@article {pmid42177534,
year = {2026},
author = {Jiang, Q and Hu, JN and Dong, HM and Xin, JY and Shi, AY and Zeng, GH and Liu, J and Wang, YJ},
title = {In vivo profiling of astrocyte secretome reveals brain-region specific regulatory networks in a mouse model of amyloid pathology.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00956-y},
pmid = {42177534},
issn = {1750-1326},
support = {82120108010//the Natural Science Foundation of China/ ; 2023YFC3605400//the National Key Research and Development Program/ ; },
abstract = {Coordinated cell-to-cell communications is crucial for the proper functioning and maintenance of brain activities, and its disruption contributes to neurological disorders, including Alzheimer's disease (AD). Altered astrocyte-neuron communications have been implicated in AD progression, yet the underlying regulatory networks remain poorly understood. Given that secretory proteins mediate both local and long-range intercellular signaling, we constructed a spatiotemporal profile of the astrocyte-derived secretome using in vivo TurboID proximity labeling in mice of amyloid pathology. Early alterations in the entorhinal cortex secretome were identified and enriched in metabolic pathways, whereas changes in the hippocampus were observed later, correlating with neuronal and synaptic maintenance. These findings suggest that early remodeling of the astrocyte secretome in the entorhinal cortex may be involved in AD pathogenesis, while later changes in the hippocampus contribute to neurodegeneration and cognitive decline. This work provides a systematic map of the dynamic, region-specific remodeling of the astrocyte secretome in AD, identifying novel spatiotemporal vulnerabilities and potential therapeutic targets.},
}

@article {pmid42177952,
year = {2026},
author = {Nieto, ÁVA and Diaz, AH and Millán, MH and Sagredo, D and Gacitua, JA},
title = {Molecular Pathways and Clinical Applications of Probiotics as Effective Supporters of Intestinal, Neurologic, and Cardiovascular Health: a Narrative Review.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110424},
doi = {10.1016/j.jnutbio.2026.110424},
pmid = {42177952},
issn = {1873-4847},
abstract = {PURPOSE OF REVIEW: This narrative review aims to synthesize current knowledge on the molecular mechanisms and clinical applications of probiotics across three major health domains: intestinal, neurologic, and cardiovascular.

RECENT FINDINGS: •Intestinal health: Probiotics such as Lactobacillus rhamnosus GG and Bifidobacterium lactis BB-12 reinforce epithelial integrity via upregulation of tight-junction proteins (occludin, claudin-1), attenuate inflammation through cytokine modulation (↑IL-10, ↓TNF-α, IL-6), and restore eubiosis in conditions including IBS, constipation, and antibiotic-associated diarrhea. • Neurologic health: "Psychobiotic" strains (e.g., L. rhamnosus JB-1, B. longum 1714, L. helveticus R0052 + B. longum R0175) modulate neurotransmitter synthesis (GABA, serotonin), dampen HPA-axis hyperactivity, and reduce neuroinflammation, yielding improvements in anxiety, stress resilience, cognitive function, and slowing brain-atrophy progression in MCI and Alzheimer's disease. • Cardiovascular health: Meta-analyses of 30+ RCTs demonstrate that probiotic supplementation (notably L. acidophilus, L. plantarum, B. longum) lowers total and LDL cholesterol (-7 to -10 mg/dL) via bile-salt hydrolase activity, SCFA-mediated GPR signaling, direct cholesterol assimilation, and modestly reduces systolic (-2 to -4 mmHg) and diastolic blood pressure through anti-inflammatory pathways and improved endothelial function. • Safety: While generally safe in healthy populations, rare adverse events (bacteremia, D-lactic acidosis, horizontal gene transfer) have been reported in immunocompromised or critically ill individuals, underscoring the need for individualized risk-benefit assessments and rigorous adverse-event surveillance.

SUMMARY: Probiotics exert strain-specific, multi-mechanistic benefits on gut barrier integrity, neuroendocrine signaling, and cardiometabolic regulation. To fully realize their therapeutic promise, future research must pursue large-scale, head-to-head clinical trials, integrate multi-omics and precision-design approaches, and establish standardized frameworks for safety monitoring and personalized formulation.},
}

@article {pmid42178007,
year = {2026},
author = {Mu, Y and Yu, S and Yang, Z and Chen, S and Sun, J},
title = {Identification and Validation of Glycosylation-Related Biomarkers in the Hippocampus for Alzheimer's Disease Diagnosis and Drug Repurposing.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179014},
doi = {10.1016/j.ejphar.2026.179014},
pmid = {42178007},
issn = {1879-0712},
abstract = {As a crucial type of post-translational modification, glycosylation plays a fundamental role in maintaining cellular homeostasis and is closely associated with the progression of Alzheimer's Disease (AD). Given the central involvement of the hippocampus in AD pathogenesis, elucidating the mechanisms of glycosylation in this brain region may provide critical insights and facilitate the development of precision medicine strategies for AD. We employed an integrated bioinformatics framework to identify glycosylation-related diagnostic biomarkers for AD. Limma and WGCNA were conducted on a hippocampal gene expression microarray dataset to detect glycosylation-associated DEGs, which were intersected with a glycosylation gene set obtained from GeneCards. Key diagnostic genes were selected using three machine learning algorithms in an independent cohort. The diagnostic model was subsequently validated in two additional independent microarrays datasets. Functional exploration and hippocampal heterogeneity were assessed at both bulk-tissue and single-cell levels. PPI analysis and NMF clustering further stratified AD patients into two subtypes. Finally, qRT-PCR validated the expression of biomarkers, and molecular docking based on the CTD suggested potential therapeutic candidates. Our analysis identified CKMT1B and AP1S1 as key downregulated glycosylation-related genes in AD. These genes were predominantly and highly enriched in hippocampal microglia at both bulk and single-cell levels and demonstrated strong diagnostic potential. PPI network analysis and NMF revealed that these hub genes could stratify AD patients into two distinct molecular subgroups. Furthermore, quercetin was identified as a potential multi-target therapeutic agent through database screening and CTD molecular docking studies. Collectively, this study bridges fundamental discovery with clinical translation by providing a diagnostic model, patient stratification subtypes, and a repositioned therapeutic candidate, outlining a promising path toward personalized AD management.},
}

@article {pmid42178013,
year = {2026},
author = {Pattanaik, S and Sahu, PK and Paidesetty, SK and Prusty, SK and Pakeeraiah, K and Panda, PK and Lopamudra, },
title = {Design, synthesis, and inhibition of oxidative, amyloidogenic, and cholinergic dysfunction of Saxagliptin-derived Schiff bases against STZ-induced sporadic AD-like pathology.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178987},
doi = {10.1016/j.ejphar.2026.178987},
pmid = {42178013},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction, and impaired neuronal survival. Herein, we report 10 Saxagliptin (SXG, a potent DPP-IV inhibitor)-derived Schiff base derivatives that were virtually designed and screened. Five leads were prioritized using ADMET profiling and molecular docking, then synthesized via Schiff base condensation with selected aryl aldehydes to target AD progression associated with diabetes. Structural integrity, redox activity, and stability were confirmed by comprehensive characterization, including chromatographic and spectroscopic analyses, DFT calculations, and in vitro antioxidant assays. Neuroprotective potential was thus assessed in vivo by inducing AD-like pathology in rats with a single i.p. dose of STZ at 45 mg/kg, thereby reproducing brain insulin resistance, oxidative-nitrosative stress, and cholinergic dysfunction. Significant neurodegeneration in STZ-treated rats was evidenced by behavioral analyses, biochemical markers (AChE, Aβ42), oxidative stress indices (SOD, CAT, GSH, GPx, MDA, NO, MPO), and hippocampal histology. Treatment with SXG and derivatives at 0.5 mg/kg, orally, resulted in significant restoration of antioxidant defenses, inhibition of lipid peroxidation and NO overproduction, reduction of inflammatory oxidative bursts, and improved cognition in treated groups. Remarkably, derivatives 3c and 3e showed superior free-radical scavenging and greater regulation of redox biomarkers, which were associated with healthy, defined hippocampal cytoarchitecture and reduced neuronal pyknosis and necrosis compared with SXG. Additionally, 3e showed strong therapeutic efficacy by targeting oxidative stress, cholinergic, and amyloidogenic pathways synchronously.},
}

@article {pmid42178051,
year = {2026},
author = {Wang, C and Liu, J and Zhou, Y and Shan, X and Li, S and Ding, S and Zhuo, X and Li, Q and Yang, W and Zhang, X and Gu, L},
title = {Acacetin targets SNX5 to promote autophagy degradation of NLRP3 inflammasome against cognitive impairment in Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118103},
doi = {10.1016/j.bcp.2026.118103},
pmid = {42178051},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a chronic, low-grade inflammatory neurodegenerative disorder. Inhibiting the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a potential therapeutic strategy for AD, but no approved NLRP3-specific inhibitors are available for clinical use, and current agents often cause significant side effects despite their anti-inflammatory benefits. Acacetin, is a flavonoid compound that can penetrate the blood-brain barrier, with potential for treating AD.The purpose of this study is to clarify the relationship between the anti-AD effect of acacetin and its mechanism of inhibiting NLRP3.acacetin improved cognitive function and reduced neuronal damage in 3xTg mice. Further Acacetin directly binds to sorting nexin-5 (SNX5) and upregulates its expression. This, in turn, activates autophagy to degrade the NLRP3 inflammasome, alleviates inflammationin HT22 cells and BV2 cells. These findings suggest that Acacetin can exert an anti-AD effect by targeting SNX5 to activate autophagy and promote the degradation of the NLRP3 inflammasome, which underscore the importance of targeting SNX5 to suppress NLRP3 inflammasome activation in AD treatment.},
}

@article {pmid42178053,
year = {2026},
author = {Elkabes, S},
title = {Sexually dimorphic roles of toll-like receptors in the central nervous system.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106830},
doi = {10.1016/j.bbi.2026.106830},
pmid = {42178053},
issn = {1090-2139},
abstract = {Many neurological and psychiatric diseases and disorders show sex differences in prevalence, incidence, disease manifestation and response to treatment. Yet, historically, most clinical and pre-clinical studies have been conducted disproportionately or exclusively in male subjects. In recent years, this research bias has been increasingly addressed through human and animal studies where both sexes are appropriately represented. These investigations have identified sex-specific disease mechanisms driven by a combination of distinct genetic, anatomical, physiological, hormonal and neural factors in males and females. Sexual dimorphism in immune function has long been recognized. Toll-like receptors (TLRs), important mediators of the innate immune response to pathogens and endogenous danger signals, play sex-biased roles in peripheral immunity. Toll-like receptors are also expressed in cells intrinsic to the central nervous system (CNS). They initiate, not only neuroinflammation in CNS infections and disease and injuries, but also influence neurodevelopment and normal aging. Emerging evidence indicates that TLRs expressed in CNS cells contribute to neural pathology in a sex-specific manner, a research area that warrants further investigations. The aim of the present review is to highlight the sex-specific contribution of TLRs expressed in the CNS to chronic pain, neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's Disease and psychiatric disorders including major depressive disorder (MDD). Major findings are highlighted, essential concepts, controversies and knowledge gaps are discussed, and potential future directions are proposed. Attention is drawn to the importance of advancing this research area given that neuroinflammation is a key player in many CNS pathologies and TLRs are the essential drivers of neuroinflammation.},
}

@article {pmid42178096,
year = {2026},
author = {Roblin, L and Sampson, H and Murillo, I and Lake, R and Yasui, L and Hastings, ML and Wallace, DG},
title = {Evaluation of open field movement organization and spatial orientation in 5xFAD mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150393},
doi = {10.1016/j.brainres.2026.150393},
pmid = {42178096},
issn = {1872-6240},
abstract = {Wandering behavior or becoming lost in familiar environments is frequently observed during progression of Alzheimer's Disease (AD) and may be a possible prodromal symptom of the disease but also is extremely dangerous for those suffering from this neurodegenerative disease. The accumulation of amyloid-beta peptide (Aβ) has been implicated in the neuropathology and cognitive deficits associated with AD. This study investigated changes in open field movement organization in a 5xFAD mouse model of AD that and the deposition of amyloid pathology. Mouse open field behavior was collected under dark and light conditions at three, six, nine, and twelve months of age. The resulting pattern of genotype differences consisted of a motor deficit rather than impaired use of self-movement or environmental cues. This work establishes a foundation for future studies to investigate the efficacy of therapeutic interventions.},
}

@article {pmid42178203,
year = {2026},
author = {Suomi, T and Kettunen, J and Pusa, T and Elo, LL},
title = {Clarifying the scope and capabilities of ROTS in differential expression analysis.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag335},
pmid = {42178203},
issn = {1367-4811},
abstract = {SUMMARY: Recently, Anwar et al. introduced a method combining the ROTS reproducibility optimisation procedure with empirical Bayes variance estimation from limma. Here, we clarify several methodological aspects to support accurate interpretation of the results. We emphasise that ROTS is a general reproducibility optimisation framework rather than a single statistical test and demonstrate that benchmarking outcomes in the reported spike-in case studies are highly sensitive to analysis and evaluation choices. Furthermore, our reanalyses of the spike-in datasets do not support the reported conclusions, and we were unable to reproduce the results of the clinical Alzheimer's disease case study. These findings highlight the importance of transparent benchmarking practices and careful interpretation of comparative results.

The ROTS package is available through Bioconductor. The reanalyses were performed using the original code, with the minimal additions described in the manuscript.},
}

@article {pmid42178337,
year = {2026},
author = {Abaspour, N and Roghani, M and Bagheri, M and Khalili, M},
title = {Pioglitazone protects against trimethyltin hippocampal injury by reducing pyroptosis, mitochondrial dysregulation and ER stress.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54103-0},
pmid = {42178337},
issn = {2045-2322},
support = {522458//shahed University/ ; },
abstract = {Hippocampus-specific neurotoxic trimethyltin (TMT) is routinely used to mimic a reliable murine phenotype of neurodegeneration as well as cognitive loss and is accordingly appropriate to analyze pathogenesis of the prevalent neurodegenerative disorders, i.e. Alzheimer's disease (AD), and to examine the effectiveness of novel therapeutics. Antidiabetic medication pioglitazone has exhibited neuroprotective effects with promising clinical indications for neurodegeneration-based illnesses. This study was accomplished for studying the neuroprotective effect of pioglitazone against TMT-initiated cognitive decline and allied hippocampal neurodegeneration. For this purpose, rats received intraperitoneal TMT (8 mg/kg) to generate a model of AD-like neurodegeneration and subsequently had oral daily administration of pioglitazone for 3 weeks (20 mg/kg). The acetylcholinesterase inhibitor and certified anti-AD drug donepezil (4 mg/kg) was similarly used as a positive control medicine. Pioglitazone treatment was accompanied by lower cognitive deficits in novel object recognition test and Barnes maze paradigm in addition to mitigation of astrogliosis severity with glial fibrillary acidic protein (GFAP) as its specific indicator and lower CA1 neuronal loss. Furthermore, pioglitazone partially normalized hippocampal factors of oxidative stress and neuroinflammation together with downregulation of pyroptotic parameters comprising caspase 1 and NLR family pyrin domain containing 3 (NLRP3). Moreover, less activity of acetylcholinesterase (AChE) and greater quantity of mitochondrial health-allied factors comprising peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial membrane potential (MMP), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ (PPARγ) were likewise detected after pioglitazone treatment. These advantageous properties of pioglitazone were accompanied by inferior quantity of specific AD-allied markers comprising presenilin1 (PSEN1) and hyperphosphorylated tau (p-tau) as well as downregulation of endoplasmic reticulum (ER) stress, as observed by lower levels of PKR-like ER kinase (PERK), C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme 1α (IRE1α). While anti-AD donepezil treatment was associated with improvement of cognitive function, however, it was not capable to significantly yield most advantageous effects of anti-diabetic PPARg agonist pioglitazone. This study disclosed the underlying pathways for neuroprotective effect of pioglitazone in TMT neurodegeneration and AD-like phenotype.},
}

@article {pmid42178415,
year = {2026},
author = {Deng, C and Zhu, M and Yuan, J and Yin, T and Chen, H and Meng, S},
title = {Catalpol and tetramethylpyrazine relieve Alzheimer's disease by facilitating AQP4 protein expression and polarized distribution in hippocampal astrocytes via inducing the STAT3-mediated UCHL1 expression.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42178415},
issn = {1432-1912},
support = {20220213//Shanghai Sixth People's Hospital Medical Service Level Improvement Project Clinical Medical Technical Backbone Team Cultivation Project/ ; ZY(2021-2023)-0205-04//Three-year Action Plan (2021-2023) of Shanghai Municipality for Further Accelerating the Inheritance, Innovation, and Development of Traditional Chinese Medicine/ ; ZY(2021-2023)-0302//Construction of East China Area and Municipal TCM Specialist Disease Alliance/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder leading to dementia. This study investigated the effects of catalpol and tetramethylpyrazine (CT) on AD. AD mice were treated with CT, TGN020, 6RK73, and Stattic. The Morris water maze task was employed to assess spatial learning and memory. Histological staining was used to evaluate hippocampal neuronal damage, Aβ1-40 clearance, and AQP4 protein distribution in the hippocampus. An AD cell model was established by inducing Aβ1-42 in mouse astrocytes, followed by CT, 6RK73, and Stattic treatments. UCHL1 siRNA was transfected into astrocytes, and ubiquitination analysis was conducted. Gene expression was assessed via qRT-PCR and Western blot. CT improved spatial learning and memory in AD mice, mitigated hippocampal neuronal damage, enhanced Aβ1-40 clearance, increased UCHL1 and p-STAT3/STAT3 expression, and promoted AQP4 protein expression and its polarized distribution in the hippocampus. The improvement in spatial learning, memory, and hippocampal neuronal damage was diminished by TGN020. 6RK73 inhibited CT-induced AQP4 expression and its polarized distribution in hippocampal astrocytes. Stattic counteracted CT-induced upregulation of UCHL1 in the hippocampus. UCHL1 facilitated AQP4 deubiquitination. Silencing UCHL1 or treating with 6RK73 blocked CT-induced AQP4 expression and its polarized distribution in Aβ1-42-treated astrocytes. Stattic abolished CT-induced UCHL1 expression in Aβ1-42-treated astrocytes. CT likely promotes STAT3 phosphorylation, enhancing UCHL1 expression, which in turn facilitates AQP4 expression and its polarized distribution in hippocampal astrocytes, providing therapeutic benefits in AD. These findings suggest CT as a potential therapeutic agent for AD.},
}

@article {pmid42178432,
year = {2026},
author = {Khobrani, M and Al-Kuraishy, HM and Hussein, NR and Mustafa, AM and Batiha, GE},
title = {Neurosteroid-Mediated Neuroprotection via mTORC1/AMPK/BDNF Signaling Pathway in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42178432},
issn = {1559-1182},
mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Brain-Derived Neurotrophic Factor/metabolism ; *Signal Transduction/drug effects ; Animals ; *Neuroprotection/drug effects ; *AMP-Activated Protein Kinases/metabolism ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; *Neurosteroids/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide. AD is a neurodegenerative disease associated with progressive synaptic dysfunction, neuronal loss, and cognitive impairment. Current pharmacological therapies for AD offer only symptomatic relief and fail to halt or reverse the progression of the disease. It has been shown that neurosteroids (NSs), the endogenous modulators synthesized within the central nervous system (CNS), have emerged as promising therapeutic candidates in the management of AD by regulating of neuronal function, synaptic plasticity, and neurogenesis. Growing evidence suggests that NSs, particularly allopregnanolone (AP) and related analogues, exert neuroprotective effects by attenuating amyloid-β (Aβ) accumulation, reducing tau hyperphosphorylation, restoring of mitochondrial function, and suppressing of neuroinflammation. Importantly, NSs modulate key intracellular pathways which implicated in AD pathogenesis, such as mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and brain-derived neurotrophic factor (BDNF). Interestingly, NSs attenuate Aβ- and tau-induced neurotoxicity and neurodegeneration by enhancing neuroprotective autophagy, activating AMPK/BDNF signaling, and suppressing the mTOR signaling pathway. However, the exact role of NSs in relation to the mTOR/AMPK/BDNF signaling axis in AD is not fully explained. Thus, this review synthesizes current knowledge on the molecular mechanisms through which NSs influence the mTORC1/AMPK/BDNF signaling axis, highlighting their therapeutic potential in mitigating AD neuropathology. Understanding the multifaceted actions of NSs may pave the way for novel neuroprotective strategies and future clinical interventions in AD management.},
}

*Alzheimer Disease/metabolism/drug therapy/pathology
Humans
*Brain-Derived Neurotrophic Factor/metabolism
*Signal Transduction/drug effects
Animals
*Neuroprotection/drug effects
*AMP-Activated Protein Kinases/metabolism
*Mechanistic Target of Rapamycin Complex 1/metabolism
*Neurosteroids/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use

@article {pmid42178577,
year = {2026},
author = {Ruthirakuhan, M and Mills, M and Rosenberg, P and Haughey, N and Mintzer, J and Craft, S and Herrmann, N and Lerner, AJ and Levey, AI and Padala, PR and Porsteinsson, A and van Dyck, CH and Shade, D and Lanctôt, KL},
title = {Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02055-y},
pmid = {42178577},
issn = {1758-9193},
support = {R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer's disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders.

METHODS: Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH.

RESULTS: Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only.

CONCLUSIONS: This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.},
}

@article {pmid42178678,
year = {2026},
author = {Hattori, Y},
title = {Neurovascular unit failure as the opening chapter of dementia pathogenesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452178},
doi = {10.1177/13872877261452178},
pmid = {42178678},
issn = {1875-8908},
abstract = {Neurovascular dysfunction is increasingly recognized as a central feature of dementia pathogenesis in the early or even preclinical stage, rather than merely a downstream effect of amyloid-tau neurodegeneration. Based on multimodal clinical evidence showing that cerebrovascular dysregulation can precede amyloid-β accumulation, this commentary emphasizes three converging lines: (1) hippocampal blood-brain barrier breakdown as an early, potentially amyloid-/tau-independent event, (2) vascular-first/parallel two-hit frameworks linking vascular risk factors to subsequent proteinopathy, and (3) early neurovascular coupling failure and chronic hypoperfusion as upstream drivers. Integrating blood-brain barrier and hemodynamic biomarkers may facilitate earlier biological subtyping and prevention.},
}

@article {pmid42178714,
year = {2026},
author = {Zeamer, AL and Lai, Y and Loew, E and Sanborn, V and Tracy, M and Jo, C and Ferdinand, D and Ward, DV and Bhattarai, SK and Drake, J and McCormick, BA and Bucci, V and Haran, JP},
title = {Microbiome functional gene pathways are indicative of cognitive performance in older adults at risk for Alzheimer's disease.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2676162},
doi = {10.1080/19490976.2026.2676162},
pmid = {42178714},
issn = {1949-0984},
mesh = {Humans ; *Alzheimer Disease/microbiology ; *Gastrointestinal Microbiome/genetics ; Aged ; Female ; Male ; *Cognition ; Middle Aged ; *Cognitive Dysfunction/microbiology ; Aged, 80 and over ; *Bacteria/classification/genetics/isolation & purification/metabolism ; Cohort Studies ; Metagenomics ; Metabolic Networks and Pathways/genetics ; },
abstract = {Disturbances in the gut microbiome are increasingly correlated with neurodegenerative disorders, including Alzheimer's disease. Multiple lines of emerging evidence are consistent with the microbiome's involvement in disease pathology in AD by triggering or potentiating systemic and neuroinflammation, thereby influencing disease pathology through the "microbiota-gut-brain axis." Currently, the copathologies contributing to cognitive decline and symptomatic progression in AD remain unknown and understudied. Changes in the gut microbiome composition may offer clues to potential systemic physiologic and neuropathologic changes that contribute to cognitive decline. Here, we recruited a cohort of 260 older adults (aged 60 y or older) living in the community and followed them over time, tracking objective measures of cognition, clinical information, and gut microbiome samples. Subjects were classified as healthy controls, exhibiting mild cognitive impairment, or having dementia based on clinical assessments. Using metagenomic sequencing and gene pathway analyses, we found that certain microbial-encoded metabolic pathways correlated with worse cognitive performance. Specifically, genes involved in the urea cycle, polyamine synthesis, or the metabolism of methionine and cysteine predicted worse cognitive performance. Our study suggests that the gut microbiome composition may be linked to cognitive impairment along the AD continuum and points to microbial metabolic pathways that may potentiate disease.},
}

Humans
*Alzheimer Disease/microbiology
*Gastrointestinal Microbiome/genetics
Aged
Female
Male
*Cognition
Middle Aged
*Cognitive Dysfunction/microbiology
Aged, 80 and over
*Bacteria/classification/genetics/isolation & purification/metabolism
Cohort Studies
Metagenomics
Metabolic Networks and Pathways/genetics

@article {pmid42178732,
year = {2026},
author = {Liu, C and Qin, X and Talisa, VB and Wang, J},
title = {Heterogeneous causal mediation analysis using Bayesian additive regression trees.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag079},
pmid = {42178732},
issn = {1541-0420},
support = {R21AG087057/NH/NIH HHS/United States ; R01AG080590/NH/NIH HHS/United States ; S10OD028483/NH/NIH HHS/United States ; 2337612//National Science Foundation Faculty Early Career Development Program (CAREER) Award/ ; R305D200031//U.S. Department of Education Institute of Education Sciences Grant/ ; },
mesh = {Bayes Theorem ; Humans ; Computer Simulation ; Alzheimer Disease/genetics/pathology ; Regression Analysis ; *Causality ; *Mediation Analysis ; Apolipoproteins E/genetics ; Models, Statistical ; Genotype ; Biometry/methods ; Cognition ; },
abstract = {Causal mediation analysis provides insights into the mechanisms through which treatments affect outcomes. While mediation effects often vary across individuals, most existing methods focus solely on population-average effects, overlooking individual-level heterogeneity. To address this limitation, we propose a Bayesian regression tree ensemble method that flexibly models nonlinear relationships and captures treatment-by-mediator interactions in the mediation process. Using hierarchical posterior sampling, our approach provides credible intervals with nominal coverage rates for inferring heterogeneous mediation effects. Additionally, we leverage regression tree summaries to identify subgroups with distinct mediation effects and employ SHapley Additive exPlanation values to highlight key moderators and their influence on the mediation process. Comprehensive simulations demonstrate the method's accuracy in estimating and inferring heterogeneous mediation effects. Finally, we apply our method to investigate the heterogeneous mediation role of Alzheimer's disease pathology burden in the effect of apolipoprotein E genotype on late-life cognition.},
}

Bayes Theorem
Humans
Computer Simulation
Alzheimer Disease/genetics/pathology
Regression Analysis
*Causality
*Mediation Analysis
Apolipoproteins E/genetics
Models, Statistical
Genotype
Biometry/methods
Cognition

@article {pmid42178834,
year = {2026},
author = {Vidoni, ED and Mahnken, JD and Morris, JK and Wilkins, HM and Almaghraby, A and Honea, RA and Billinger, SA and Brunette, A and Parks, A and Perales-Puchalt, J and Hunt, SL and Baker, J and Arthur, AK and Fikru, SA and Cox, K and Burns, JM and Townley, RA},
title = {Operationalizing AD Biomarker Return of Research Results: Methods from the KU ADRC.},
journal = {Biopreservation and biobanking},
volume = {},
number = {},
pages = {19475535261447837},
doi = {10.1177/19475535261447837},
pmid = {42178834},
issn = {1947-5543},
abstract = {INTRODUCTION: Widespread implementation of Alzheimer's disease (AD) biomarkers in research settings introduces new opportunities and challenges for managing and returning complex, multi-modal testing results to research participants.

OBJECTIVES: To describe a structured, participant-centered biomarker data management and return of results workflow developed at a U.S. Alzheimer's Disease Research Center (ADRC), and to provide preliminary data on participant and clinician experience with return of results.

METHODS: We developed an automated, interdisciplinary workflow to integrate multimodal biomarker data (neuroimaging, fluid, and genetics) into research consensus diagnostic conferences and individualized participant Return of Results reports. To evaluate feasibility and participant experience, we conducted a non-randomized study in which participants receiving biomarker results rated anxiety, depression, and decision regret within one week and at 3-month follow-up.

RESULTS: The workflow was implemented using non-proprietary tools, with semi-automated data aggregation and nightly updates. Survey data indicated statistically significant changes in anxiety and depression following biomarker return of results, though the clinical relevance of these changes remains unclear, highlighting opportunities to improve utility.

CONCLUSIONS: Using and returning biomarker results is feasible, scalable, and well-tolerated within a research setting. This model may guide broader adoption of AD biomarker management and return of results to participants in future study designs.},
}

@article {pmid42178898,
year = {2026},
author = {Sousa, BP and Santos, KMD and Antunes, VR},
title = {Chemogenetic Stimulation of the Dorsal Motor Nucleus of the Vagus Mitigates Autonomic Dysfunction and Memory Decline in Rat Model of Alzheimer-Like Disease.},
journal = {Acta physiologica (Oxford, England)},
volume = {242},
number = {7},
pages = {e70261},
doi = {10.1111/apha.70261},
pmid = {42178898},
issn = {1748-1716},
support = {2023/08762-9//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 140359/2020-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 305570/2023-4//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Animals ; Male ; *Alzheimer Disease/physiopathology ; Female ; Rats ; *Memory Disorders/physiopathology/therapy ; Disease Models, Animal ; Rats, Long-Evans ; Rats, Transgenic ; *Vagus Nerve ; *Autonomic Nervous System Diseases/physiopathology ; Cholinergic Neurons ; Hippocampus/metabolism ; Chemogenetics ; },
abstract = {AIM: To test the hypothesis that Alzheimer-like metabolic neurodegeneration rat model leads to an autonomic dysfunction, memory impairment, and hippocampal amyloid pathology and that long-term chemogenetic stimulation of the dorsal motor nucleus of the vagus reverses these alterations.

METHODS: Male and female transgenic Long Evans rats received intracerebroventricular streptozotocin to induce sporadic Alzheimer-like pathology. Cardiovascular parameters and sympathetic and parasympathetic tone were evaluated in conscious animals. Episodic-like memory was assessed using the novel object recognition test. Hippocampal amyloid density was quantified by immunofluorescence. In male rats, cholinergic neurons of the dorsal motor nucleus of the vagus were selectively activated for 15 days using a chemogenetic approach, and autonomic, cognitive, and neuropathological outcomes were reassessed.

RESULTS: In male rats, the intracerebroventricular streptozotocin induced a significant increase in cardiac sympathetic tone, reduced object discrimination index performance, and increased hippocampal amyloid density compared with vehicle-treated controls, without altering mean arterial pressure or heart rate. Female rats showed no significant autonomic, memory, or hippocampal alterations at the same time point. Long-term chemogenetic stimulation of cholinergic neurons in the dorsal motor nucleus of the vagus in male rats reduced sympathetic tone to control levels, improved recognition memory, and attenuated hippocampal amyloid density compared with the non-stimulated control group.

CONCLUSION: These findings demonstrate a link between autonomic imbalance, memory dysfunction, and hippocampal amyloid pathology, and selective stimulation of the dorsal motor nucleus of the vagus restores autonomic balance and improves episodic-like memory and neuropathological outcomes, identifying this brainstem nucleus as a physiologically relevant therapeutic target in Alzheimer-related neuropathology.},
}

Animals
Male
*Alzheimer Disease/physiopathology
Female
Rats
*Memory Disorders/physiopathology/therapy
Disease Models, Animal
Rats, Long-Evans
Rats, Transgenic
*Vagus Nerve
*Autonomic Nervous System Diseases/physiopathology
Cholinergic Neurons
Hippocampus/metabolism
Chemogenetics

@article {pmid42178983,
year = {2026},
author = {Liu, JQ and Liu, H and Sun, YX and Li, Y and Liu, X and Wang, LQ and Yang, Z and Fu, Q and Xu, X and Chen, J and Zhang, Y and Zhou, J and Le, W and Cui, M and Liang, Y},
title = {Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e16846},
doi = {10.1002/advs.202516846},
pmid = {42178983},
issn = {2198-3844},
support = {U1967221//National Natural Science Foundation of China/ ; 32071212//National Natural Science Foundation of China/ ; U1967221//National Natural Science Foundation of China/ ; 22022601//National Natural Science Foundation of China/ ; 2024YFA1307300//National Key Research and Development Program of China/ ; 2023ZD0507202//National Major Science and Technology Projects of China/ ; },
abstract = {Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.},
}

@article {pmid42179001,
year = {2026},
author = {Rocha, IO and Delgado, CP and Nogara, PA and Rocha, JBT and Martins, MAP and Zanatta, N and Bonacorso, HG},
title = {Promising Flavonoid-Fused Aminoquinolines as Synthetic Alzheimer's Disease Models: Design, Synthesis, Anticholinesterase Activity, ADMET and Molecular Docking.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {27},
number = {10},
pages = {e70391},
doi = {10.1002/cbic.70391},
pmid = {42179001},
issn = {1439-7633},
support = {Code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 23038.004173/2019-93//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 043/2019//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88887511828/2020-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; Propesp 08-2023:PE08230723/026//Instituto Federal Sul-riograndense/ ; 305.379/2020-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Molecular Docking Simulation ; Humans ; Acetylcholinesterase/metabolism/chemistry ; *Drug Design ; *Aminoquinolines/chemistry/chemical synthesis/pharmacology ; *Flavonoids/chemistry/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Molecular Structure ; },
abstract = {An efficient one-pot, two-step [4 + 2] cyclocondensation reaction of (±)-2-phenylchroman-4-ones (1) with various scaffolds of 2-aminobenzonitriles (2) was employed using AlCl3 as the catalyst in the presence of toluene as a solvent under conventional thermal heating. This method was used to synthesize a series of six novel examples of (±)-7-amino-6-aryl-6H-chromeno[4,3-b]quinolines (3), which were designed as potential cholinesterase inhibitors. Subsequently, the new chromeno[4,3-b]quinolines were evaluated for their AChE and BChE inhibitory activity and subjected to molecular docking studies. In vitro cholinesterase assays and in silico docking demonstrated that all newly modified tacrine analogs 3 exhibited higher HsBChE inhibitory activity compared to HsAChE. Specifically, the most effective human cholinesterase inhibitor was the compound (±)-7-amino-6-phenyl-6H-chromeno[4,3-b]quinoline (3aa), with an IC50 of 2.73 μM for HsAChE and 0.096 μM for HsBChE. These findings suggest that compound 3aa is a promising candidate for further assessment in synthetic Alzheimer's disease models.},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology/metabolism
*Alzheimer Disease/drug therapy/metabolism
Molecular Docking Simulation
Humans
Acetylcholinesterase/metabolism/chemistry
*Drug Design
*Aminoquinolines/chemistry/chemical synthesis/pharmacology
*Flavonoids/chemistry/pharmacology
Butyrylcholinesterase/metabolism/chemistry
Structure-Activity Relationship
Molecular Structure

@article {pmid42179062,
year = {2026},
author = {Li, D and Dai, W and Li, X and Li, H and Li, L and Zhao, Y and Wang, X and Zhang, L},
title = {Amyloid-β suppresses oligodendrocyte differentiation in adult oligodendrocyte precursor cells (OPCs), with inflammatory gene changes distinguishing it from developmental OPCs.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451403},
doi = {10.1177/13872877261451403},
pmid = {42179062},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves white matter deterioration, but how amyloid-β (Aβ) affects oligodendrocyte lineage cells at different maturation stages remains unclear.ObjectiveTo determine whether Aβ impairs oligodendrocyte differentiation and myelination in adult oligodendrocyte precursor cells (OPCs) and to identify molecular correlates via RNA-seq.MethodsOligodendrocyte lineage cells were examined in plaque-associated regions of 8-month-old 5x familial Alzheimer's disease (FAD) mice by immunohistochemistry. Primary OPCs from neonatal and adult rats were cultured with or without amyloid-β1-42 oligomers (oAβ42) to assess differentiation. Myelination was evaluated in organotypic slice cultures. RNA-seq and qPCR were performed to identify oAβ42-induced gene expression changes.ResultsIn 5xFAD mice, Olig2[+] cells were reduced near plaques, with CC1[+] mature oligodendrocytes showing a pronounced decrease, while PDGFRα[+] OPCs remained unchanged. In vitro, oAβ42 inhibited differentiation of both neonatal and adult OPCs, with adult OPCs exhibiting intrinsically slower maturation. Slice cultures revealed selective hypomyelination (reduced myelin basic protein) after oAβ42 treatment. RNA-seq showed that oAβ42 induced a distinct transcriptomic profile in adult OPCs, with upregulated genes enriched in immune/inflammatory pathways. Core inflammatory genes Nr4a1 and Tnf were significantly upregulated, validated by qPCR.ConclusionsoAβ42 plaque pathology is associated with oligodendrocyte maturation blockade. Aβ impairs OPC differentiation in purified cultures accompanied by inflammatory transcriptional changes. These findings highlight oligodendrocyte dysfunction in AD white matter pathology and reveal a specific oAβ42 response in adult OPCs.},
}

@article {pmid42179067,
year = {2026},
author = {Wang, X and Liu, T and Guo, Y and Huang, M and Lv, C and Huang, W and Zhang, K and Chen, H and Chen, F},
title = {Cerebral blood flow-iron susceptibility decoupling links cognition, amyloid pathology, and neuroinflammation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452664},
doi = {10.1177/13872877261452664},
pmid = {42179067},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by decreased cerebral blood flow (CBF) and abnormal iron deposition, whereas their relationship remains unclear.ObjectiveTo investigate the spatial pattern of CBF-iron deposition coupling across the AD spectrum and its associations with cognition, plasma biomarkers, and inflammation.Methods34 AD dementia, 86 mild cognitive impairment (MCI), and 26 cognitively normal (CN) were enrolled. Voxel-wise CBF-susceptibility coupling was calculated using three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping (QSM). Whole-brain region-based analyses of CBF, QSM, and CBF-susceptibility coupling were subsequently performed. Correlation and mediation analyses were conducted to evaluate the relationships of CBF-susceptibility coupling with plasma biomarkers, inflammatory factors, and cognitive function.ResultsCBF was significantly reduced in the AD dementia group and MCI group. No significant group differences were observed in QSM susceptibility. The AD dementia group showed significantly lower CBF-susceptibility coupling in multiple brain regions than CN and MCI groups, which was positively correlated with Mini-Mental State Examination (MMSE), Animal Fluency Test scores, and the plasma amyloid-β 42/40 (Aβ42/Aβ40) ratio. In the MCI group, coupling values were negatively correlated with IL-2 levels. CBF-susceptibility coupling in the bilateral supplementary motor areas of AD patients partially mediated the association between Aβ42/Aβ40 ratio and MMSE.ConclusionsCBF-susceptibility coupling is significantly decreased in AD dementia and appears more sensitive than single-modality measures, and is associated with cognitive decline, amyloid pathology, and inflammation. These findings suggest that disrupted CBF-iron metabolism coupling may be a pathogenic mechanism underlying cognitive impairment in AD, possibly driven by early neuroinflammation.},
}

@article {pmid42179068,
year = {2026},
author = {Kanani, K and Ramakrishnan, P and Neupane, S and Misra, M and Balmer-Brown, K and Halteman, S and Warrick, T and , },
title = {Environmental risk and genetic susceptibility in Alzheimer's disease: Impacts on cognitive function and biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451855},
doi = {10.1177/13872877261451855},
pmid = {42179068},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves interactions among genetic, environmental, and lifestyle factors, yet the contribution of environmental exposures to cognitive decline and biomarker changes remains unclear. Detoxification genes such as EPHX1 may influence susceptibility to environmental neurotoxicants.ObjectiveTo evaluate associations between environmental risk, cognitive outcomes, and AD biomarkers, and to examine potential contributions of detoxification genes.MethodsWe analyzed 5101 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) across four study phases. Environmental exposure was summarized using a composite Environmental Risk Score (ERS) derived from Rural-Urban Continuum Codes, Rural-Urban Commuting Area codes, Risk-Screening Environmental Indicators, and occupational exposure. Cognitive outcomes included Mini-Mental State Examination, Clinical Dementia Rating, Montreal Cognitive Assessment, Neuropsychological Test Battery, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Executive Dysfunction Cognitive Assessment. Biomarkers included PET amyloid/tau, MRI hippocampal volume, and cerebrospinal fluid amyloid-β, tau, and neurofilament light chain. Multivariable regression models adjusted for sociodemographic factors and APOE ε4 carrier status.ResultsERS was significantly associated with CDR (β = -1.13E-07; 95% CI -1.98E-07, -2.75E-08; p = 0.00956) but not with other cognitive measures. EPHX1 showed a significant main effect on ADAS-Cog (β = 0.479; 95% CI 0.0305, 0.927; p = 0.0356). ERS × gene interaction terms were not significant. ERS was not associated with amyloid PET SUVR.ConclusionsEnvironmental risk showed limited associations with AD-related outcomes, while EPHX1 demonstrated a significant main effect on cognitive performance. Longitudinal studies are needed to clarify mechanisms linking environmental exposure and AD.},
}

@article {pmid42179069,
year = {2026},
author = {Zhang, T and He, M and Wang, Y and Gao, P and Xia, X and Li, J and Yin, Y and Zhao, G and Chen, O and Qu, M and Tang, Y and Qin, Q},
title = {Lipidomics reveals TREM2-associated dysregulation of plasma lipid metabolism in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450934},
doi = {10.1177/13872877261450934},
pmid = {42179069},
issn = {1875-8908},
abstract = {BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease (AD). While TREM2 facilitates central nervous system lipid clearance, its influence on peripheral lipid metabolism remains unclear.ObjectiveTo investigate the association between plasma sTREM2 and peripheral lipid profiles in AD and to explore the mechanistic role of TREM2 in peripheral lipid regulation.MethodsWe conducted a cross-sectional study of 59 AD patients and 54 healthy controls and measured plasma biomarkers including sTREM2 as well as performed targeted lipidomics profiling. Mechanistic exploration was performed via plasma and hippocampal lipidomics in Trem2 knockout and APP/PS1 mice.ResultsPlasma sTREM2 levels were elevated in AD and were negatively correlated with the plasma p-tau217/Aβ42 ratio and p-tau217. Multivariate analysis revealed a distinct lipidomics signature in AD, in which 30 lipid species were significantly altered. We prioritized significantly altered biomarkers to inform a composite biomarker panel combining sTREM2 with a set of sphingomyelins, phosphatidylinositols, diacylglycerols, fatty acids, and cholesteryl esters, which showed strong discrimination between AD and controls (AUC = 0.93). In a mouse model of APP/PS1, we found that Trem2 knockout partially normalized plasma sphingomyelins and hexosylceramide levels. Finally, cross-tissue comparisons further suggested that TREM2 exerted distinct effects on peripheral sphingolipid metabolism that were less evident in hippocampal tissue.ConclusionsOur findings associate TREM2 with lipid dysregulation in AD and support development of a plasma sTREM2-lipid panel for patient classification.},
}

@article {pmid42179082,
year = {2026},
author = {Dong, L and Liu, C and Lv, X and Song, X and He, Y and Shi, F and Qian, Y and Liu, Y},
title = {Visualization of perivascular spaces in Alzheimer's disease using 5.0 T MRI: A preliminary study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451167},
doi = {10.1177/13872877261451167},
pmid = {42179082},
issn = {1875-8908},
abstract = {BackgroundPerivascular spaces (PVS) have been associated with neurodegenerative diseases such as Alzheimer's disease (AD); however, the added value of 5.0 T magnetic resonance imaging (MRI) for PVS visualization in AD remains unclear.ObjectiveThis study aimed to investigate the utility of 5.0 T MRI for PVS in AD patients and healthy controls (HCs).MethodsA total of 186 participants were enrolled, including 62 AD patients and 124 age- and sex-matched HCs. All AD patients underwent paired 3.0 T and 5.0 T MRI scans on the same day, while 62 HCs underwent only 3.0 T MRI and 62 HCs underwent only 5.0 T MRI. Axial T2-weighted imaging was used for PVS assessment. Evaluations included qualitative and quantitative analysis in the basal ganglia (BG) and centrum semiovale (CSO).ResultsIn AD patients, 5.0 T MRI demonstrated significantly higher PVS image quality scores and severity scores in the BG and CSO than 3.0 T MRI (p < 0.05). Quantitatively, 5.0 T MRI detected a greater PVS burden, evidenced by increased number, larger volume, longer length, and higher curvature of PVS in the bilateral BG (p < 0.001), and increased number and volume of PVS in the bilateral CSO (p < 0.05) compared to 3.0 T MRI. Furthermore, when compared to HCs using 5.0 T MRI, AD patients exhibited higher PVS severity scores and greater PVS burden in most regions than HCs (p < 0.05).Conclusions5.0 T high-resolution images provide superior image quality for PVS visualization and reveal more detailed morphological information of PVS in AD patients compared to 3.0 T MRI.},
}

@article {pmid42179083,
year = {2026},
author = {Aiello, EN and Cazzini, F and Moreschi, A and Curti, B and De Luca, G and Frisco, F and Saba, S and Patisso, V and Maranzano, A and Silani, V and Ticozzi, N and Verde, F and Poletti, B},
title = {The head turning sign "outside the clinic walls" in patients with mild cognitive impairment and dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452271},
doi = {10.1177/13872877261452271},
pmid = {42179083},
issn = {1875-8908},
abstract = {BackgroundIn clinical settings, the head turning sign (HTS) occurs when patients with cognitive complaints turn their head toward the accompanying person seeking assistance. Due to its nature, and unlike other non-canonical neurological signs of cognitive impairment, the HTS is likely to occur in ecological, daily-life scenarios too. However, this hypothesis has not been tested yet.ObjectiveTo assess the prevalence and clinical correlates of the "ecological HTS" (eHTS) in MCI and dementia due to chronic-degenerative etiologies.MethodsThis retrospective cohort included 112 patients with MCI/dementia due to Alzheimer's disease (AD; N = 71), frontotemporal lobar degeneration (N = 6), Lewy body disease (N = 6), chronic cerebrovascular diseases (CVD; N = 11), mixed (i.e., AD + CVD; N = 15) unspecified non-AD neurodegenerative etiologies (N = 3). We recorded the number of HTSs displayed by patients during the MMSE and inquired accompanying persons whether the HTS occurred in daily life too.ResultsThe overall prevalence of the eHTS in the cohort was 50%; its distribution was independent of demographics, disease severity (i.e., MCI versus dementia), and etiology. Within multiple logistic models, the presence of the eHTS + proved to be predicted both by lower scores on the Spatial Orientation subtest of the MMSE and by a higher number of HTSs during the execution of the MMSE. Moreover, a trend towards longer disease duration and the occurrence of the eHTS was found.ConclusionsIn MCI and dementia, the HTS is an ecologically valid non-canonical sign, frequently occurs in daily life too, associated with longer disease duration and spatial disorientation.},
}

@article {pmid42179084,
year = {2026},
author = {Kim, D and Jeong, H and Lim, HK and Ahn, SM and Song, M},
title = {Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450638},
doi = {10.1177/13872877261450638},
pmid = {42179084},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.},
}

@article {pmid42179085,
year = {2026},
author = {Macoir, J and Lavoie, M and Laforce, R},
title = {Beyond language: A structured profile of number processing impairment in logopenic primary progressive aphasia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450931},
doi = {10.1177/13872877261450931},
pmid = {42179085},
issn = {1875-8908},
abstract = {BackgroundThe logopenic variant of primary progressive aphasia (lvPPA) is a language-led neurodegenerative syndrome commonly associated with Alzheimer's disease pathology and temporo-parietal degeneration. Although acalculia has been reported in lvPPA, numerical cognition has not been systematically investigated, and the specific profile of impairment remains poorly defined.ObjectiveTo characterize numerical cognition impairment in lvPPA using a comprehensive, theory-driven assessment battery and to examine its clinical relevance for diagnosis and cognitive characterization.MethodsFourteen individuals with lvPPA and twenty-eight demographically matched healthy controls completed the dCALQ, a standardized battery assessing number recognition and comprehension, number production (transcoding), and calculation. Participants also underwent global cognitive screening (Montreal Cognitive Assessment), language assessment (Detection Test for Language Impairments in Adults and the Aged), and measures of working memory and executive functioning. Group comparisons, intra-group domain analyses, correlation analyses, and receiver operating characteristic (ROC) analyses were performed.ResultsIndividuals with lvPPA showed significant impairments across all numerical domains compared with controls, with the most severe deficits in calculation, followed by transcoding, and milder impairment in number recognition and comprehension. Within the lvPPA group, performance differed significantly across domains, revealing a graded pattern of impairment. ROC analyses demonstrated excellent diagnostic accuracy for the dCALQ total score and strong discrimination for the calculation and transcoding domains.ConclusionsNumerical impairment is a robust and systematic feature of lvPPA rather than an incidental finding. The distinct numerical profile identified highlights the contribution of parietal-based cognitive dysfunction and supports the clinical utility of structured numerical assessment for cognitive characterization and diagnosis in dementia syndromes.},
}

@article {pmid42179089,
year = {2026},
author = {Tristão-Pereira, C and Casquero-Veiga, M and Malotaux, V and Quiroz, YT},
title = {Uncovering the causal link between cerebral glucose metabolism and cognitive function in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452181},
doi = {10.1177/13872877261452181},
pmid = {42179089},
issn = {1875-8908},
abstract = {Cerebral glucose metabolism is distinctly disrupted in Alzheimer's disease (AD), though its role in downstream cognitive decline remains unclear. Ueda et al. leverage Mendelian Randomization by integrating genetics, imaging and cognitive data to demonstrate that cerebral glucose metabolism is causally linked to cognitive performance. This approach lays the groundwork for novel therapeutic strategies by suggesting that metabolism-focused interventions may mitigate cognitive impairment in AD. Future studies should further integrate single-cell and multi-omics strategies to elucidate cellular and molecular pathways related to causal effects and explore the influence of co-pathologies and epigenetics on metabolic and cognitive performance.},
}

@article {pmid42179092,
year = {2026},
author = {Guilliams, C and Abner, E},
title = {Potential biases associated with reported parental history of dementia in the Alzheimer's Disease Research Center cohorts: Implications for secondary data analyses.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450630},
doi = {10.1177/13872877261450630},
pmid = {42179092},
issn = {1875-8908},
abstract = {AbstractBackgroundDeterminants of reported parental history of dementia among older adult research volunteers, and its relation to participation in brain aging studies, are incompletely understood.ObjectiveWe aimed to characterize older adults enrolled in Alzheimer's Disease Research Center (ADRC) cohorts by reported history of parental dementia according to age, APOE ε4 dose, sex, race, Hispanic ethnicity, education, and baseline cognitive status.MethodsData were drawn from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS). We included all participants who were age ≥ 65 at their most recent visit (N = 34,154). Participants were classified according to reported parental history of dementia (neither parent, mother only, father only, both parents, and unknown). Multinomial regression was used to estimate the adjusted odds ratios for reported parental history of dementia.ResultsDementia in at least one parent was reported by 40% of participants (n = 13,596), 52% (n = 17,881) reported that neither parent had dementia, and 8% (n = 2677) did not know. Participants reporting neither parent had dementia, or reported unknown history, were older, less educated, more likely to be minoritized, and were also most likely to be missing APOE genotype (28% and 37%, respectively) and to be diagnosed with cognitive impairment at baseline (62% and 75%, respectively).ConclusionsADRC participants who report no parental dementia history may represent a meaningfully different group of volunteers, and within this group there is also substantial heterogeneity among all of the characteristics of interest investigated, especially by race. These differences need to be carefully considered during secondary analyses of NACC UDS data.},
}

@article {pmid42179099,
year = {2026},
author = {Zhao, QF and Huang, LY and Zhu, YK and Hu, HY and Wang, HF and Zhang, W and Hu, H and Tan, L and , },
title = {YWHAG as a novel biomarker in Alzheimer's disease biological research framework.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450474},
doi = {10.1177/13872877261450474},
pmid = {42179099},
issn = {1875-8908},
abstract = {BackgroundYWHAG has been recognized as a promising biomarker for Alzheimer's disease (AD). However, the precise role of YWHAG within the revised 2024 diagnostic framework for AD remains unclear.ObjectiveOur study aimed to evaluate YWHAG with established biomarkers to delinea te the role of YWHAG and determine whether it could serve as a complementary biomarker within the 2024 diagnostic criteria.MethodsWe compared YWHAG with established biomarkers among 708 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) across three domains: 1) diagnostic utility, 2) cross-sectional associations with clinical variables and brain structure, and 3) predictive value for clinical progression risk.ResultsOur results demonstrated the accuracy of YWHAG (AUC = 0.856) was comparable to that of FDG-PET (AUC = 0.912) and HVA (AUC = 0.879), but superior to that of T-tau (AUC = 0.796), NFL (AUC = 0.712), and GFAP (AUC = 0.617) in distinguishing AD versus controls. Moreover, YWHAG was consistently among the top three biomarkers most strongly associated with cognitive decline and brain atrophy, alongside HVA and FDG-PET. Furthermore, the YWHAG positive (Y+) group had a significantly higher risk of AD progression (HR = 2.45, 95% CI: 1.75-3.43) compared to the YWHAG negative (Y-) group (p < 0.001).ConclusionsWe identify YWHAG as a novel biomarker predictive of cognitive decline, brain atrophy, and AD progression. The performances of YWHAG are comparable to established biomarkers such as FDG-PET, HVA and T-tau, thereby providing a complement to the current AD diagnostic framework.},
}

@article {pmid42179352,
year = {2026},
author = {Yuan, C and Zhao, S and Li, S and Song, X and Chen, Z and , },
title = {Interpretable Deep Regression Models With Interval-Censored Failure Time Data.},
journal = {Statistics in medicine},
volume = {45},
number = {13-14},
pages = {e70609},
doi = {10.1002/sim.70609},
pmid = {42179352},
issn = {1097-0258},
support = {12471251//National Nature Science Foundation of China/ ; 2025A1515012851//Nature Science Foundation of Guangdong Province of China/ ; 2025A03J3083//Science and Technology Program of Guangzhou of China/ ; 14301918//Research Grant Council of the Hong Kong Special Administrative Region/ ; 14302519//Research Grant Council of the Hong Kong Special Administrative Region/ ; 14300425//Research Grant Council of the Hong Kong Special Administrative Region/ ; },
mesh = {Humans ; Likelihood Functions ; Computer Simulation ; Alzheimer Disease/diagnostic imaging ; Survival Analysis ; Regression Analysis ; Algorithms ; *Neural Networks, Computer ; *Models, Statistical ; *Deep Learning ; },
abstract = {Deep neural networks (DNNs) have become powerful tools for modeling complex data structures through sequentially integrating simple functions in each hidden layer. In survival analysis, recent advances of DNNs primarily focus on enhancing model capabilities, especially in exploring nonlinear covariate effects under right censoring. However, deep learning methods for interval-censored data, where the unobservable failure time is only known to lie in an interval, remain underexplored and limited to specific data types or models. This work proposes a general regression framework for interval-censored data with a broad class of partially linear transformation models, where key covariate effects are modeled parametrically while nonlinear effects of nuisance covariates are approximated via DNNs, balancing interpretability and flexibility. We employ sieve maximum likelihood estimation by leveraging monotone splines to approximate the cumulative baseline hazard function. To ensure reliable and tractable estimation, we develop an EM algorithm incorporating stochastic gradient descent. We establish the asymptotic properties of parameter estimators and show that the DNN estimator achieves minimax-optimal convergence. Extensive simulations demonstrate superior estimation and prediction accuracy over state-of-the-art methods. Applying our method to the Alzheimer's Disease Neuroimaging Initiative dataset yields novel insights and improved predictive performance compared to traditional approaches.},
}

Humans
Likelihood Functions
Computer Simulation
Alzheimer Disease/diagnostic imaging
Survival Analysis
Regression Analysis
Algorithms
*Neural Networks, Computer
*Models, Statistical
*Deep Learning

@article {pmid42179353,
year = {2026},
author = {Li, X and Diao, L and Cook, RJ},
title = {Variable Selection for Illness-Death Processes Under Dual Observation Schemes.},
journal = {Statistics in medicine},
volume = {45},
number = {13-14},
pages = {e70608},
doi = {10.1002/sim.70608},
pmid = {42179353},
issn = {1097-0258},
support = {FRN 13887/CAPMC/CIHR/Canada ; 1280961//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Humans ; Likelihood Functions ; *Disease Progression ; Computer Simulation ; Algorithms ; Alzheimer Disease/mortality ; *Models, Statistical ; Dementia/mortality ; },
abstract = {The classical illness-death process offers a useful framework for studying the progression of chronic disease while jointly modeling death. In many settings the time of disease progression is not observed directly, but progression status is recorded at intermittent assessment times. This creates a dual observation scheme where progression times are interval-censored and death is subject to right censoring. We present a penalized observed data likelihood for variable selection in multiplicative intensity-based models for the joint process, involving different penalty functions for different sets of regression coefficients. Optimization is carried out based on an innovative expectation-maximization algorithm that can be implemented using existing software. Simulation studies demonstrate the finite sample performance of the method, and an application to a dementia study from the National Alzheimer's Coordinating Center (NACC) illustrates the insights that can be gained.},
}

Humans
Likelihood Functions
*Disease Progression
Computer Simulation
Algorithms
Alzheimer Disease/mortality
*Models, Statistical
Dementia/mortality

@article {pmid42179444,
year = {2026},
author = {El Bitar, F and Al Dawsari, G and Qadi, N and Al Rajeh, S and Abouelhoda, M and Al Subaie, S and Majrashi, N and Magrashi, A and Al Amari, H and Alghamdi, F and Abdulaziz, S and Al-Mubarak, B and Al Tassan, N},
title = {Rare and novel genetic variants in sporadic and familial Alzheimer's disease: insights from the first Saudi cohort.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1765569},
pmid = {42179444},
issn = {2673-6217},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex brain disorder that is greatly affected by genetics. Next-generation sequencing (NGS) has facilitated the discovery of rare variants in new genes that may be linked to AD in different populations. However, we still know very little about the genetic makeup of AD in Saudi Arabia and other Arab populations.

OBJECTIVES: This study aims to explore rare variants that are predicted to be deleterious in a group of 64 Saudi patients diagnosed with sporadic and familial Alzheimer's disease (AD). These patients previously tested negative for mutations in genes known to cause AD and were genotyped for APOE alleles.

METHODS: We performed whole-exome sequencing (WES) on the Ion Proton platform. Then, we used our internal process for filtering, validating, and prioritizing variants.

RESULTS: Using stringent selection criteria, we identified 107 rare candidate variants with potential functional relevance. Of these, 26 (24.3%) were novel, while the remaining variants had been previously reported in public databases. Among these candidates, 33 were connected to AD, 28 to both AD and other neurodegenerative disorders (OND), 34 to OND-related functions, and 11 to broader processes like aging, inflammation, and neuronal regulation. We found rare missense variants in genes involved in important processes related to Alzheimer's disease. These processes include mainly Aβ and Tau pathology, kinase signaling, stress response, and neuroinflammation.

CONCLUSION: Our analysis reveals diverse genetic contributors to Alzheimer's disease in a population that remains largely underrepresented in genomic studies. We identified candidate variants in 53% of the patients, highlighting the value of expanding AD genetics research to non-European populations.},
}

@article {pmid42179525,
year = {2026},
author = {Ryu, DH and Cho, JY and Jung, JW and Cha, HH and Kim, HM and Park, NY and Ahn, NH and Lee, JH and Park, JS and Lee, DS and Yang, SH and Kim, HY},
title = {Lactic Acid Bacteria-Mediated Fermentation Drives Metabolic Remodeling of Centella Asiatica (L.) Urb. toward Acidic Triterpenoids with Neuroinflammation-Related Bioactivity.},
journal = {ACS omega},
volume = {11},
number = {19},
pages = {28607-28618},
pmid = {42179525},
issn = {2470-1343},
abstract = {Centella asiatica Urb. is a medicinal plant rich in triterpenoid constituents with a reported neurobiological relevance. Its major metabolites are glycosylated triterpenoids, such as asiaticoside and madecassoside, whereas the corresponding acidic triterpenoids, including asiatic acid and madecassic acid, are typically present at low abundance. Given the increasing interest in how metabolic forms of natural products influence biological activity, this study investigated whether lactic acid bacteria (LAB)-mediated fermentation could induce metabolic remodeling of C. asiatica through microbial biotransformation. LAB fermentation markedly altered the secondary metabolite profile, which was characterized by a reduction in phenolic compounds and glycosylated triterpenoids and a pronounced enrichment of acidic triterpenoids. This compositional shift was accompanied by changes in bioactivity, including a decreased antioxidant capacity but enhanced anti-inflammatory effects in macrophage cells. Fermented C. asiatica significantly suppressed the expression of proinflammatory cytokines (TNF-α and IL-1β) and modulated amyloid-β and tau protein aggregation behavior in vitro. Furthermore, in an Alzheimer's disease transgenic mouse model, fermented extracts were associated with reduced amyloid plaque deposition, as assessed by Thioflavin S staining. Collectively, these results demonstrate that LAB-mediated fermentation drives functional metabolic remodeling of C. asiatica by altering the triterpenoid composition and bioactivity profiles. This work highlights microbial biotransformation as a versatile strategy for modulating the biological attributes of plant-derived natural products and for exploring relationships between chemical form and bioactivity in complex biological systems.},
}

@article {pmid42179538,
year = {2026},
author = {Acharya, K and Ainavarapu, SRK and Das, R},
title = {Cosolutes Modulate Polyubiquitin Fibrillation.},
journal = {ACS omega},
volume = {11},
number = {19},
pages = {28004-28014},
pmid = {42179538},
issn = {2470-1343},
abstract = {Ubiquitin, a 76-residue polypeptide, functions as a post-translational modifier and forms polyubiquitin (polyUb) chains on substrate proteins to activate diverse cellular functions. Ubiquitin is often found in the lesions associated with neurodegenerative disorders like Alzheimer's and Huntington's disease. It was recently observed that polyubiquitin chains, under in vitro conditions, often form β-sheet-rich fibrillar amyloid aggregates. However, the exact mechanism of conversion from monomer polyUb to amyloid-like fibrils is poorly understood. We report that polyubiquitin forms higher-order oligomeric fibrils and temperature, pH, and ionic strength modulate polyubiquitin (polyUb) fibrillation. Cosolutes such as ionic liquids and macromolecular crowding agents also enhance the aggregation rate. These findings uncover that temperature/cosolutes lower the energy barrier to populate a partially unfolded form (M*), which drives amyloid-like fibril formation. Other factors increase the effective protein concentration of these partially unfolded forms, accelerating aggregation. These insights provide the fundamental basis for ubiquitin chain aggregation, which is necessary to guide the development of therapies and diagnostics.},
}

@article {pmid42179740,
year = {2026},
author = {Chen, R and Chiu, SY and DeSimone, JC and Wang, WE and Barmpoutis, A and Mcmillan, CT and Radhakrishnan, H and Irwin, DJ and Clark, L and Kantarci, K and Boeve, BF and Vaillancourt, DE},
title = {Automated Imaging Differentiation for Dementia: Including Alzheimer Disease Dementia and Dementia with Lewy Bodies.},
journal = {Neurology open access},
volume = {2},
number = {2},
pages = {},
pmid = {42179740},
issn = {2998-7601},
abstract = {BACKGROUND AND OBJECTIVES: Differentiation of Alzheimer's disease dementia (ADD) and dementia with Lewy bodies (DLB) remains a challenge. Free-water imaging has been investigated in neurodegenerative diseases and was found to be associated with neurodegeneration and neuroinflammation. This retrospective cohort study tested whether Automated Imaging Differentiation for Dementia (AIDD), combining diffusion free-water imaging (FWI) and support vector machine, predicts ADD vs DLB with high accuracy.

METHODS: Diffusion MRI data was rendered from ADNI, NACC, and PDBP. Free-water and free-water corrected fractional anisotropy were calculated for each participant using a bi-tensor model. Diffusion metrics were randomly assigned to training and testing sets. The primary outcome was the area under the curve (AUC) in the test set. AIDD was paired with antemortem MRI to predict postmortem pathology.

RESULTS: A total of 519 diffusion scans were processed with 258 ADD (mean age 73.7 (8.8), 50% male), 129 DLB (mean age 69.3, 88% male), and 132 controls (mean age 73.6 (6.8), 40% male). The machine learning sample included 387 scans,129 ADD with a mean age of 72.8 (8.7), 52.7% male; 129 DLB with a mean age of 69.3 (8.1), 87.6% male; and 129 controls with a mean age of 73.7 (6.8), 39.5% male). AIDD showed high training AUC for ADD vs DLB = 0.995 (95% CI, 0.985-1.000), ADD vs controls = 0.992 (95% CI, 0.982-1.000), DLB vs controls = 0.991 (95% CI, 0.983-0.999), and controls vs ADD/DLB = 0.990 (95% CI, 0.979-1.000). The testing AUCs were similar: ADD vs DLB = 0.995, ADD vs controls = 0.958, DLB vs controls = 0.939, controls vs ADD/DLB = 0.903. AIDD predictions were confirmed pathologically in a cohort of 13 patients.

DISCUSSION: This study demonstrates that machine learning in combination with free-water imaging can differentiate ADD, DLB, and normal aging with high clinical and pathological accuracy. Advancement in early detection of dementia can lead to more appropriate treatment plans, especially for DLB, and improved disease stratification that have hindered drug development trials.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that Automated Imaging Differentiation for Dementia, combining diffusion free-water imaging and machine learning accurately distinguishes Alzheimer's Disease from Dementia with Lewy bodies.},
}

@article {pmid42179743,
year = {2026},
author = {Yu, Z and Li, H and Wang, Y and Shen, F and Wang, Y},
title = {Aerobic exercise versus acupuncture as adjuncts to acetylcholinesterase inhibitors in Alzheimer's disease: a systematic review and Bayesian network meta-analysis.},
journal = {American journal of clinical and experimental immunology},
volume = {15},
number = {2},
pages = {37-49},
pmid = {42179743},
issn = {2164-7712},
abstract = {Acetylcholinesterase inhibitors (AChEIs) remain the standard therapy for Alzheimer's disease (AD), yet their cognitive and functional benefits are limited, creating a strong need for effective adjunctive treatments. Aerobic exercise and acupuncture have been proposed as promising complements to AChEIs because of their potentially synergistic neurotrophic and cholinergic effects. To compare these treatment combinations, we carried out a Bayesian network meta-analysis (BNMA) of randomized controlled trials (RCTs). These studies were sourced from major English and Chinese databases and examined cognitive and functional outcomes. In total, 37 RCTs were included, covering 2,188 participants. Among all, combined acupuncture (SUCRA = 78.92%) and fire needle therapy (SUCRA = 78%) demonstrated the highest probability of improving Mini Mental State Examination scores, while moderate intensity aerobic exercise ranked best for the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, SUCRA = 23.3%) and the Barthel Index (SUCRA = 71.1%). Combined acupuncture was ranked highest for the Alzheimer's Disease Assessment Scale-Activities of Daily Living (ADAS-ADL, SUCRA = 94.3%), although its effects did not reach statistical significance. Across analyses, heterogeneity was minimal (I[2] ≤ 4%), model convergence was stable, and no publication bias was detected. Overall, this BNMA suggests that combined or thermal acupuncture offers the strongest cognitive gains alongside AChEIs, whereas moderate-intensity aerobic exercise provides the most reliable functional support. Because overall functional improvements were modest and evidence for some interventions remains limited, the benefits appear selective rather than broad. Larger, standardized trials are needed to clarify these patterns and guide their use in practice.},
}

@article {pmid42179817,
year = {2026},
author = {Hosseini, I and Northey, JM and D'Cunha, NM and Fernandez Rojas, R and Shrestha, A and Ghahramani, M},
title = {A systematic review and meta-analysis on dual-task sensor-based motion analysis for dementia detection.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1728588},
pmid = {42179817},
issn = {2673-253X},
abstract = {INTRODUCTION: Early diagnosis of dementia may be improved by objective, scalable tests that capture how cognitive tasks interfere with movement. This study examined the use of instrumented dual-task paradigms for dementia detection and characterisation.

METHODS: We performed a PRISMA-guided systematic review and meta-analysis of peer-reviewed studies that used dual-task paradigms in adults with clinically defined dementia and an appropriate comparator. We extracted primary motor tasks, secondary cognitive or motor loads, sensor modalities, and analytic approaches. Walking outcomes were meta-analysed using inverse-variance weighted random-effects models, including subgroup analyses for single-task versus dual-task conditions and for arithmetic versus memory and verbal fluency assessments.

RESULTS: The literature was dominated by cognitive-motor dual-task paradigms in Alzheimer's disease cohorts. Inertial measurement units and force plates were the most common instruments, and most studies used classical statistics, with fewer applying machine learning. Pooled effects showed consistent group differences; compared with controls, people with dementia walked more slowly, took shorter steps, and showed less steady timing. Although heterogeneity was substantial across studies, the direction of effects was stable, and dual-task conditions generally amplified group differences relative to single-task performance. Arithmetic loads tended to accentuate changes linked to speed and cadence, whereas memory and verbal fluency assessments tended to prolong timing measures. Balance, turning, and some upper-limb outcomes also differentiated groups.

DISCUSSION: Instrumented dual-task assessments appear to enhance detection of cognitive-motor impairment in dementia and may complement existing evaluations. To support clinical translation, future work should extend beyond Alzheimer's disease, standardise task instructions and reporting, and evaluate multi-modal, validated analytic approaches across different dementia subtypes.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251114199, CRD420251114199.},
}

@article {pmid42179845,
year = {2026},
author = {Nakazaki, M and Lankford, KL and Ukai, R and Hirota, R and Oka, S and Sasaki, M and Kocsis, JD and Honmou, O},
title = {Mesenchymal stromal/stem cell-derived extracellular vesicles in brain disorders: mechanisms of repair and recovery.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1819046},
pmid = {42179845},
issn = {1662-5102},
abstract = {Mesenchymal stem/stromal cell-derived small extracellular vesicles (MSC-sEVs) have emerged as promising cell-free therapeutics for central nervous system (CNS) disorders including stroke, traumatic brain injury (TBI), dementia, and multiple sclerosis (MS). MSC-sEVs offer advantages of low immunogenicity, ease of storage, and ability to cross the blood-brain barrier. This review provides a comprehensive analysis of the mechanisms by which MSC-sEVs have been reported to promote neural repair and recovery in preclinical models, through two convergent categories of action. First, MSC-sEVs exert direct neurorestorative effects, including activation of endogenous neural stem cells via Wnt/beta-catenin and PI3K/Akt/mTOR signaling, neuroprotection through PTEN/Akt-mediated anti-apoptotic and antioxidant pathways, preservation of mitochondrial function through mitophagy regulation, and promotion of neurite outgrowth and synaptogenesis through cytoskeletal remodeling and growth signaling. Second, MSC-sEVs modulate the injury microenvironment by shifting microglia and infiltrating macrophages toward anti-inflammatory phenotypes through NF-kB pathway modulation, converting reactive astrocytes to neuroprotective states, promoting angiogenesis and blood-brain barrier restoration, and enhancing oligodendrogenesis and remyelination. These effects are mediated largely through the transfer of microRNAs and other bioactive cargo to target cells at the injury site, although the relative contribution of individual cargo components remains to be fully established. We discuss how these actions address the pathophysiology of stroke, Alzheimer's disease, vascular dementia, TBI, and MS, highlighting disease-specific mechanisms and the current gap between preclinical evidence and clinical validation. Finally, we address challenges for clinical translation, including standardization of critical quality attributes and potency assays, route-dependent biodistribution, safety considerations, and dosing optimization. We also discuss engineering strategies for enhanced efficacy, including surface modification for CNS-targeted delivery, source cell preconditioning, cargo engineering, and scaffold-based sustained release systems. Although no clinical trials have yet evaluated MSC-sEV therapy specifically for neurological disorders, the growing body of safety data from non-neurological MSC-sEV trials and the extensive clinical experience with parent MSC therapies provide a foundation for future CNS-focused studies. MSC-sEVs hold substantial potential as a cell-free approach for neurological disorders that currently lack effective regenerative therapies, although realization of this potential will require rigorous clinical validation.},
}

@article {pmid42179865,
year = {2026},
author = {Arp, AM and Bloom, GS and D'Abreu, A and Fansler, A and Meegan, K and Ratcliffe, S and Kapur, J and Manning, C},
title = {The use of memantine for prevention of Alzheimer's disease: Pilot feasibility study rationale and protocol.},
journal = {Contemporary clinical trials communications},
volume = {51},
number = {},
pages = {101644},
pmid = {42179865},
issn = {2451-8654},
abstract = {BACKGROUND: Alzheimer's disease (AD) affects over 6 million older adults in the Untiled States. Evidence suggests the neuropathology leading to the disorder begins decades earlier, calling for a preventative treatment that can be administered to at risk individuals. Memantine hydrochloride, an NMDA receptor antagonist, is a possible candidate for prophylactic treatment by diminishing excessive NMDA receptor activity.

METHODS: This is a 2-year, double-blind, randomized, placebo-controlled trial of memantine hydrochloride (1:1 randomization allocation using randomly permutated blocks of unequal size). Participants are APOε4 carriers slightly under the average age of AD symptom onset (50-65 years of age) with a positive family history of a first degree relative with AD. Amyloid PET scans are performed pre and post treatment. Cognitive assessments and physical and neurological examinations are completed at regular intervals throughout the feasibility trial.

DISCUSSION: This study will assess the feasibility of the use of memantine hydrochloride for prevention of AD. The primary aim is to determine feasibility of participants who a) enrolled among those found eligible, and b) completed the study among those randomized to a study arm. Exploratory aims include examination of cognitive and safety assessments. Although not powered to determine efficacy, the study will provide direction on design elements needed for a Phase III clinical trial. No formal hypotheses are included in this feasibility trial.

TRIAL REGISTRATION: Clinical Trials NCT05063851.},
}

@article {pmid42179887,
year = {2026},
author = {Wang, R and Wang, J and Cai, J and Wang, S and Bai, Z and Che, Y},
title = {Feature fusion and WOA-GWO optimization for Alzheimer's disease detection with sparse EEG channels.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1835802},
pmid = {42179887},
issn = {1662-5188},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder with insidious onset, making early diagnosis challenging. Electroencephalogram (EEG) is a promising noninvasive tool for AD diagnosis, but high-density EEG configurations cause computational burdens and hinder clinical translation. Thus, developing an efficient sparse EEG channel selection method with high classification accuracy is urgent for AD auxiliary diagnosis. This study proposes a multi-strategy enhanced Whale Optimization Algorithm-Grey Wolf Optimizer (WOA-GWO) hybrid model for EEG channel selection, combined with a nonlinear dynamic feature fusion framework. We extracted geometric features from second-order difference plot (SODP) and complexity features (sample entropy, fuzzy entropy) of EEG signals, then adopted the ReliefF algorithm for feature fusion and key feature selection. The WOA-GWO model was improved via chaotic initialization, nonlinear convergence factors, spiral-hierarchical position update, and random perturbation to avoid local optima. Experimental results show that the proposed framework achieves a classification accuracy of 96.97% for AD detection, with significantly reduced EEG channel dimensions (four optimal channels identified: T5, FP1, T4, F4). The WOA-GWO model outperforms the original WOA and GWO in convergence speed and optimization accuracy, and the fused features exhibit strong discriminability for AD-related EEG abnormalities. This work provides a reliable computational framework for developing lightweight, portable AD diagnostic systems, and the identified optimal EEG channels offer neurophysiological evidence for AD electrophysiological biomarkers.},
}

@article {pmid42180238,
year = {2026},
author = {Wang, Y and Li, H and Zhou, J and Zhao, S and Yang, A and Li, Z},
title = {The clinical value of multimodal neuroimaging in monoclonal antibody therapy for Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1761380},
pmid = {42180238},
issn = {1664-2295},
abstract = {Multimodal neuroimaging plays an indispensable role in the diagnosis, monitoring, and therapeutic evaluation of monoclonal antibody (mAb) therapies for Alzheimer's disease (AD). Structural MRI (sMRI) enables early detection of cerebral atrophy and amyloid-related imaging abnormalities (ARIA), a critical adverse effect associated with anti-Aβ immunotherapies. Positron emission tomography (PET) provides direct visualization and quantification of Aβ plaque clearance, serving as an objective biomarker of target engagement. Functional MRI (fMRI) has been investigated as a means to detect dynamic changes in brain network connectivity following treatment, though the evidence remains preliminary. The integration of these modalities significantly enhances diagnostic accuracy and allows for personalized assessment of treatment response. Furthermore, artificial intelligence (AI) technologies improve the efficiency and predictive power of imaging data analysis, supporting clinical decision-making. Despite these advances, challenges remain regarding the sensitivity and specificity of current imaging techniques, heterogeneity in treatment responses, and the need for long-term safety monitoring. Standardized imaging protocols, combined with multidisciplinary collaboration and robust AI-assisted modeling, are essential to optimize therapeutic outcomes and minimize risks in mAb-based AD treatment.},
}

@article {pmid42180249,
year = {2026},
author = {Miranda, DG and Carrouel, F and Attik, N and Araujo, GF and Lopes, NFDS and Marcucci, MC and Rodrigues, FP and Caires, GA and Vigerelli, H and Godoi, BH and Pacheco-Soares, C and Ramos, LP},
title = {Correction: Juglans regia and Pfaffia paniculata extracts: implications for periodontal disease treatment and correlation with Alzheimer's risk.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1850828},
doi = {10.3389/fcimb.2026.1850828},
pmid = {42180249},
issn = {2235-2988},
abstract = {[This corrects the article DOI: 10.3389/fcimb.2025.1585438.].},
}

@article {pmid42180263,
year = {2026},
author = {Guo, X and Zheng, Y and Zhang, W and Yao, H},
title = {Biomolecular and cellular chirality: Novel diagnostic perspectives for diseases.},
journal = {APL bioengineering},
volume = {10},
number = {2},
pages = {021504},
pmid = {42180263},
issn = {2473-2877},
abstract = {Chirality is an intrinsic characteristic of living systems, manifesting as a pervasive asymmetry from the molecular to the cellular level. This asymmetry regulates normal life activities through precise stereospecific recognition between molecules and between molecules and cells. Under physiological conditions, L-amino acids constitute proteins that support metabolic functions, right-handed helical deoxyribonucleic acid (DNA) stores genetic information, and right-handed sugars provide energy. At the cellular level, the non-centrosymmetric arrangement of the cytoskeleton guides the left-right axial positioning during embryonic development and organ formation. A certain degree of chiral inversion occurs under normal physiological conditions-for instance, trace amounts of D-amino acids modulate neurotransmitter release, and low level of left-handed DNA promotes double-strand unwinding, facilitating transcription. However, excessive accumulation of D-amino acids is closely associated with Alzheimer's disease, chronic kidney di'ease, diabetes, and aging. Similarly, the presence of substantial left-handed DNA fragments can lead to genomic instability, "increasin" sus'eptibility to tumorigenesis. Moreover, abnormalities in cellular chirality may contribute to vascular endothelial barrier disruption and improper left-right organ positioning. Therefore, monitoring aberrant chiral molecules and cells that deviate from the normal range holds promise for the early diagnosis of diseases such as nephropathy, Alzheimer's disease, diabetes, and cancer. This article primarily reviews the dynamic chiral balance under physiological and pathological conditions, providing a reference for the application of chirally inverted molecules and cells Is potential novel biomarkers for the early diagnosis of diseases.},
}

@article {pmid42180326,
year = {2026},
author = {Haddad, E and Bhatt, RR and Dhillon, A and Nir, TM and Salminen, L and Al-Rousan, T and Ajrouch, K and Church, A and Sheikh-Bahaei, N and Jahanshad, N},
title = {Biopsychosocial risk factors for Alzheimer's disease and related dementias in UK immigrants from the Middle East and North Africa (MENA).},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.08.26352762},
pmid = {42180326},
abstract = {The Middle East and North Africa (MENA) region represents the area of greatest projected growth in instances of Alzheimer's disease and related dementias (ADRDs) globally, yet, it remains virtually uncharacterized in health studies of aging and ADRDs. The UK Biobank is one of the largest and well characterized datasets of aging immigrants in the UK, offering an unprecedented opportunity to identify risk factors for ADRDs in individuals from MENA regions. Here we used the UK Biobank to compare sociodemographic, disease, lifestyle, genetic, and neuroimaging risk factors for ADRDs among UK immigrants from MENA countries (N=3,552) with two other large immigrant populations from Germany (N=1,097) and India (N=2,935), as well as a genetically British white control group born outside the UK (N=1,925). MENA immigrants exhibited a distinct and adverse risk profile characterized by greater socioeconomic deprivation, higher exposure to air pollution, poorer diet quality, lower physical activity, worse sleep, and higher smoking prevalence compared to European immigrant groups. The same trends were observed when comparing MENA to Indian immigrants, though these differences were less pronounced. These behavioral and environmental risk factors were accompanied by markedly higher rates of obesity, diabetes, hypertension, and other cardiometabolic conditions. Despite this substantial phenotypic burden, MENA participants carried a lower frequency of established AD genetic risk variants, including ApoE4, highlighting a discordance between genetic risk and observed disease related vulnerability. Neuroimaging analyses revealed lower hippocampal volume in MENA and Indian participants relative to European groups despite younger average age, consistent with early limbic vulnerability associated with metabolic and inflammatory stress. Overall, our results indicate that dementia risk in MENA populations is driven by a multidimensional framework of metabolic, systemic, and social environmental exposures that may shape vulnerability independently of canonical European-derived genetic risk factors. These findings highlight the urgent need for ancestry- and context-specific frameworks to support equitable dementia prevention and avoid under-predicting risk in underrepresented populations.},
}

@article {pmid42180327,
year = {2026},
author = {Raeesi, S and Metz, A and Chadwick, K and Zeighami, Y and , and , and Morrison, C and Dadar, M},
title = {Education, Cognitive Reserve, and Brain Pathology in Aging and Alzheimer's Disease: Evidence from Preclinical and Symptomatic Cohorts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.07.26352659},
pmid = {42180327},
abstract = {INTRODUCTION: Educational attainment is a key proxy of cognitive reserve (CR), but whether its association with cognition persists after accounting for multimodal brain pathology remains unclear.

METHODS: Data from PREVENT-AD and CIMA-Q were analyzed using cross-sectional, longitudinal, and residual-based models adjusted for multimodal pathology, including MRI-based white matter hyperintensities and atrophy measures, and plasma Alzheimer's disease biomarkers. Education was examined in both cohorts. A multidimensional CR questionnaire was also examined in CIMA-Q.

RESULTS: Higher education was associated with better performance across multiple cognitive domains after accounting for pathology (p < 0.05). The CR composite score showed less consistent associations, and non-education subdomains showed limited added value. Longitudinally, education was more consistently associated with baseline cognitive levels than cognitive change, with executive-function trajectory differences observed in PREVENT-AD.

DISCUSSION: Findings support a CR framework in which education relates to better cognition despite pathology, while effects on decline are limited and domain-specific.},
}

@article {pmid42180365,
year = {2026},
author = {Moallemian, S and Raminfard, S and Mhatre-Winters, I and Budak, M and Fausto, BA and Richardson, JR and Gluck, MA},
title = {Peripheral TARC (CCL17) Levels Track Widespread Microstructural Vulnerability in Cognitively Unimpaired Older African Americans.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.12.26353011},
pmid = {42180365},
abstract = {INTRODUCTION: Neuroinflammation and immune dysregulation are increasingly recognized as early drivers of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), often emerging decades before the onset of clinical symptoms. Despite this, there remains a critical need for non-invasive biomarkers that can capture these early processes, particularly in African Americans, a population at elevated risk for AD/ADRD yet underrepresented in neuroimaging research. In this study, we investigated the relationship between systemic plasma inflammatory markers and brain microstructural integrity in cognitively unimpaired older African Americans.

METHODS: Forty-one participants (mean age = 68.68 years) underwent MRI scanning and multi-plex plasma-based inflammatory marker quantification. Microstructural changes were quantified using Diffusion Weighted Imaging (DWI) metrics, including mean diffusivity (MD), radial diffusivity (RD), mean kurtosis (MK), and radial kurtosis (RK). Voxel-wise general linear models, and cluster-based models were used to examine associations between plasma-derived inflammatory markers and brain microstructure.

RESULTS: Higher TARC levels were associated with widespread increases in MD and RD across both gray and white matter, implicating reduced microstructural integrity and potential myelin disruption. In contrast, kurtosis-based metrics demonstrated more spatially selective and generally weaker associations, with MK and RK showing limited decreases primarily within white matter tracts. Cluster-level analyses confirmed the robustness of diffusivity findings and highlighted consistent effect sizes across multiple regions.

DISCUSSION: These findings suggest that elevated TARC is linked to early microstructural alterations detectable with diffusion MRI, with diffusivity metrics demonstrating greater sensitivity to inflammation-related changes than kurtosis measures in this cohort. This work underscores the importance of incorporating inflammatory biomarkers in neuroimaging studies of aging and highlights diffusion MRI as a promising tool for detecting early neurobiological signatures of AD/ADRD risk in African American populations.},
}

@article {pmid42180376,
year = {2026},
author = {Andrieieva, D and Falltrick, I and Chiang, CY and Beaumont, B and Guen, YL and Liu, C and Pergolesi, S and Ma, CT and Jackson, MR and Hyman, BT and Jackson, RJ},
title = {APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.09.26352797},
pmid = {42180376},
abstract = {Apolipoprotein E (ApoE) is the principal lipid transport protein in the central nervous system and the strongest genetic modifier of late-onset Alzheimer's disease (AD) risk. The three common isoforms, ApoE2, ApoE3, and ApoE4, differ in their propensity to self-associate, with ApoE4 forming oligomers more readily than ApoE3 or ApoE2. This enhanced self-association is proposed to reduce the pool of lipid-competent monomeric ApoE4 available for cholesterol transport and amyloid-β clearance, contributing to AD pathogenesis. Here we describe a quantitative, cell-based split-luciferase complementation assay for ApoE self-association using the NanoBiT system, in which SmBiT- and LgBiT-tagged ApoE produced by HEK293 cells are combined and luminescence is measured. ApoE4 shows significantly enhanced self-association relative to ApoE3, while ApoE2 is no different from ApoE3. Testing a panel of naturally occurring and engineered variants demonstrates that the C-terminal self-association interface is the primary determinant of isoform-specific differences: two APOE ε3-backbone C-terminal variants, Jacksonville (V236E) and W276C, both reduce self-association below ApoE3 levels, while the APOE ε 4 -backbone protective variant R251G and the engineered domain-interaction probe R61T both reduce ApoE4 self-association to the level of ApoE3. In contrast, the Christchurch variant (R136S), the African-ancestry risk variant R145C, and the Admixed American risk variant R189C do not alter self-association. These findings establish a sensitive cell-based assay for ApoE self-association and highlight the C-terminal domain as a potential therapeutic target for normalizing ApoE4 function.},
}

@article {pmid42180382,
year = {2026},
author = {Rathmell, CS and Sun, H and Ge, W and Magdamo, C and Das, S and Moura, LMVR and Zafar, SF and Akeju, O and Mukherji, SS and Shaw, KM and Westover, MB},
title = {Delirium and Increased Risk of Developing Dementia: An Emulated Target Trial Analysis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.11.26352925},
pmid = {42180382},
abstract = {BACKGROUND: Multiple studies suggest bidirectional links between delirium and Alzheimer's Disease and Related Dementias (ADRD). Although they establish a strong association between delirium and subsequent ADRD, it has not been explored using statistical causal inference which makes the best use of observational data to minimize biases.

METHODS: We conducted an emulated clinical trial to estimate the effect of experiencing delirium during hospitalization between April 2017 and September 2019 on the cumulative incidence of ADRD over two years following hospital admission in patients 65 and older. The emulated trial used observational data from individuals in the Mass General Brigham Electronic Medical Record (EMR). We carried out statistical causal survival analysis using methods that adjust for confounding, censoring, competing risks, and immortal-time bias, including inverse propensity weighting (IPW) and g-formula approaches.

RESULTS: Of the 6029 patients hospitalized in this time frame who were 65 or older with evidence of a PCP in the EMR, 5901 were included in the analysis based on no history of dementia diagnosis or medications 12 months prior to admission. At two years post-admission, the adjusted cumulative incidence of ADRD in individuals who did not experience delirium was 7.6% (95% Confidence Interval [CI] 4.0-12.1%) while it was 20.2% (95% CI 13.2-27.9%) for those who did experience delirium when calculated using the IPW method.

CONCLUSIONS: Our emulated trial results argue for a strong association between delirium during hospitalization and the risk of developing ADRD in the two years following hospital admission in individuals 65 and older.},
}

@article {pmid42180383,
year = {2026},
author = {Petersen, KK and Li, Y and Schindler, SE},
title = {Time until symptoms and design-related associations in Alzheimer's disease clinical progression analyses.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.10.26352825},
pmid = {42180383},
abstract = {INTRODUCTION: Studies of the risk and timing of symptomatic Alzheimer's disease (AD) in cognitively unimpaired individuals are challenging due to the relatively small number of clinical progressors and limited clinical follow-up, which can lead to design-related associations. Clock models can be used to anchor the timing of events to biological events such as biomarker positivity. We hypothesized that estimated age at plasma %p-tau217 positivity based on clock models is less affected by design-related associations as compared to baseline age.

METHODS: Data from the Knight Alzheimer Disease Research Center (Knight ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed. Age at %p-tau217 positivity was estimated using two clock model approaches, TIRA and SILA. The C-index of estimated age at plasma %p-tau217 positivity and age at the baseline plasma sample (baseline age) for ranking age of AD symptom onset was evaluated in initially cognitively unimpaired individuals, including progressors and non-progressors. In progressor sub-cohorts, baseline age and time from %p-tau217 positivity to baseline were associated with time from baseline until symptom onset; baseline age and estimated age at %p-tau217 positivity were associated with age at symptom onset. Commonality analyses partitioned the variance unique to each predictor and shared between predictors. Randomization analyses evaluated whether observed associations exceeded those expected by chance.

RESULTS: Estimated age at %p-tau217 positivity enabled analyses of a greater number of progressors in the research cohorts, which did not have plasma %p-tau217 data from every clinical assessment. The estimated age at %p-tau217 positivity had a higher C-index than baseline age for ordering the likelihood of AD symptom onset when all follow-up was considered; when follow-up was truncated, the C-index for estimated age at %p-tau217 positivity remained stable while the C-index for baseline age became inflated. In progressors, estimated age at %p-tau217 positivity contributed unique variance beyond baseline age in associations with age at symptom onset. Randomization analyses in the larger Knight ADRC found that associations between clock-derived measures and time from baseline until symptom onset and age at symptom onset exceeded the permuted null distribution, with some mixed results in the smaller ADNI cohort.

CONCLUSIONS: Compared to baseline age, the biologically-anchored estimated age at %p-tau217 positivity is less susceptible to design-related associations and incrementally improves prediction of age at symptom onset in analyses conditional on progression.},
}

@article {pmid42180384,
year = {2026},
author = {Mhatre-Winters, I and Cirillo, PM and Factor-Litvak, P and Han, Y and Krigbaum, NY and Zimmermann, LM and Link, BG and Go, YM and Jones, DP and Cohn, BA and Richardson, JR},
title = {Prenatal Pesticide Exposure and Early Alzheimer Disease-Related Biomarker and Cognitive Changes in Midlife.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.13.26352896},
pmid = {42180384},
abstract = {IMPORTANCE: Alzheimer disease (AD) pathogenesis begins decades before clinical symptoms, yet environmental determinants of early disease risk, particularly during fetal development, remain largely uncharacterized. Prenatal exposure to dichlorodiphenyldichloroethylene (DDE), the primary persistent metabolite of DDT, is a biologically plausible early contributor to AD risk given its long half-life in human tissue and higher levels observed in AD patients. However, prospective human evidence linking prenatal DDE to midlife AD-relevant outcomes is absent.

OBJECTIVE: To determine whether prenatal DDE exposure is associated with plasma AD biomarkers and cognitive performance in midlife, and whether APOE ε4 genotype modifies these associations.

DESIGN: Observational cohort analysis nested within the Child Health and Development Studies (CHDS), a population-based birth cohort.

SETTING: CHDS enrolled pregnant women between 1959-1967 in the San Francisco Bay Area.

PARTICIPANTS: Among 367 eligible adult offspring who participated in a follow-up study (2010-2013) at mean age 49.3 years, 179 with available prenatal DDE measurements were included.

MAIN OUTCOMES AND MEASURES: Primary outcomes were prenatal DDE levels from maternal serum, plasma Aβ42/40 ratio and Digit Symbol Substitution Test (DSST) performance and APOE genotype. Secondary outcomes included plasma pTau217, GFAP, NfL and measures of verbal fluency (VF) and the Wechsler Test of Adult Reading (WTAR).

RESULTS: Among 179 participants (56% female; 26% APOE ε4 carriers), mean prenatal DDE was 47.4 (25.4) ng/mL. Higher prenatal DDE was associated with lower DSST scores (β=-0.021; 95% CI, -0.041 to -0.001; P=0.039) and lower plasma Aβ42/40 ratio (β=-0.079; 95% CI, -0.133 to -0.024; P=0.005) per ng/mL DDE, adjusting for sex, race, education, and APOE ε4 status. Associations were strongest among APOE ε4 non-carriers for DSST (β=-0.033; 95% CI, -0.050 to -0.016; P=0.001) and Aβ42/40 ratio (β=-0.101; 95% CI, -0.161 to -0.040; P=0.001). No significant associations were observed for pTau217, GFAP, NfL, VF or WTAR.

CONCLUSIONS AND RELEVANCE: In this prospective birth cohort study, prenatal exposure to a persistent environmental toxicant was associated with lower plasma Aβ42/40 ratio and worse cognitive performance in midlife, consistent with DDE accelerating the preclinical trajectory of AD-related biological changes decades before symptom onset. These findings support a life-course framework for AD risk and identify prenatal DDE as a potentially modifiable determinant of early AD-related pathology amenable to prevention.

KEY POINTS: Question: Is prenatal exposure to dichlorodiphenyldichloroethylene (DDE), primary persistent metabolite of DDT, associated with plasma Alzheimer disease biomarkers and cognitive performance in early midlife offspring?Findings: In 179 participants from a prospective birth cohort followed for 50 years, higher prenatal DDE was associated with lower plasma Aβ42/40 and worse cognitive performance at mean age 49.3 years. Associations were substantially stronger among APOE ε4 non-carriers.Meaning: Prenatal exposure to a ubiquitous environmental toxicant is associated with amyloid-related biomarker and cognitive changes in early midlife, consistent with an accelerated preclinical Alzheimer disease trajectory and supporting fetal environmental exposures as modifiable determinants of long-term AD risk.},
}

@article {pmid42180526,
year = {2026},
author = {Zhang, X and Yu, X and Sha, L and Li, Y and Qiao, Q and Yu, X and Xu, Q},
title = {Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2964-2981},
pmid = {42180526},
issn = {2211-3835},
abstract = {Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors can reduce seizures in temporal lobe epilepsy (TLE) by upregulating excitatory amino acid transporter 2 (EAAT2, also known as GLT-1). While the Hsp90 inhibitor 17-AAG is effective, its long-term use raises toxicity concerns. This study aimed to identify a safer Hsp90 inhibitor by screening benzenoid ansamycin derivatives for higher binding affinity and lower toxicity. Among nine natural benzenoid ansamycins and their derivatives screened, reblastatin emerged as the top candidate, exhibiting the highest binding affinity to Hsp90. Compared to geldanamycin and 17-AAG, reblastatin demonstrated significantly lower cytotoxicity in HEK293 and HepG2 cells. Like 17-AAG, reblastatin upregulated EAAT2 levels by disrupting the association among Hsp90, EAAT2, and the 20S proteasome. In a kainic acid-induced TLE mouse model, reblastatin reduced seizure frequency by 50%, with long-term treatment showing toxicity comparable to vehicle controls. Additionally, behavioral tests revealed neuroprotective effects of reblastatin in mouse models of Alzheimer's disease and Parkinson's disease. These findings collectively suggest that reblastatin is a promising Hsp90 inhibitor for treating TLE and excitotoxic conditions associated with neurodegenerative diseases.},
}

@article {pmid42180530,
year = {2026},
author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L},
title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2601-2644},
pmid = {42180530},
issn = {2211-3835},
abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.},
}

@article {pmid42180543,
year = {2026},
author = {Yang, Y and Liu, J and Liu, J and Wei, S and Kong, X and Mu, W and Liu, Y and Zhang, N},
title = {Advances in immune cell-based therapeutic agents for the treatment of inflammation-related diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2794-2837},
pmid = {42180543},
issn = {2211-3835},
abstract = {Inflammation-related diseases account for over 50% of global disease-associated mortality; the core pathological mechanisms of these diseases are closely linked to functional dysregulation of immune cells such as macrophages and T cells. Aberrantly activated immune cells excessively secrete inflammatory mediators, which drive chronic inflammatory cascades and trigger irreversible tissue damage. In recent years, immune cell-based therapeutic agents (ICTAs) have garnered significant attention due to their inherent targeting specificity and immunomodulatory capabilities, encompassing whole immune cells, cell membranes, or extracellular vesicles serving as active therapeutics or delivery carriers. This review systematically elaborates on strategies for constructing ICTAs through nanoengineering, genetic engineering, and membrane-fused engineering, while outlining their integrating applications with other delivery devices. Furthermore, we summarize the preclinical and clinical trial advancements of ICTAs in various diseases such as tumors, rheumatoid arthritis, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, ischemia/reperfusion injury, sepsis, and hemophagocytic lymphohistiocytosis. These insights establish an interdisciplinary design framework for developing clinically applicable ICTAs and propose novel therapeutic approaches for inflammation-related diseases.},
}

@article {pmid42180649,
year = {2025},
author = {Zhang, J and Shi, Y},
title = {Anatomy-Guided Surface Diffusion Model for Alzheimer's Disease Normative Modeling.},
journal = {Proceedings of machine learning research},
volume = {301},
number = {},
pages = {1866-1878},
pmid = {42180649},
issn = {2640-3498},
abstract = {Normative modeling has emerged as a pivotal approach for characterizing heterogeneity and individual variance in neurodegenerative diseases, notably Alzheimer's disease (AD). One of the challenges of cortical normative modeling is the anatomical structure mismatch due to folding pattern variability. Traditionally, registration is applied to address this issue and recently deep generative models are employed to generate anatomically aligned samples for analyzing disease progression; however, these models are predominantly applied to volume-based data, which often falls short in capturing intricate morphological changes on the brain cortex. As an alternative, surface-based analysis has been proven to be more sensitive in disease modeling such as AD. Yet, like volume-based data, it also suffers from the mismatch problem. To address these limitations, we propose a novel generative normative modeling framework by transferring the conditional diffusion generative model to the spherical domain. Furthermore, the proposed model generates normal feature map distributions by explicitly conditioning on individual anatomical segmentation to ensure better geometrical alignment which helps to reduce variance between subjects in normative analysis. We find that our model can generate samples that are better anatomically aligned than registered reference data and through ablation study and normative assessment experiments, the samples are able to better measure individual differences from the normal distribution and increase sensitivity in differentiating cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) patients.},
}

@article {pmid42180652,
year = {2026},
author = {Sauvé, F and Martinez-Gómez, R and Mbouamboua, Y and Ternier, G and Nampoothiri, S and Dupré, E and Garcia, L and Couralet, M and Dewisme, J and Lebouvier, T and Danis, C and Rasika, S and Dhenain, M and Kim, YB and Ciofi, P and Buée, L and Landrieu, I and Pasquier, F and Lilamand, M and Paquet, C and Giacobini, P and Barbry, P and Maurage, CA and Nogueiras, R and Schwaninger, M and Prevot, V},
title = {Tanycytic degeneration impairs tau clearance and contributes to Alzheimer's disease pathology.},
journal = {Cell press blue},
volume = {1},
number = {1},
pages = {},
pmid = {42180652},
issn = {3051-3839},
abstract = {Alzheimer's disease (AD) is characterized by pathological Tau protein accumulation in the brain and cerebrospinal fluid (CSF), instead of timely efflux into the blood. However, the underlying mechanisms are unclear. We show, using animal and cellular models and patient tissues, that tanycytes of the hypothalamic median eminence, which bridge the blood and CSF, are involved in Tau transport and AD pathogenesis. In mice, tanycytes take up CSF-borne Tau and release it into pituitary portal capillaries, whence it enters the systemic circulation. Blocking tanycytic vesicular transport blunts CSF-to-blood Tau efflux and potentiates Tau pathology. In AD patients, plasma-to-CSF ratios of total and p181 Tau are decreased. Tanycytes from postmortem AD patient brains display dramatically fragmented processes and significant transcriptomic alterations by single-nucleus RNA sequencing, notably in vesicular-transport-related genes, explaining this clearance deficit. The involvement of tanycytic dysfunction in human pathophysiology and evidence for a brain-to-blood tanycytic shuttle has far-reaching implications.},
}

@article {pmid42180720,
year = {2026},
author = {Tan, Z and Jin, Y and Niu, Z},
title = {Exercise intervention on sleep quality in Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1796892},
pmid = {42180720},
issn = {2296-858X},
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) are often accompanied by severe sleep disorders, which exacerbate with disease progression. Currently, pharmacological treatments have limitations, and the effect of exercise as a non-pharmacological intervention on improving sleep quality in AD patients requires systematic evaluation.

METHODS: This study systematically searched six databases up to December 31, 2025, and included randomized controlled trials (RCTs) investigating the effects of exercise interventions on sleep quality in patients with Alzheimer's disease. Two researchers independently completed literature screening, data extraction, and risk of bias assessment. Data analysis and literature quality evaluation were performed using Review Manager 5.4 software, and effect sizes were pooled using standardized mean differences (SMD).

RESULTS: A total of 12 RCTs involving 893 patients were finally included. Meta-analysis results showed that exercise interventions significantly improved patients' subjective sleep quality, with a pooled effect size (SMD) of -0.81 for the Pittsburgh Sleep Quality Index (PSQI) score (95%CI: -1.55 to -0.06, p = 0.030). However, regarding objective sleep indicators, the improving effects of exercise on sleep efficiency (SMD = -0.23, 95%CI: -0.98 to 0.52, p = 0.850) and total sleep duration (SMD = 0.25, 95%CI: -0.53 to 1.03, p = 0.530) did not reach statistical significance. Subgroup analyses showed that the intervention effects were more significant in the subgroup with baseline PSQI > 10 (SMD = -1.92, 95% CI: -3.61 to -0.24, p = 0.03), the subgroup with single exercise duration ≥ 1 h (SMD = -1.34, 95% CI: -2.65 to -0.02, p = 0.05), and the aerobic exercise intervention subgroup (SMD = -1.34, 95% CI: -2.65 to -0.02, p = 0.05).

CONCLUSION: Exercise interventions may improve subjective sleep quality in patients with Alzheimer's disease, with potentially greater benefits observed in those with more severe baseline sleep disturbances or exercise sessions lasting ≥1 h; however, their effects on objective sleep outcomes have not yet been fully established. Further large-scale studies with more rigorous methodology and combined subjective and objective assessments are needed to clarify the true benefits of exercise on sleep in patients with Alzheimer's disease and to determine the optimal intervention regimen.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251270397.},
}

@article {pmid42180831,
year = {2026},
author = {Shi, L and Xie, J and Dai, T and Zhang, M and Yang, T and Sheng, L and Jin, Q and Dai, J},
title = {Exercise-induced modulation of astrocyte in Alzheimer's disease: mechanisms and therapeutic implications.},
journal = {Frontiers in physiology},
volume = {17},
number = {},
pages = {1827919},
pmid = {42180831},
issn = {1664-042X},
abstract = {Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, tau pathology, and chronic neuroinflammatory responses, although the relative contribution of these processes varies across disease stage and patient population. Current pharmacological therapies provide limited symptomatic benefit or modest disease-slowing effects in selected populations, underscoring the need for safe and sustainable adjunctive interventions. Astrocytes are central regulators of synaptic homeostasis, metabolic support, vascular coupling, and perivascular solute clearance, and these functions are profoundly altered in AD. For heuristic purposes, reactive astrocytes are often described along an A1-like to A2-like spectrum, with the former associated with pro-inflammatory and neurotoxic programs and the latter with reparative and neurotrophic functions; however, emerging single-cell and spatial transcriptomic data indicate that astrocyte states in AD are heterogeneous and context dependent rather than strictly binary. Growing evidence, predominantly from preclinical studies, suggests that exercise may remodel astrocyte-associated inflammatory, metabolic, and clearance pathways, with potential benefits for AD-related pathology and cognition. In several rodent models, exercise has been associated with reduced expression of A1-like reactive markers, enhanced protective astrocyte-associated programs, improved astrocyte-neuron metabolic coupling, and better perivascular localization of aquaporin-4 (AQP4). These changes may contribute to reduced inflammatory signaling and more efficient clearance of Aβ and tau, although the extent to which AQP4-dependent perivascular clearance mechanisms mediate exercise benefits in humans remains uncertain. Here, we review current evidence on how exercise influences astrocyte biology in AD, distinguish preclinical from clinical findings, and discuss key translational modifiers-including exercise modality, disease stage, sex, and APOE genotype-to inform glia-aware therapeutic strategies and future exercise prescriptions.},
}

@article {pmid42181353,
year = {2026},
author = {Deonarine, A and Elkomi, R and Bisrat, M and Gillani, SF and Ononenyi, C and Elkomi, R and Michael, MB and Azinge, N},
title = {Association of Lithium Exposure With Alzheimer's Disease: A Propensity Score-Matched Cohort Study.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107597},
pmid = {42181353},
issn = {2168-8184},
abstract = {BACKGROUND: Lithium has been widely studied for its potential neuroprotective effects through mechanisms implicated in Alzheimer's disease (AD), yet evidence from large real-world populations remains inconsistent. Clarifying the association between lithium exposure and AD risk in routine clinical practice is important given lithium's widespread use in mood disorders.

OBJECTIVE: This study aims to examine the association between lithium exposure and the incidence and time to diagnosis of AD among adults with bipolar disorder or recurrent major depressive disorder.

METHODS: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults aged 50 years or older with bipolar disorder or recurrent major depressive disorder and no prior diagnosis of dementia or neurodegenerative disease were identified. Patients with documented lithium exposure for at least one year were propensity score-matched 1:1 to patients without lithium exposure on demographic and clinical covariates. Follow-up began one year after cohort entry. The primary outcome was incident AD, identified using the International Classification of Diseases, 10th Revision, code G30. Cumulative risk measures, Kaplan-Meier survival analysis, and Cox proportional hazards models were used to assess associations.

RESULTS: The matched cohorts included 67,020 patients each. Incident AD occurred in 34 patients in the lithium cohort and 69 patients in the no lithium cohort. Lithium exposure was associated with a lower recorded risk of AD, with a risk ratio of 0.49 (95% confidence interval (CI) = 0.33-0.74) and an odds ratio of 0.49 (95% CI = 0.33-0.74). Time-to-event analysis demonstrated a lower hazard of AD diagnosis among lithium-exposed patients (hazard ratio = 0.48; 95% CI = 0.32-0.73; log rank p < 0.001). Among patients who developed AD, the number of AD-coded encounters did not differ significantly between the cohorts.

CONCLUSION: In this large real-world cohort of older adults with mood disorders, lithium exposure was associated with a lower recorded incidence and hazard of AD. Although absolute event rates were low, the consistency of findings across analytic approaches supports a potential protective association and highlights the need for prospective studies with detailed exposure and cognitive assessments.},
}

@article {pmid42181583,
year = {2026},
author = {Myers, SJ and Medapati, MR and Allman, BL and Pasternak, SH and Whitehead, SN and Roseborough, AD},
title = {Increased circulating TREM2[+] microglial extracellular vesicles in aged APP/PS1 Alzheimer's disease rats.},
journal = {Brain, behavior, & immunity - health},
volume = {54},
number = {},
pages = {101261},
pmid = {42181583},
issn = {2666-3546},
abstract = {TREM2 is a microglial marker important in Alzheimer's disease (AD) risk and pathogenesis, but current methods to detect microglial TREM2 expression in vivo are limited. Circulating extracellular vesicles (EVs) show promise as potential biomarkers for AD, and microglial EVs (MEVs) may offer valuable insight into brain TREM2 activity. Here, we investigated plasma-derived TREM2[+] MEVs as a potential peripheral indicator of brain microglial TREM2 activity and cognition in a rat model of aging and AD. TMEM119[+]/TREM2[+] EVs were fluorescently labelled and assessed using nanoscale flow cytometry directly in plasma collected from wildtype and APP/PS1 rats aged to 3-, 9-, and 15-months-old. Molecular and histological assays were used to assess microglial markers in rat brain tissue, and a radial arm water maze task was employed to evaluate spatial working and reference memory. We demonstrated that TMEM119[+]/TREM2[+] EVs can be detected in the systemic circulation and were increased in 15-month APP/PS1 rats. Further, the amount of TMEM119[+]/TREM2[+] EVs showed a modest association with the severity of cognitive impairment in aged rats, while TREM2 brain expression varied by anatomical region, age, transgene, and assay. Collectively, this study provides the first assessment of TMEM119[+]/TREM2[+] EVs as a peripheral indicator of brain microglial expression and their relationship to cognitive impairment in a rat model of aging and AD.},
}

@article {pmid42181986,
year = {2026},
author = {Rudravaram, G and Zuo, L and Saunders, AM and Kim, ME and Kanakaraj, P and Newlin, NR and Krishnan, AR and McMaster, EM and Cho, C and Resnick, SM and Beason Held, LL and Archer, D and Hohman, TJ and Moyer, DC and Landman, BA},
title = {Characterizing Continuous and Discrete Hybrid Latent Spaces for Structural Connectomes.},
journal = {Proceedings of SPIE--the International Society for Optical Engineering},
volume = {13925},
number = {},
pages = {},
pmid = {42181986},
issn = {0277-786X},
abstract = {Structural connectomes are detailed graphs that map how different brain regions are physically connected, offering critical insight into aging, cognition, and neurodegenerative diseases. However, these connectomes are high-dimensional and densely interconnected, which makes them difficult to interpret and analyze at scale. While low-dimensional spaces like PCA and autoencoders are often used to capture major sources of variation, their latent spaces are generally continuous and cannot fully reflect the mixed nature of variability in connectomes---which often include both continuous (e.g., connectivity strength) and discrete factors (e.g., imaging site). Motivated by this, we propose a variational autoencoder (VAE) with a hybrid latent space that jointly models the discrete and continuous components. We analyze a large dataset of 5,761 connectomes from 6 Alzheimer's disease studies with 10 unique acquisition protocols. Each connectome represents a single scan from a unique subject (3579 females, 2182 males), aged 22 to 102, with 4338 cognitively normal, 809 with mild cognitive impairment (MCI), and 614 with Alzheimer's disease (AD). Each connectome contains 121 brain regions defined by the BrainCOLOR atlas. We train our hybrid VAE in an unsupervised way and study what each component captures. We find that the discrete space is particularly effective at capturing subtle site-related differences, achieving an Adjusted Rand Index (ARI) of 0.65 with site labels, significantly outperforming traditional methods like PCA and standard VAE followed by clustering (p << 0.05). These results demonstrate that the hybrid latent space can disentangle distinct sources of variability in connectomes in an unsupervised manner, offering potential for large-scale connectome analysis.},
}

@article {pmid42182070,
year = {2026},
author = {Li, J and Lv, Z and Chen, X and Fu, F and Yang, K and Lai, G and Wu, H and Xie, G},
title = {Amyloid-β clearance: an astrocytic perspective.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1812081},
pmid = {42182070},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) represents a major global public health challenge in the 21st century, recognized as the neurodegenerative disorder with the highest mortality rate and socioeconomic burden. The core pathological feature of AD is an imbalance in Aβ production and clearance, leading to conformational changes and pathological aggregation of Aβ peptides. This imbalance triggers neurodegenerative cascades 20-30 years before clinical symptoms appear. Therapeutic approaches targeting Aβ production, including β-secretase and γ-secretase inhibitors, have thus far shown limited clinical benefit in late-stage trials and have been further constrained by safety and tolerability concerns. As a result, early interventions aimed at enhancing Aβ clearance have attracted increasing attention. While microglia-mediated phagocytosis of Aβ has been extensively studied, the multifaceted roles of astrocytes in this process remain underexplored. This review synthesizes recent findings to elucidate the molecular mechanisms of astrocyte-mediated Aβ clearance, focusing on endocytic uptake and intracellular degradation, maintenance of the blood-brain barrier, and aquaporin-4 (AQP4)-dependent glymphatic drainage. Additionally, this review dissects key regulatory nodes, including the dynamic modulation of Aβ clearance capacity through astrocyte phenotypic transitions and functional decline associated with pathology. These insights offer a theoretical foundation and translational perspective for the development of astrocyte-targeted interventions in early-stage AD.},
}

@article {pmid42182136,
year = {2026},
author = {Olejniczak-Gniadek, K and de Leon, MJ and Li, Y and Butler, T and Wang, XH and Manchineella, S and Mardy, C and Rusinek, H and Peña, J and Ma, Y and Maharjan, S and Zhou, L and Jones, A and Tanzi, E and Pahlajani, S and Foldi, NS and Maloney, T and Castellanos, CB and Wartchow, K and McIntire, LBJ and Chiang, GC and Glodzik, L},
title = {Hypertension is related to a slower radiotracer removal from lateral ventricles.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.07.723657},
pmid = {42182136},
issn = {2692-8205},
abstract = {BACKGROUND: Impairment of brain waste removal contributes to Alzheimer's disease etiology and progression. Although hypertension is a risk factor for dementia, little is known about how it affects measures of clearance in human brain.

METHODS: Cross-sectional (n=159) and longitudinal (n=94) analysis of the relationship between blood pressure (BP) and brain clearance. The estimate of brain clearance was measured using positron emission tomography (PET) as the rate of radiotracer (MK-6240) efflux from the lateral ventricles in the 10-30-minute window after tracer injection. We also examined cerebral blood flow, PET-derived tau deposition in the medial temporal lobe, cognition and plasma biomarkers of neurodegeneration. At baseline we compared participants with (n=88) and without (n=71) hypertension. For longitudinal analyses we defined two groups based on systolic BP trajectories from baseline to follow-up: as long-term controlled (n=76) or uncontrolled BP (n=18).

RESULTS: At baseline, subjects with hypertension had lower ventricular clearance than normotensive controls (Cohen's d=0.53, p=0.001). Over the course of the observation period (median 1.85 years) subjects in the uncontrolled BP group experienced a steeper reduction in clearance rates (β=-5.88) than subjects in the controlled BP group (β=-0.81, interaction p=0.039).

CONCLUSIONS: Our study suggests that hypertension impairs brain clearance of fluids.},
}

@article {pmid42182150,
year = {2026},
author = {Alia, AO and Urquhart, K and Carson, H and Killinger, B and Janson, C and Romanova, L},
title = {Proximity labeling reveals unique and shared interactomes of unmodified and pyroglutamate amyloid beta in human hippocampus in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.13.724866},
pmid = {42182150},
issn = {2692-8205},
abstract = {Amyloid plaques are a hallmark neuropathological feature of Alzheimer's disease (AD), composed of insoluble amyloid beta (Aβ) peptide. Aβ undergoes post-translational modifications that alter their biophysical properties, aggregation kinetics, and neurotoxicity, creating a heterogeneous pool of species that differentially affect AD pathogenesis. Pyroglutamate-modified Aβ (pEAβ) is a particularly aggregation-prone and proteolytically resistant variant that preferentially accumulates within plaque cores, is implicated in early plaque seeding, and is a major target of emerging anti-amyloid immunotherapies. However, the molecular environment surrounding pEAβ versus unmodified Aβ (pan-Aβ) in the human hippocampus remains incompletely defined. Here, we used Biotinylation by Antibody Recognition (BAR), an in-situ proximity labeling approach, to map and compare the protein-protein interactions (proteomes) of pEAβ and pan-Aβ in formalin-fixed postmortem human hippocampal tissue from pathologically confirmed AD cases and cognitively normal (CN) controls. Differential proteomic analysis identified 48 significantly enriched proteins in AD pEAβ captures, 28 in AD pan-Aβ captures, and 15 in CN pan-Aβ captures. Whereas no significant enrichment was detected in CN pEAβ captures, supporting pEAβ as a pathology-associated species. pEAβ in AD demonstrated the largest variant-specific signature with 31 unique proteins, pan-Aβ showed 11 unique proteins in AD, and 14 unique proteins in CN, 16 proteins were shared between AD pEAβ and AD pan-Aβ, with PCSK1N shared across AD pEAβ, and AD/CN pan-Aβ. Pathway enrichment analysis revealed broader biological disruptions linked to pEAβ, including synaptogenesis signaling, clathrin-mediated endocytosis, mitochondrial division signaling, and neurotransmitter release. Shared pathways included SNARE signaling, glutamatergic receptor signaling, and netrin signaling. These findings demonstrate that pEAβ engages an expanded, variant-specific interactome in human AD hippocampus and designate intracellular trafficking, synaptic signaling, and mitochondrial pathways as network-level vulnerabilities relevant to pEAβ pathology in AD. Notably, comparison of CN versus AD pan-Aβ further distinguished protein networks associated with physiological Aβ engagement versus pathological pan-Aβ deposition.},
}

@article {pmid42182203,
year = {2026},
author = {Balistreri, A and Turner, N and Compher, J and Almaraz, M and Prabhavalkar, A and Chittal, S and Labra, SR and Ezekiel, K and Baal, C and Cedeño Kwong, C and Ghatak, S and Schäfer, JH and Vanderpool, K and Spencer, K and Yates, JR and Nolan, JP and Henderson, S and Lipton, SA and Kelly, JW},
title = {Molecular and Structural Characterization Reveals Divergent Extracellular Vesicle Profiles Between Wild Type and Alzheimer's Disease Cerebrocortical Organoids.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.13.724352},
pmid = {42182203},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of patients globally. Despite significant efforts from researchers in recent decades, there are still many unanswered questions about AD pathogenesis. AD patient brains manifest changes in extracellular vesicles (EVs) secreted from diseased neurons, and the effect of this phenomenon remains poorly understood. EVs contain a variety of biomolecules and play a critical role in cell-to-cell communication in all eukaryotic organisms. Here, we report a thorough characterization of small EVs purified from cultures of human cerebrocortical organoids. These organoids are differentiated from human patient-derived stem cells that bear a familial AD mutation in the presenilin 1 (PSEN1) gene, or from an isogenic wildtype (WT) control. The organoid conditioned media was aspirated from cultures and processed for EV enrichment using a non-invasive technique that requires no cellular disruption. EVs purified from AD organoid conditioned media have a wider size distribution and show differential expression of tetraspanins CD63, CD9, and CD81 when compared to WT organoid-derived EVs. AD organoid-derived EVs can have single, double, and even triple membranes and display luminal fibrillar material. A deep proteomic profiling of the EVs reveals several statistically significant differences, including evidence for modifications in secretory autophagy. EV isolates from both WT and AD organoids show strong binding to amyloid detecting dyes, both in bulk fluorescence and fluorescence microscopy assays. After a 1-week co-culture of AD organoids with WT organoids, there is evidence of endosomal membrane transfer between the isogenic cultures with an increase in amyloid-β peptides in the WT organoids. These observations support the notion that non-cell-autonomous spread of amyloid-containing EVs in human AD brains can be modeled in a cerebral organoid system.},
}

@article {pmid42182268,
year = {2026},
author = {Saha, J and Dindinger, J and Ramamoorthy, A},
title = {SEC Purified Monomeric Aβ42 Produces Reproducible and Reliable Aggregation Measurements.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.12.724608},
pmid = {42182268},
issn = {2692-8205},
abstract = {The accumulation of amyloid-beta (Aβ) plaques is a hallmark of Alzheimer's disease (AD), with Aβ42 representing the predominant and most aggregation-prone isoform. Reliable preparation of monomeric Aβ42 is essential for investigating the kinetics and mechanisms of its aggregation into oligomers and fibrils. This study provides a direct comparison of two monomerization protocols for recombinantly expressed Aβ42: one incorporating size-exclusion chromatography (SEC) and the other relying solely on chemical denaturation, using agents such as NaOH and NH 4 OH. Aβ42 was produced in E. coli , purified through urea solubilization followed by HPLC, and subjected to monomerization via the respective methods. Monomeric preparations were evaluated using Thioflavin T (ThT) fluorescence to assess aggregation kinetics, TEM to detect fibrils and preformed aggregates, and NMR spectroscopy. SEC-isolated monomers displayed sigmoidal aggregation profiles in ThT assays, featuring distinct lag, growth, and plateau phases consistent with secondary nucleation-dominated models as determined by AmyloFit analysis. Increasing the initial peptide concentration resulted in higher fibril yields, which was further supported by TEM images showing extensive fibrillization following incubation. In contrast, non-SEC preparations containing pre-existing aggregates detectable by TEM and showed attenuated NMR signals, leading to impaired aggregation behavior. NaOH-denatured samples predominantly exhibited flat ThT curves, whereas NH 4 OH-denatured samples displayed extended lag phases. NH 4 OH performance better than NaOH, likely because its gradual pH neutralization reduced peptide structural perturbation. Overall, these findings demonstrate that SEC is critical for obtaining highly pure monomeric Aβ42 and improving the reproducibility of aggregation assays, highlighting the importance of standardized monomer preparation protocols in AD research.},
}

@article {pmid42182271,
year = {2026},
author = {Shee, S and Huang, M and Baghel, MS and Zheng, Y and Lun, S and Yadav, SK and Yadav, NN and Ruiz-Gonzalez, CE and Tyagi, S and Nuermberger, E and Jain, SK and Bhujwalla, ZM and Slusher, BS and Wong, PC and Bishai, W},
title = {BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.12.724591},
pmid = {42182271},
issn = {2692-8205},
abstract = {UNLABELLED: Retrospective studies in patients with non-muscle invasive bladder cancer (NMIBC) have reported a significant reduction in Alzheimer's disease (AD) incidence (12-78%) among Bacillus Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-MRI demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted CEST-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test (NORT), as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature towards that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of the co-stimulatory marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of FITC-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and CNS myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.

ONE SENTENCE SUMMARY: BCG therapy prevents tauopathy in PS19 mouse model.},
}

@article {pmid42182276,
year = {2026},
author = {Upadhayaya, R and Pradhan, M and Metzger, V and Malec, SA},
title = {CausalKnowledgeTrace: A Novel Computational Framework for Automated Literature-Based Causal Graph Construction and Evidence-Based Variable Selection in Biomedical Research.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.07.723601},
pmid = {42182276},
issn = {2692-8205},
abstract = {BACKGROUND: Variable selection for causal inference from observational biomedical data is challenging, as overlooking confounders or conditioning on colliders leads to biased estimates. While vast causal knowledge exists in biomedical literature, manually extracting this information for principled variable selection is impractical at scale.

METHODS: We developed CausalKnowledgeTrace, a Python-based computational framework with Django web interface that systematically leverages structured causal knowledge from the Semantic MEDLINE Database (SemMedDB) to inform variable selection in causal studies. The system implements a six-stage analysis pipeline using NetworkX for graph operations, including graph parsing, basic analysis, comprehensive cycle detection, systematic generic node removal, post-removal analysis, and formal causal inference with bias detection.

RESULTS: Analysis of the hypertension-Alzheimer's relationship across three degree neighborhoods (1-3) demonstrated systematic scaling of causal complexity: 361-866 variables, 429-1,442 relationships, with graph densities of 0.0033-0.0019. The analysis revealed complex cyclic structures with 54-606 baseline cycles across degree levels. Processing times ranged from 0.3-1.0 seconds for all three degrees, demonstrating computational efficiency for complex biomedical networks. Key confounders identified across all degrees included inflammation, diabetes, insulin resistance, obesity, and ischemia. In the third degree of graph, the pipeline structurally identified 39 confounders, 11 mediators, and 3 colliders from the causal graph. Among the key identified confounders and mediators-including obesity, oxidative stress, ischemia, and vascular diseases-all were found to have strong supporting evidence in established epidemiological and pathophysiological literature.

CONCLUSIONS: CausalKnowledgeTrace provides a scalable, evidence-based approach to causal graph construction that systematically identifies confounders and bias structures often missed by conventional approaches. The Python-Django architecture enables both standalone analysis and integration into larger computational workflows, representing a significant advance in computational support for causal inference in biomedical research.

STATEMENT OF SIGNIFICANCE: Problem or Issue: Selecting proper confounders and variables for causal inference from observational biomedical datasets is challenging and often biased by limited expertise or manual review.What is Already Known: Existing approaches rely on domain experts, statistical variable screening, or manual construction of causal graphs, but these often overlook literature-documented confounders and complex biases.What this Paper Adds: This paper introduces an automated, literature-based framework for synthesizing and validating causal graphs, identifying critical variables and complex bias structures, such as M-bias and butterfly bias, with full evidentiary traceability.Who would benefit from the new knowledge in this paper?: Epidemiologists, biomedical researchers, informaticians, and clinical investigators seeking reliable and transparent causal modeling for observational studies.},
}

@article {pmid42182345,
year = {2026},
author = {Cassidy, J and Collier, MEW and Giorgini, F},
title = {Physiological levels of 3-hydroxykynurenine alter mitochondrial function and morphology in neuronal cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.13.724856},
pmid = {42182345},
issn = {2692-8205},
abstract = {Mitochondrial morphology and function are critical determinants of neuronal function and survival, with disruptions in mitochondrial dynamics often preceding the overt neuronal dysfunction seen in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The kynurenine pathway accounts for 95% of dietary tryptophan catabolism and many of the metabolites are neuroactive, including redox-active 3-hydroxykynurenine (3-HK). 3-HK is present under normal physiological conditions in the central nervous system (CNS) and is elevated during inflammation. While supraphysiological levels of 3-HK have been associated with neurotoxicity, the effects of physiological concentrations on neuronal cells, and specifically their mitochondria, remain poorly understood. Here we assessed viability, ATP levels and redox status to determine cellular health and function in neuronal cells exposed to physiological levels of 3-HK, alongside confocal imaging and transcriptomic profiling, finding significant alterations in mitochondrial function and morphology. Interestingly, a biphasic influence of 3-HK on mitochondrial morphology was observed, with an elongated network as well as decreased surface area and volume being observed only at the lowest concentration of 3-HK, reflecting normal physiological levels. At the highest 3-HK concentration tested, reflecting an inflammatory situation, an increased number of mitochondria were present, accompanied by increased activation of caspase-3/7 and enhanced production of mitochondrial superoxide. These results highlight a previously unknown role for 3-HK in regulating mitochondrial function and structure, possibly through altered fission and fusion events, suggesting that subtle changes in kynurenine pathway metabolism may contribute to early mitochondrial dysfunction in neurological disease.},
}

@article {pmid42182396,
year = {2026},
author = {Lucy, TT and Mamun-Or-Rashid, ANM and Lee, DC and Lefterov, I and Koldamova, R and Fitz, NF},
title = {Integration of transcriptional signatures from brain tissue and plasma extracellular vesicles of a preclinical tauopathy mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.06.723062},
pmid = {42182396},
issn = {2692-8205},
abstract = {Tauopathies, including Alzheimer's disease, involve progressive neurodegeneration and sustained neuroinflammation. We present a multi-compartment transcriptomic atlas of 9.6-month-old PS19 tauopathy mice compared with wild-type (WT) controls (n=8/group), profiling cortical mRNA, cortical non-coding RNA (ncRNA), and plasma small extracellular vesicle (pEV) ncRNA. In the PS19 cortex, mRNA sequencing identified 917 differentially expressed genes (DEGs), with microglial deconvolution revealing a robust transition toward disease-associated microglia (DAM) gene signature and downregulation of genes involved in oxidative phosphorylation and cholesterol biosynthesis relative to WT. Cortical ncRNA profiling identified 466 differentially expressed ncRNAs, primarily circular RNAs (circRNAs; n=331). In pEVs, 822 ncRNAs were differentially abundant, of which 657 circRNAs were identified in PS19 compared to WT mice. Cross-compartment integration demonstrated that pEV miRNA gene targets functionally mirrored genes involved in the brain's inflammatory and metabolic failure. We identified a core shared signature of 33 ncRNAs, including miR-5114 (up in brain, down in pEV), circ_0008242 and circ_0002153 (up in brain and pEV), and circ_0007688 (down in brain and pEV) differentially enriched across both brain and periphery in PS19 compared to WT mice. These results demonstrate that the pEV non-coding landscape effectively tracks central tau-mediated changes in the brain transcriptional response. This study identifies circRNAs as the most numerically perturbed ncRNA class and provides a foundation for non-invasive biomarker development in tauopathy.},
}

@article {pmid42182402,
year = {2026},
author = {Pandey, R and Zarrouk, A and Dey, P and Levendosky, E and Carpentier, G and Hof, PR and Georgakopoulos, A and Robakis, NK},
title = {PS FAD mutants and γ-secretase inhibition accumulate VEGFR2-derived peptide VCTF1 suppressing brain VEGFR2 dimerization, angiogenesis and neuroprotection.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.12.724648},
pmid = {42182402},
issn = {2692-8205},
abstract = {Efficient cerebrovasculature is vital to neuronal health and cognition and evidence shows most dementia patients have cerebrovascular abnormalities. Brain vasculature is regulated by Vascular Endothelial Growth Factors (VEGFs) binding VEGF receptor2 (VEGFR2) and stimulating angiogenesis, and neuroprotection. Presenilin1 (PS1) is the main proteolytic component of γ-secretase and PS1 mutants are the most common cause of Familial Alzheimer Disease (FAD). Here we show that an ADAM17 cleavage of extracellular VEGFR2 produces the membrane-bound γ-secretase substrate VEGFR2/CTF1 (called VCTF1), comprising the transmembrane and intracellular domains of VEGFR2. PS1 FAD mutants and γ-secretase inhibitors both accumulate VCTF1 and suppress VEGF-A-induced brain angiogenesis. Moreover, PS1 FAD mutants, γ-secretase inhibitors, and PS1 downregulation, all decrease γ secretase processing of VCTF1, thereby increasing its accumulation and impairing VEGF-A-induced VEGFR2 dimerization/activation, signaling, and endothelial cell (EC) functions. Importantly, VCTF1 binds fulllength VEGFR2 monomers suppressing VEGFR2 dimerization/activation, signaling, and EC functions. These data show that VCTF1 suppresses VEGFR2 dimerization and downstream signaling and functions of the brain VEGF-A-/VEGFR2 system. PS1 FAD mutants increase vulnerability of brain neurons to ischemic stress and exert antimorphic effects on γ-secretase cleavage of VCTF1, increasing its concentration and abolishing VEGF-A-induced VEGFR2 dimerization/activation, signaling, neuroprotection and cognition. Importantly, we detected molecular markers of decreased VEGFR2 dimerization and angiogenic dysfunction in human brain tissue from PS1 FAD mutant genotypes. Together, our data suggest a pathway through which FAD mutants promote dementia by increasing VCTF1 and decreasing brain angiogenesis and neuroprotection, suggesting that PS1 FAD patients may benefit from therapeutic methods that decrease brain VCTF1.},
}

@article {pmid42182406,
year = {2026},
author = {Perl, AT and Wu, J and Dong, JD and Brooks, AM and Yoblinski, AR and Vierling, TT and Li, JL and Ruby, DR and Radzicki, D and Dudek, SM and Cushman, JD and Gjoneska, E},
title = {Immune receptor LAG3 regulates microglia function during Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.08.723911},
pmid = {42182406},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's Disease (AD) remains the leading cause of dementia globally, yet the exact etiology is not well defined and effective treatments remain unavailable. Here, we report that deletion of the immune checkpoint receptor lymphocyte activation gene 3 (Lag3) in a familial AD mouse model, 5xFAD [+] , can rescue molecular, cellular and behavioral phenotypes of neurodegeneration. Specifically, we demonstrate that amyloidosis and microgliosis in the 5xFAD [+] mice are significantly reduced by Lag3 deletion. Moreover, we show that Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes in the 5xFAD [+] mice. Transcriptional profiling reveals that Lag3 deletion suppresses aberrant overexpression of disease associated microglia (DAM) genes in 5xFAD [+] microglia, effectively restoring homeostatic transcriptional programs. Finally, we observe reduced CD8 [+] T cell infiltration in the brain of 5xFAD [+] animals after Lag3 deletion which likely mediates molecular, cellular and behavioral effects resulting from microglia DAM gene activation. Our results highlight a previously unrecognized role for Lag3 in AD as a critical regulator of microglia function and suggest Lag3 might be a viable target for novel AD therapeutic interventions.

HIGHLIGHTS: Immune receptor Lag3 deletion ameliorates amyloidosis and microgliosis during AD Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes Lag3 deletion reverses aberrant activation of DAM genes and restores microglia homeostasis Lag3 inhibition presents a viable approach for novel AD therapeutic interventions.},
}

@article {pmid42182410,
year = {2026},
author = {Baghel, MS and Burns, GD and Mallika, AP and Chen, XK and Liu, F and Renganathan, S and Li, T and Troncoso, JC and Wong, PC},
title = {Tauopathy primes co-filament assembly and dysfunction of TDP-43.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.11.723888},
pmid = {42182410},
issn = {2692-8205},
abstract = {While most Alzheimer's disease (AD) which is associated with L imbic P redominant A ge-related T DP-43 E ncephalopathy (LATE) exhibits accelerated brain atrophy, the pathogenic mechanism remains elusive. We show here, in mice harboring depositions of amyloid-β and tau, the age-dependent emergence of TDP-43 proteinopathy. We demonstrate that TDP-43 dysfunction facilitates caspase 3-mediated endoproteolysis of tau, accelerates tauopathy and exacerbates neuron loss. Unexpectedly, we found that the emergence and spread of TDP-43 proteinopathy is associated with the spread of tauopathy and correlated with co-filament assembly of tau and TDP-43. Importantly, TDP-43 dysfunction precedes such co-filament assembly and TDP-43 cytoplasmic aggregates. Consistent with the idea that tauopathy could prime co-filament assembly and proteinopathy of TDP-43 to exacerbate neurodegeneration, we found tau co-filament assembly with TDP-43 in AD and AD-LATE cases. These findings suggest that TDP-43 dysfunction accelerates tauopathy, which, in turn, primes co-filament assembly and dysfunction of TDP-43 to exacerbate neuron loss in AD-LATE, a pathogenic mechanism disclosing novel targets and therapeutic strategies.},
}

@article {pmid42182430,
year = {2026},
author = {Berisha, DE and Dave, A and Sattari, N and Chappel-Farley, MG and Sprecher, KE and Bock, J and Riedner, BA and Grover, EM and Jonaitis, EM and Zetterberg, H and Bendlin, BB and Mander, BA and Benca, RM},
title = {Longitudinal Alterations in Sleep EEG Biomarkers of Memory Consolidation in Middle-Aged and Older Adults.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.11.724419},
pmid = {42182430},
issn = {2692-8205},
abstract = {The precise coordination of slow oscillations (SO) and sleep spindles during non-rapid eye movement (NREM) sleep supports memory consolidation and may serve as a sensitive marker of cognitive aging. However, longitudinal changes in their oscillatory dynamics in midlife and older age remain poorly understood. Using polysomnography with high-density EEG at two timepoints over ∼2.5 years, we examined changes in local NREM slow wave (SW), sleep spindle (occurring in the 11-16 Hz sigma range), and SO-sigma coupling strength in cognitively unimpaired middle-aged to older adults at risk for Alzheimer's disease. Fronto-central SO-sigma power coupling strength significantly declined over time, independent of changes in multiple measures of SW and sleep spindle expression. Local declines in multiple sleep spindle measures were also observed. Greater baseline levels of cerebrospinal fluid (CSF) neurogranin, a postsynaptic protein abundantly expressed in the dendritic spines of the hippocampus and cerebral cortex and implicated in calcium-dependent synaptic plasticity, predicted the magnitude of longitudinal decline in SO-fast sigma coupling strength, which in turn predicted episodic memory performance changes. These findings suggest that longitudinal changes in local sleep oscillatory dynamics are related to decreased synaptic integrity and may serve as an early indicator of memory decline in older adults at risk for Alzheimer's disease.},
}

@article {pmid42182446,
year = {2026},
author = {Marchi, AJ and Brooks, AM and Gjoneska, E},
title = {Alzheimer's Disease Risk Allele APOE4 Interacts with Arsenic Exposure to Drive Microglial Dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.09.723490},
pmid = {42182446},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is influenced by both genetic risk and environmental exposures, but how these factors interact in human microglia remains unclear. Here, we investigate whether the late-onset AD risk allele APOE4 impacts microglial vulnerability to arsenite exposure. To that end, we used CRISPR/Cas9 to generate an isogenic APOE4 [+/+] iPSC-derived transcription factor-induced microglia-like cells (iTFM). We demonstrate that APOE4 [+/+] iTFM exhibit decreased survival following arsenite exposure, as evidenced by a lower LC [50] compared to APOE3 [+/+] controls. Transcriptomic profiling identified arsenite concentration as the primary driver of gene expression changes, while genotype contributed a secondary, distinct component of the response. Weighted gene co-expression network analysis revealed genotype-dependent modules enriched for phagocytic and oxidative stress pathways, including KEAP1-NFE2L2 signaling. These transcriptomic changes were further supported by functional assays. APOE4 [+/+] iTFM had a high proportion of phagocytic cells and altered mitochondrial phenotypes including increased mitochondrial mass, reduced membrane potential, and reduced superoxide production, all of which were further perturbed by low dose arsenite exposure. These results support a gene-environment interaction-dependent increase in microglial vulnerability via reshaping of transcriptional and functional stress responses, and provide a human cell-based framework for studying environmentally mediated microglial contributions to AD.},
}

@article {pmid42182449,
year = {2026},
author = {Revanna, JS and Wessendorf-Rodriguez, K and Xiao, Q and Sabedot, TS and Cuoco, MS and Sarkar, S and Zhou-Yang, L and Lim, CK and Prozapas, VN and Wooldridge, RS and Chadarevian, JP and Pratt, JM and Steiner, SC and Katz, A and Mertens, J and Kelly, JW and Solé-Domènech, S and Melchior, JT and Metallo, CM and Jones, JR and Gage, FH},
title = {Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.12.724612},
pmid = {42182449},
issn = {2692-8205},
abstract = {While Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for late-onset Alzheimer's disease, its mechanistic role in the brain-resident macrophage, microglia, remains elusive. Microglia are important in the clearance of pathology in disease, heavily relying on lysosome functionality; therefore, we sought to understand the impact of APOE4 on microglial function. APOE44 microglia have been shown to have lipid accumulation, yet the mechanisms leading to this accumulation are unknown. Using induced pluripotent stem cell-derived microglia, we found that the APOE4 haplotype resulted in transcriptional state shifts in microglia, suppressing activated-response microglia (ARMs) and promoting a G2 senescent-like state. We found that APOE44 microglia accumulate cholesterol esters and provide less lipid support to fibroblast-induced neurons, decreasing their synaptic connections. APOE44 microglia secrete significantly less lipoproteins, leading to the accumulation of lipoproteins within the cells including the lysosomes. APOE44 microglia exhibit impaired lysosomal acidification and degradation capacity. Further, our results elucidated that APOE44 microglia are proinflammatory and shift away from fatty acid oxidation towards glycolysis, due to dysfunctional mitochondria. Taken together, our findings indicate that a loss-of-function in lipoprotein secretion drives intracellular lipid accumulation, including within lysosomes, ultimately disrupting the lysosome-endoplasmic reticulum-mitochondrial axis. This drives a proinflammatory and metabolically compromised microglial phenotype with impaired neuro-supportive functions.},
}

@article {pmid42182453,
year = {2026},
author = {Pao, PC and Liu, L and Watson, LA and Lee, A and Seguin, A and Dong, D and Rasheed, S and Staab, C and King, O and Geigenmüller, U and Penney, J and Gao, F and Muhtaseb, A and Raju, RM and Tsai, LH},
title = {DNA double-strand break signaling induces aberrant neuronal activity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.11.724110},
pmid = {42182453},
issn = {2692-8205},
abstract = {Aberrant neuronal activity is an early pathological feature of numerous neurodegenerative disorders, including tauopathy, and is thought to play a role in disease progression. However, the mechanism underlying abnormal neuronal activity remains elusive. Here, we reveal a relationship between DNA double-strand break (DSB)/p53 pathway activation and aberrant neuronal activity. Activating p53 as part of the DNA damage response via DSB induction, or by preventing MDM2-mediated p53 degradation, causes aberrant activity in both mouse and human neurons. p53 activation induces the expression of genes regulating synaptic transmission, and p53-responsive gene upregulation is overrepresented in postmortem human Alzheimer's disease neurons burdened with neurofibrillary tangles (NFTs). Using a human iPSC-based cerebral organoid model of frontotemporal dementia that exhibits relevant pathologies including elevated DSBs, aberrant neuronal activity, and NFTs, we show that inhibiting p53 transcriptional activity with a small molecule ameliorates aberrant calcium fluctuations in neurons. Together, our findings highlight p53 inhibition as a novel therapeutic strategy to counter aberrant neuronal activity in neurodegenerative diseases characterized by tauopathy.},
}

@article {pmid42182496,
year = {2026},
author = {Li, WF and Mohammed, N and Bennett, DA and Kellis, M and Tanigawa, Y},
title = {Dissecting Alzheimer's disease heterogeneity by cross-trait polygenic prediction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.15.725551},
pmid = {42182496},
issn = {2692-8205},
abstract = {Mapping the genetic basis of inter-individual heterogeneity in multifactorial diseases opens the door to mechanistic insights and opportunities for targeted intervention. In Alzheimer's disease (AD), clinical and pathological heterogeneity is well recognized, but genetic dissection is limited by a lack of well-powered cohorts with deep phenotypic characterization. Here, we introduce a polygenic score (PGS) analysis strategy to address these limitations by leveraging the inherent pleiotropy in complex trait genetics. We perform a cross-cohort, cross-trait application of pre-trained PGS, integrating 713 UK Biobank-derived PGS with 36 deep AD phenotypes across 1678 ROSMAP participants. We identify 268 statistically significant (FDR<0.1) associations between 12 prioritized PGS and 36 AD phenotypes. Prioritized PGS include blood lipid measurements, inflammatory biomarkers, and cancer traits; observed AD phenotypes include cognition, amyloid, and tangles. Of the 268 associations, 49 persist with APOE -excluded PGS. Predictive models trained on multiple prioritized PGS outperform the AD PGS or APOE alone for predicting amyloid and cognition. Lastly, our approach identifies six individual-level AD polygenic subtypes supported by distinct pathological patterns. Overall, we combine large-scale biobank resources and deeply-phenotyped cohorts using PGS, reveal genetic features underlying AD heterogeneity, and provide a general model for stratifying heterogeneous disease-focused cohorts using genomics.},
}

@article {pmid42182561,
year = {2026},
author = {Iizuka, T and Watanabe, T and Kameyama, M},
title = {Aging modulates amyloid clearance kinetics during anti-amyloid therapy: evidence from real-world serial amyloid PET.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801267},
pmid = {42182561},
issn = {1663-4365},
abstract = {BACKGROUND: Anti-amyloid antibodies have been shown to reduce cerebral amyloid burden in early Alzheimer's disease (AD), yet considerable interindividual variability in treatment-associated amyloid reduction has been observed. The biological factors underlying this variability remain unclear. In particular, the influence of aging on amyloid clearance dynamics during anti-amyloid therapy has not been well characterized in real-world clinical settings.

METHODS: We conducted a prospective observational study of 23 patients with early-stage AD receiving lecanemab who underwent serial [18]F-flutemetamol amyloid PET at baseline and after 6 and 12 months. Amyloid burden was quantified in centiloid units. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Baseline cerebral perfusion was evaluated using [123]I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP) analysis.

RESULTS: All participants showed reductions in amyloid burden on serial PET; however, the magnitude of reduction varied substantially across individuals. Older patients tended to exhibit larger and more rapid reductions in amyloid burden, whereas younger patients demonstrated more modest decreases despite comparable baseline amyloid levels and standardized dosing. Amyloid reduction at 6 months strongly predicted the magnitude of reduction at 12 months, suggesting that early PET changes capture subsequent amyloid clearance trajectories. Cognitive decline occurred in a subset of patients despite substantial amyloid reduction and was associated with marked baseline temporo-parietal hypoperfusion on SPECT rather than insufficient amyloid removal.

CONCLUSION: In this real-world cohort, aging appeared to influence the observable kinetics of amyloid reduction during anti-amyloid therapy. Early serial amyloid PET may provide useful information regarding longer-term amyloid dynamics, while baseline perfusion imaging may help identify patients with substantial downstream neurodegenerative burden who remain at risk for cognitive decline despite amyloid clearance. These findings highlight biological heterogeneity in treatment response and underscore the value of multimodal imaging for monitoring disease-modifying therapies in AD.},
}

@article {pmid42182562,
year = {2026},
author = {Rogers, N and SanMartín, CD and More, J and Romero, C and Ponce, DP and Valdés, JL and Behrens, MI},
title = {Route efficiency in spatial navigation as an early indicator of cognitive decline in amnestic mild cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1797674},
pmid = {42182562},
issn = {1663-4365},
abstract = {INTRODUCTION: The hippocampus is one of the brain regions most affected by neurodegeneration in Alzheimer's disease (AD). This structure and its neural circuits are critically involved in spatial learning and memory. Poor spatial navigation performance in virtual environments such as the Virtual Morris Water Navigation Task (VMWNT) may precede other clinical findings in amnestic mild cognitive impairment (aMCI), a pre-dementia stage of AD. To explore this idea, we correlated aMCI and cognitively healthy control (HC) performance in the VMWNT with Montreal Cognitive Assessment (MoCA) and Memory Index Score (MoCA-MIS), testing whether navigation-derived metrics are associated with cognitive performance within a framework of shared medial temporal lobe vulnerability.

METHODS: Thirty-eight participants (18 aMCI, 20 HC) were assessed for neurologic evaluation and VMWNT performance. Neuropsychological tests, including MoCA, MoCA-MIS, Clinical Dementia Rating (CDR), CDR sum of boxes (CDR-SOB) and AD8, were performed. Group differences were assessed using Mann-Whitney U tests on participant-level means and complemented with mixed-effects models to account for the repeated-measures structure of trial-level data. All behavioral parameters obtained in the VMWNT were reduced to a single variable, "Route Efficiency," through Principal Component Analysis (PCA) on five navigation variables, with the aim to correlate spatial memory performance with clinical findings.

RESULTS: Significant differences in VMWNT performance were observed. aMCI patients displayed longer path lengths (p = 0.006), more quadrant crossings (p = 0.010), reduced time in target quadrant (p < 0.001), and fewer target crossings (p = 0.006), with group differences most evident in Stage 2; Stage 3 showed no significant differences for most variables. Route Efficiency was significantly lower in aMCI than HC (p < 0.001); correlations with MoCA and MoCA-MIS were observed across the full sample but were nonsignificant within groups. Stage 3 allocentric navigation did not reveal consistent group differences. Using nested cross-validation, the AUC for aMCI detection was 0.78 (95% CI: 0.63-0.91).

DISCUSSION: Group differences in Route Efficiency and correlations with cognitive measures were observed, though these associations primarily reflected between-group rather than individual variation. Allocentric significant findings were not observed. These preliminary results support further exploration of virtual navigation paradigms in clinical settings.},
}

@article {pmid42182563,
year = {2026},
author = {Capraru, TD and Bauer, TC and Jordan, P and Weidner, NM and Oensal, M and Froelich, L and Beisel, C and Hausner, L and Thi, VLD},
title = {Investigating hepatitis E virus seroprevalence in patients with Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1831973},
pmid = {42182563},
issn = {1663-4365},
abstract = {BACKGROUND: Hepatitis E virus (HEV) exposure has been linked to neurologic manifestations and dementia. This study aims to clarify a possible association between HEV and Alzheimer's disease (AD).

METHODS: We performed a single-center retrospective case-control study of 453 cognitively impaired adults from southern Germany, comparing anti-HEV IgG seropositivity between patients with AD and those with non-AD cognitive impairment. Associations were evaluated using chi-square testing and multivariable logistic regression, including age-stratified analyses.

RESULTS: Overall HEV IgG seroprevalence was higher in the AD group than in the non-AD group (44.5% vs. 37.7%, p = 0.138), with a significant difference in patients aged 60-69 years (46.5% vs. 35.1%, p = 0.040) but not in those aged 70-79 years (46.7% vs. 50.0%, p = 0.646).

CONCLUSION: These findings suggest that anti-HEV antibodies are more frequent in younger elderly AD patients compared with cognitively impaired individuals of the same age without AD, raising the hypothesis that prior HEV infection may represent a candidate environmental risk factor for AD.},
}

@article {pmid42182564,
year = {2026},
author = {Saleh Velez, F and Cedeno-Bruzual, M and Zuniga-Gutierrez, M and Mercado Pena, D and Ballard, CL and Kong, JS and Pinaffi-Langley, ACDC and Owens, CD and TucsekCardon, Z and Szarvas, Z and Muranyi, M and Kaposzta, Z and Mukli, P and Boada Robayo, L and Tarantini, S and Ungvari, Z and Yabluchanskiy, A and Pinto, CB},
title = {Transcranial magnetic stimulation from healthy brain aging to Alzheimer's disease: a review on mechanisms, therapeutic potential, and future clinical directions.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1778992},
pmid = {42182564},
issn = {1663-4365},
abstract = {Transcranial magnetic stimulation (TMS), a non-invasive and non-pharmacological intervention, is increasingly being explored for mitigating age-related cognitive decline and dementia. Its therapeutic potential is largely attributed to its capacity to modulate neuronal firing rates and induce neuroplastic changes and modulate neurovascular coupling within distributed neural networks that support memory, attention, and executive function. Despite growing interest, gaps remain in understanding how specific stimulation parameters engage in neural circuits and translate into meaningful cognitive outcomes in aging and neurodegeneration. This narrative review synthesizes current evidence on the neurophysiological and hemodynamic mechanisms and clinical effects of repetitive TMS (rTMS) across the spectrum of cognitive aging, from healthy older adults to those experiencing age-related cognitive decline and Alzheimer's disease. By integrating mechanistic and clinical perspectives, this review bridges basic neuroscience and clinical practice, highlighting rTMS's emerging role in promoting cognitive resilience and healthier brain aging.},
}

@article {pmid42183041,
year = {2026},
author = {Scalese, A and Giuffrè, GM and Di Lazzaro, G and Cimmino, AT and Musso, F and Orsini, M and Quaranta, D and Vita, MG and Piano, C and Calabresi, P and Marra, C and Bentivoglio, AR},
title = {Predictive value of cerebrospinal fluid Alzheimer's disease biomarkers and neuropsychological measures for cognitive and motor outcomes in Parkinson's disease.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag166},
pmid = {42183041},
issn = {2632-1297},
abstract = {Cognitive impairment is a major non-motor feature of Parkinson's disease (PD). Alzheimer's disease CSF biomarkers-amyloid-β (Aβ42, Aβ42/40), phosphorylated tau (p-tau) and total tau (t-tau)-may influence both cognitive and motor outcomes, but their role in relation to Parkinson's disease phenotype or progression remains unclear. Moreover, few studies have investigated these associations using extensive neuropsychological batteries. The aim of the study was to examine the associations between CSF Alzheimer's disease biomarkers, domain-specific neuropsychological performance and motor impairment in Parkinson's disease and to evaluate their predictive value for longitudinal changes. Seventy-eight Parkinson's disease patients underwent extensive neuropsychological examination, along with motor evaluation and Alzheimer's disease CSF biomarkers quantification. Fifty-two patients completed follow-up motor assessment and 43 repeated cognitive evaluation after 18-24 months. Correlation and regression models adjusted for demographic and clinical covariates were applied. Thirty-nine patients were classified as mild cognitive impaired (PD-MCI), mostly with multidomain impairment. Amyloid-β biomarkers were associated with poorer attention, working memory, executive and language performance. Tau proteins were inversely associated with motor scores. PD-MCI patients tended to experience greater motor decline than cognitive unimpaired subjects. Over time, higher p-tau and t-tau predicted global cognitive decline (MMSE), while lower Aβ42/40 predicted worsening in verbal memory and reasoning. Higher t-tau and lower baseline MMSE independently predicted greater motor deterioration. CSF Alzheimer's disease biomarkers showed domain-specific relationships with cognitive function and predicted both neuropsychological decline and motor progression. Combining detailed neuropsychological profiling with Alzheimer's disease biomarkers assessment may improve identification of high-risk patients and support integrated biological definitions of Parkinson's disease.},
}

@article {pmid42183044,
year = {2026},
author = {He, D and Langhough, R and Jonaitis, E and Wilson, R and Hermann, B and Zetterberg, H and Johnson, S and Mueller, KD},
title = {Enhanced sensitivity to plasma p-tau217 with proper names recall in the preclinical Alzheimer's cognitive composite.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag163},
pmid = {42183044},
issn = {2632-1297},
abstract = {A pivotal debate in Alzheimer's disease (AD) revolves around the clinical utility of a purely biomarker-based diagnostic framework, making it imperative to identify early functional signs that are both clinically meaningful and sensitive to biological biomarkers in the preclinical stages. While the development of the Preclinical Alzheimer's Cognitive Composite (PACC) addresses this need, its lack of language-specific markers might limit its sensitivity, given that language deficits are among the earliest manifestations of AD. To address this limitation, we developed PACC variants incorporating proper names delayed recall, a novel lexical-semantic marker robustly linked to PET and CSF biomarkers. We analysed 824 dementia-free participants (mean age ≈ 62 at baseline) from the Wisconsin Registry for Alzheimer's Prevention, stratifying them by plasma phosphorylated tau 217 (p-tau217) levels (using established amyloid PET positivity cut-offs: negative [<0.40 pg/mL; N = 539], intermediate [0.40-0.63 pg/mL; N = 163], positive [>0.63 pg/mL; N = 122]). We constructed six PACC variants: (1) traditional PACC4 (Rey Auditory Verbal Learning Test immediate learning, Logical Memory II [LM II; delayed recall], Digit Symbol, Mini-Mental State Examination [MMSE]); (2) PACC3 (excluding MMSE to mitigate ceiling effects); (3-4) PACC4_PN and PACC3_PN, replacing LM II's total score with proper-name recall; and (5-6) PACC4 + VF and PACC3 + VF, adding animal fluency. Cognitive composites were calculated as the equally weighted sum of component z-scores. We compared PACC variants'sensitivity (i.e. longitudinal decline rates) associated with plasma p-tau217, using linear mixed models adjusted for age, gender, literacy and practice (total visits minus one). We showed individuals with positive plasma p-tau217 status exhibited significantly faster cognitive decline across all PACCs. Notably, the proper name enhanced-PACC, especially the parsimonious PACC3_PN, demonstrated the steepest decline-6.4-19% faster than the traditional and animal fluency-appended versions. Our optimized measure offers critical advantages in clinical utility: an 82% reduction in scoring burden for clinicians (9-point proper names versus 50-point total LM score), finer semantic memory granularity within an episodic memory task and enhanced sensitivity to AD biomarkers. Our findings position proper name-enhanced PACC as a clinically practical tool for tracking longitudinal cognitive trajectories, highlighting proper names delayed recall as a sensitive marker due to AD-type brain changes. Future work will validate its utility for trial enrichment and clinical screening.},
}

@article {pmid42183357,
year = {2026},
author = {Grabowska, ME and Chen, R and Zhou, Y and Vaidya, AU and Zhong, X and Guardo, C and Dickson, AL and Babanejad, M and Yan, C and Xin, Y and Mundo, S and Peterson, JF and Li, L and Embí, P and Feng, Q and Eaton, J and Wen, Z and Li, B and Wei, WQ},
title = {Integrating genetically predicted transcriptomic signatures with longitudinal real-world data enables scalable drug repurposing for Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9518587/v1},
pmid = {42183357},
issn = {2693-5015},
abstract = {Drug repurposing offers a potential strategy to expand treatment options for conditions with limited therapies, but advancing repurposing candidates toward clinical implementation remains a challenge. Large-scale data, together with advanced genetic and epidemiological methods, may help address this gap. Here, we present an integrative digital medicine approach that combines genetically predicted transcriptomic signatures and perturbation screening for candidate identification with multi-cohort real-world validation for systematic evaluation of prioritized candidates. We applied this approach to Alzheimer's disease (AD), a disease with substantial unmet clinical need and persistent difficulty in developing effective therapies. We constructed AD signatures from genetically predicted expression changes across bulk tissues and microglia, then queried Connectivity Map profiles to identify compounds predicted to oppose these signatures. Aspirin emerged as a reproducible candidate across multiple signatures and underwent further evaluation. We then examined its association with incident AD in longitudinal electronic health record data from Vanderbilt University Medical Center and the NIH All of Us Research Program, as well as national insurance claims data. Across independent cohorts, aspirin initiation before age 65 was consistently associated with lower risk of incident AD, with signals suggesting that cumulative exposure and APOE ε4 status may influence effect size. Transcriptomic analysis of human cortical organoids provided additional experimental support, showing that aspirin more strongly opposed AD-related neuronal pathway alterations in wild-type organoids than in an organoid model of AD. This integrative approach offers a scalable strategy for genetically informed drug repurposing that bridges candidate discovery and clinical evaluation.},
}

@article {pmid42183361,
year = {2026},
author = {Yang, X and Lyu, J and Wang, J and Quan, Y},
title = {APOE ε4-related structural vulnerability in mild cognitive impairment: a subsystem-based analysis of the default mode network.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9447482/v1},
pmid = {42183361},
issn = {2693-5015},
abstract = {Background Mild cognitive impairment (MCI) is a critical prodromal stage of progressive cognitive decline. As a core cognitive brain network, the default mode network (DMN) exhibits structural alterations in MCI that are closely associated with cognitive impairment. Apolipoprotein E ε4 (APOE ε4) , the strongest genetic risk factor for pathological cognitive decline, has been shown to disrupt the structural integrity of the DMN's three core subsystems: the Midline Core, Medial Temporal Lobe (MTL), and Dorsomedial Prefrontal Cortex (DMPFC) subsystems. However, the subsystem-specific effects of APOE ε4 and the cognitive mechanisms through which they operate in MCI remain unclear. Methods We enrolled 176 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 116 patients with MCI and 60 cognitively normal (CN) individuals, with balanced APOE ε4 carrier status within each diagnostic group. Standardized volumes of eight DMN regions were analyzed using permutational multivariate analysis of variance (PERMANOVA) to test diagnosis-by-genotype interactions, followed by false discovery rate (FDR)-corrected univariate analyses and multiple linear regression to identify regional volume differences. Bootstrap-based mediation analysis and receiver operating characteristic (ROC) analysis were further performed to examine clinical relevance. Results A significant diagnosis-by- APOE ε4 interaction was observed in the global structural pattern of the DMN, primarily driven by the DMPFC and MTL subsystems. Among patients with MCI, APOE ε4 carriers exhibited selective atrophy within the DMPFC subsystem, specifically in the gyrus rectus (REC) and superior temporal pole (TPOsup), relative to non-carriers. Critically, TPOsup atrophy mediated 30.43% of the negative effect of APOE ε4 on global cognition, as measured by the Mini-Mental State Examination (MMSE), and was significantly associated with impaired orientation. Conclusion The TPOsup may represent a key neural hub linking APOE ε4 to cognitive decline in MCI and may serve as a specific imaging marker for risk stratification in this population.},
}

@article {pmid42183381,
year = {2026},
author = {Yang, X and Lyu, J and Wang, J and Quan, Y},
title = {Disentangling global atrophy burden from local structural patterns reveals clinically relevant heterogeneity in mild cognitive impairment.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9443570/v1},
pmid = {42183381},
issn = {2693-5015},
abstract = {Background Mild cognitive impairment (MCI) is a heterogeneous prodromal stage of Alzheimer's disease (AD). Imaging-based subtyping studies, however, often confound overall disease severity with local anatomical variation, limiting biological interpretability and clinical utility. We aimed to separate global neurodegenerative burden from local structural patterns and examine their clinical relevance in MCI. Methods Baseline ADNI-1 data from 731 participants were analyzed, including 205 cognitively normal individuals, 351 with MCI, and 175 with AD. A global atrophy index (GAI) was constructed from whole-brain gray matter volume, white matter volume, cerebrospinal fluid volume, and mean cortical thickness to quantify overall neurodegenerative burden. Candidate regions of interest were screened in the full sample. Within MCI, regional measures were residualized against age, sex, education, and GAI to derive local structural features independent of global atrophy. Principal component analysis and unsupervised clustering were then used to identify subtypes. Associations with cognition, daily functioning, and neuropsychiatric symptoms were assessed using multivariable linear regression, and nested models were compared to quantify incremental explained variance (ΔR[2]) from continuous local residual features beyond subtype labels. Results The GAI showed a clear gradient across cognitively normal, MCI, and AD groups. After controlling for GAI, two reproducible local structural patterns were identified within MCI: a thalamic-subcortical subtype and a frontal-paralimbic subtype. Subtype differences remained associated with cognition and daily functioning after adjustment for demographic factors and GAI, whereas associations with neuropsychiatric symptoms were not significant or were markedly weaker. Adding PC-based continuous local residual features provided incremental explanatory value for ADAS-Cog13 and FAQ beyond models including subtype labels. Conclusions MCI heterogeneity is not explained solely by global brain atrophy. Local structural patterns independent of overall neurodegenerative burden capture clinically meaningful variation and may improve imaging-based stratification in prodromal AD.},
}

@article {pmid42183385,
year = {2026},
author = {Kou, Z and Zhang, J and Gong, C and Ji, J and Sekaran, N and Wang, Z and Miller, R and Yang, Y and Llano, D and Zhou, Q and Oelze, M},
title = {Ultrasound phase microscopy for rapid label-free super-resolution vascular imaging.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9488223/v1},
pmid = {42183385},
issn = {2693-5015},
abstract = {Mapping deep microvascular structure and dynamics is essential for understanding organ function, neurovascular coupling and disease progression. Ultrasound localization microscopy (ULM) achieves super-resolution vascular imaging in deep tissue, but its dependence on exogenous contrast agents and prolonged stochastic tracking limits throughput and impedes the capture of transient hemodynamics. Here we introduce ultrasound phase microscopy (UPM), a label-free super-resolution ultrasound approach based on spatiotemporal phase decoding. UPM operates entirely on the receive side by converting motion-induced blood-signal phase shifts into sub-wavelength spatial gating through engineered phase gradients. A theoretical analysis shows that the effective gate width scales inversely with the square root of the signal-to-noise ratio, shifting the operative resolution boundary away from the classical diffraction limit. UPM achieves in vivo vascular resolution down to 4.8 µm without contrast agents. We apply UPM to whole-brain vascular mapping in a mouse model of Alzheimer's disease, functional ultrasound imaging of visually evoked hemodynamics, and handheld renal imaging in vivo. UPM thus provides a rapid, contrast-free strategy for super-resolved vascular imaging in deep tissue.},
}

@article {pmid42183628,
year = {2026},
author = {Wei, Z and Zhang, M and Tang, W and Singh, BK and Zhiwei, Z and Lei, Z and Goh Kim Wee, J and Tan Rui En, F and Jingxiu, H and Qiaoyang, S and Bin, X and Priyanka, G and Xuyang, AS and Li, Z and Han-Ming, S and King, TE},
title = {CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2678427},
pmid = {42183628},
issn = {1554-8635},
abstract = {Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of CHCHD2, and also in human iPSC-derived CHCHD2[-/-] or CHCHD2[T61I] dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.},
}

@article {pmid42183640,
year = {2026},
author = {Neal, SJ and Magden, ER and Chitta, S and Bisbal, J and Simmons, JH},
title = {Metabolic Biomarkers in Captive Olive Baboons (Papio anubis): Characterization and Relationships With Biomarkers of Neurodegeneration and Neuroinflammation.},
journal = {American journal of primatology},
volume = {88},
number = {5},
pages = {e70168},
doi = {10.1002/ajp.70168},
pmid = {42183640},
issn = {1098-2345},
support = {3P40OD024628-05S1//Office of Research Infrastructure Programs, National Institutes of Health/ ; },
mesh = {Animals ; Biomarkers/cerebrospinal fluid/blood ; Male ; Female ; *Papio anubis/metabolism ; *Neurodegenerative Diseases/veterinary/metabolism/blood/cerebrospinal fluid ; *Neuroinflammatory Diseases/veterinary/blood/metabolism/cerebrospinal fluid ; *Monkey Diseases/metabolism/cerebrospinal fluid/blood ; Obesity/veterinary ; },
abstract = {Diabetic patients are at an increased risk for neurodegeneration, neuroinflammation, and cognitive impairment, likely due to insulin dysregulation and subsequent hyperglycemia in the brain. This leads to cell apoptosis, amyloid beta accumulation, and tau hyperphosphorylation, all hallmarks of Alzheimer's disease and related dementias (ADRD). Baboons show neurological hallmarks of ADRD, including age-dependent tau pathology in neurons and glial cells, cerebral amyloid beta (Aβ) deposit-associated microvascular degeneration, and age-related increases in neurodegenerative and neuroinflammatory biomarkers. Here, we aim to characterize biomarkers of metabolic function according to age, sex, rearing, and obesity in captive olive baboons. We also examined associations between metabolic biomarkers (MBs) and biomarkers related to neurodegeneration (ND) and neuroinflammation (NI) (together, referred to NDNIBs) as well as between MBs and a behavioral indicator of aging and metabolic health (walking speed). We collected plasma in 133 baboons and cerebrospinal fluid (CSF) in 44 baboons, and recorded walking speeds in 128 baboons. For both NDNIB and MB, we calculated load scores using quartiles, and deviation scores using z-scores, where higher scores indicated higher biomarker levels and greater deviation from the mean, respectively. There were few significant differences across MBs as a function of age, sex, and rearing, and no differences as a function of obesity status. However, higher MB load scores were correlated with greater NDNIB deviation scores in CSF. Additionally, MB deviation scores predicted walking speeds. These data support previous studies showing that higher metabolic dysfunction is associated with greater concurrent burden of neurodegenerative indicators in nonhuman primates.},
}

Animals
Biomarkers/cerebrospinal fluid/blood
Male
Female
*Papio anubis/metabolism
*Neurodegenerative Diseases/veterinary/metabolism/blood/cerebrospinal fluid
*Neuroinflammatory Diseases/veterinary/blood/metabolism/cerebrospinal fluid
*Monkey Diseases/metabolism/cerebrospinal fluid/blood
Obesity/veterinary

@article {pmid42184025,
year = {2026},
author = {Richardson, TE and Cherry, J and Kandoi, S and Rohde, SK and Uretsky, M and Tuz-Zahra, F and Bieniek, KF and Farrell, K and Hefti, MM and Miller, MB and Tripodis, Y and Stein, TD and Maldonado-Díaz, C and Hiya, S and Beach, TG and Corrada, MM and Dugger, BN and Flanagan, ME and Frosch, MP and Gearing, M and Grinberg, LT and Hansen, LA and Hawes, D and Head, E and Keene, CD and Kofler, J and Lee, EB and Nelson, PT and Oakley, DH and Perrin, RJ and Rissman, RA and Salamat, S and Schneider, JA and Serrano, GE and Teich, AF and Troncoso, JC and Wisniewski, T and Woltjer, RL and Crary, JF and Dickson, DW and McKee, AC and Walker, JM},
title = {Neocortical tau burden determines the degree of cognitive impairment in individuals with Braak stage V neurofibrillary degeneration.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42184025},
issn = {1432-0533},
support = {RF1 AG062348/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/metabolism ; Female ; Male ; *Neurofibrillary Tangles/pathology/metabolism ; *Neocortex/pathology/metabolism ; Aged ; *Cognitive Dysfunction/pathology/metabolism ; Aged, 80 and over ; *Alzheimer Disease/pathology/metabolism ; Middle Aged ; },
abstract = {Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with the topographical distribution of β-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs). While cognitive decline correlates with the level of ADNC, there remains a great deal of variation in cognitive outcomes between individuals that is unaccounted for by current neuropathologic evaluation metrics. We leveraged quantitative computer-assisted positive pixel assessments to establish the neocortical p-tau burden in the middle frontal and superior temporal gyri of 61 individuals with Braak NFT stage V who had a wide range of cognitive outcomes and trajectories. Frontal and temporal neocortical p-tau burden varied between 0.2% and 53.7%. Both frontal and temporal p-tau burden directly affected cognitive outcome and correlated with function of multiple cognitive domains, including measures of language/semantic memory and attention/working memory. In multivariable analysis, only p-tau burden and microinfarcts significantly impacted cognitive decline, while Aβ, limbic-predominant age-related TDP-43 encephalopathy, Lewy body pathology, and other measures of cerebrovascular disease did not. Additionally, individuals with low mean neocortical p-tau burden (≤ 13%) had significantly better longitudinal cognitive trajectories over the final 15 years of life compared to those with high burden (≥ 23.5%). These results suggest that while all individuals with Braak stage V have some degree of neurofibrillary degeneration in the neocortex, the significant variation in cognitive decline observed between these individuals can be partially understood as a reflection of the variation in quantitatively assessed neocortical p-tau burden, which had a greater impact on progression to dementia than common comorbid neuropathologies associated with dementia risk. This argues for the incorporation of the density of ADNC-related pathology, in addition to its regional location, as an adjunct to future staging systems for Alzheimer disease.},
}

Humans
*tau Proteins/metabolism
Female
Male
*Neurofibrillary Tangles/pathology/metabolism
*Neocortex/pathology/metabolism
Aged
*Cognitive Dysfunction/pathology/metabolism
Aged, 80 and over
*Alzheimer Disease/pathology/metabolism
Middle Aged

@article {pmid42184087,
year = {2026},
author = {Abdelaziz, AM and Shokr, MM and Fathy, MK and Fawzy, MN},
title = {Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42184087},
issn = {1559-1166},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *ADP-ribosyl Cyclase 1/metabolism ; *Mitochondria/metabolism ; *rho GTP-Binding Proteins/metabolism ; Animals ; *Neurons/metabolism ; *Astrocytes/metabolism ; *Membrane Glycoproteins/metabolism ; *Mitochondrial Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by early bioenergetic failure, contributing to synaptic dysfunction and neuronal vulnerability. This review examines a critical compensatory mechanism, the transfer of functional mitochondria from astrocytes to neurons, and its profound failure in AD. We detail the coordinated molecular cascade of this mitochondrial shunt, initiated by neuronal distress signals that activate astrocytic CD38. CD38-generated cyclic ADP-ribose triggers calcium release, which then binds to the mitochondrial Rho GTPase Miro1, modulating mitochondrial trafficking and promoting peripheral positioning via kinesin motor complexes for intercellular transport through tunneling nanotubes (TNTs). Transient, localized Ca[2+] signals bias mitochondria toward docking at the plasma membrane for export, whereas sustained pathologic Ca[2+] overload impairs trafficking via motor disengagement and Miro1 dysfunction. In AD, this rescue pathway is catastrophically disrupted by NAD+ depletion, Aβ-induced calcium dysregulation, tau-mediated microtubule instability, and oxidative stress, leading to inhibited CD38 signaling, Miro1 dysfunction/impairment, and TNT dismantlement. We systematically explain how this multi-level impairment initiates a vicious cycle of bioenergetic collapse. We also look at promising treatment options that could help restore this shunt, such as NAD+ augmentation to reactivate CD38, Miro1 stabilizers to help with trafficking, and interventions to keep TNT intact. Targeting the astrocyte-neuron mitochondrial shunt may represent an innovative, disease-modifying strategy that could transform the therapeutic framework from simple protein clearance to the proactive restoration of intercellular metabolic support, offering a promising direction for next-generation AD therapeutics.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*ADP-ribosyl Cyclase 1/metabolism
*Mitochondria/metabolism
*rho GTP-Binding Proteins/metabolism
Animals
*Neurons/metabolism
*Astrocytes/metabolism
*Membrane Glycoproteins/metabolism
*Mitochondrial Proteins/metabolism

@article {pmid42184217,
year = {2026},
author = {Hilsabeck, RC and Santiago-Mejias, S and Fletcher, TL and Rhodes, SL and Maestre, GE and Seshadri, S and Patel, NK and Epps, FR},
title = {Detecting Cognitive Impairment Early in Hispanic and Black Older Adults: Community Voices From South Central Texas.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {42184217},
issn = {1546-4156},
abstract = {BACKGROUND: Alzheimer disease and related dementias (ADRD) are more prevalent in Black and Hispanic older adults and are also more likely to be undetected and misdiagnosed. The purpose of this study was to engage with Black and Hispanic communities about interest in and support needed for memory screening.

METHODS: Participants were recruited from established community partners of the South Texas Alzheimer's Disease Research Center to engagein a 90-minute listening session. The session was recorded with participants' permission, and a thematic analysis was conducted by 2 independent coders.

RESULTS: Sixteen individuals (81% female, 88% Hispanic or Black) from various perspectives participated (eg, health care workers, persons with dementia, caregivers). Four core themes emerged: building trust, access and time barriers, community-specific literature, and representative messengers. Trust was noted to be foundational, encompassing who delivers the screening and where it takes place. Transportation, time burden, competing caregiving responsibilities, work schedules, and limited access to technology/internet were key barriers. The need to create accessible and relatable literature and videos tailored to diverse educational levels and cultural backgrounds was also emphasized.

CONCLUSIONS: Trusted members of the community could be accepted to perform memory screenings and provide education. Partnering with faith-based organizations, senior centers, and other community hubs would help overcome barriers to screening.},
}

@article {pmid42184234,
year = {2026},
author = {El Haj, M and Boutoleau-Bretonnière, C and Moustafa, A and Chapelet, G},
title = {Pupillometry as a Differential Indicator of Cognitive Processing in Alzheimer Disease and Behavioral Variant Frontotemporal Dementia.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {42184234},
issn = {1546-4156},
abstract = {INTRODUCTION: While extensive research has explored cognitive processing with pupillometry in the general population, limited attention has been given to its application in neurodegenerative diseases. This study, for the first time, investigates general cognitive processing using pupillometry in both Alzheimer disease (AD) and behavioral variant frontotemporal dementia (bvFTD).

METHODS: Pupil diameter was monitored in patients with AD, patients with bvFTD, and control participants under 2 conditions. The first condition involved subtraction (ie, subtracting 9 from 100 and continuing to subtract to a total of 5 subtractions). The second control condition involved counting aloud from 1.

RESULTS: Analysis demonstrated increased pupil diameters during subtraction than during counting in patients with bvFTD, patients with AD, and control participants. During both counting and subtraction, smaller pupil diameters were observed in patients with bvFTD compared with patients with AD and in patients with AD compared with control participants.

CONCLUSIONS: These findings indicate that pupil size can effectively reflect the cognitive load intensity in patients with bvFTD and patients with AD, suggesting the potential of pupillometry as a differential indicator of cognitive processing in neurodegenerative diseases.},
}

@article {pmid42184266,
year = {2026},
author = {Ix, M and Dodel, R and Ross, JA},
title = {Alpha-Synuclein-Specific RT-QuIC As a Tool for the Differential Diagnosis of Neurodegenerative Diseases Using Peripheral Tissues.},
journal = {Clinical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/clinchem/hvag037},
pmid = {42184266},
issn = {1530-8561},
abstract = {BACKGROUND: The diagnosis of neurodegenerative diseases (NDDs), such as Alzheimer disease (AD), Creutzfeldt-Jakob disease (CJD), Parkinson disease (PD), and other α-synucleinopathies, is traditionally based on clinical signs and symptoms. By the time symptoms emerge, neurodegeneration has already advanced, limiting the window for early treatment and research. Early diagnosis could improve therapeutic outcomes and deepen insights into disease onset, making the search for novel diagnostic tools and early biomarkers a major focus of current research. A key pathological hallmark of these prion-like diseases is the misfolding and aggregation of proteins such as prion protein, α-synuclein (αSyn), and tau, which are detectable early in the preclinical phase and are already used diagnostically.

CONTENT: The real-time quaking-induced conversion (RT-QuIC) assay is a thioflavin T-based in vitro method capable of detecting minute amounts of misfolded proteins in various biofluids with high sensitivity and specificity. It offers a promising approach for the early diagnosis of prion-like diseases. In recent years, RT-QuIC has been further developed, particularly to enhance the detection of αSyn-specific pathologies such as PD and related disorders. Additionally, increasing efforts have aimed to use peripheral and minimally invasive tissues or biofluids, such as skin, saliva, or nasal mucosa, for RT-QuIC analysis to support early and patient-friendly diagnostics.

SUMMARY: This review summarizes recent advances in αSyn-specific RT-QuIC, with a particular focus on peripheral sample materials. The diagnostic potential of this technique for α-synucleinopathies and other NDDs is discussed and its future applications in biomarker discovery are explored.},
}

@article {pmid42184493,
year = {2026},
author = {Hu, JX and Wen, Q and Zhou, H and Hui, Q and Yuan, QX and Cai, H and Cheng, X and Liu, J and Lin, L},
title = {Summary of the evidence on TCM nonpharmacological interventions for cognitive impairment in patients with Alzheimer's disease.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {71},
number = {},
pages = {104096},
doi = {10.1016/j.gerinurse.2026.104096},
pmid = {42184493},
issn = {1528-3984},
abstract = {OBJECTIVE: To systematically synthesize the best available evidence on nonpharmacological interventions in traditional Chinese medicine (TCM) for cognitive impairment in patients with Alzheimer's disease (AD).

METHODS: Guided by the "6S" evidence pyramid model, a comprehensive search was conducted across multiple databases from their inception to March 2025. Two researchers independently assessed the quality of the literature, while four researchers extracted the evidence using a standardized form. The best available evidence was ultimately identified through group discussion.

RESULTS: A total of ten articles were included, comprising two guidelines, one expert consensus statement, and seven systematic reviews. Eighteen evidence items were summarized across five areas: acupuncture, acupuncture combined with Chinese herbal medicine (CHM), five-element music therapy, Baduanjin exercise, and Tai Chi.

CONCLUSION: Evidence regarding TCM nonpharmacological interventions for AD-related cognitive impairment is both scientific and comprehensive. However, further high-quality, large-scale clinical trials are still warranted.},
}

@article {pmid42184581,
year = {2026},
author = {Van, HTK and Thanh, ND},
title = {β-Maltose-conjugated acetophenone thiosemicarbazones as multitarget inhibitors of diabetes- and Alzheimer's disease-related enzymes: Design, synthesis, and mechanistic evaluation.},
journal = {Bioorganic chemistry},
volume = {179},
number = {},
pages = {110019},
doi = {10.1016/j.bioorg.2026.110019},
pmid = {42184581},
issn = {1090-2120},
abstract = {This study describes the design, synthesis, and biological evaluation of a series of β-maltose-conjugated acetophenone thiosemicarbazones (6a-p) as multitarget inhibitors against enzymes associated with Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). The synthesized compounds were evaluated for their inhibitory activities against α-amylase, α-glucosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The biological results demonstrated that the nature and position of substituents on the phenyl ring strongly influenced both potency and selectivity. Among the tested compounds, derivative 6 m emerged as the most promising multitarget inhibitor, exhibiting potent α-glucosidase inhibition (IC50 = 6.75 μM), superior to the reference drug acarbose, together with remarkable selectivity toward BChE (IC50 = 0.035 μM). Compound 6 k displayed balanced inhibitory activity, showing potent AChE inhibition (IC50 = 0.045 μM), comparable to donepezil, while retaining significant antidiabetic activity. Structure-activity relationship (SAR) analysis revealed that hydroxyl substituents were crucial for antidiabetic activity, whereas halogen substitution markedly enhanced cholinesterase inhibition. Kinetic studies demonstrated that the most active compounds acted as competitive inhibitors. Furthermore, molecular docking and molecular dynamics simulations confirmed stable binding interactions within the catalytic pockets of the target enzymes through hydrogen bonding, hydrophobic interactions, and interactions with catalytic and anionic residues. Overall, these findings identify β-maltose-conjugated thiosemicarbazones as promising multitarget-directed ligands for the development of therapeutic agents against metabolic and neurodegenerative disorders.},
}

@article {pmid42184608,
year = {2026},
author = {Gonzalez, MM and Magondu, B and Rowan, MJM and Forest, CR},
title = {Regional alterations of parvalbumin interneurons in human App knock-in mouse model of Alzheimer's disease pathology.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {41-49},
doi = {10.1016/j.neurobiolaging.2026.05.005},
pmid = {42184608},
issn = {1558-1497},
abstract = {Early-stage Alzheimer's disease pathology correlates with disrupted neuronal excitability, which can drive network and cognitive dysfunction even prior to neurodegeneration. However, the emergence and extent of these changes may vary by brain region and cell types situated in those regions. Here we aimed to investigate the effects of Alzheimer's disease pathology on different neuron subtypes in both the entorhinal cortex, a region known to be affected early in Alzheimer's disease, and the primary visual cortex, a relatively unaffected region. We designed and employed a semi-automated patch clamp electrophysiology apparatus to record from fast-spiking parvalbumin interneurons and excitatory neurons in these regions, recording from over 150 cells in 2 month old amyloid precursor protein knock-in (APP-KI) mice. In entorhinal cortex, amyloid overproduction resulted in parvalbumin interneuron hypoexcitability, whereas excitatory neurons were concurrently hyperexcitable. Conversely, neurons of either subclass were largely unaffected in the visual cortex. Together, these findings suggest that fast-spiking parvalbumin interneurons in the entorhinal cortex exhibit selective functional alterations in an early APP-driven state.},
}

@article {pmid42184681,
year = {2026},
author = {Zheng, W and Zhou, Y and Xia, Y and Wang, Y},
title = {Association between obstructive sleep apnea severity and glymphatic-related DTI-ALPS alterations in newly diagnosed, Drug-Naïve Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100597},
doi = {10.1016/j.tjpad.2026.100597},
pmid = {42184681},
issn = {2426-0266},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in Alzheimer's disease (AD) patients and is associated with cognitive decline. However, the mechanisms linking OSA to Alzheimer's pathophysiology, especially regarding glymphatic function, remain unclear. This study investigated the relationship between OSA severity and glymphatic-related diffusion abnormalities, as assessed by the DTI-ALPS index, in newly diagnosed, drug-naïve AD patients.

METHODS: A total of 162 newly diagnosed, drug-naïve AD patients and 98 healthy controls were enrolled. Polysomnography (PSG) was used to assess OSA severity and sleep parameters, while diffusion tensor imaging along the perivascular space (DTI-ALPS) was employed to measure glymphatic function. Correlation analyses, multivariable regression models with interaction terms, and sensitivity analyses were performed to explore the relationship between OSA and glymphatic dysfunction, and whether this relationship was specific to AD.

RESULTS: In AD patients, greater OSA severity was associated with lower ALPS-index values, including AHI (rho = -0.38, P < 0.001) and ODI (rho = -0.35, P < 0.001), whereas these associations were not observed in healthy controls. Lower ALPS-index values were also associated with more fragmented sleep, including higher N1 proportion and arousal index, and with reduced REM sleep. Clinically, the ALPS-index was positively correlated with better cognitive performance on MMSE (rho = 0.28, P = 0.001) and MoCA (rho = 0.31, P < 0.001), and negatively correlated with greater cognitive impairment on ADAS-Cog (rho = -0.34, P < 0.001).

CONCLUSION: Glymphatic dysfunction is related to OSA severity in de novo AD but not in Healthy controls. The study demonstrated that OSA may contribute to neurodegeneration via glymphatic impairment in AD.},
}

@article {pmid42184775,
year = {2026},
author = {Feijão, JMS and Oliveira, DS and Chiussi, S and Pêgo, AP and Santos, SD and Moreira, FTC},
title = {NanoGold-enhanced biomimetic sensor for Tau-441 protein detection in serum for Alzheimer's disease diagnosis.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {172},
number = {},
pages = {109335},
doi = {10.1016/j.bioelechem.2026.109335},
pmid = {42184775},
issn = {1878-562X},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, and early identification of molecular biomarkers in blood offers a promising avenue for diagnosis and monitoring treatment. Tau-441 stands out as a particularly promising biomarker among the potential molecular targets. This research describes the development of a highly sensitive and cost-effective biomimetic sensor, capable of selectively detecting Tau-441 at femtomolar concentrations. This is achieved through the synergistic combination of gold nanoparticles (AuNPs) with molecularly imprinted polymer (MIP) technology. The MIP layer was sensitised by electropolymerising phenylenediamine (o-PDA) in the presence of Tau-441 and AuNPs onto a gold screen-printed electrode (Au-SPE) using cyclic voltammetry (CV). After polymerisation, the entrapped proteins were removed by proteolytic digestion, generating well-defined imprinted cavities within the polymer matrix. Scanning electron microscopy (SEM) and Raman analysis were conducted to monitor the surface modification of the Au-SPE working electrode. The device displayed linear responses to Tau-441 protein within the range 2.0 pg mL[-1] to 200 ng mL[-1], with a limit of detection of 1.51 fg mL[-1]. The analytical performance of the device was validated in complex matrices, including Cormay serum and cell media from primary cultures of hippocampal neurons, using a competitive assay. The platform showed high sensitivity, good reproducibility, and reliable performance in biologically relevant media, demonstrating strong robustness. Its excellent analytical characteristics, together with the potential for integration into portable electrochemical devices, make this sensor a promising tool for rapid and accurate point-of-care testing, enhancing the detection and monitoring of AD.},
}