), and caffeoyl ester of apionic acid (7). Compounds 1-4 are undescribed, with their structures elucidated mainly by HRESIMS, 2D NMR, ECD, and acid hydrolysis. Neuroprotective effects were evaluated in BV2 microglial cells, while acetylcholinesterase inhibition assays were performed to assess potential cognitive benefits. Compound 2 markedly suppressed nitric oxide production and exhibited anti-acetylcholinesterase activity. Transcriptomic analysis further revealed that compound 2 modulated multiple pathways associated with neuroinflammation and neuroprotection-including Toll-like receptor, TNF-α, MAPK, and NF-κB signaling-and upregulated genes related to cholinergic synapses. Collectively, our data demonstrate that compound 2 possesses dual functionality-conferring neuroprotection and enhancing cognition-thereby laying the mechanistic groundwork for its future development as a therapeutic agent for Alzheimer's disease and related neurodegenerative conditions.},
}

@article {pmid42014116,
year = {2026},
author = {Mangini, C and Leo, RD and Castagnoli, J and Nocentini, A and Gratteri, P and Taliani, S and Supuran, CT and Rossello, A and Cuffaro, D and Nuti, E},
title = {A New Series of Amino Alcohol Oxime Ethers as Activators of Human Brain Carbonic Anhydrases: Advances in Selective Activation of Human Carbonic Anhydrase VII.},
journal = {ChemMedChem},
volume = {21},
number = {8},
pages = {e70272},
doi = {10.1002/cmdc.70272},
pmid = {42014116},
issn = {1860-7187},
support = {PRIN 2017XYBP2R//Ministero dell'Università e della Ricerca/ ; Fondi di ateneo 2024//Università di Pisa/ ; },
mesh = {Humans ; *Oximes/chemistry/pharmacology/chemical synthesis ; *Carbonic Anhydrases/metabolism ; Structure-Activity Relationship ; *Brain/enzymology ; *Ethers/chemistry/pharmacology/chemical synthesis ; *Amino Alcohols/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; Molecular Docking Simulation ; Dose-Response Relationship, Drug ; },
abstract = {Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the interconversion of carbon dioxide and water to bicarbonate and proton. Given CA crucial role in carbon-based life, CA inhibition is a well-known therapeutic strategy for several diseases. However, in recent years, CA activation has emerged as a promising therapeutic approach for neurodegenerative conditions such as Alzheimer's disease, generalized anxiety, phobias and post-traumatic stress disorder. In this study, a new series of amino alcohol oxime ethers was synthesized from hit compound A to enhance its activity and selectivity towards four brain hCA isoforms, particularly hCA VII, which plays a key role in regulating neuronal pH related to synaptic plasticity and cognitive performance. Herein, we report a structure-activity relationship analysis to identify compounds that are both potent and selective activators for hCA VII. Among the synthesized derivatives, the morpholino propyl compound 12 emerged as the most active (KA = 72 nM) and selective over other brain isoforms. These results were further supported by in silico studies, which revealed favorable binding interactions at site A due to structural features present in both R and S enantiomers of compound 12.},
}

Humans
*Oximes/chemistry/pharmacology/chemical synthesis
*Carbonic Anhydrases/metabolism
Structure-Activity Relationship
*Brain/enzymology
*Ethers/chemistry/pharmacology/chemical synthesis
*Amino Alcohols/chemistry/pharmacology/chemical synthesis
Molecular Structure
Molecular Docking Simulation
Dose-Response Relationship, Drug

@article {pmid42014236,
year = {2026},
author = {Corcoran, E and Kettlety, M and Mogul, U and Azah, JN and Cork, SC},
title = {The effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104091},
doi = {10.1016/j.mcn.2026.104091},
pmid = {42014236},
issn = {1095-9327},
abstract = {BACKGROUND: The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Aβ.

METHODS: A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified.

RESULTS: This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer's disease pathology, particularly Aβ plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models while also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. An EXSCEL trial showed significant changes in systemic inflammatory markers. While pre-clinical data has been encouraging, clinical evidence remains limited.

CONCLUSIONS: There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ levels and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings have so far failed to demonstrate an arresting effect on cognitive.

REGISTRATION: PROSPERO CRD420251029748.},
}

@article {pmid42014279,
year = {2026},
author = {Mazzoli, R and Chiari, A and Rothman, KJ and Vitolo, M and Boriani, G and De Girolamo, G and Carrozzi, G and Tondelli, M and Filippini, T and Vinceti, M},
title = {Cardiometabolic diseases and risk of early-onset dementia: a population-based case-control study in Northern Italy.},
journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD},
volume = {},
number = {},
pages = {104760},
doi = {10.1016/j.numecd.2026.104760},
pmid = {42014279},
issn = {1590-3729},
abstract = {BACKGROUND AND AIMS: Early-onset dementia (EOD), defined by symptom onset before 65 years, has an uncertain etiology. Cardiovascular and metabolic diseases have been suggested to increase risk for EOD, but evidence remains limited and inconsistent. We investigated the extent to which history of cardiometabolic conditions is associated with EOD, and the extent to which the associations vary by sex, age at onset, and dementia subtype.

METHODS AND RESULTS: We conducted a population-based case-control study in Modena, Northern Italy, including 334 EOD cases diagnosed from 1999 to 2021, and 1991 controls matched by sex, year of birth, and calendar year. Hospitalization records and drug prescriptions were retrieved from administrative databases to estimate cardiometabolic disease history before EOD onset. We estimated odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression in the entire study population and within subgroups of age and sex. EOD cases showed higher rates of hospitalization for hypertension and diabetes. History of antidiabetic drugs (OR = 1.49, 95% CI 1.01-2.19), lipid-lowering agents (OR = 1.36, 95% CI 1.03-1.79), and antihypertensive drugs (OR = 1.47, 95% CI 0.93-2.32) was associated with higher EOD risk. Associations were stronger in males for antidiabetics (OR = 1.78, 95% CI 1.08-2.93) and antithrombotics (OR = 1.57, 95% CI 1.06-2.33), and in individuals <55 years for most antihypertensive classes. Non-Alzheimer's EOD generally showed higher associations with cardiovascular drug use than Alzheimer's type.

CONCLUSIONS: The associations we found between cardiometabolic diseases and EOD, particularly non-Alzheimer's subtypes, are consistent with a role of cardiometabolic burden or shared etiologic factors in early cognitive decline.},
}

@article {pmid42014397,
year = {2026},
author = {Timsina, J and Jiang, C and McCartney, DL and Tao, F and Dalmasso, MC and Najar, J and Anastasi, F and Ohlei, O and Puerta Fuentes, R and Yang, C and Bradley, J and Western, D and Ali, M and Wang, C and Yang, C and Wu, Y and Liu, M and Budde, J and Williams, J and Mahoney, R and Castillo Morales, A and Hohman, TJ and Dumitrescu, L and Wang, TC and Tesi, N and Kern, S and Waern, M and Skoog, I and van Harten, A and Pijnenburg, YAL and van der Flier, WM and Sánchez-Juan, P and Rodriguez-Rodriguez, E and Kleineidam, L and Peters, O and Schneider, A and Küçükali, F and Bellenguez, C and Grenier-Boley, B and Heikkinen, S and de Rojas, I and Rujescu, D and Scherbaum, N and Hausner, L and Düzel, E and Grimmer, T and Wiltfang, J and Vandenberghe, R and Engelborghs, S and Heilmann-Heimbach, S and Schmid, M and Tegos, T and Scarmeas, N and Dols-Icardo, O and Moreno, F and Pérez-Tur, J and Bullido, MJ and Sánchez-Valle, R and Álvarez, V and García-González, P and Mir, P and Real, LM and Piñol-Ripoll, G and García-Alberca, JM and Seelaar, H and Ramakers, I and Papma, J and Hulsman, M and Laske, C and Teipel, S and Priller, J and Perneczky, R and Buerger, K and Nöthen, MM and Lewczuk, P and Kornhuber, J and Hampel, H and Giegling, I and Goldhardt, O and Diehl-Schmid, J and Andrade, V and Heneka, MM and Frölich, L and Vogelgsang, J and Graff, C and Thonberg, H and Ullgren, A and Papenberg, G and Deleuze, JF and Dufouil, C and Wagner, M and Jessen, F and Holstege, H and van Duijn, C and Lebouvier, T and Hannon, O and Leinonen, V and Soininen, H and Herukka, SK and Giedraitis, V and Löwenmark, M and Kilander, L and Genius, P and Rodríguez, B and Luckett, ES and Navarro, A and Cano, A and Marquié, M and Blennow, K and Zetterberg, H and Lleo, A and Boada, M and Ruiz, A and Lee, VM and Van Deerlin, VM and Deming, Y and Johnson, SC and Engelman, CD and Pastor, P and Alvarez, I and Peskind, ER and Heslegrave, AJ and Saykin, AJ and Nho, K and Schindler, SE and Morris, JC and Holtzman, DM and McDade, E and Renton, AE and Goate, A and Ibanez, L and Riemenschneider, M and Albert, MS and Laws, SM and Porter, T and O'Brien, EK and Shaw, LM and Tijms, BM and Ingelsson, M and Visser, PJ and Hiltunen, M and Sleegers, K and Ritchie, CW and Sims, R and Belloy, M and Lambert, JC and Vilor-Tejedor, N and Fernández, MV and Li, QS and Nagle, MW and Marioni, RE and Ramirez, A and Bertram, L and van der Lee, SJ and Cruchaga, C},
title = {GWAS meta-analysis of cerebrospinal fluid Alzheimer's biomarkers reveals loci regulating lipids, brain volume and autophagy.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-71682-8},
pmid = {42014397},
issn = {2041-1723},
support = {R01AG044546//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; ZEN-22-848604/ALZ/Alzheimer's Association/United States ; },
abstract = {Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.},
}

@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